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ANTIMICROBIAL DRUG
Dr. Muh. Nasrum Massi, Ph.DBagian Mikrobiologi Fak. Kedokteran Unhas
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Antimicrobial Agents
Microbiocidal kills, e.g. bacteriocidal Microbiostatic inhibits growth but does not kill, e.g.
bacteriostatic Narrow spectrum drug specific for one genus, e.g.
Mycobacterium, or one group of organisms, e.g. Gram negatives Broad spectrum good for all bacteria Selection of Drugs depends on: - microbial sensitivity - side effects - biotransformation will it remain active in the body? - distribution must reach correct site of infection
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Antibiotic ResistanceMechanisms:
1. Antibiotic is inactivated by microbial enzymes, e.g.penicillinase will destroy
penicillin
2. Antibiotic is prevented from reaching its target, e.g. effluxpumps in the bacterial
membrane pump actively pump out drugs; e.g. antibioticcannot penetrate across
the cell wall or membranes3. Target for the antibiotic has been altered by mutation Genes for several different drug resistance mechanisms
are often found on R plasmids which can be readily transferred from bacterium to
bacterium
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Antibacterial Agents1. Cell Wall Inhibiters
- excellent selective toxicity (means will only harmbacteria not us!)
- targets peptidoglycana) Penicillins and Cephalosporins
Penicillins Pen G, Ampicillin, Amoxicillin, Methicillin Cephalosporins Cefoxitin, Cephalothin, Cephadrine o all have similar structures and inhibit the cross-linking of
PG o only work on actively growing and dividing cells when PG
is being made
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o most differ due to particular side groups which are added toenhance
activity, e.g. Pen G only works with Gram positives but once youadd
the amino group (NH2) to make Ampicillin the drug can get past
the bulky LPS on Gram negative cell surfaces and work for them too o many penicillin resistant bacteria exist, make -lactamase (penicillinase) which cleaves the lactam ring structure of these antibiotics, cephalosporins are still left intactb) Vancomycin blocks linkage of NAG and NAM of the PG o used for MRSA (methicillin resistant Staphylococcus aureus)c) Bacitracin same function as vancomycin, very toxic so used
externally as an ointment, e.g. Polysporin
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2. Protein Synthesis
Inhibitersa. Aminoglycosides Streptomycin, Gentamycin, Neomycin o bind to ribosomes and block translation o good for aerobes, Gram negativesb. Tetracyclines Chlorotetracycline, Doxycycline, Methacycline o binds ribosome and prevents the addition of new amino acids to the growing peptide chain, blocks t-RNA o broad spectrumc. Erythromycin binds ribosome and prevents its movement along the mRNA o broad sprectrumd. Rifampcin (Rifampin) o blocks RNA Polymerase so inhibits transcription no mRNA made
o no mRNA means no protein o can penetrate tissues so good for treating abcesses, spinal cords infections, brain infections o orange colour so when excreted can get orange urine, tears, sweat o broad spectrum
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3. Membrane Inhibiters Polymyxin B o incorporates into the cell membrane and pokes holes causes cell lysis o very toxic targets our membranes too o used for antibiotic resistant bacteria , e.g. Pseudomonas aeruginosa
4. DNA Replication Inhibiters Quinilones Ciprofloxacin, Norfloxacin, Nalidixic Acid o binds DNA Gyrase and blocks unwinding of DNA o broad sprectrum5. Sulfa Drugs (Sulfonamides) Para-amino benzoic acid (PABA) analogs Trimethoprim,
Sulfamethoxazole PABA is the bacterial metabolic building block to make Folic Acid o Folic Acid is an essential metabolite o Drugs block folic acid production o We get folic acid from our diet and do not produce it like bacteria o Broad spectrum
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6. Isoniazid (INH)
o very narrow spectrum, only
Mycobacterium species, e.g. Mycobacterium tuberculosis
o blocks the synthesis of the
unusual compounds found only in mycobacterial cell walls (mycolic
acids)
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Antifungal Agents
