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By As Prof OPokryshko
Chair of Medical biology Microbiology Virology and Immunology
Antibiotics classificaions and mechanism of action
The main principles of rational antibiotic therapy
of diseases
Lectures schedule
1 History of antibiotics discovery
2 Classification of antibiotics
3 Examination of bacterial susceptibility to antibiotics
4 The main principles of rational antibiotic therapy of diseases
5 Complication of antibioticotherapy
- Diarrheal diseases - 4 billions cases
- Malaria - 500 mln
- acute infection of respiratory tract - 395 mln
- sexual transmitted diseases - 330 mln
- measles - 42 mln
- whooping cough - 40 mln
- tuberculosis ndash 19 bln of infected persons
9 mln of new cases of diseases
- AIDS ndash 50 mln cases 6 mln people died
- SARS hemorrhagic fever
Modern chemotherapy has been dated to the work of Paul Ehrlich (Germany)
Ehrlich postulated that it would be possible to find chemicals that were selectively toxic for parasites but not toxic to humans
He introduced the concept of chemotherapy dealing with the treatment of diseases with chemicals This idea has been called the magic bullet concept
A Fleming
The first antibiotic Penicillin G was discovered in 1929 by Alexander Fleming
1940s Penicillin was tested clinically and mass produced
He observed that Penicillium fungus made an antibiotic penicillin that killed S aureus
Figure 15
In 1944 Waksman isolated streptomycin and subsequently found agents such as chloramphenicol tetracyclines and erythromycin in soil samples
S Waksman
In 1939 Florey and colleagues at Oxford University again isolated penicillin
G Florey E Chainy
AntibioticsAntibiotics are chemical substances produced by microorganisms (such as bacteria fungi actinomyces) or other organisms which suppress the growth of other microorganisms and eventually destroy them
Some antibiotics have been produced by chemical synthesis or semi-synthetically from natural substances
The term ldquoantibioticsrdquo proposed in 1942 S Waksman
It means anti ndash against bios - life
Microbial antagonism is the basis of modern use of antibiotics
L Pasteur
Peculiarities of antibiotics
- high level of biological activity
- high election specificity
Activity of antibiotics is evaluated in International Unit
Classification of antibiotics according to their origin
11 Antibiotics from fungiAntibiotics from fungi
Penicillins (Penicillium notatum Pchryzogenum)
Cephalosporins (Cephalosporium salmosynnematum)
Griseofulvinum (P griseofulvum P patulum P nigricans)
Fusidin (Fusidium coccineum)
2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces Aminoglicosides Streptomycin (Streptomyces griseus) neomycin (S fradiae) kanamycin (S kanamyseticus) tobramycin (S tenebrarius) gentamycin (Micromonospora purpurea) sisomicin (Micromonospora inyoensis)
Tetracyclines chlortetracycline (S aureofaciens) oxytetracycline (S rimosus)
Chloramphenicol (S venezuelae)
Macrolides oleandomycin (S antibioticus) erythromycin (S erythreus)
2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces
Linkomycin (S lincolniensis) е) Rifampicin (S mediterranei)
Polyenes nystatin (S noursei) levorin (S levorys Krass) amphotericin B (S nodosus)
Inhibitors of beta-lactamases klavulanic acid (S clavuligerus)
Carbapenem (S olivaceus)
Thienamycin (S cattleya)
33 Antibiotics from bacteriaAntibiotics from bacteria
Bacillus polymyxin (B polymyxa) licheniformin (B licheniformis) gramicidin С (B brevis) subtilin (B subtilis)
Pseudomonas piocianin (P aeruginosa) sorbistin (P sorbistini)
other bacteria monobactams (Chromobacterium violaceum) nisin (Streptococcus lactis) prodigiosin (Serratia marcescens) coliformin (E coli) streptosin diplococcin (Streptococcus spp) azomycin nocardamin (Nocardia)
4 Antibiotics from plants4 Antibiotics from plants
Chorellin (Chlorella vulgaris)
Arenarin (Helichrysum arenarium)
Gordecin (barley)
Chinin (cinchona tree)
Alicin (garlic Allium sativum)
Raphanin (radish Raphanus sativum)
Phaseolin (haricot bean Phaseolus vulgaris)
55 Antibiotics from animal tissuesAntibiotics from animal tissues
interferons (spleen macrophages tissue cells)
lysozyme (most body fluid salive eggs)
erythrin (red cells liver)
ecmolin (fish)
Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action
1 Antibacterial
А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes
Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones
2 Antifungal (amphotericin)
3 Antiviral (amantadin vidarabin)
4 Antiprotozoal (emethin chinin)
5 Antineoplastic (bleomycin mitomycin C actinomycines)
Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action
Spectrum of ActivityRelates to the number of microbes that are
susceptible to the action of the drugndashNarrow (limited number) Broad (wide)
bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-
positive and gram-negative microbes (Broad)
Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)
Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms
BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate
BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate
Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action
Mechanism of Action1 Inhibition of Cell Wall Synthesis
2 Disruption of Cell Membrane
3 Inhibition of Protein Synthesis
4 Interference with Metabolic
Processes
NBBactericidalBacteriostatic
Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis
Most bacteria possess a cell wall to protect from osmotic pressures
Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being
susceptible to external influencesndash Cell ruptures Microbe death
Eg Penicillinsm cephalosporins vancomycin and bacitracin
Disruption of the microbial cell Disruption of the microbial cell membranemembrane
Essentially affect cell membrane transportation in and out
Increases permeability of membranendash External influences have greater effectndash Microbe death
Eg Polymyxin Colistin
Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis
Inhibition of Protein SynthesisInhibition of Protein Synthesis
Proteins vital for growth and repairAct either at
ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic
acidsbull DNA replication RNA synthesis = TRANSCRIPTION
Eg Tetracyclines aminoglycosides and macrolides (erythromycin)
Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity
Interference with metabolic Interference with metabolic processesprocesses
bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it
microbes can not produce the proteins for growth
ndash Exploits microbes need to create their own folic acid whilst we get it in our diets
bull Eg Sulphonamides Trimethoprim
Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics
Serial dilutions
- in a liquid medium
- in a solid medium
Disc diffusion method
Rapid methods
Demands to nutrient media
1 to be standard and provide optimal conditions for microbial growth
2do not have inhibitors of bacterial growth and a lot of stimulators
3do not have substances which inhibit antibiotic activity
Disc diffusion methodDisc diffusion method
Serial dilution in liquid mediumSerial dilution in liquid medium
Serial dilution in solid mediumSerial dilution in solid medium
Minimal Inhibitory Concentration (MIC)
10487091048709Lowest concentration of antibiotic that prevents visible growth
bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic
bull 1048709Accurate but time-consuming
bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method
Minimal Bactericidal Concentration (MBC)
10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold
bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media
bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies
ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
Lectures schedule
1 History of antibiotics discovery
2 Classification of antibiotics
3 Examination of bacterial susceptibility to antibiotics
4 The main principles of rational antibiotic therapy of diseases
5 Complication of antibioticotherapy
- Diarrheal diseases - 4 billions cases
- Malaria - 500 mln
- acute infection of respiratory tract - 395 mln
- sexual transmitted diseases - 330 mln
- measles - 42 mln
- whooping cough - 40 mln
- tuberculosis ndash 19 bln of infected persons
9 mln of new cases of diseases
- AIDS ndash 50 mln cases 6 mln people died
- SARS hemorrhagic fever
Modern chemotherapy has been dated to the work of Paul Ehrlich (Germany)
Ehrlich postulated that it would be possible to find chemicals that were selectively toxic for parasites but not toxic to humans
He introduced the concept of chemotherapy dealing with the treatment of diseases with chemicals This idea has been called the magic bullet concept
A Fleming
The first antibiotic Penicillin G was discovered in 1929 by Alexander Fleming
1940s Penicillin was tested clinically and mass produced
He observed that Penicillium fungus made an antibiotic penicillin that killed S aureus
Figure 15
In 1944 Waksman isolated streptomycin and subsequently found agents such as chloramphenicol tetracyclines and erythromycin in soil samples
S Waksman
In 1939 Florey and colleagues at Oxford University again isolated penicillin
G Florey E Chainy
AntibioticsAntibiotics are chemical substances produced by microorganisms (such as bacteria fungi actinomyces) or other organisms which suppress the growth of other microorganisms and eventually destroy them
Some antibiotics have been produced by chemical synthesis or semi-synthetically from natural substances
The term ldquoantibioticsrdquo proposed in 1942 S Waksman
It means anti ndash against bios - life
Microbial antagonism is the basis of modern use of antibiotics
L Pasteur
Peculiarities of antibiotics
- high level of biological activity
- high election specificity
Activity of antibiotics is evaluated in International Unit
Classification of antibiotics according to their origin
11 Antibiotics from fungiAntibiotics from fungi
Penicillins (Penicillium notatum Pchryzogenum)
Cephalosporins (Cephalosporium salmosynnematum)
Griseofulvinum (P griseofulvum P patulum P nigricans)
Fusidin (Fusidium coccineum)
2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces Aminoglicosides Streptomycin (Streptomyces griseus) neomycin (S fradiae) kanamycin (S kanamyseticus) tobramycin (S tenebrarius) gentamycin (Micromonospora purpurea) sisomicin (Micromonospora inyoensis)
Tetracyclines chlortetracycline (S aureofaciens) oxytetracycline (S rimosus)
Chloramphenicol (S venezuelae)
Macrolides oleandomycin (S antibioticus) erythromycin (S erythreus)
2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces
Linkomycin (S lincolniensis) е) Rifampicin (S mediterranei)
Polyenes nystatin (S noursei) levorin (S levorys Krass) amphotericin B (S nodosus)
Inhibitors of beta-lactamases klavulanic acid (S clavuligerus)
Carbapenem (S olivaceus)
Thienamycin (S cattleya)
33 Antibiotics from bacteriaAntibiotics from bacteria
Bacillus polymyxin (B polymyxa) licheniformin (B licheniformis) gramicidin С (B brevis) subtilin (B subtilis)
Pseudomonas piocianin (P aeruginosa) sorbistin (P sorbistini)
other bacteria monobactams (Chromobacterium violaceum) nisin (Streptococcus lactis) prodigiosin (Serratia marcescens) coliformin (E coli) streptosin diplococcin (Streptococcus spp) azomycin nocardamin (Nocardia)
4 Antibiotics from plants4 Antibiotics from plants
Chorellin (Chlorella vulgaris)
Arenarin (Helichrysum arenarium)
Gordecin (barley)
Chinin (cinchona tree)
Alicin (garlic Allium sativum)
Raphanin (radish Raphanus sativum)
Phaseolin (haricot bean Phaseolus vulgaris)
55 Antibiotics from animal tissuesAntibiotics from animal tissues
interferons (spleen macrophages tissue cells)
lysozyme (most body fluid salive eggs)
erythrin (red cells liver)
ecmolin (fish)
Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action
1 Antibacterial
А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes
Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones
2 Antifungal (amphotericin)
3 Antiviral (amantadin vidarabin)
4 Antiprotozoal (emethin chinin)
5 Antineoplastic (bleomycin mitomycin C actinomycines)
Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action
Spectrum of ActivityRelates to the number of microbes that are
susceptible to the action of the drugndashNarrow (limited number) Broad (wide)
bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-
positive and gram-negative microbes (Broad)
Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)
Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms
BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate
BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate
Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action
Mechanism of Action1 Inhibition of Cell Wall Synthesis
2 Disruption of Cell Membrane
3 Inhibition of Protein Synthesis
4 Interference with Metabolic
Processes
NBBactericidalBacteriostatic
Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis
Most bacteria possess a cell wall to protect from osmotic pressures
Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being
susceptible to external influencesndash Cell ruptures Microbe death
Eg Penicillinsm cephalosporins vancomycin and bacitracin
Disruption of the microbial cell Disruption of the microbial cell membranemembrane
Essentially affect cell membrane transportation in and out
Increases permeability of membranendash External influences have greater effectndash Microbe death
Eg Polymyxin Colistin
Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis
Inhibition of Protein SynthesisInhibition of Protein Synthesis
Proteins vital for growth and repairAct either at
ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic
acidsbull DNA replication RNA synthesis = TRANSCRIPTION
Eg Tetracyclines aminoglycosides and macrolides (erythromycin)
Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity
Interference with metabolic Interference with metabolic processesprocesses
bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it
microbes can not produce the proteins for growth
ndash Exploits microbes need to create their own folic acid whilst we get it in our diets
bull Eg Sulphonamides Trimethoprim
Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics
Serial dilutions
- in a liquid medium
- in a solid medium
Disc diffusion method
Rapid methods
Demands to nutrient media
1 to be standard and provide optimal conditions for microbial growth
2do not have inhibitors of bacterial growth and a lot of stimulators
3do not have substances which inhibit antibiotic activity
Disc diffusion methodDisc diffusion method
Serial dilution in liquid mediumSerial dilution in liquid medium
Serial dilution in solid mediumSerial dilution in solid medium
Minimal Inhibitory Concentration (MIC)
10487091048709Lowest concentration of antibiotic that prevents visible growth
bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic
bull 1048709Accurate but time-consuming
bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method
Minimal Bactericidal Concentration (MBC)
10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold
bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media
bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies
ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
- Diarrheal diseases - 4 billions cases
- Malaria - 500 mln
- acute infection of respiratory tract - 395 mln
- sexual transmitted diseases - 330 mln
- measles - 42 mln
- whooping cough - 40 mln
- tuberculosis ndash 19 bln of infected persons
9 mln of new cases of diseases
- AIDS ndash 50 mln cases 6 mln people died
- SARS hemorrhagic fever
Modern chemotherapy has been dated to the work of Paul Ehrlich (Germany)
Ehrlich postulated that it would be possible to find chemicals that were selectively toxic for parasites but not toxic to humans
He introduced the concept of chemotherapy dealing with the treatment of diseases with chemicals This idea has been called the magic bullet concept
A Fleming
The first antibiotic Penicillin G was discovered in 1929 by Alexander Fleming
1940s Penicillin was tested clinically and mass produced
He observed that Penicillium fungus made an antibiotic penicillin that killed S aureus
Figure 15
In 1944 Waksman isolated streptomycin and subsequently found agents such as chloramphenicol tetracyclines and erythromycin in soil samples
S Waksman
In 1939 Florey and colleagues at Oxford University again isolated penicillin
G Florey E Chainy
AntibioticsAntibiotics are chemical substances produced by microorganisms (such as bacteria fungi actinomyces) or other organisms which suppress the growth of other microorganisms and eventually destroy them
Some antibiotics have been produced by chemical synthesis or semi-synthetically from natural substances
The term ldquoantibioticsrdquo proposed in 1942 S Waksman
It means anti ndash against bios - life
Microbial antagonism is the basis of modern use of antibiotics
L Pasteur
Peculiarities of antibiotics
- high level of biological activity
- high election specificity
Activity of antibiotics is evaluated in International Unit
Classification of antibiotics according to their origin
11 Antibiotics from fungiAntibiotics from fungi
Penicillins (Penicillium notatum Pchryzogenum)
Cephalosporins (Cephalosporium salmosynnematum)
Griseofulvinum (P griseofulvum P patulum P nigricans)
Fusidin (Fusidium coccineum)
2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces Aminoglicosides Streptomycin (Streptomyces griseus) neomycin (S fradiae) kanamycin (S kanamyseticus) tobramycin (S tenebrarius) gentamycin (Micromonospora purpurea) sisomicin (Micromonospora inyoensis)
Tetracyclines chlortetracycline (S aureofaciens) oxytetracycline (S rimosus)
Chloramphenicol (S venezuelae)
Macrolides oleandomycin (S antibioticus) erythromycin (S erythreus)
2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces
Linkomycin (S lincolniensis) е) Rifampicin (S mediterranei)
Polyenes nystatin (S noursei) levorin (S levorys Krass) amphotericin B (S nodosus)
Inhibitors of beta-lactamases klavulanic acid (S clavuligerus)
Carbapenem (S olivaceus)
Thienamycin (S cattleya)
33 Antibiotics from bacteriaAntibiotics from bacteria
Bacillus polymyxin (B polymyxa) licheniformin (B licheniformis) gramicidin С (B brevis) subtilin (B subtilis)
Pseudomonas piocianin (P aeruginosa) sorbistin (P sorbistini)
other bacteria monobactams (Chromobacterium violaceum) nisin (Streptococcus lactis) prodigiosin (Serratia marcescens) coliformin (E coli) streptosin diplococcin (Streptococcus spp) azomycin nocardamin (Nocardia)