- some risk of toxicity as fungi are eucaryotes like us - most target fungal lipid production so tend to be quite specific for fungi1. Polyenes o Amphoteracin B, Nystatin o Alter the permeability of fungal membranes by inserting into membranes and poking holes o Used topically for yeast infection, e.g. thrush, vaginitis2. Imidazoles o Miconazole, Ketoconazole o Interfere with fungal sterol production o Side effects liver damage and liver is the site of our sterol production o Yeast infections3. Griseofulvin
o interferes with fungal cell division o taken orally but locates in the skin and nails o used for nail infections o must take for 6-8 months, or until infected nail grows out
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Antiprotozoan Agents
- high toxicity problem - very few drugs, all highly specific for one type of
protozoa1. Quinine
o Chloroquinine, Fluoroquinine o Antimalarial agent o Interferes with DNA replication of the malaria protozoa
during a specific stage of its life cycle2. Metronidazole (shelf name Flagyl) o inhibits metabolism of anaerobic organisms o used for certain protozoa (Giardia lamblia beaver
fever), certain bacteria (Clostridium difficle), and yeast infections
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Antiviral Agents
1. Nucleotide Analogs
o block viral replication
o many, e.g. Acyclovir Herpes infections; AZT
targets Reverse Transcriptase of HIV
2. Interferons
o just like our naturally produce compound
o triggers cells to produce an enzyme thatblocks viral replication
o best for RNA viruses
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INTRODUCTION Antibiotic: chemical substance produced by mo (mainly
fungi) low concentration: inhibit growth of other mo used to treat infectious disease
Antimicrobials(AM): a substance that can prevent mogrowth or can kill mo:
Natural AM, synthetic or semisynthetic AM
Chemotherapeuticals: chemicals used to prevent or treatdisease.
Antibiotic as chemotherapeutical can work as:
Bacteriostatic and bactericidal
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Desired antibioticcharacteristic:
Prevent growth or disrupt pathogenic mo butcause no damage to host.
Bactericidal > bacteriostatic.
Does not result in bacterial resistance
Effective to as much bacteria as possible
Does not cause allergy or other side effects.
Must be steadily active in plasma, exudate, andother body fluid.
Soluble in water and stable.
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Rational treatment: right target, right dose, right
regiment and right method of drug administration
For a rational antibiotic treatment, it is important to
know:
1. Microbiology : the etiological agent of infection &
still sensitive tests are needed
2. Clinical: infected tissue
3. Pharmacology: drug mechanism, toxic
characteristic, side effects
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ANTIBIOTIC CLASSIFICATION BASED
ON ACTIVITY MECHANISM
A. Antimicrobials that inhibit cell wallsynthesis
B. Antibiotics that inhibit cell membranefunction
C. Antimicrobials that inhibit DNAstructure and function
D. Antimicrobials that inhibit proteinsynthesis
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A. Antimicrobial that inhibit cell wall
synthesis
Bacterial cell wall containmucopeptides=peptidoglycan
Gram positive bacteria: >> peptidoglycan incomparison to Gram negative bacteria
Peptidoglycan: polysaccharide that is cross boundwith polypetide. the cross binding is the resultof transpeptidase reaction.
Inhibiting substance to this enzyme inhibitcross binding formation inhibit cell wallsynthesis.
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-lactam antibioticA. Penicillin
Synthetic penicillin :methicillin, nafcillin, andisozazolyl penicillin (cloxacillin, dicloxacillin,
oxacillin) Penicillin with broad spectrum:
aminopenicillin ( ampicillin, amoxycillin),carboxy-penicillin ( : cerbenicillin, ticarcillin),and piperacillin.
Penicillin with broad spectrum could not stand penicillinase used together with antibiotics which inhibit -laktamase, exp. asam clavulanic, sulbactam.
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B. Cephalosporin Produced by Cephalosporin. Structure
and mechanism is similar to penicillin, structural basis of syntheticcephalosporin
Spectrum: broad. Toxicity : more toxic than penicillin
subtly nephrotoxic.
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Circulating Cephalosporin:
First generation cephalosporin : oral andinjection cefazolin, cephalexin, dancephalothin.
Second generation cephalosporin:ke>an injection: cefamandole,cefaclor, cefoxitin, dan cefuroxime.
Third generation cephalosporin: ke>aninjection cefotaxime, dan ceftriaxone.
Fourth generation cephalosporin: Ke>aninjection.
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3. Other -laktam antibiotics Carbapenem: imipenem: very broad
spectrum
Monobactam: Aztreonam : negative gram aerobic, member of Pseudomonas
B Other cell all s nthesis
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B. Other cell wall synthesis
inhibiting antibiotics
Cycloserine: autotoxic, should not be used
Produced by: Streptomyces orchidceus
Active to coliform, proteus & bsl tbc
Vancomycin: inhibit peptidoglycan
polymerization, narrow spectrum,
bactericidal to Gram positive coccus
> toxic than penicillin, renal toxicity target
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Bacitracin:
Produced by: Bacil lus subti l is,
Prevent peptidoglycan polymerization
Bactericidal to Gram positive bacteria
Nephrotoxic & autotoxic by parenteral
administration
> Used topically
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C. Antibiotic that inhibit membrane
function Cell membrane functions as osmotic barrier to
regulate diffusion of intracellular and
extracellular fluid.
Substance working on cell membrane is
independent and starts soon after bacterial cell
encounters the antibacterial agent
This substance can hardly differentiate betweenmicrobial cell and host tissue cell toxic seldom used.
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Antimicrobials that inhibit
membrane function
Polymyxin: produced by Bacil lus polymyxa (A, B, C, D, and E.) only polymyxin B
and polymyxin-E (colisin) are usedMechanism: forms bond with outer part ofcell membrane cell structure & osmoticfeatures change.
Bactericidal mainly for: P. aeruginosa
Not active against fungi.
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. Polyenes:
Microlide antibiotics selectively inhibit growth of
microorganism with sterol containing membrane.Important in this group: antifungal amphotericin B & nystatin yeast, fungi,other eukaryotic cells
Does not inhibit procaryotic bacteria that lack
sterol in their membranes.
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D. Antimicrobials that interfere with
DNA structure & function
Only few are clinically used because of its
toxicity
DNA have two main functions: duplication& transcription
All substances interfere with DNA
structure effects all levels ofmetabolism and cell growth
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Antimikrob yang mengganggu DNA
Mitomycin: produced by Streptomycesspp.
Bacteriostatic because interference in DNAreplication
Not recommended for treatment becase its toxic Quinolone (Nalidixic acid) & Fluoroquinolone
(oflxacine, ciprofloxacin)
All are synthetic, and have similar structure and
unique mechanism
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Obat golongan quinolone:
Nalidixic acid: first introduced from this group it was used for treatment withoutcomplication now replaced with newquinolones
Norfloxacine & Ciprofloxacine
Spectrum:belongs to enterococcus, streptococci,and Pseudomonas
Ciprofloxacine is the most potential activefor most part of gram negative and grampositive bacteria, used orally forrespiratory tract infection and digestivetract infection
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Metronindazole: for treatment of anaerobicinfection and infection of several protozoans
Not useful for facultative anaerobes and
aerobes
Synthetic as derivative of 5-nitromidazole
Novobiocin: Produced by Streptomyces
niveus, inhibit DNA multiplicationBactericide maily for Gram positive
bacteria. Currently not used for treatment
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E. Antimicrobials that inhibit
protein synthesis
Protein synthesis is the end result of two
processes:
RNA synthesis on DNA template(Transcription)
RNA dependent protein synthesis
(Translation)
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1. Antimicrobials that inhibit
transcription
In transcription inhibition the following
things occur:
- change in DNA template
Inhibition in RNA polymerase.
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Antibiotics that belong to this group are : Actinomycin, produced by Streptomyces inhibit RNA
polymerase along DNA template.
Spectrum: positive Gram and negative Gram bacteria-
Gram not much used for its toxicity. Rifampicin: produced by Streptomyces mediterrane
binds to RNA-polymerase enzyme so there is no RNA
formation.
Broad spectrum: mainly against Gram positive bacteria m& mycobacteria. Main drug to treat tuberculosis and
leprae & for meningitis prophylaxis or meningococci.
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2. Antimicrobials that inhibittranslation
Inhibiton of translation occur if:
a. There is disturbance to sub-unit 30S ribosome
b. There is disturbace to sub-unit 50S ribosome.
Inhibition to sub-unit 30S ribosome
Mechanism of activity of this group is: Prevent binding of m-RNA to template DNA
Inhibit acceptance of aminocyl
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Antimicrobials that belong to
this group are:
1. Aminoglykosides: similar chemical,pharmacological, toxic, and antimicrobialfeatures.
Included: Streptomycin, Neomycin, Kanamycin,Gentamycin, Tobramycin, Amikacin, andNetilmicin.