4 Antibiotics from plants4 Antibiotics from plants
Chorellin (Chlorella vulgaris)
Arenarin (Helichrysum arenarium)
Gordecin (barley)
Chinin (cinchona tree)
Alicin (garlic Allium sativum)
Raphanin (radish Raphanus sativum)
Phaseolin (haricot bean Phaseolus vulgaris)
55 Antibiotics from animal tissuesAntibiotics from animal tissues
interferons (spleen macrophages tissue cells)
lysozyme (most body fluid salive eggs)
erythrin (red cells liver)
ecmolin (fish)
Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action
1 Antibacterial
А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes
Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones
2 Antifungal (amphotericin)
3 Antiviral (amantadin vidarabin)
4 Antiprotozoal (emethin chinin)
5 Antineoplastic (bleomycin mitomycin C actinomycines)
Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action
Spectrum of ActivityRelates to the number of microbes that are
susceptible to the action of the drugndashNarrow (limited number) Broad (wide)
bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-
positive and gram-negative microbes (Broad)
Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)
Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms
BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate
BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate
Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action
Mechanism of Action1 Inhibition of Cell Wall Synthesis
2 Disruption of Cell Membrane
3 Inhibition of Protein Synthesis
4 Interference with Metabolic
Processes
NBBactericidalBacteriostatic
Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis
Most bacteria possess a cell wall to protect from osmotic pressures
Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being
susceptible to external influencesndash Cell ruptures Microbe death
Eg Penicillinsm cephalosporins vancomycin and bacitracin
Disruption of the microbial cell Disruption of the microbial cell membranemembrane
Essentially affect cell membrane transportation in and out
Increases permeability of membranendash External influences have greater effectndash Microbe death
Eg Polymyxin Colistin
Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis
Inhibition of Protein SynthesisInhibition of Protein Synthesis
Proteins vital for growth and repairAct either at
ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic
acidsbull DNA replication RNA synthesis = TRANSCRIPTION
Eg Tetracyclines aminoglycosides and macrolides (erythromycin)
Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity
Interference with metabolic Interference with metabolic processesprocesses
bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it
microbes can not produce the proteins for growth
ndash Exploits microbes need to create their own folic acid whilst we get it in our diets
bull Eg Sulphonamides Trimethoprim
Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics
Serial dilutions
- in a liquid medium
- in a solid medium
Disc diffusion method
Rapid methods
Demands to nutrient media
1 to be standard and provide optimal conditions for microbial growth
2do not have inhibitors of bacterial growth and a lot of stimulators
3do not have substances which inhibit antibiotic activity
Disc diffusion methodDisc diffusion method
Serial dilution in liquid mediumSerial dilution in liquid medium
Serial dilution in solid mediumSerial dilution in solid medium
Minimal Inhibitory Concentration (MIC)
10487091048709Lowest concentration of antibiotic that prevents visible growth
bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic
bull 1048709Accurate but time-consuming
bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method
Minimal Bactericidal Concentration (MBC)
10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold
bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media
bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies
ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
Modern chemotherapy has been dated to the work of Paul Ehrlich (Germany)
Ehrlich postulated that it would be possible to find chemicals that were selectively toxic for parasites but not toxic to humans
He introduced the concept of chemotherapy dealing with the treatment of diseases with chemicals This idea has been called the magic bullet concept
A Fleming
The first antibiotic Penicillin G was discovered in 1929 by Alexander Fleming
1940s Penicillin was tested clinically and mass produced
He observed that Penicillium fungus made an antibiotic penicillin that killed S aureus
Figure 15
In 1944 Waksman isolated streptomycin and subsequently found agents such as chloramphenicol tetracyclines and erythromycin in soil samples
S Waksman
In 1939 Florey and colleagues at Oxford University again isolated penicillin
G Florey E Chainy
AntibioticsAntibiotics are chemical substances produced by microorganisms (such as bacteria fungi actinomyces) or other organisms which suppress the growth of other microorganisms and eventually destroy them
Some antibiotics have been produced by chemical synthesis or semi-synthetically from natural substances
The term ldquoantibioticsrdquo proposed in 1942 S Waksman
It means anti ndash against bios - life
Microbial antagonism is the basis of modern use of antibiotics
L Pasteur
Peculiarities of antibiotics
- high level of biological activity
- high election specificity
Activity of antibiotics is evaluated in International Unit
Classification of antibiotics according to their origin
11 Antibiotics from fungiAntibiotics from fungi
Penicillins (Penicillium notatum Pchryzogenum)
Cephalosporins (Cephalosporium salmosynnematum)
Griseofulvinum (P griseofulvum P patulum P nigricans)
Fusidin (Fusidium coccineum)
2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces Aminoglicosides Streptomycin (Streptomyces griseus) neomycin (S fradiae) kanamycin (S kanamyseticus) tobramycin (S tenebrarius) gentamycin (Micromonospora purpurea) sisomicin (Micromonospora inyoensis)
Tetracyclines chlortetracycline (S aureofaciens) oxytetracycline (S rimosus)
Chloramphenicol (S venezuelae)
Macrolides oleandomycin (S antibioticus) erythromycin (S erythreus)
2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces
Linkomycin (S lincolniensis) е) Rifampicin (S mediterranei)
Polyenes nystatin (S noursei) levorin (S levorys Krass) amphotericin B (S nodosus)
Inhibitors of beta-lactamases klavulanic acid (S clavuligerus)
Carbapenem (S olivaceus)
Thienamycin (S cattleya)
33 Antibiotics from bacteriaAntibiotics from bacteria
Bacillus polymyxin (B polymyxa) licheniformin (B licheniformis) gramicidin С (B brevis) subtilin (B subtilis)
Pseudomonas piocianin (P aeruginosa) sorbistin (P sorbistini)
other bacteria monobactams (Chromobacterium violaceum) nisin (Streptococcus lactis) prodigiosin (Serratia marcescens) coliformin (E coli) streptosin diplococcin (Streptococcus spp) azomycin nocardamin (Nocardia)
4 Antibiotics from plants4 Antibiotics from plants
Chorellin (Chlorella vulgaris)
Arenarin (Helichrysum arenarium)
Gordecin (barley)
Chinin (cinchona tree)
Alicin (garlic Allium sativum)
Raphanin (radish Raphanus sativum)
Phaseolin (haricot bean Phaseolus vulgaris)
55 Antibiotics from animal tissuesAntibiotics from animal tissues
interferons (spleen macrophages tissue cells)
lysozyme (most body fluid salive eggs)
erythrin (red cells liver)
ecmolin (fish)
Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action
1 Antibacterial
А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes
Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones
2 Antifungal (amphotericin)
3 Antiviral (amantadin vidarabin)
4 Antiprotozoal (emethin chinin)
5 Antineoplastic (bleomycin mitomycin C actinomycines)
Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action
Spectrum of ActivityRelates to the number of microbes that are
susceptible to the action of the drugndashNarrow (limited number) Broad (wide)
bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-
positive and gram-negative microbes (Broad)
Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)
Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms
BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate
BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate
Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action
Mechanism of Action1 Inhibition of Cell Wall Synthesis
2 Disruption of Cell Membrane
3 Inhibition of Protein Synthesis
4 Interference with Metabolic
Processes
NBBactericidalBacteriostatic
Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis
Most bacteria possess a cell wall to protect from osmotic pressures
Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being
susceptible to external influencesndash Cell ruptures Microbe death
Eg Penicillinsm cephalosporins vancomycin and bacitracin
Disruption of the microbial cell Disruption of the microbial cell membranemembrane
Essentially affect cell membrane transportation in and out
Increases permeability of membranendash External influences have greater effectndash Microbe death
Eg Polymyxin Colistin
Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis
Inhibition of Protein SynthesisInhibition of Protein Synthesis
Proteins vital for growth and repairAct either at
ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic
acidsbull DNA replication RNA synthesis = TRANSCRIPTION
Eg Tetracyclines aminoglycosides and macrolides (erythromycin)
Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity
Interference with metabolic Interference with metabolic processesprocesses
bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it
microbes can not produce the proteins for growth
ndash Exploits microbes need to create their own folic acid whilst we get it in our diets
bull Eg Sulphonamides Trimethoprim
Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics
Serial dilutions
- in a liquid medium
- in a solid medium
Disc diffusion method
Rapid methods
Demands to nutrient media
1 to be standard and provide optimal conditions for microbial growth
2do not have inhibitors of bacterial growth and a lot of stimulators
3do not have substances which inhibit antibiotic activity
Disc diffusion methodDisc diffusion method
Serial dilution in liquid mediumSerial dilution in liquid medium
Serial dilution in solid mediumSerial dilution in solid medium
Minimal Inhibitory Concentration (MIC)
10487091048709Lowest concentration of antibiotic that prevents visible growth
bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic
bull 1048709Accurate but time-consuming
bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method
Minimal Bactericidal Concentration (MBC)
10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold
bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media
bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies
ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
A Fleming
The first antibiotic Penicillin G was discovered in 1929 by Alexander Fleming
1940s Penicillin was tested clinically and mass produced
He observed that Penicillium fungus made an antibiotic penicillin that killed S aureus
Figure 15
In 1944 Waksman isolated streptomycin and subsequently found agents such as chloramphenicol tetracyclines and erythromycin in soil samples
S Waksman
In 1939 Florey and colleagues at Oxford University again isolated penicillin
G Florey E Chainy
AntibioticsAntibiotics are chemical substances produced by microorganisms (such as bacteria fungi actinomyces) or other organisms which suppress the growth of other microorganisms and eventually destroy them
Some antibiotics have been produced by chemical synthesis or semi-synthetically from natural substances
The term ldquoantibioticsrdquo proposed in 1942 S Waksman
It means anti ndash against bios - life
Microbial antagonism is the basis of modern use of antibiotics
L Pasteur
Peculiarities of antibiotics
- high level of biological activity
- high election specificity
Activity of antibiotics is evaluated in International Unit
Classification of antibiotics according to their origin
11 Antibiotics from fungiAntibiotics from fungi
Penicillins (Penicillium notatum Pchryzogenum)
Cephalosporins (Cephalosporium salmosynnematum)
Griseofulvinum (P griseofulvum P patulum P nigricans)
Fusidin (Fusidium coccineum)
2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces Aminoglicosides Streptomycin (Streptomyces griseus) neomycin (S fradiae) kanamycin (S kanamyseticus) tobramycin (S tenebrarius) gentamycin (Micromonospora purpurea) sisomicin (Micromonospora inyoensis)
Tetracyclines chlortetracycline (S aureofaciens) oxytetracycline (S rimosus)
Chloramphenicol (S venezuelae)
Macrolides oleandomycin (S antibioticus) erythromycin (S erythreus)
2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces
Linkomycin (S lincolniensis) е) Rifampicin (S mediterranei)
Polyenes nystatin (S noursei) levorin (S levorys Krass) amphotericin B (S nodosus)
Inhibitors of beta-lactamases klavulanic acid (S clavuligerus)
Carbapenem (S olivaceus)
Thienamycin (S cattleya)
33 Antibiotics from bacteriaAntibiotics from bacteria
Bacillus polymyxin (B polymyxa) licheniformin (B licheniformis) gramicidin С (B brevis) subtilin (B subtilis)
Pseudomonas piocianin (P aeruginosa) sorbistin (P sorbistini)
other bacteria monobactams (Chromobacterium violaceum) nisin (Streptococcus lactis) prodigiosin (Serratia marcescens) coliformin (E coli) streptosin diplococcin (Streptococcus spp) azomycin nocardamin (Nocardia)
4 Antibiotics from plants4 Antibiotics from plants
Chorellin (Chlorella vulgaris)
Arenarin (Helichrysum arenarium)
Gordecin (barley)
Chinin (cinchona tree)
Alicin (garlic Allium sativum)
Raphanin (radish Raphanus sativum)
Phaseolin (haricot bean Phaseolus vulgaris)
55 Antibiotics from animal tissuesAntibiotics from animal tissues
interferons (spleen macrophages tissue cells)
lysozyme (most body fluid salive eggs)
erythrin (red cells liver)
ecmolin (fish)
Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action
1 Antibacterial
А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes
Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones
2 Antifungal (amphotericin)
3 Antiviral (amantadin vidarabin)
4 Antiprotozoal (emethin chinin)
5 Antineoplastic (bleomycin mitomycin C actinomycines)
Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action
Spectrum of ActivityRelates to the number of microbes that are
susceptible to the action of the drugndashNarrow (limited number) Broad (wide)
bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-
positive and gram-negative microbes (Broad)
Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)
Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms
BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate
BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate
Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action
Mechanism of Action1 Inhibition of Cell Wall Synthesis
2 Disruption of Cell Membrane
3 Inhibition of Protein Synthesis
4 Interference with Metabolic
Processes
NBBactericidalBacteriostatic
Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis
Most bacteria possess a cell wall to protect from osmotic pressures
Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being
susceptible to external influencesndash Cell ruptures Microbe death
Eg Penicillinsm cephalosporins vancomycin and bacitracin
Disruption of the microbial cell Disruption of the microbial cell membranemembrane
Essentially affect cell membrane transportation in and out
Increases permeability of membranendash External influences have greater effectndash Microbe death
Eg Polymyxin Colistin
Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis
Inhibition of Protein SynthesisInhibition of Protein Synthesis
Proteins vital for growth and repairAct either at
ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic
acidsbull DNA replication RNA synthesis = TRANSCRIPTION
Eg Tetracyclines aminoglycosides and macrolides (erythromycin)
Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity
Interference with metabolic Interference with metabolic processesprocesses
bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it
microbes can not produce the proteins for growth
ndash Exploits microbes need to create their own folic acid whilst we get it in our diets
bull Eg Sulphonamides Trimethoprim
Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics
Serial dilutions
- in a liquid medium
- in a solid medium
Disc diffusion method
Rapid methods
Demands to nutrient media
1 to be standard and provide optimal conditions for microbial growth
2do not have inhibitors of bacterial growth and a lot of stimulators
3do not have substances which inhibit antibiotic activity
Disc diffusion methodDisc diffusion method
Serial dilution in liquid mediumSerial dilution in liquid medium
Serial dilution in solid mediumSerial dilution in solid medium
Minimal Inhibitory Concentration (MIC)
10487091048709Lowest concentration of antibiotic that prevents visible growth
bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic
bull 1048709Accurate but time-consuming
bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method
Minimal Bactericidal Concentration (MBC)
10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold
bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media
bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies
ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
He observed that Penicillium fungus made an antibiotic penicillin that killed S aureus
Figure 15
In 1944 Waksman isolated streptomycin and subsequently found agents such as chloramphenicol tetracyclines and erythromycin in soil samples
S Waksman
In 1939 Florey and colleagues at Oxford University again isolated penicillin
G Florey E Chainy
AntibioticsAntibiotics are chemical substances produced by microorganisms (such as bacteria fungi actinomyces) or other organisms which suppress the growth of other microorganisms and eventually destroy them
Some antibiotics have been produced by chemical synthesis or semi-synthetically from natural substances
The term ldquoantibioticsrdquo proposed in 1942 S Waksman
It means anti ndash against bios - life
Microbial antagonism is the basis of modern use of antibiotics
L Pasteur
Peculiarities of antibiotics
- high level of biological activity
- high election specificity
Activity of antibiotics is evaluated in International Unit
Classification of antibiotics according to their origin
11 Antibiotics from fungiAntibiotics from fungi
Penicillins (Penicillium notatum Pchryzogenum)
Cephalosporins (Cephalosporium salmosynnematum)
Griseofulvinum (P griseofulvum P patulum P nigricans)
Fusidin (Fusidium coccineum)
2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces Aminoglicosides Streptomycin (Streptomyces griseus) neomycin (S fradiae) kanamycin (S kanamyseticus) tobramycin (S tenebrarius) gentamycin (Micromonospora purpurea) sisomicin (Micromonospora inyoensis)
Tetracyclines chlortetracycline (S aureofaciens) oxytetracycline (S rimosus)
Chloramphenicol (S venezuelae)
Macrolides oleandomycin (S antibioticus) erythromycin (S erythreus)
2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces
Linkomycin (S lincolniensis) е) Rifampicin (S mediterranei)
Polyenes nystatin (S noursei) levorin (S levorys Krass) amphotericin B (S nodosus)
Inhibitors of beta-lactamases klavulanic acid (S clavuligerus)
Carbapenem (S olivaceus)
Thienamycin (S cattleya)
33 Antibiotics from bacteriaAntibiotics from bacteria
Bacillus polymyxin (B polymyxa) licheniformin (B licheniformis) gramicidin С (B brevis) subtilin (B subtilis)
Pseudomonas piocianin (P aeruginosa) sorbistin (P sorbistini)
other bacteria monobactams (Chromobacterium violaceum) nisin (Streptococcus lactis) prodigiosin (Serratia marcescens) coliformin (E coli) streptosin diplococcin (Streptococcus spp) azomycin nocardamin (Nocardia)
4 Antibiotics from plants4 Antibiotics from plants
Chorellin (Chlorella vulgaris)
Arenarin (Helichrysum arenarium)
Gordecin (barley)
Chinin (cinchona tree)
Alicin (garlic Allium sativum)
Raphanin (radish Raphanus sativum)
Phaseolin (haricot bean Phaseolus vulgaris)
55 Antibiotics from animal tissuesAntibiotics from animal tissues
interferons (spleen macrophages tissue cells)
lysozyme (most body fluid salive eggs)
erythrin (red cells liver)
ecmolin (fish)
Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action
1 Antibacterial
А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes
Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones
2 Antifungal (amphotericin)
3 Antiviral (amantadin vidarabin)
4 Antiprotozoal (emethin chinin)
5 Antineoplastic (bleomycin mitomycin C actinomycines)
Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action
Spectrum of ActivityRelates to the number of microbes that are
susceptible to the action of the drugndashNarrow (limited number) Broad (wide)
bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-
positive and gram-negative microbes (Broad)
Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)
Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms
BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate
BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate
Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action
Mechanism of Action1 Inhibition of Cell Wall Synthesis
2 Disruption of Cell Membrane
3 Inhibition of Protein Synthesis
4 Interference with Metabolic
Processes
NBBactericidalBacteriostatic
Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis
Most bacteria possess a cell wall to protect from osmotic pressures
Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being
susceptible to external influencesndash Cell ruptures Microbe death
Eg Penicillinsm cephalosporins vancomycin and bacitracin
Disruption of the microbial cell Disruption of the microbial cell membranemembrane
Essentially affect cell membrane transportation in and out
Increases permeability of membranendash External influences have greater effectndash Microbe death
Eg Polymyxin Colistin
Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis
Inhibition of Protein SynthesisInhibition of Protein Synthesis
Proteins vital for growth and repairAct either at
ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic
acidsbull DNA replication RNA synthesis = TRANSCRIPTION
Eg Tetracyclines aminoglycosides and macrolides (erythromycin)
Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity
Interference with metabolic Interference with metabolic processesprocesses
bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it
microbes can not produce the proteins for growth
ndash Exploits microbes need to create their own folic acid whilst we get it in our diets
bull Eg Sulphonamides Trimethoprim
Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics
Serial dilutions
- in a liquid medium
- in a solid medium
Disc diffusion method
Rapid methods
Demands to nutrient media
1 to be standard and provide optimal conditions for microbial growth
2do not have inhibitors of bacterial growth and a lot of stimulators
3do not have substances which inhibit antibiotic activity
Disc diffusion methodDisc diffusion method
Serial dilution in liquid mediumSerial dilution in liquid medium
Serial dilution in solid mediumSerial dilution in solid medium
Minimal Inhibitory Concentration (MIC)
10487091048709Lowest concentration of antibiotic that prevents visible growth
bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic
bull 1048709Accurate but time-consuming
bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method
Minimal Bactericidal Concentration (MBC)
10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold
bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media
bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies
ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
In 1944 Waksman isolated streptomycin and subsequently found agents such as chloramphenicol tetracyclines and erythromycin in soil samples
S Waksman
In 1939 Florey and colleagues at Oxford University again isolated penicillin
G Florey E Chainy
AntibioticsAntibiotics are chemical substances produced by microorganisms (such as bacteria fungi actinomyces) or other organisms which suppress the growth of other microorganisms and eventually destroy them
Some antibiotics have been produced by chemical synthesis or semi-synthetically from natural substances
The term ldquoantibioticsrdquo proposed in 1942 S Waksman
It means anti ndash against bios - life
Microbial antagonism is the basis of modern use of antibiotics
L Pasteur
Peculiarities of antibiotics
- high level of biological activity
- high election specificity
Activity of antibiotics is evaluated in International Unit
Classification of antibiotics according to their origin
11 Antibiotics from fungiAntibiotics from fungi
Penicillins (Penicillium notatum Pchryzogenum)
Cephalosporins (Cephalosporium salmosynnematum)
Griseofulvinum (P griseofulvum P patulum P nigricans)
Fusidin (Fusidium coccineum)
2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces Aminoglicosides Streptomycin (Streptomyces griseus) neomycin (S fradiae) kanamycin (S kanamyseticus) tobramycin (S tenebrarius) gentamycin (Micromonospora purpurea) sisomicin (Micromonospora inyoensis)
Tetracyclines chlortetracycline (S aureofaciens) oxytetracycline (S rimosus)
Chloramphenicol (S venezuelae)
Macrolides oleandomycin (S antibioticus) erythromycin (S erythreus)
2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces
Linkomycin (S lincolniensis) е) Rifampicin (S mediterranei)
Polyenes nystatin (S noursei) levorin (S levorys Krass) amphotericin B (S nodosus)
Inhibitors of beta-lactamases klavulanic acid (S clavuligerus)
Carbapenem (S olivaceus)
Thienamycin (S cattleya)
33 Antibiotics from bacteriaAntibiotics from bacteria
Bacillus polymyxin (B polymyxa) licheniformin (B licheniformis) gramicidin С (B brevis) subtilin (B subtilis)
Pseudomonas piocianin (P aeruginosa) sorbistin (P sorbistini)
other bacteria monobactams (Chromobacterium violaceum) nisin (Streptococcus lactis) prodigiosin (Serratia marcescens) coliformin (E coli) streptosin diplococcin (Streptococcus spp) azomycin nocardamin (Nocardia)
4 Antibiotics from plants4 Antibiotics from plants
Chorellin (Chlorella vulgaris)
Arenarin (Helichrysum arenarium)
Gordecin (barley)
Chinin (cinchona tree)
Alicin (garlic Allium sativum)
Raphanin (radish Raphanus sativum)
Phaseolin (haricot bean Phaseolus vulgaris)
55 Antibiotics from animal tissuesAntibiotics from animal tissues
interferons (spleen macrophages tissue cells)
lysozyme (most body fluid salive eggs)
erythrin (red cells liver)
ecmolin (fish)
Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action
1 Antibacterial
А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes
Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones
2 Antifungal (amphotericin)
3 Antiviral (amantadin vidarabin)
4 Antiprotozoal (emethin chinin)
5 Antineoplastic (bleomycin mitomycin C actinomycines)
Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action
Spectrum of ActivityRelates to the number of microbes that are
susceptible to the action of the drugndashNarrow (limited number) Broad (wide)
bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-
positive and gram-negative microbes (Broad)
Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)
Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms
BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate
BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate
Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action
Mechanism of Action1 Inhibition of Cell Wall Synthesis
2 Disruption of Cell Membrane
3 Inhibition of Protein Synthesis
4 Interference with Metabolic
Processes
NBBactericidalBacteriostatic
Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis
Most bacteria possess a cell wall to protect from osmotic pressures
Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being
susceptible to external influencesndash Cell ruptures Microbe death
Eg Penicillinsm cephalosporins vancomycin and bacitracin
Disruption of the microbial cell Disruption of the microbial cell membranemembrane
Essentially affect cell membrane transportation in and out
Increases permeability of membranendash External influences have greater effectndash Microbe death
Eg Polymyxin Colistin
Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis
Inhibition of Protein SynthesisInhibition of Protein Synthesis
Proteins vital for growth and repairAct either at
ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic
acidsbull DNA replication RNA synthesis = TRANSCRIPTION
Eg Tetracyclines aminoglycosides and macrolides (erythromycin)
Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity
Interference with metabolic Interference with metabolic processesprocesses
bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it
microbes can not produce the proteins for growth
ndash Exploits microbes need to create their own folic acid whilst we get it in our diets
bull Eg Sulphonamides Trimethoprim
Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics
Serial dilutions
- in a liquid medium
- in a solid medium
Disc diffusion method
Rapid methods
Demands to nutrient media
1 to be standard and provide optimal conditions for microbial growth
2do not have inhibitors of bacterial growth and a lot of stimulators
3do not have substances which inhibit antibiotic activity
Disc diffusion methodDisc diffusion method
Serial dilution in liquid mediumSerial dilution in liquid medium
Serial dilution in solid mediumSerial dilution in solid medium
Minimal Inhibitory Concentration (MIC)
10487091048709Lowest concentration of antibiotic that prevents visible growth
bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic
bull 1048709Accurate but time-consuming
bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method
Minimal Bactericidal Concentration (MBC)
10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold
bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media
bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies
ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
In 1939 Florey and colleagues at Oxford University again isolated penicillin
G Florey E Chainy
AntibioticsAntibiotics are chemical substances produced by microorganisms (such as bacteria fungi actinomyces) or other organisms which suppress the growth of other microorganisms and eventually destroy them
Some antibiotics have been produced by chemical synthesis or semi-synthetically from natural substances
The term ldquoantibioticsrdquo proposed in 1942 S Waksman
It means anti ndash against bios - life
Microbial antagonism is the basis of modern use of antibiotics
L Pasteur
Peculiarities of antibiotics
- high level of biological activity
- high election specificity
Activity of antibiotics is evaluated in International Unit
Classification of antibiotics according to their origin
11 Antibiotics from fungiAntibiotics from fungi
Penicillins (Penicillium notatum Pchryzogenum)
Cephalosporins (Cephalosporium salmosynnematum)
Griseofulvinum (P griseofulvum P patulum P nigricans)
Fusidin (Fusidium coccineum)
2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces Aminoglicosides Streptomycin (Streptomyces griseus) neomycin (S fradiae) kanamycin (S kanamyseticus) tobramycin (S tenebrarius) gentamycin (Micromonospora purpurea) sisomicin (Micromonospora inyoensis)
Tetracyclines chlortetracycline (S aureofaciens) oxytetracycline (S rimosus)
Chloramphenicol (S venezuelae)
Macrolides oleandomycin (S antibioticus) erythromycin (S erythreus)
2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces
Linkomycin (S lincolniensis) е) Rifampicin (S mediterranei)
Polyenes nystatin (S noursei) levorin (S levorys Krass) amphotericin B (S nodosus)
Inhibitors of beta-lactamases klavulanic acid (S clavuligerus)
Carbapenem (S olivaceus)
Thienamycin (S cattleya)
33 Antibiotics from bacteriaAntibiotics from bacteria
Bacillus polymyxin (B polymyxa) licheniformin (B licheniformis) gramicidin С (B brevis) subtilin (B subtilis)
Pseudomonas piocianin (P aeruginosa) sorbistin (P sorbistini)
other bacteria monobactams (Chromobacterium violaceum) nisin (Streptococcus lactis) prodigiosin (Serratia marcescens) coliformin (E coli) streptosin diplococcin (Streptococcus spp) azomycin nocardamin (Nocardia)
4 Antibiotics from plants4 Antibiotics from plants
Chorellin (Chlorella vulgaris)
Arenarin (Helichrysum arenarium)
Gordecin (barley)
Chinin (cinchona tree)
Alicin (garlic Allium sativum)
Raphanin (radish Raphanus sativum)
Phaseolin (haricot bean Phaseolus vulgaris)
55 Antibiotics from animal tissuesAntibiotics from animal tissues
interferons (spleen macrophages tissue cells)
lysozyme (most body fluid salive eggs)
erythrin (red cells liver)
ecmolin (fish)
Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action
1 Antibacterial
А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes
Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones
2 Antifungal (amphotericin)
3 Antiviral (amantadin vidarabin)
4 Antiprotozoal (emethin chinin)
5 Antineoplastic (bleomycin mitomycin C actinomycines)
Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action
Spectrum of ActivityRelates to the number of microbes that are
susceptible to the action of the drugndashNarrow (limited number) Broad (wide)
bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-
positive and gram-negative microbes (Broad)
Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)
Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms
BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate
BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate
Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action
Mechanism of Action1 Inhibition of Cell Wall Synthesis
2 Disruption of Cell Membrane
3 Inhibition of Protein Synthesis
4 Interference with Metabolic
Processes
NBBactericidalBacteriostatic
Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis
Most bacteria possess a cell wall to protect from osmotic pressures
Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being
susceptible to external influencesndash Cell ruptures Microbe death
Eg Penicillinsm cephalosporins vancomycin and bacitracin
Disruption of the microbial cell Disruption of the microbial cell membranemembrane
Essentially affect cell membrane transportation in and out
Increases permeability of membranendash External influences have greater effectndash Microbe death
Eg Polymyxin Colistin
Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis
Inhibition of Protein SynthesisInhibition of Protein Synthesis
Proteins vital for growth and repairAct either at
ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic
acidsbull DNA replication RNA synthesis = TRANSCRIPTION
Eg Tetracyclines aminoglycosides and macrolides (erythromycin)
Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity
Interference with metabolic Interference with metabolic processesprocesses
bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it
microbes can not produce the proteins for growth
ndash Exploits microbes need to create their own folic acid whilst we get it in our diets
bull Eg Sulphonamides Trimethoprim
Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics
Serial dilutions
- in a liquid medium
- in a solid medium
Disc diffusion method
Rapid methods
Demands to nutrient media
1 to be standard and provide optimal conditions for microbial growth
2do not have inhibitors of bacterial growth and a lot of stimulators
3do not have substances which inhibit antibiotic activity
Disc diffusion methodDisc diffusion method
Serial dilution in liquid mediumSerial dilution in liquid medium
Serial dilution in solid mediumSerial dilution in solid medium
Minimal Inhibitory Concentration (MIC)
10487091048709Lowest concentration of antibiotic that prevents visible growth
bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic
bull 1048709Accurate but time-consuming
bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method
Minimal Bactericidal Concentration (MBC)
10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold
bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media
bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies
ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
AntibioticsAntibiotics are chemical substances produced by microorganisms (such as bacteria fungi actinomyces) or other organisms which suppress the growth of other microorganisms and eventually destroy them
Some antibiotics have been produced by chemical synthesis or semi-synthetically from natural substances
The term ldquoantibioticsrdquo proposed in 1942 S Waksman
It means anti ndash against bios - life
Microbial antagonism is the basis of modern use of antibiotics
L Pasteur