If administered together with antibiotic goodsynergy, because both are bactericidal.
Toxic to the nervous system and kidney.
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2. Tetracyclines
Natural antibiotic produced by Streptomyces,(tetracycline and derivatives: chlortetracycline,oxytetracyclin.
Synthetic: methacyclin doxycyclin, and minocyclin
Bakteriostatic with broad spectrum.
Effective for intracellular bacterial infection &alternative drug to penicillin.
Tetracycline is not useful for treatment because it is notsecreted by kidney.
Tetracycline toxicity: GI & candida superinfection &other fungi
Not allowed for children & pregnant woman
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2. Inhibition to sub-unit 50S
ribosome
Inhibition to sub-unit 50S ribosome occur if
there is disturbance in:
binding of peptidyl-t-RNA peptidyl bond formation
translocation
A ti i bi l th t b l t thi
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Antimicrobials that belong to this
group are:
Chloramphenicol: first antimicrobia tobe synthesized in laboratory. Broadspectrum, anaerobic bacteria included.
First choice for treatment of tiphoidfever, and meningitis by N. meningitidis.
Toxicity : can cause pansitopenia
because of obstruction tohaematopoetik system
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The macrolides a (erythromycin, azitromycin): A specialantibiotic containing lactone macrocyclic circle consistsof 12-22 carbon atom binding to one or more sugars.
Narrow spectrum & toxic to the heart.
Antibiotic of this group:
Erythromycin: the most important in macrolides.Mainly bacteriostatic, but bactericidal if applied in highconcentration.
First choice in treatment ofMycoplasma pneumoniae, L.pneumophila, diphteria, and pertussis.
Also used as an alternetive to infection of strept. Group Aand patients allergic to penicillin.
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The linkomycines (lincomycin dan clindamycin).
Second spectrum of this drug = erythromycin, althoughthere is no chemical relationship.
Both are active against strept. group A, & staph.Producing penicillinase.
Clindamycin: lincomycin derivative absorbed bettercompared to lincomycin.
Activity > to anaerobic bacterial infection mainly
Bacteroides fragil is.
Because of its spectrum, low toxicity, and clinical efficay is most suitable to replace penicillin.
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Griseofulvin: specifically for treating
fungi with chitinous cell wall
Not useful for bacteria and fungi with cellwalls composed of cellulose, exp. Yeasts.
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F. Antibacteria that inhibit
metabolite intermediates
Most of bacteria need folic acid self synthesized
using PABA (para-amino-benzoic acid) as basic
material.
Antibiotic group that inhibit folic acid synthesis
and interferes with purine and pyrimidine
metabolism are antibiotics with similar structures
to PABA, such that folic acid synthesis isdisrupted because PABA is replaced by the
antibiotic.
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Antibacteria that belong to this
group are:
Sulphonamides: sulfadiazine,
sulfafurazole, sulfamethoxazole,sulfoxazole, sulfamethoxazole
Bacteriostatic with broad spectrum.
Well reabsorbed in the intestine inadequate amount in the blood after pre-
oral treatment.
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Minor features of sulphonamides:
Second administration could result in
hypersensitivity reaction.
High dosis administration: cause
haemotological abnormality & crystal
formation in genitourinary tract.
Causes: an. Haemolitic because of its toxic
effect to the liver.
Toxic to kidney.
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Trimetoprim: structure is similar to
hydrofolic acid able to bind to
dihydrofolate reductase enzyme needed
for folat metabolism.
Sulphamethoxazole-trimetoprim (co-
trimoxazole): combination synergistic
Frequently used for ISK and bacterial
gastroenteritis.
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Other drug similar to PABA
Sulphones
Sulphon derivative known as Dapsone:Treatment of infection by genus Mycob.,
commonly used for treating leprae.Toxic reaction in dapson administration: an.haemolytic, peripheral neuropathy, dermatitis,and eritema nodosum.
P-Aminosalicylic acid (PAS). PAS activity isspecifically against M. tbc
Bacteriostatic: similar structure to PABA invivo could be inhibited by PABA.
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BACTERIAL RESISTANCE TO
ANTIBACTERIAL DRUG
A. Intrinsic Resistance
B. Mutational Resistance
C. Acquisition of Resistance genes
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Intrinsic resistance
Related to bacterial structure: bacterial cell wall
permeability. Bacterial natural immunity is
carried by genes inside the chromosome. Exp.Immunity of P. aeroginosato antibiotic.