Peculiarities of antibiotics
- high level of biological activity
- high election specificity
Activity of antibiotics is evaluated in International Unit
Classification of antibiotics according to their origin
11 Antibiotics from fungiAntibiotics from fungi
Penicillins (Penicillium notatum Pchryzogenum)
Cephalosporins (Cephalosporium salmosynnematum)
Griseofulvinum (P griseofulvum P patulum P nigricans)
Fusidin (Fusidium coccineum)
2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces Aminoglicosides Streptomycin (Streptomyces griseus) neomycin (S fradiae) kanamycin (S kanamyseticus) tobramycin (S tenebrarius) gentamycin (Micromonospora purpurea) sisomicin (Micromonospora inyoensis)
Tetracyclines chlortetracycline (S aureofaciens) oxytetracycline (S rimosus)
Chloramphenicol (S venezuelae)
Macrolides oleandomycin (S antibioticus) erythromycin (S erythreus)
2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces
Linkomycin (S lincolniensis) е) Rifampicin (S mediterranei)
Polyenes nystatin (S noursei) levorin (S levorys Krass) amphotericin B (S nodosus)
Inhibitors of beta-lactamases klavulanic acid (S clavuligerus)
Carbapenem (S olivaceus)
Thienamycin (S cattleya)
33 Antibiotics from bacteriaAntibiotics from bacteria
Bacillus polymyxin (B polymyxa) licheniformin (B licheniformis) gramicidin С (B brevis) subtilin (B subtilis)
Pseudomonas piocianin (P aeruginosa) sorbistin (P sorbistini)
other bacteria monobactams (Chromobacterium violaceum) nisin (Streptococcus lactis) prodigiosin (Serratia marcescens) coliformin (E coli) streptosin diplococcin (Streptococcus spp) azomycin nocardamin (Nocardia)
4 Antibiotics from plants4 Antibiotics from plants
Chorellin (Chlorella vulgaris)
Arenarin (Helichrysum arenarium)
Gordecin (barley)
Chinin (cinchona tree)
Alicin (garlic Allium sativum)
Raphanin (radish Raphanus sativum)
Phaseolin (haricot bean Phaseolus vulgaris)
55 Antibiotics from animal tissuesAntibiotics from animal tissues
interferons (spleen macrophages tissue cells)
lysozyme (most body fluid salive eggs)
erythrin (red cells liver)
ecmolin (fish)
Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action
1 Antibacterial
А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes
Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones
2 Antifungal (amphotericin)
3 Antiviral (amantadin vidarabin)
4 Antiprotozoal (emethin chinin)
5 Antineoplastic (bleomycin mitomycin C actinomycines)
Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action
Spectrum of ActivityRelates to the number of microbes that are
susceptible to the action of the drugndashNarrow (limited number) Broad (wide)
bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-
positive and gram-negative microbes (Broad)
Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)
Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms
BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate
BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate
Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action
Mechanism of Action1 Inhibition of Cell Wall Synthesis
2 Disruption of Cell Membrane
3 Inhibition of Protein Synthesis
4 Interference with Metabolic
Processes
NBBactericidalBacteriostatic
Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis
Most bacteria possess a cell wall to protect from osmotic pressures
Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being
susceptible to external influencesndash Cell ruptures Microbe death
Eg Penicillinsm cephalosporins vancomycin and bacitracin
Disruption of the microbial cell Disruption of the microbial cell membranemembrane
Essentially affect cell membrane transportation in and out
Increases permeability of membranendash External influences have greater effectndash Microbe death
Eg Polymyxin Colistin
Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis
Inhibition of Protein SynthesisInhibition of Protein Synthesis
Proteins vital for growth and repairAct either at
ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic
acidsbull DNA replication RNA synthesis = TRANSCRIPTION
Eg Tetracyclines aminoglycosides and macrolides (erythromycin)
Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity
Interference with metabolic Interference with metabolic processesprocesses
bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it
microbes can not produce the proteins for growth
ndash Exploits microbes need to create their own folic acid whilst we get it in our diets
bull Eg Sulphonamides Trimethoprim
Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics
Serial dilutions
- in a liquid medium
- in a solid medium
Disc diffusion method
Rapid methods
Demands to nutrient media
1 to be standard and provide optimal conditions for microbial growth
2do not have inhibitors of bacterial growth and a lot of stimulators
3do not have substances which inhibit antibiotic activity
Disc diffusion methodDisc diffusion method
Serial dilution in liquid mediumSerial dilution in liquid medium
Serial dilution in solid mediumSerial dilution in solid medium
Minimal Inhibitory Concentration (MIC)
10487091048709Lowest concentration of antibiotic that prevents visible growth
bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic
bull 1048709Accurate but time-consuming
bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method
Minimal Bactericidal Concentration (MBC)
10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold
bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media
bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies
ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
The term ldquoantibioticsrdquo proposed in 1942 S Waksman
It means anti ndash against bios - life
Microbial antagonism is the basis of modern use of antibiotics
L Pasteur
Peculiarities of antibiotics
- high level of biological activity
- high election specificity
Activity of antibiotics is evaluated in International Unit
Classification of antibiotics according to their origin
11 Antibiotics from fungiAntibiotics from fungi
Penicillins (Penicillium notatum Pchryzogenum)
Cephalosporins (Cephalosporium salmosynnematum)
Griseofulvinum (P griseofulvum P patulum P nigricans)
Fusidin (Fusidium coccineum)
2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces Aminoglicosides Streptomycin (Streptomyces griseus) neomycin (S fradiae) kanamycin (S kanamyseticus) tobramycin (S tenebrarius) gentamycin (Micromonospora purpurea) sisomicin (Micromonospora inyoensis)
Tetracyclines chlortetracycline (S aureofaciens) oxytetracycline (S rimosus)
Chloramphenicol (S venezuelae)
Macrolides oleandomycin (S antibioticus) erythromycin (S erythreus)
2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces
Linkomycin (S lincolniensis) е) Rifampicin (S mediterranei)
Polyenes nystatin (S noursei) levorin (S levorys Krass) amphotericin B (S nodosus)
Inhibitors of beta-lactamases klavulanic acid (S clavuligerus)
Carbapenem (S olivaceus)
Thienamycin (S cattleya)
33 Antibiotics from bacteriaAntibiotics from bacteria
Bacillus polymyxin (B polymyxa) licheniformin (B licheniformis) gramicidin С (B brevis) subtilin (B subtilis)
Pseudomonas piocianin (P aeruginosa) sorbistin (P sorbistini)
other bacteria monobactams (Chromobacterium violaceum) nisin (Streptococcus lactis) prodigiosin (Serratia marcescens) coliformin (E coli) streptosin diplococcin (Streptococcus spp) azomycin nocardamin (Nocardia)
4 Antibiotics from plants4 Antibiotics from plants
Chorellin (Chlorella vulgaris)
Arenarin (Helichrysum arenarium)
Gordecin (barley)
Chinin (cinchona tree)
Alicin (garlic Allium sativum)
Raphanin (radish Raphanus sativum)
Phaseolin (haricot bean Phaseolus vulgaris)
55 Antibiotics from animal tissuesAntibiotics from animal tissues
interferons (spleen macrophages tissue cells)
lysozyme (most body fluid salive eggs)
erythrin (red cells liver)
ecmolin (fish)
Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action
1 Antibacterial
А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes
Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones
2 Antifungal (amphotericin)
3 Antiviral (amantadin vidarabin)
4 Antiprotozoal (emethin chinin)
5 Antineoplastic (bleomycin mitomycin C actinomycines)
Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action
Spectrum of ActivityRelates to the number of microbes that are
susceptible to the action of the drugndashNarrow (limited number) Broad (wide)
bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-
positive and gram-negative microbes (Broad)
Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)
Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms
BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate
BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate
Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action
Mechanism of Action1 Inhibition of Cell Wall Synthesis
2 Disruption of Cell Membrane
3 Inhibition of Protein Synthesis
4 Interference with Metabolic
Processes
NBBactericidalBacteriostatic
Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis
Most bacteria possess a cell wall to protect from osmotic pressures
Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being
susceptible to external influencesndash Cell ruptures Microbe death
Eg Penicillinsm cephalosporins vancomycin and bacitracin
Disruption of the microbial cell Disruption of the microbial cell membranemembrane
Essentially affect cell membrane transportation in and out
Increases permeability of membranendash External influences have greater effectndash Microbe death
Eg Polymyxin Colistin
Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis
Inhibition of Protein SynthesisInhibition of Protein Synthesis
Proteins vital for growth and repairAct either at
ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic
acidsbull DNA replication RNA synthesis = TRANSCRIPTION
Eg Tetracyclines aminoglycosides and macrolides (erythromycin)
Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity
Interference with metabolic Interference with metabolic processesprocesses
bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it
microbes can not produce the proteins for growth
ndash Exploits microbes need to create their own folic acid whilst we get it in our diets
bull Eg Sulphonamides Trimethoprim
Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics
Serial dilutions
- in a liquid medium
- in a solid medium
Disc diffusion method
Rapid methods
Demands to nutrient media
1 to be standard and provide optimal conditions for microbial growth
2do not have inhibitors of bacterial growth and a lot of stimulators
3do not have substances which inhibit antibiotic activity
Disc diffusion methodDisc diffusion method
Serial dilution in liquid mediumSerial dilution in liquid medium
Serial dilution in solid mediumSerial dilution in solid medium
Minimal Inhibitory Concentration (MIC)
10487091048709Lowest concentration of antibiotic that prevents visible growth
bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic
bull 1048709Accurate but time-consuming
bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method
Minimal Bactericidal Concentration (MBC)
10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold
bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media
bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies
ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
Microbial antagonism is the basis of modern use of antibiotics
L Pasteur
Peculiarities of antibiotics
- high level of biological activity
- high election specificity
Activity of antibiotics is evaluated in International Unit
Classification of antibiotics according to their origin
11 Antibiotics from fungiAntibiotics from fungi
Penicillins (Penicillium notatum Pchryzogenum)
Cephalosporins (Cephalosporium salmosynnematum)
Griseofulvinum (P griseofulvum P patulum P nigricans)
Fusidin (Fusidium coccineum)
2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces Aminoglicosides Streptomycin (Streptomyces griseus) neomycin (S fradiae) kanamycin (S kanamyseticus) tobramycin (S tenebrarius) gentamycin (Micromonospora purpurea) sisomicin (Micromonospora inyoensis)
Tetracyclines chlortetracycline (S aureofaciens) oxytetracycline (S rimosus)
Chloramphenicol (S venezuelae)
Macrolides oleandomycin (S antibioticus) erythromycin (S erythreus)
2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces
Linkomycin (S lincolniensis) е) Rifampicin (S mediterranei)
Polyenes nystatin (S noursei) levorin (S levorys Krass) amphotericin B (S nodosus)
Inhibitors of beta-lactamases klavulanic acid (S clavuligerus)
Carbapenem (S olivaceus)
Thienamycin (S cattleya)
33 Antibiotics from bacteriaAntibiotics from bacteria
Bacillus polymyxin (B polymyxa) licheniformin (B licheniformis) gramicidin С (B brevis) subtilin (B subtilis)
Pseudomonas piocianin (P aeruginosa) sorbistin (P sorbistini)
other bacteria monobactams (Chromobacterium violaceum) nisin (Streptococcus lactis) prodigiosin (Serratia marcescens) coliformin (E coli) streptosin diplococcin (Streptococcus spp) azomycin nocardamin (Nocardia)
4 Antibiotics from plants4 Antibiotics from plants
Chorellin (Chlorella vulgaris)
Arenarin (Helichrysum arenarium)
Gordecin (barley)
Chinin (cinchona tree)
Alicin (garlic Allium sativum)
Raphanin (radish Raphanus sativum)
Phaseolin (haricot bean Phaseolus vulgaris)
55 Antibiotics from animal tissuesAntibiotics from animal tissues
interferons (spleen macrophages tissue cells)
lysozyme (most body fluid salive eggs)
erythrin (red cells liver)
ecmolin (fish)
Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action
1 Antibacterial
А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes
Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones
2 Antifungal (amphotericin)
3 Antiviral (amantadin vidarabin)
4 Antiprotozoal (emethin chinin)
5 Antineoplastic (bleomycin mitomycin C actinomycines)
Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action
Spectrum of ActivityRelates to the number of microbes that are
susceptible to the action of the drugndashNarrow (limited number) Broad (wide)
bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-
positive and gram-negative microbes (Broad)
Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)
Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms
BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate
BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate
Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action
Mechanism of Action1 Inhibition of Cell Wall Synthesis
2 Disruption of Cell Membrane
3 Inhibition of Protein Synthesis
4 Interference with Metabolic
Processes
NBBactericidalBacteriostatic
Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis
Most bacteria possess a cell wall to protect from osmotic pressures
Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being
susceptible to external influencesndash Cell ruptures Microbe death
Eg Penicillinsm cephalosporins vancomycin and bacitracin
Disruption of the microbial cell Disruption of the microbial cell membranemembrane
Essentially affect cell membrane transportation in and out
Increases permeability of membranendash External influences have greater effectndash Microbe death
Eg Polymyxin Colistin
Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis
Inhibition of Protein SynthesisInhibition of Protein Synthesis
Proteins vital for growth and repairAct either at
ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic
acidsbull DNA replication RNA synthesis = TRANSCRIPTION
Eg Tetracyclines aminoglycosides and macrolides (erythromycin)
Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity
Interference with metabolic Interference with metabolic processesprocesses
bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it
microbes can not produce the proteins for growth
ndash Exploits microbes need to create their own folic acid whilst we get it in our diets
bull Eg Sulphonamides Trimethoprim
Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics
Serial dilutions
- in a liquid medium
- in a solid medium
Disc diffusion method
Rapid methods
Demands to nutrient media
1 to be standard and provide optimal conditions for microbial growth
2do not have inhibitors of bacterial growth and a lot of stimulators
3do not have substances which inhibit antibiotic activity
Disc diffusion methodDisc diffusion method
Serial dilution in liquid mediumSerial dilution in liquid medium
Serial dilution in solid mediumSerial dilution in solid medium
Minimal Inhibitory Concentration (MIC)
10487091048709Lowest concentration of antibiotic that prevents visible growth
bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic
bull 1048709Accurate but time-consuming
bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method
Minimal Bactericidal Concentration (MBC)
10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold
bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media
bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies
ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
Peculiarities of antibiotics
- high level of biological activity
- high election specificity
Activity of antibiotics is evaluated in International Unit
Classification of antibiotics according to their origin
11 Antibiotics from fungiAntibiotics from fungi
Penicillins (Penicillium notatum Pchryzogenum)
Cephalosporins (Cephalosporium salmosynnematum)
Griseofulvinum (P griseofulvum P patulum P nigricans)
Fusidin (Fusidium coccineum)
2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces Aminoglicosides Streptomycin (Streptomyces griseus) neomycin (S fradiae) kanamycin (S kanamyseticus) tobramycin (S tenebrarius) gentamycin (Micromonospora purpurea) sisomicin (Micromonospora inyoensis)
Tetracyclines chlortetracycline (S aureofaciens) oxytetracycline (S rimosus)
Chloramphenicol (S venezuelae)
Macrolides oleandomycin (S antibioticus) erythromycin (S erythreus)
2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces
Linkomycin (S lincolniensis) е) Rifampicin (S mediterranei)
Polyenes nystatin (S noursei) levorin (S levorys Krass) amphotericin B (S nodosus)
Inhibitors of beta-lactamases klavulanic acid (S clavuligerus)
Carbapenem (S olivaceus)
Thienamycin (S cattleya)
33 Antibiotics from bacteriaAntibiotics from bacteria
Bacillus polymyxin (B polymyxa) licheniformin (B licheniformis) gramicidin С (B brevis) subtilin (B subtilis)
Pseudomonas piocianin (P aeruginosa) sorbistin (P sorbistini)
other bacteria monobactams (Chromobacterium violaceum) nisin (Streptococcus lactis) prodigiosin (Serratia marcescens) coliformin (E coli) streptosin diplococcin (Streptococcus spp) azomycin nocardamin (Nocardia)
4 Antibiotics from plants4 Antibiotics from plants
Chorellin (Chlorella vulgaris)
Arenarin (Helichrysum arenarium)
Gordecin (barley)
Chinin (cinchona tree)
Alicin (garlic Allium sativum)
Raphanin (radish Raphanus sativum)
Phaseolin (haricot bean Phaseolus vulgaris)
55 Antibiotics from animal tissuesAntibiotics from animal tissues
interferons (spleen macrophages tissue cells)
lysozyme (most body fluid salive eggs)
erythrin (red cells liver)
ecmolin (fish)
Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action
1 Antibacterial
А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes
Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones
2 Antifungal (amphotericin)
3 Antiviral (amantadin vidarabin)
4 Antiprotozoal (emethin chinin)
5 Antineoplastic (bleomycin mitomycin C actinomycines)
Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action
Spectrum of ActivityRelates to the number of microbes that are
susceptible to the action of the drugndashNarrow (limited number) Broad (wide)
bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-
positive and gram-negative microbes (Broad)
Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)
Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms
BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate
BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate
Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action
Mechanism of Action1 Inhibition of Cell Wall Synthesis
2 Disruption of Cell Membrane
3 Inhibition of Protein Synthesis
4 Interference with Metabolic
Processes
NBBactericidalBacteriostatic
Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis
Most bacteria possess a cell wall to protect from osmotic pressures
Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being
susceptible to external influencesndash Cell ruptures Microbe death
Eg Penicillinsm cephalosporins vancomycin and bacitracin
Disruption of the microbial cell Disruption of the microbial cell membranemembrane
Essentially affect cell membrane transportation in and out
Increases permeability of membranendash External influences have greater effectndash Microbe death
Eg Polymyxin Colistin
Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis
Inhibition of Protein SynthesisInhibition of Protein Synthesis
Proteins vital for growth and repairAct either at
ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic
acidsbull DNA replication RNA synthesis = TRANSCRIPTION
Eg Tetracyclines aminoglycosides and macrolides (erythromycin)
Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity
Interference with metabolic Interference with metabolic processesprocesses
bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it
microbes can not produce the proteins for growth
ndash Exploits microbes need to create their own folic acid whilst we get it in our diets
bull Eg Sulphonamides Trimethoprim
Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics
Serial dilutions
- in a liquid medium
- in a solid medium
Disc diffusion method
Rapid methods
Demands to nutrient media
1 to be standard and provide optimal conditions for microbial growth
2do not have inhibitors of bacterial growth and a lot of stimulators
3do not have substances which inhibit antibiotic activity
Disc diffusion methodDisc diffusion method
Serial dilution in liquid mediumSerial dilution in liquid medium
Serial dilution in solid mediumSerial dilution in solid medium
Minimal Inhibitory Concentration (MIC)
10487091048709Lowest concentration of antibiotic that prevents visible growth
bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic
bull 1048709Accurate but time-consuming
bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method
Minimal Bactericidal Concentration (MBC)
10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold
bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media
bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies
ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
Activity of antibiotics is evaluated in International Unit
Classification of antibiotics according to their origin
11 Antibiotics from fungiAntibiotics from fungi
Penicillins (Penicillium notatum Pchryzogenum)
Cephalosporins (Cephalosporium salmosynnematum)
Griseofulvinum (P griseofulvum P patulum P nigricans)
Fusidin (Fusidium coccineum)
2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces Aminoglicosides Streptomycin (Streptomyces griseus) neomycin (S fradiae) kanamycin (S kanamyseticus) tobramycin (S tenebrarius) gentamycin (Micromonospora purpurea) sisomicin (Micromonospora inyoensis)
Tetracyclines chlortetracycline (S aureofaciens) oxytetracycline (S rimosus)
Chloramphenicol (S venezuelae)
Macrolides oleandomycin (S antibioticus) erythromycin (S erythreus)
2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces
Linkomycin (S lincolniensis) е) Rifampicin (S mediterranei)
Polyenes nystatin (S noursei) levorin (S levorys Krass) amphotericin B (S nodosus)
Inhibitors of beta-lactamases klavulanic acid (S clavuligerus)
Carbapenem (S olivaceus)
Thienamycin (S cattleya)
33 Antibiotics from bacteriaAntibiotics from bacteria
Bacillus polymyxin (B polymyxa) licheniformin (B licheniformis) gramicidin С (B brevis) subtilin (B subtilis)
Pseudomonas piocianin (P aeruginosa) sorbistin (P sorbistini)
other bacteria monobactams (Chromobacterium violaceum) nisin (Streptococcus lactis) prodigiosin (Serratia marcescens) coliformin (E coli) streptosin diplococcin (Streptococcus spp) azomycin nocardamin (Nocardia)
4 Antibiotics from plants4 Antibiotics from plants
Chorellin (Chlorella vulgaris)
Arenarin (Helichrysum arenarium)
Gordecin (barley)
Chinin (cinchona tree)
Alicin (garlic Allium sativum)
Raphanin (radish Raphanus sativum)
Phaseolin (haricot bean Phaseolus vulgaris)
55 Antibiotics from animal tissuesAntibiotics from animal tissues
interferons (spleen macrophages tissue cells)
lysozyme (most body fluid salive eggs)
erythrin (red cells liver)
ecmolin (fish)
Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action
1 Antibacterial
А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes
Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones
2 Antifungal (amphotericin)
3 Antiviral (amantadin vidarabin)
4 Antiprotozoal (emethin chinin)
5 Antineoplastic (bleomycin mitomycin C actinomycines)
Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action
Spectrum of ActivityRelates to the number of microbes that are
susceptible to the action of the drugndashNarrow (limited number) Broad (wide)
bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-
positive and gram-negative microbes (Broad)
Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)
Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms
BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate
BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate
Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action
Mechanism of Action1 Inhibition of Cell Wall Synthesis
2 Disruption of Cell Membrane
3 Inhibition of Protein Synthesis
4 Interference with Metabolic
Processes
NBBactericidalBacteriostatic
Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis
Most bacteria possess a cell wall to protect from osmotic pressures
Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being
susceptible to external influencesndash Cell ruptures Microbe death
Eg Penicillinsm cephalosporins vancomycin and bacitracin
Disruption of the microbial cell Disruption of the microbial cell membranemembrane
Essentially affect cell membrane transportation in and out
Increases permeability of membranendash External influences have greater effectndash Microbe death
Eg Polymyxin Colistin
Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis
Inhibition of Protein SynthesisInhibition of Protein Synthesis
Proteins vital for growth and repairAct either at
ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic
acidsbull DNA replication RNA synthesis = TRANSCRIPTION
Eg Tetracyclines aminoglycosides and macrolides (erythromycin)
Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity
Interference with metabolic Interference with metabolic processesprocesses
bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it
microbes can not produce the proteins for growth
ndash Exploits microbes need to create their own folic acid whilst we get it in our diets
bull Eg Sulphonamides Trimethoprim
Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics
Serial dilutions
- in a liquid medium
- in a solid medium
Disc diffusion method
Rapid methods
Demands to nutrient media
1 to be standard and provide optimal conditions for microbial growth
2do not have inhibitors of bacterial growth and a lot of stimulators
3do not have substances which inhibit antibiotic activity
Disc diffusion methodDisc diffusion method
Serial dilution in liquid mediumSerial dilution in liquid medium
Serial dilution in solid mediumSerial dilution in solid medium
Minimal Inhibitory Concentration (MIC)
10487091048709Lowest concentration of antibiotic that prevents visible growth
bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic
bull 1048709Accurate but time-consuming
bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method
Minimal Bactericidal Concentration (MBC)
10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold
bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media
bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies
ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
Classification of antibiotics according to their origin
11 Antibiotics from fungiAntibiotics from fungi
Penicillins (Penicillium notatum Pchryzogenum)
Cephalosporins (Cephalosporium salmosynnematum)
Griseofulvinum (P griseofulvum P patulum P nigricans)
Fusidin (Fusidium coccineum)
2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces Aminoglicosides Streptomycin (Streptomyces griseus) neomycin (S fradiae) kanamycin (S kanamyseticus) tobramycin (S tenebrarius) gentamycin (Micromonospora purpurea) sisomicin (Micromonospora inyoensis)
Tetracyclines chlortetracycline (S aureofaciens) oxytetracycline (S rimosus)
Chloramphenicol (S venezuelae)
Macrolides oleandomycin (S antibioticus) erythromycin (S erythreus)
2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces
Linkomycin (S lincolniensis) е) Rifampicin (S mediterranei)
Polyenes nystatin (S noursei) levorin (S levorys Krass) amphotericin B (S nodosus)
Inhibitors of beta-lactamases klavulanic acid (S clavuligerus)
Carbapenem (S olivaceus)
Thienamycin (S cattleya)
33 Antibiotics from bacteriaAntibiotics from bacteria
Bacillus polymyxin (B polymyxa) licheniformin (B licheniformis) gramicidin С (B brevis) subtilin (B subtilis)
Pseudomonas piocianin (P aeruginosa) sorbistin (P sorbistini)
other bacteria monobactams (Chromobacterium violaceum) nisin (Streptococcus lactis) prodigiosin (Serratia marcescens) coliformin (E coli) streptosin diplococcin (Streptococcus spp) azomycin nocardamin (Nocardia)
4 Antibiotics from plants4 Antibiotics from plants
Chorellin (Chlorella vulgaris)
Arenarin (Helichrysum arenarium)
Gordecin (barley)
Chinin (cinchona tree)
Alicin (garlic Allium sativum)
Raphanin (radish Raphanus sativum)
Phaseolin (haricot bean Phaseolus vulgaris)
55 Antibiotics from animal tissuesAntibiotics from animal tissues
interferons (spleen macrophages tissue cells)
lysozyme (most body fluid salive eggs)
erythrin (red cells liver)
ecmolin (fish)
Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action
1 Antibacterial
А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes
Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones
2 Antifungal (amphotericin)
3 Antiviral (amantadin vidarabin)
4 Antiprotozoal (emethin chinin)
5 Antineoplastic (bleomycin mitomycin C actinomycines)
Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action
Spectrum of ActivityRelates to the number of microbes that are
susceptible to the action of the drugndashNarrow (limited number) Broad (wide)
bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-
positive and gram-negative microbes (Broad)
Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)
Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms
BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate
BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate
Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action
Mechanism of Action1 Inhibition of Cell Wall Synthesis
2 Disruption of Cell Membrane
3 Inhibition of Protein Synthesis
4 Interference with Metabolic
Processes
NBBactericidalBacteriostatic
Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis
Most bacteria possess a cell wall to protect from osmotic pressures
Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being
susceptible to external influencesndash Cell ruptures Microbe death
Eg Penicillinsm cephalosporins vancomycin and bacitracin
Disruption of the microbial cell Disruption of the microbial cell membranemembrane
Essentially affect cell membrane transportation in and out
Increases permeability of membranendash External influences have greater effectndash Microbe death
Eg Polymyxin Colistin
Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis
Inhibition of Protein SynthesisInhibition of Protein Synthesis
Proteins vital for growth and repairAct either at
ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic
acidsbull DNA replication RNA synthesis = TRANSCRIPTION
Eg Tetracyclines aminoglycosides and macrolides (erythromycin)
Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity
Interference with metabolic Interference with metabolic processesprocesses
bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it
microbes can not produce the proteins for growth
ndash Exploits microbes need to create their own folic acid whilst we get it in our diets
bull Eg Sulphonamides Trimethoprim
Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics
Serial dilutions
- in a liquid medium
- in a solid medium
Disc diffusion method
Rapid methods
Demands to nutrient media
1 to be standard and provide optimal conditions for microbial growth
2do not have inhibitors of bacterial growth and a lot of stimulators
3do not have substances which inhibit antibiotic activity
Disc diffusion methodDisc diffusion method
Serial dilution in liquid mediumSerial dilution in liquid medium
Serial dilution in solid mediumSerial dilution in solid medium
Minimal Inhibitory Concentration (MIC)
10487091048709Lowest concentration of antibiotic that prevents visible growth
bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic
bull 1048709Accurate but time-consuming
bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method
Minimal Bactericidal Concentration (MBC)
10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold
bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media
bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies
ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces Aminoglicosides Streptomycin (Streptomyces griseus) neomycin (S fradiae) kanamycin (S kanamyseticus) tobramycin (S tenebrarius) gentamycin (Micromonospora purpurea) sisomicin (Micromonospora inyoensis)
Tetracyclines chlortetracycline (S aureofaciens) oxytetracycline (S rimosus)
Chloramphenicol (S venezuelae)
Macrolides oleandomycin (S antibioticus) erythromycin (S erythreus)
2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces
Linkomycin (S lincolniensis) е) Rifampicin (S mediterranei)
Polyenes nystatin (S noursei) levorin (S levorys Krass) amphotericin B (S nodosus)
Inhibitors of beta-lactamases klavulanic acid (S clavuligerus)
Carbapenem (S olivaceus)
Thienamycin (S cattleya)
33 Antibiotics from bacteriaAntibiotics from bacteria
Bacillus polymyxin (B polymyxa) licheniformin (B licheniformis) gramicidin С (B brevis) subtilin (B subtilis)
Pseudomonas piocianin (P aeruginosa) sorbistin (P sorbistini)
other bacteria monobactams (Chromobacterium violaceum) nisin (Streptococcus lactis) prodigiosin (Serratia marcescens) coliformin (E coli) streptosin diplococcin (Streptococcus spp) azomycin nocardamin (Nocardia)
4 Antibiotics from plants4 Antibiotics from plants
Chorellin (Chlorella vulgaris)
Arenarin (Helichrysum arenarium)
Gordecin (barley)
Chinin (cinchona tree)
Alicin (garlic Allium sativum)
Raphanin (radish Raphanus sativum)
Phaseolin (haricot bean Phaseolus vulgaris)
55 Antibiotics from animal tissuesAntibiotics from animal tissues
interferons (spleen macrophages tissue cells)
lysozyme (most body fluid salive eggs)
erythrin (red cells liver)
ecmolin (fish)
Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action
1 Antibacterial
А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes
Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones
2 Antifungal (amphotericin)
3 Antiviral (amantadin vidarabin)
4 Antiprotozoal (emethin chinin)
5 Antineoplastic (bleomycin mitomycin C actinomycines)
Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action
Spectrum of ActivityRelates to the number of microbes that are
susceptible to the action of the drugndashNarrow (limited number) Broad (wide)
bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-
positive and gram-negative microbes (Broad)
Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)
Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms
BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate
BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate
Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action
Mechanism of Action1 Inhibition of Cell Wall Synthesis
2 Disruption of Cell Membrane
3 Inhibition of Protein Synthesis
4 Interference with Metabolic
Processes
NBBactericidalBacteriostatic
Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis
Most bacteria possess a cell wall to protect from osmotic pressures
Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being
susceptible to external influencesndash Cell ruptures Microbe death
Eg Penicillinsm cephalosporins vancomycin and bacitracin
Disruption of the microbial cell Disruption of the microbial cell membranemembrane
Essentially affect cell membrane transportation in and out
Increases permeability of membranendash External influences have greater effectndash Microbe death
Eg Polymyxin Colistin
Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis
Inhibition of Protein SynthesisInhibition of Protein Synthesis