Resistance caused by mutation (Mutational
resistance)
Bacterial resistance is the result of chromosomal
mutation bacteria previously sensitive to
antimicrobial drug becomes resistant.
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Mutations
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Acquisition of resistance genes
Bacteria resistance occur as the result of:
- movement of plasmid carryingresistance gene ( R ) from other bacteria
already resistant to a particular antibiotic.
- formation of a new chromosomal gene.
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MECHANISM OF BACTERIAL
RESISTANCE TO ANTIBIOTIC
Antimicrobial inactivation by enzym activity(Enzymatics inactivation)
Resistance occur by change in bacterial cell wall
permeability. Change in target molecule.
Bacteria alters synthetic pathway utilized byantimicrobials.
Antimicrobials is actively excreted out ofbacterial cell.
Occurrence of tolerance
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A. Inactivation of antimicrobials by enzyme
activity (Enzymatics inactivation)
Penicillin inactivation: hydrolysis of -lactam ring by -lactamases.
Aminoglycoside inactivation: alteration
caused by acetyltransferase andphophorylase, nucleotidases activities unable to bind to ribosome.
Chloramphenicol inactivation:
chloramphinecol acetyltransferases havesimilar activity mechanism to aminoglycosidetransferases.
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B. Resistance by change in cell wall
permeability.
Porin: outer membrane protein specific to Gramnegative bacteria plays a role in entrance ofhydrophilic antimicrobials.
Porin mutation: antimicrobial transportation into thecell is hindered bacteria becomes resistent tomultiple antimicrobials (multi-resistant)
Lipopolysaccharide (LPS): inhibit the entrance ofhydrophilic antimicrobials through the cell wall.
Mutant containing small amount of polysaccharidecapsules & small amount of LPS will be morepermeable to many antimicrobials.
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Membr. transport proteins. Mutation of
membrane transport protein causes bacterial
resistance to tetracycline as the result of
reduction of transportation into the cell. Electron transport. The entrance of
aminoglycosides into the cell is dependent on
electron transport into oxygen. Thats why
aminoglycoside is not effective against
anaerobic bacteria & facultative bacteria in
anaerobic environment, like abscess.
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D. Change in target molecule.
Antimicrobial targets could be:
Cytoplasm: penicillin-binding protein (PBP),
Membr. Cytoplasm: ribosom 30S atau ribosom 50S.
Change in target molecule reduced bacterial affinitytowards antibacterial.
Example
Change of 30S ribosome bacterial resistance toaminoglyside.
Change of 50S ribosome bacterial resistance tomacrolide
Change of DNA gyrase: bacterial resistance toquinolone.
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E. Bacteria changes synthetic pathway
utilized by antimicrobials.
The formation of mutant enzyme change
in synthetic pathway. Exp. Bacteriaresistant to vancomycin produce an enzyme
with low affinity to vancomycin.
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F. Antimicrobials are actively excreted from the
bacteria.
Bacterial resistance to tetracycline is caused by
the formation of a new transport protein whichcould actively excreted antimicrobials out of
bacterial cell.
G. Occurrence of tolerance
With the lost of outer membrane permeability &
autolytic enzyme inactivation, changes of
bactericidal substance into bacteriostatic
substance would occur.
THE DANGER OF IRRATIONAL
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THE DANGER OF IRRATIONAL
ANTIMICROBIAL USE
Increase in strains resistant ( R) to
antibody.
Disease suffered by patients gets moresevere.
Increase in mortality.
Increase in infection.
Increase in treatment cost.
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ANTIBACTERIAL SENSITIVITY
TESTING
Sensitivity testing: to understand bacterial
sensitivity towards a particular antibiotic.
There are two methods frequently used toobserve sensitivity to antibiotic, which are:
Tube Dilution Method
Diffusion Method
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Diffusion Method: only to see resistance
Diffusion Method is recommended by the
National Committee of ClinicalLaboratory Standard (NCCLS) United
States.
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Tube Dilution Method : to determine MIC &
MBC
MIC : minimum concentration ofantibacterials which could still inhibit the
growth of bacteria.
MBC :minimum concentration ofantibacterials which could still kill
bacteria.