Proteins vital for growth and repairAct either at
ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic
acidsbull DNA replication RNA synthesis = TRANSCRIPTION
Eg Tetracyclines aminoglycosides and macrolides (erythromycin)
Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity
Interference with metabolic Interference with metabolic processesprocesses
bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it
microbes can not produce the proteins for growth
ndash Exploits microbes need to create their own folic acid whilst we get it in our diets
bull Eg Sulphonamides Trimethoprim
Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics
Serial dilutions
- in a liquid medium
- in a solid medium
Disc diffusion method
Rapid methods
Demands to nutrient media
1 to be standard and provide optimal conditions for microbial growth
2do not have inhibitors of bacterial growth and a lot of stimulators
3do not have substances which inhibit antibiotic activity
Disc diffusion methodDisc diffusion method
Serial dilution in liquid mediumSerial dilution in liquid medium
Serial dilution in solid mediumSerial dilution in solid medium
Minimal Inhibitory Concentration (MIC)
10487091048709Lowest concentration of antibiotic that prevents visible growth
bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic
bull 1048709Accurate but time-consuming
bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method
Minimal Bactericidal Concentration (MBC)
10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold
bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media
bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies
ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
2 Antibiotics from Actinomyces2 Antibiotics from Actinomyces
Linkomycin (S lincolniensis) е) Rifampicin (S mediterranei)
Polyenes nystatin (S noursei) levorin (S levorys Krass) amphotericin B (S nodosus)
Inhibitors of beta-lactamases klavulanic acid (S clavuligerus)
Carbapenem (S olivaceus)
Thienamycin (S cattleya)
33 Antibiotics from bacteriaAntibiotics from bacteria
Bacillus polymyxin (B polymyxa) licheniformin (B licheniformis) gramicidin С (B brevis) subtilin (B subtilis)
Pseudomonas piocianin (P aeruginosa) sorbistin (P sorbistini)
other bacteria monobactams (Chromobacterium violaceum) nisin (Streptococcus lactis) prodigiosin (Serratia marcescens) coliformin (E coli) streptosin diplococcin (Streptococcus spp) azomycin nocardamin (Nocardia)
4 Antibiotics from plants4 Antibiotics from plants
Chorellin (Chlorella vulgaris)
Arenarin (Helichrysum arenarium)
Gordecin (barley)
Chinin (cinchona tree)
Alicin (garlic Allium sativum)
Raphanin (radish Raphanus sativum)
Phaseolin (haricot bean Phaseolus vulgaris)
55 Antibiotics from animal tissuesAntibiotics from animal tissues
interferons (spleen macrophages tissue cells)
lysozyme (most body fluid salive eggs)
erythrin (red cells liver)
ecmolin (fish)
Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action
1 Antibacterial
А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes
Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones
2 Antifungal (amphotericin)
3 Antiviral (amantadin vidarabin)
4 Antiprotozoal (emethin chinin)
5 Antineoplastic (bleomycin mitomycin C actinomycines)
Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action
Spectrum of ActivityRelates to the number of microbes that are
susceptible to the action of the drugndashNarrow (limited number) Broad (wide)
bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-
positive and gram-negative microbes (Broad)
Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)
Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms
BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate
BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate
Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action
Mechanism of Action1 Inhibition of Cell Wall Synthesis
2 Disruption of Cell Membrane
3 Inhibition of Protein Synthesis
4 Interference with Metabolic
Processes
NBBactericidalBacteriostatic
Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis
Most bacteria possess a cell wall to protect from osmotic pressures
Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being
susceptible to external influencesndash Cell ruptures Microbe death
Eg Penicillinsm cephalosporins vancomycin and bacitracin
Disruption of the microbial cell Disruption of the microbial cell membranemembrane
Essentially affect cell membrane transportation in and out
Increases permeability of membranendash External influences have greater effectndash Microbe death
Eg Polymyxin Colistin
Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis
Inhibition of Protein SynthesisInhibition of Protein Synthesis
Proteins vital for growth and repairAct either at
ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic
acidsbull DNA replication RNA synthesis = TRANSCRIPTION
Eg Tetracyclines aminoglycosides and macrolides (erythromycin)
Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity
Interference with metabolic Interference with metabolic processesprocesses
bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it
microbes can not produce the proteins for growth
ndash Exploits microbes need to create their own folic acid whilst we get it in our diets
bull Eg Sulphonamides Trimethoprim
Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics
Serial dilutions
- in a liquid medium
- in a solid medium
Disc diffusion method
Rapid methods
Demands to nutrient media
1 to be standard and provide optimal conditions for microbial growth
2do not have inhibitors of bacterial growth and a lot of stimulators
3do not have substances which inhibit antibiotic activity
Disc diffusion methodDisc diffusion method
Serial dilution in liquid mediumSerial dilution in liquid medium
Serial dilution in solid mediumSerial dilution in solid medium
Minimal Inhibitory Concentration (MIC)
10487091048709Lowest concentration of antibiotic that prevents visible growth
bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic
bull 1048709Accurate but time-consuming
bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method
Minimal Bactericidal Concentration (MBC)
10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold
bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media
bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies
ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
33 Antibiotics from bacteriaAntibiotics from bacteria
Bacillus polymyxin (B polymyxa) licheniformin (B licheniformis) gramicidin С (B brevis) subtilin (B subtilis)
Pseudomonas piocianin (P aeruginosa) sorbistin (P sorbistini)
other bacteria monobactams (Chromobacterium violaceum) nisin (Streptococcus lactis) prodigiosin (Serratia marcescens) coliformin (E coli) streptosin diplococcin (Streptococcus spp) azomycin nocardamin (Nocardia)
4 Antibiotics from plants4 Antibiotics from plants
Chorellin (Chlorella vulgaris)
Arenarin (Helichrysum arenarium)
Gordecin (barley)
Chinin (cinchona tree)
Alicin (garlic Allium sativum)
Raphanin (radish Raphanus sativum)
Phaseolin (haricot bean Phaseolus vulgaris)
55 Antibiotics from animal tissuesAntibiotics from animal tissues
interferons (spleen macrophages tissue cells)
lysozyme (most body fluid salive eggs)
erythrin (red cells liver)
ecmolin (fish)
Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action
1 Antibacterial
А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes
Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones
2 Antifungal (amphotericin)
3 Antiviral (amantadin vidarabin)
4 Antiprotozoal (emethin chinin)
5 Antineoplastic (bleomycin mitomycin C actinomycines)
Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action
Spectrum of ActivityRelates to the number of microbes that are
susceptible to the action of the drugndashNarrow (limited number) Broad (wide)
bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-
positive and gram-negative microbes (Broad)
Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)
Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms
BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate
BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate
Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action
Mechanism of Action1 Inhibition of Cell Wall Synthesis
2 Disruption of Cell Membrane
3 Inhibition of Protein Synthesis
4 Interference with Metabolic
Processes
NBBactericidalBacteriostatic
Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis
Most bacteria possess a cell wall to protect from osmotic pressures
Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being
susceptible to external influencesndash Cell ruptures Microbe death
Eg Penicillinsm cephalosporins vancomycin and bacitracin
Disruption of the microbial cell Disruption of the microbial cell membranemembrane
Essentially affect cell membrane transportation in and out
Increases permeability of membranendash External influences have greater effectndash Microbe death
Eg Polymyxin Colistin
Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis
Inhibition of Protein SynthesisInhibition of Protein Synthesis
Proteins vital for growth and repairAct either at
ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic
acidsbull DNA replication RNA synthesis = TRANSCRIPTION
Eg Tetracyclines aminoglycosides and macrolides (erythromycin)
Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity
Interference with metabolic Interference with metabolic processesprocesses
bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it
microbes can not produce the proteins for growth
ndash Exploits microbes need to create their own folic acid whilst we get it in our diets
bull Eg Sulphonamides Trimethoprim
Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics
Serial dilutions
- in a liquid medium
- in a solid medium
Disc diffusion method
Rapid methods
Demands to nutrient media
1 to be standard and provide optimal conditions for microbial growth
2do not have inhibitors of bacterial growth and a lot of stimulators
3do not have substances which inhibit antibiotic activity
Disc diffusion methodDisc diffusion method
Serial dilution in liquid mediumSerial dilution in liquid medium
Serial dilution in solid mediumSerial dilution in solid medium
Minimal Inhibitory Concentration (MIC)
10487091048709Lowest concentration of antibiotic that prevents visible growth
bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic
bull 1048709Accurate but time-consuming
bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method
Minimal Bactericidal Concentration (MBC)
10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold
bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media
bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies
ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
4 Antibiotics from plants4 Antibiotics from plants
Chorellin (Chlorella vulgaris)
Arenarin (Helichrysum arenarium)
Gordecin (barley)
Chinin (cinchona tree)
Alicin (garlic Allium sativum)
Raphanin (radish Raphanus sativum)
Phaseolin (haricot bean Phaseolus vulgaris)
55 Antibiotics from animal tissuesAntibiotics from animal tissues
interferons (spleen macrophages tissue cells)
lysozyme (most body fluid salive eggs)
erythrin (red cells liver)
ecmolin (fish)
Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action
1 Antibacterial
А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes
Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones
2 Antifungal (amphotericin)
3 Antiviral (amantadin vidarabin)
4 Antiprotozoal (emethin chinin)
5 Antineoplastic (bleomycin mitomycin C actinomycines)
Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action
Spectrum of ActivityRelates to the number of microbes that are
susceptible to the action of the drugndashNarrow (limited number) Broad (wide)
bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-
positive and gram-negative microbes (Broad)
Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)
Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms
BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate
BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate
Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action
Mechanism of Action1 Inhibition of Cell Wall Synthesis
2 Disruption of Cell Membrane
3 Inhibition of Protein Synthesis
4 Interference with Metabolic
Processes
NBBactericidalBacteriostatic
Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis
Most bacteria possess a cell wall to protect from osmotic pressures
Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being
susceptible to external influencesndash Cell ruptures Microbe death
Eg Penicillinsm cephalosporins vancomycin and bacitracin
Disruption of the microbial cell Disruption of the microbial cell membranemembrane
Essentially affect cell membrane transportation in and out
Increases permeability of membranendash External influences have greater effectndash Microbe death
Eg Polymyxin Colistin
Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis
Inhibition of Protein SynthesisInhibition of Protein Synthesis
Proteins vital for growth and repairAct either at
ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic
acidsbull DNA replication RNA synthesis = TRANSCRIPTION
Eg Tetracyclines aminoglycosides and macrolides (erythromycin)
Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity
Interference with metabolic Interference with metabolic processesprocesses
bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it
microbes can not produce the proteins for growth
ndash Exploits microbes need to create their own folic acid whilst we get it in our diets
bull Eg Sulphonamides Trimethoprim
Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics
Serial dilutions
- in a liquid medium
- in a solid medium
Disc diffusion method
Rapid methods
Demands to nutrient media
1 to be standard and provide optimal conditions for microbial growth
2do not have inhibitors of bacterial growth and a lot of stimulators
3do not have substances which inhibit antibiotic activity
Disc diffusion methodDisc diffusion method
Serial dilution in liquid mediumSerial dilution in liquid medium
Serial dilution in solid mediumSerial dilution in solid medium
Minimal Inhibitory Concentration (MIC)
10487091048709Lowest concentration of antibiotic that prevents visible growth
bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic
bull 1048709Accurate but time-consuming
bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method
Minimal Bactericidal Concentration (MBC)
10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold
bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media
bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies
ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
55 Antibiotics from animal tissuesAntibiotics from animal tissues
interferons (spleen macrophages tissue cells)
lysozyme (most body fluid salive eggs)
erythrin (red cells liver)
ecmolin (fish)
Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action
1 Antibacterial
А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes
Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones
2 Antifungal (amphotericin)
3 Antiviral (amantadin vidarabin)
4 Antiprotozoal (emethin chinin)
5 Antineoplastic (bleomycin mitomycin C actinomycines)
Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action
Spectrum of ActivityRelates to the number of microbes that are
susceptible to the action of the drugndashNarrow (limited number) Broad (wide)
bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-
positive and gram-negative microbes (Broad)
Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)
Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms
BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate
BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate
Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action
Mechanism of Action1 Inhibition of Cell Wall Synthesis
2 Disruption of Cell Membrane
3 Inhibition of Protein Synthesis
4 Interference with Metabolic
Processes
NBBactericidalBacteriostatic
Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis
Most bacteria possess a cell wall to protect from osmotic pressures
Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being
susceptible to external influencesndash Cell ruptures Microbe death
Eg Penicillinsm cephalosporins vancomycin and bacitracin
Disruption of the microbial cell Disruption of the microbial cell membranemembrane
Essentially affect cell membrane transportation in and out
Increases permeability of membranendash External influences have greater effectndash Microbe death
Eg Polymyxin Colistin
Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis
Inhibition of Protein SynthesisInhibition of Protein Synthesis
Proteins vital for growth and repairAct either at
ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic
acidsbull DNA replication RNA synthesis = TRANSCRIPTION
Eg Tetracyclines aminoglycosides and macrolides (erythromycin)
Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity
Interference with metabolic Interference with metabolic processesprocesses
bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it
microbes can not produce the proteins for growth
ndash Exploits microbes need to create their own folic acid whilst we get it in our diets
bull Eg Sulphonamides Trimethoprim
Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics
Serial dilutions
- in a liquid medium
- in a solid medium
Disc diffusion method
Rapid methods
Demands to nutrient media
1 to be standard and provide optimal conditions for microbial growth
2do not have inhibitors of bacterial growth and a lot of stimulators
3do not have substances which inhibit antibiotic activity
Disc diffusion methodDisc diffusion method
Serial dilution in liquid mediumSerial dilution in liquid medium
Serial dilution in solid mediumSerial dilution in solid medium
Minimal Inhibitory Concentration (MIC)
10487091048709Lowest concentration of antibiotic that prevents visible growth
bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic
bull 1048709Accurate but time-consuming
bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method
Minimal Bactericidal Concentration (MBC)
10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold
bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media
bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies
ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
Classification of antibiotics according Classification of antibiotics according to the spectrum of biological actionto the spectrum of biological action
1 Antibacterial
А Narrow spectrum of action which are active against gram-positive bacteria а) natural Penicillins b) semi-synthetic Penicillins (methicillin oxacillin) c) Cephalosporins d) Lincomycin е) Macrolodes
Б Broad spectrum of action а) semi-synthetic Penicillins (Ampicillin Amoxicillin) b) Cephalocporins of ІІ-IV generation c) Tetracyclines d) Chloramphenocol e) Aminoglycosides f) Polymixins g) Fluoride quinolones
2 Antifungal (amphotericin)
3 Antiviral (amantadin vidarabin)
4 Antiprotozoal (emethin chinin)
5 Antineoplastic (bleomycin mitomycin C actinomycines)
Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action
Spectrum of ActivityRelates to the number of microbes that are
susceptible to the action of the drugndashNarrow (limited number) Broad (wide)
bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-
positive and gram-negative microbes (Broad)
Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)
Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms
BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate
BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate
Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action
Mechanism of Action1 Inhibition of Cell Wall Synthesis
2 Disruption of Cell Membrane
3 Inhibition of Protein Synthesis
4 Interference with Metabolic
Processes
NBBactericidalBacteriostatic
Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis
Most bacteria possess a cell wall to protect from osmotic pressures
Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being
susceptible to external influencesndash Cell ruptures Microbe death
Eg Penicillinsm cephalosporins vancomycin and bacitracin
Disruption of the microbial cell Disruption of the microbial cell membranemembrane
Essentially affect cell membrane transportation in and out
Increases permeability of membranendash External influences have greater effectndash Microbe death
Eg Polymyxin Colistin
Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis
Inhibition of Protein SynthesisInhibition of Protein Synthesis
Proteins vital for growth and repairAct either at
ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic
acidsbull DNA replication RNA synthesis = TRANSCRIPTION
Eg Tetracyclines aminoglycosides and macrolides (erythromycin)
Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity
Interference with metabolic Interference with metabolic processesprocesses
bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it
microbes can not produce the proteins for growth
ndash Exploits microbes need to create their own folic acid whilst we get it in our diets
bull Eg Sulphonamides Trimethoprim
Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics
Serial dilutions
- in a liquid medium
- in a solid medium
Disc diffusion method
Rapid methods
Demands to nutrient media
1 to be standard and provide optimal conditions for microbial growth
2do not have inhibitors of bacterial growth and a lot of stimulators
3do not have substances which inhibit antibiotic activity
Disc diffusion methodDisc diffusion method
Serial dilution in liquid mediumSerial dilution in liquid medium
Serial dilution in solid mediumSerial dilution in solid medium
Minimal Inhibitory Concentration (MIC)
10487091048709Lowest concentration of antibiotic that prevents visible growth
bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic
bull 1048709Accurate but time-consuming
bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method
Minimal Bactericidal Concentration (MBC)
10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold
bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media
bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies
ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
2 Antifungal (amphotericin)
3 Antiviral (amantadin vidarabin)
4 Antiprotozoal (emethin chinin)
5 Antineoplastic (bleomycin mitomycin C actinomycines)
Classification of antibiotics according to Classification of antibiotics according to the spectrum of biological actionthe spectrum of biological action
Spectrum of ActivityRelates to the number of microbes that are
susceptible to the action of the drugndashNarrow (limited number) Broad (wide)
bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-
positive and gram-negative microbes (Broad)
Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)
Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms
BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate
BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate
Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action
Mechanism of Action1 Inhibition of Cell Wall Synthesis
2 Disruption of Cell Membrane
3 Inhibition of Protein Synthesis
4 Interference with Metabolic
Processes
NBBactericidalBacteriostatic
Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis
Most bacteria possess a cell wall to protect from osmotic pressures
Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being
susceptible to external influencesndash Cell ruptures Microbe death
Eg Penicillinsm cephalosporins vancomycin and bacitracin
Disruption of the microbial cell Disruption of the microbial cell membranemembrane
Essentially affect cell membrane transportation in and out
Increases permeability of membranendash External influences have greater effectndash Microbe death
Eg Polymyxin Colistin
Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis
Inhibition of Protein SynthesisInhibition of Protein Synthesis
Proteins vital for growth and repairAct either at
ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic
acidsbull DNA replication RNA synthesis = TRANSCRIPTION
Eg Tetracyclines aminoglycosides and macrolides (erythromycin)
Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity
Interference with metabolic Interference with metabolic processesprocesses
bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it
microbes can not produce the proteins for growth
ndash Exploits microbes need to create their own folic acid whilst we get it in our diets
bull Eg Sulphonamides Trimethoprim
Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics
Serial dilutions
- in a liquid medium
- in a solid medium
Disc diffusion method
Rapid methods
Demands to nutrient media
1 to be standard and provide optimal conditions for microbial growth
2do not have inhibitors of bacterial growth and a lot of stimulators
3do not have substances which inhibit antibiotic activity
Disc diffusion methodDisc diffusion method
Serial dilution in liquid mediumSerial dilution in liquid medium
Serial dilution in solid mediumSerial dilution in solid medium
Minimal Inhibitory Concentration (MIC)
10487091048709Lowest concentration of antibiotic that prevents visible growth
bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic
bull 1048709Accurate but time-consuming
bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method
Minimal Bactericidal Concentration (MBC)
10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold
bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media
bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies
ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
Spectrum of ActivityRelates to the number of microbes that are
susceptible to the action of the drugndashNarrow (limited number) Broad (wide)
bullPenicillin G is a narrow spectrum drug as it is only effective against gram-positive microbebullTetracyclines are effective against gram-
positive and gram-negative microbes (Broad)
Note Never confusion these terms with potency levels of the drugs or efficacy (ie Narrow are weak Broad are strong)
Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms
BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate
BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate
Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action
Mechanism of Action1 Inhibition of Cell Wall Synthesis
2 Disruption of Cell Membrane
3 Inhibition of Protein Synthesis
4 Interference with Metabolic
Processes
NBBactericidalBacteriostatic
Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis
Most bacteria possess a cell wall to protect from osmotic pressures
Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being
susceptible to external influencesndash Cell ruptures Microbe death
Eg Penicillinsm cephalosporins vancomycin and bacitracin
Disruption of the microbial cell Disruption of the microbial cell membranemembrane
Essentially affect cell membrane transportation in and out
Increases permeability of membranendash External influences have greater effectndash Microbe death
Eg Polymyxin Colistin
Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis
Inhibition of Protein SynthesisInhibition of Protein Synthesis
Proteins vital for growth and repairAct either at
ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic
acidsbull DNA replication RNA synthesis = TRANSCRIPTION
Eg Tetracyclines aminoglycosides and macrolides (erythromycin)
Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity
Interference with metabolic Interference with metabolic processesprocesses
bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it
microbes can not produce the proteins for growth
ndash Exploits microbes need to create their own folic acid whilst we get it in our diets
bull Eg Sulphonamides Trimethoprim
Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics
Serial dilutions
- in a liquid medium
- in a solid medium
Disc diffusion method
Rapid methods
Demands to nutrient media
1 to be standard and provide optimal conditions for microbial growth
2do not have inhibitors of bacterial growth and a lot of stimulators
3do not have substances which inhibit antibiotic activity
Disc diffusion methodDisc diffusion method
Serial dilution in liquid mediumSerial dilution in liquid medium
Serial dilution in solid mediumSerial dilution in solid medium
Minimal Inhibitory Concentration (MIC)
10487091048709Lowest concentration of antibiotic that prevents visible growth
bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic
bull 1048709Accurate but time-consuming
bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method
Minimal Bactericidal Concentration (MBC)
10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold
bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media
bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies
ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
Bactericidal agents are more effective but bacteriostatic agents can be extremely beneficial since they permit the normal defenses of the host to destroy the microorganisms
BacteriostaticBacteriostatic1048709 Reversible inhibition of growthWhen the antibiotic is removed almost all of the bacteria can replicate
BactericidalBactericidal1048709Irreversible inhibition of growthWhen the antibiotic is removed almost none of the bacteria (10-7to 10-3) can replicate
Classification of antibiotics according to Classification of antibiotics according to the spectrum of actionthe spectrum of action
Mechanism of Action1 Inhibition of Cell Wall Synthesis
2 Disruption of Cell Membrane
3 Inhibition of Protein Synthesis
4 Interference with Metabolic
Processes
NBBactericidalBacteriostatic
Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis
Most bacteria possess a cell wall to protect from osmotic pressures
Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being
susceptible to external influencesndash Cell ruptures Microbe death
Eg Penicillinsm cephalosporins vancomycin and bacitracin
Disruption of the microbial cell Disruption of the microbial cell membranemembrane
Essentially affect cell membrane transportation in and out
Increases permeability of membranendash External influences have greater effectndash Microbe death
Eg Polymyxin Colistin
Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis
Inhibition of Protein SynthesisInhibition of Protein Synthesis
Proteins vital for growth and repairAct either at
ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic
acidsbull DNA replication RNA synthesis = TRANSCRIPTION
Eg Tetracyclines aminoglycosides and macrolides (erythromycin)
Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity
Interference with metabolic Interference with metabolic processesprocesses
bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it
microbes can not produce the proteins for growth
ndash Exploits microbes need to create their own folic acid whilst we get it in our diets
bull Eg Sulphonamides Trimethoprim
Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics
Serial dilutions
- in a liquid medium
- in a solid medium
Disc diffusion method
Rapid methods
Demands to nutrient media
1 to be standard and provide optimal conditions for microbial growth
2do not have inhibitors of bacterial growth and a lot of stimulators
3do not have substances which inhibit antibiotic activity
Disc diffusion methodDisc diffusion method
Serial dilution in liquid mediumSerial dilution in liquid medium
Serial dilution in solid mediumSerial dilution in solid medium
Minimal Inhibitory Concentration (MIC)
10487091048709Lowest concentration of antibiotic that prevents visible growth
bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic
bull 1048709Accurate but time-consuming
bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method
Minimal Bactericidal Concentration (MBC)
10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold
bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media
bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies
ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
Mechanism of Action1 Inhibition of Cell Wall Synthesis
2 Disruption of Cell Membrane
3 Inhibition of Protein Synthesis
4 Interference with Metabolic
Processes
NBBactericidalBacteriostatic
Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis
Most bacteria possess a cell wall to protect from osmotic pressures
Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being
susceptible to external influencesndash Cell ruptures Microbe death
Eg Penicillinsm cephalosporins vancomycin and bacitracin
Disruption of the microbial cell Disruption of the microbial cell membranemembrane
Essentially affect cell membrane transportation in and out
Increases permeability of membranendash External influences have greater effectndash Microbe death
Eg Polymyxin Colistin
Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis
Inhibition of Protein SynthesisInhibition of Protein Synthesis
Proteins vital for growth and repairAct either at
ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic
acidsbull DNA replication RNA synthesis = TRANSCRIPTION
Eg Tetracyclines aminoglycosides and macrolides (erythromycin)
Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity
Interference with metabolic Interference with metabolic processesprocesses
bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it
microbes can not produce the proteins for growth
ndash Exploits microbes need to create their own folic acid whilst we get it in our diets
bull Eg Sulphonamides Trimethoprim
Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics
Serial dilutions
- in a liquid medium
- in a solid medium
Disc diffusion method
Rapid methods
Demands to nutrient media
1 to be standard and provide optimal conditions for microbial growth
2do not have inhibitors of bacterial growth and a lot of stimulators
3do not have substances which inhibit antibiotic activity
Disc diffusion methodDisc diffusion method
Serial dilution in liquid mediumSerial dilution in liquid medium
Serial dilution in solid mediumSerial dilution in solid medium
Minimal Inhibitory Concentration (MIC)
10487091048709Lowest concentration of antibiotic that prevents visible growth
bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic
bull 1048709Accurate but time-consuming
bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method
Minimal Bactericidal Concentration (MBC)
10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold
bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media
bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies
ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
Inhibition of Cell Wall SynthesisInhibition of Cell Wall Synthesis
Most bacteria possess a cell wall to protect from osmotic pressures
Microbe divides ndash needs to create a new cell wallndash Interrupt this leads to new microbes being
susceptible to external influencesndash Cell ruptures Microbe death
Eg Penicillinsm cephalosporins vancomycin and bacitracin
Disruption of the microbial cell Disruption of the microbial cell membranemembrane
Essentially affect cell membrane transportation in and out
Increases permeability of membranendash External influences have greater effectndash Microbe death
Eg Polymyxin Colistin
Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis
Inhibition of Protein SynthesisInhibition of Protein Synthesis
Proteins vital for growth and repairAct either at
ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic
acidsbull DNA replication RNA synthesis = TRANSCRIPTION
Eg Tetracyclines aminoglycosides and macrolides (erythromycin)
Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity
Interference with metabolic Interference with metabolic processesprocesses
bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it
microbes can not produce the proteins for growth
ndash Exploits microbes need to create their own folic acid whilst we get it in our diets
bull Eg Sulphonamides Trimethoprim
Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics
Serial dilutions
- in a liquid medium
- in a solid medium
Disc diffusion method
Rapid methods
Demands to nutrient media
1 to be standard and provide optimal conditions for microbial growth
2do not have inhibitors of bacterial growth and a lot of stimulators
3do not have substances which inhibit antibiotic activity
Disc diffusion methodDisc diffusion method
Serial dilution in liquid mediumSerial dilution in liquid medium
Serial dilution in solid mediumSerial dilution in solid medium
Minimal Inhibitory Concentration (MIC)
10487091048709Lowest concentration of antibiotic that prevents visible growth
bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic
bull 1048709Accurate but time-consuming
bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method
Minimal Bactericidal Concentration (MBC)
10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold
bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media
bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies
ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
Disruption of the microbial cell Disruption of the microbial cell membranemembrane
Essentially affect cell membrane transportation in and out
Increases permeability of membranendash External influences have greater effectndash Microbe death
Eg Polymyxin Colistin
Note These agents are more toxic systemically than those agents that inhibit cell wall synthesis
Inhibition of Protein SynthesisInhibition of Protein Synthesis
Proteins vital for growth and repairAct either at
ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic
acidsbull DNA replication RNA synthesis = TRANSCRIPTION
Eg Tetracyclines aminoglycosides and macrolides (erythromycin)
Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity
Interference with metabolic Interference with metabolic processesprocesses
bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it
microbes can not produce the proteins for growth
ndash Exploits microbes need to create their own folic acid whilst we get it in our diets
bull Eg Sulphonamides Trimethoprim
Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics
Serial dilutions
- in a liquid medium
- in a solid medium
Disc diffusion method
Rapid methods
Demands to nutrient media
1 to be standard and provide optimal conditions for microbial growth
2do not have inhibitors of bacterial growth and a lot of stimulators
3do not have substances which inhibit antibiotic activity
Disc diffusion methodDisc diffusion method
Serial dilution in liquid mediumSerial dilution in liquid medium
Serial dilution in solid mediumSerial dilution in solid medium
Minimal Inhibitory Concentration (MIC)
10487091048709Lowest concentration of antibiotic that prevents visible growth
bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic
bull 1048709Accurate but time-consuming
bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method
Minimal Bactericidal Concentration (MBC)
10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold
bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media
bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies
ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
Inhibition of Protein SynthesisInhibition of Protein Synthesis
Proteins vital for growth and repairAct either at
ndash Site of protein synthesis (ribosome)ndash Within the nucleus by inhibiting synthesis of nucleic
acidsbull DNA replication RNA synthesis = TRANSCRIPTION
Eg Tetracyclines aminoglycosides and macrolides (erythromycin)
Exploit structural differences between microbial and human cellsndash High dose can lead to toxicity
Interference with metabolic Interference with metabolic processesprocesses
bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it
microbes can not produce the proteins for growth
ndash Exploits microbes need to create their own folic acid whilst we get it in our diets
bull Eg Sulphonamides Trimethoprim
Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics
Serial dilutions
- in a liquid medium
- in a solid medium
Disc diffusion method
Rapid methods
Demands to nutrient media
1 to be standard and provide optimal conditions for microbial growth
2do not have inhibitors of bacterial growth and a lot of stimulators
3do not have substances which inhibit antibiotic activity
Disc diffusion methodDisc diffusion method
Serial dilution in liquid mediumSerial dilution in liquid medium
Serial dilution in solid mediumSerial dilution in solid medium
Minimal Inhibitory Concentration (MIC)
10487091048709Lowest concentration of antibiotic that prevents visible growth
bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic
bull 1048709Accurate but time-consuming
bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method
Minimal Bactericidal Concentration (MBC)
10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold
bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media
bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies
ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
Interference with metabolic Interference with metabolic processesprocesses
bull Agents are structurally similar to Para-aminobensoic acid (PABA) ndash component of folic acidndash Essential for nucleic acid synthesis without it
microbes can not produce the proteins for growth
ndash Exploits microbes need to create their own folic acid whilst we get it in our diets
bull Eg Sulphonamides Trimethoprim
Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics
Serial dilutions
- in a liquid medium
- in a solid medium
Disc diffusion method
Rapid methods
Demands to nutrient media
1 to be standard and provide optimal conditions for microbial growth
2do not have inhibitors of bacterial growth and a lot of stimulators
3do not have substances which inhibit antibiotic activity
Disc diffusion methodDisc diffusion method
Serial dilution in liquid mediumSerial dilution in liquid medium
Serial dilution in solid mediumSerial dilution in solid medium
Minimal Inhibitory Concentration (MIC)
10487091048709Lowest concentration of antibiotic that prevents visible growth
bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic
bull 1048709Accurate but time-consuming
bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method
Minimal Bactericidal Concentration (MBC)
10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold
bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media
bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies
ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
Examination of susceptibility of Examination of susceptibility of bacteria to antibioticsbacteria to antibiotics
Serial dilutions
- in a liquid medium
- in a solid medium
Disc diffusion method
Rapid methods
Demands to nutrient media
1 to be standard and provide optimal conditions for microbial growth
2do not have inhibitors of bacterial growth and a lot of stimulators
3do not have substances which inhibit antibiotic activity
Disc diffusion methodDisc diffusion method
Serial dilution in liquid mediumSerial dilution in liquid medium
Serial dilution in solid mediumSerial dilution in solid medium
Minimal Inhibitory Concentration (MIC)
10487091048709Lowest concentration of antibiotic that prevents visible growth
bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic
bull 1048709Accurate but time-consuming
bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method
Minimal Bactericidal Concentration (MBC)
10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold
bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media
bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies
ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
Demands to nutrient media
1 to be standard and provide optimal conditions for microbial growth
2do not have inhibitors of bacterial growth and a lot of stimulators
3do not have substances which inhibit antibiotic activity
Disc diffusion methodDisc diffusion method
Serial dilution in liquid mediumSerial dilution in liquid medium
Serial dilution in solid mediumSerial dilution in solid medium
Minimal Inhibitory Concentration (MIC)
10487091048709Lowest concentration of antibiotic that prevents visible growth
bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic
bull 1048709Accurate but time-consuming
bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method
Minimal Bactericidal Concentration (MBC)
10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold
bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media
bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies
ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
Disc diffusion methodDisc diffusion method
Serial dilution in liquid mediumSerial dilution in liquid medium
Serial dilution in solid mediumSerial dilution in solid medium
Minimal Inhibitory Concentration (MIC)
10487091048709Lowest concentration of antibiotic that prevents visible growth
bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic
bull 1048709Accurate but time-consuming
bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method
Minimal Bactericidal Concentration (MBC)
10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold
bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media
bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies
ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
Serial dilution in liquid mediumSerial dilution in liquid medium
Serial dilution in solid mediumSerial dilution in solid medium
Minimal Inhibitory Concentration (MIC)
10487091048709Lowest concentration of antibiotic that prevents visible growth
bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic
bull 1048709Accurate but time-consuming
bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method
Minimal Bactericidal Concentration (MBC)
10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold
bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media
bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies
ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
Serial dilution in solid mediumSerial dilution in solid medium
Minimal Inhibitory Concentration (MIC)
10487091048709Lowest concentration of antibiotic that prevents visible growth
bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic
bull 1048709Accurate but time-consuming
bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method
Minimal Bactericidal Concentration (MBC)
10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold
bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media
bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies
ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
Minimal Inhibitory Concentration (MIC)
10487091048709Lowest concentration of antibiotic that prevents visible growth
bull 1048709Broth or tube dilution method1048709Serial 2-fold dilutions of the antibiotic
bull 1048709Accurate but time-consuming
bull 1048709Disk sensitivity test1048709Rapid but must be related to results from the tube dilution method
Minimal Bactericidal Concentration (MBC)
10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold
bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media
bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies
ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
Minimal Bactericidal Concentration (MBC)
10487091048709Lowest concentration of antibiotic that reduces the number of viable cells by at least 1000-fold
bull 1048709Performed in conjunction with MIC by the tube dilution method1048709Aliquots from the tubes at and above the MIC are plated onto agar media
bull 1048709The antibiotic is diluted so that the remaining viable cells grow and form colonies
ndash 1048709The MBC of a truly bactericidal agent is equal to or just slightly above its MIC
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
Rapid methodsRapid methods
examination of changes of microbial enzymes activity under the influence of antibiotics
examination of color of redox-indicators
cytological evaluation of morphological changes
automatic
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
Automatic metod of examination of bacterial susceptibility
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
1 Selective toxicity - destroys or inhibits microbe without affecting host cells
2 Broad spectrum - effective against a wide variety of organisms
3 Non-mutagenic - does not induce development of resistant strains
4 Soluble in body fluids - distributed through body (in bloodstream)
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
Criteria that determines the effectiveness of
antimicrobial agents used in the treatment
of infectious diseases
5 Stable in body fluids - not easily broken down or excreted to maintain constant and effective levels
6 Absorbed by tissues - to reach site of infection7 Non-allergenic to host - should not cause
adverse reactions in host8 Should not disturb hostrsquos normal flora
(organisms normally living in body) causing secondary (super) infections produced by opportunists
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
General principles
1 The first question to ask before prescribing an antibiotic is whether its use is really necessary There is no point in prescribing it if for instance the disease is not due to an infection (fever does not always indicate the presence of an infection) or if the infection is due to agents such as viruses which do not respond to antibiotics
All therapy is a calculated risk in which the probable benefits must outweigh the draw backs and antibiotics are no exception to this rule To use them when they are not indicated and when the probable benefits are non-existent means exposing the patient to the risk of adverse reactions or worse
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
2 Patients with similar infections react differently This may be due to previous contact with the same pathogen or to the individual immune response The presence of hepatic or renal disease may necessitate changes in the dosage or the choice of antibiotic Knowledge of any past adverse reactions to antibiotics is also essential
3 The doctor must be familiar with the typical response of infections to proper antibiotic treatment Acute infection with group A streptococci or pneumococci responds rapidly (usually within 48 hours) to penicillin G while the temperature curve in typhoid fever treated with chloramphenicol may not show any change for four or five days
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
4 The doctor must know which bacteria are commonly found in which situations for instance Pseudomonas in extensive burns (sepsis is frequent and often fatal) and in the expectoration of children with cystic fibrosis or Streptococcus pneumoniae and Haemophilus influenzae in chronic bronchitis of the adult
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
5 Ideally treatment with antibiotics should not be instituted before samples for sensitivity testing have been collected Such tests can be dispensed with however when the causative organism is known and its response to the antibiotic is predictable But the sensitivity of for instance many gram-negative strains can change even during treatment making an alternative treatment necessary In addition the clinical results may be at odds with the findings of the sensitivity tests Even a severe infection may show a satisfactory clinical response despite apparent lack of sensitivity
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
Antibiotic treatment is considered a failure if no response is seen within three days Failure may be due to various causes
1 Wrong diagnosis (a viral infection does not respond to antibiotics)
2 Wrong choice of antibiotic
3 Wrong dosage (wrongly dosed by doctor or poor patient compliance)
4 Development of resistance during therapy (as sometimes occurs in tuberculosis and infections due to gram-negative pathogens)
FailureFailure of antibiotic therapy
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
5 Superinfection by resistant bacteria
6 Accumulation of pus necessitating surgical drainage (buttock abscess)
7 Underlying disease (lymphoma neoplasia) of which the infection is only an intercurrent complication
8 Drug fever
Failure of antibiotic therapyFailure of antibiotic therapy
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
І Allergic reactions
ІІ Toxic effects on normal tissues
ІІІ Disturbs host normal flora secondary infections (Dysbacteriosis)
Disadvantages of Disadvantages of Antimicrobial TherapyAntimicrobial Therapy
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
І Allergic reactions
- dangerous for life (anaphylactic shock angioneurotic oedema of larynx)
- non-dangerous for life (skin itching urticaria rash rhinitis glossitis conjunctivitis photodermatoses (tetracyclines)
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
ІІ Toxic reactions
- dangerous for life (agranulocytosis aplastic anemia endotoxic shock)
- non-dangerous (neuritis of N vestibularis and N auricularis - aminoglycosides periferal neuritis vomiting nausea diarrhea hepatotoxic and nephrotoxic effects embriotoxic effect pigmentation of the teeth)
Disadvantages Disadvantages of Antimicrobial Therapyof Antimicrobial Therapy
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
ІІІ ІІІ DysbacteriosisDysbacteriosis
- dangerous for life (generalized candidiases sepsis staphylococcal enterocolitis secondary pneumonia which cause gram-negative bacteria)
- non-dangerous for life (local candidiases)
Secondary action of antibioticsSecondary action of antibiotics
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
Natural resistance
Acquired resistanse
primary
secondary
Types of resistanceTypes of resistance
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
Mechanisms of ResistanceMechanisms of Resistance
Development of resistant strains ndash spontaneous mutations DNA transfer
a Ability to destroy AMA by producing enzymes (Staph ndashpenicillinase or -lactamase)b Mutations causing structural changes in cell so
bypass metabolic step inhibited by AMA (L-forms - no cell wall)
c Over produce target molecules increase in quantity overcomes action of AMA
d R-factors (resistant genes) in plasmids transferred to bacterial cells by conjugation transformation transduction
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
R-Plasmids
Resistance transfer factors or RTFs
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
Transposons
Staphylococci Enterobacteria ndash transposon Tn551 (erythromycin) Tn552 (penicillin) Tn554 (erythromycin spectinomycin) They can integrate with R-plasmids and phages
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community
Mechanism to Reduce Bacterial Resistance Mechanism to Reduce Bacterial Resistance
Proper selection of new antibiotics will be a major force in slowing the development of antimicrobial resistance Proper hygiene practices will reduce plasmid transfer and the establishment of multiple drug-resistant bacteria in the hospital and will delay the appearance of such species in the community There are a number of mechanisms to prevent bacterial resistance The health care provider must be continually alert to the appearance of antibiotic resistance within the hospital and community