ANTIBIOTIC USEANTIBIOTIC USE

PRESENTOR: DR HASSANPRESENTOR: DR HASSAN

FACILITATOR: DR MUASYAFACILITATOR: DR MUASYA

OUTLINEOUTLINE

IntroductionIntroduction

Overview of antibiotics mechanism of actionOverview of antibiotics mechanism of action

Rationale use and choice of antibiotics.Rationale use and choice of antibiotics.

Combination therapy.Combination therapy.

Resistance to antibioticsResistance to antibiotics

SummarySummary

IntroductionIntroduction Antibiotics are substances produced by various microorganisms ( or synthetic Antibiotics are substances produced by various microorganisms ( or synthetic

agents ) that suppress growth of other microorganisms.agents ) that suppress growth of other microorganisms.

Among the most prescribed drugs.Among the most prescribed drugs.

Proper use can be life savingProper use can be life saving

Indiscriminate use: more cost of h/care, side effects, drug interactions and foster Indiscriminate use: more cost of h/care, side effects, drug interactions and foster emergence of drug resistance.emergence of drug resistance.

Bacteriostatic vs bacteriocidalBacteriostatic vs bacteriocidal

BacteriocidalBacteriocidal BacteriostaticBacteriostatic

AminoglycosidesAminoglycosides ChloramphenicalChloramphenical

B-lactam antibioticsB-lactam antibiotics ClindamycinClindamycin

VancomycinVancomycin MacrolidesMacrolides

QuinolonesQuinolones SulfonamidesSulfonamides

IsoniazidIsoniazid TetracyclineTetracycline

PyrazinamidePyrazinamide EthambutolEthambutol

RifampicinRifampicin

Rationale use of antibioticsRationale use of antibiotics

Is an antimicrobial agent indicated on the basis of clinical finding?Is an antimicrobial agent indicated on the basis of clinical finding?

Have appropriate clinical specimens been obtained?Have appropriate clinical specimens been obtained?

What are the likely etiologic agents for the patients illness?What are the likely etiologic agents for the patients illness?

What measures should be taken to protect individuals exposed to the index case to What measures should be taken to protect individuals exposed to the index case to prevent secondary cases?prevent secondary cases?

Is there clinical evidence that antimicrobial therapy will confer clinical benefit for Is there clinical evidence that antimicrobial therapy will confer clinical benefit for the patient?the patient?

Choice of an antibioticChoice of an antibiotic

To choose the appropriate antibiotic to use, one needs to consider:To choose the appropriate antibiotic to use, one needs to consider:

1.1. Infectious agent.Infectious agent.

2.2. Antimicrobial agent to use.Antimicrobial agent to use.

3.3. Host factors.Host factors.

Factors affecting choice of an antibioticFactors affecting choice of an antibiotic

Host factorsHost factors

Concomitant disease states (e.g immune status)Concomitant disease states (e.g immune status)

Prior adverse drug effectsPrior adverse drug effects

Impaired elimination of the drugsImpaired elimination of the drugs

Age of the patientAge of the patient

Pregnancy statusPregnancy status

Factors affecting choice of an antibioticsFactors affecting choice of an antibiotics

Pharmacologic factorsPharmacologic factors Pharmacodynamics of the drug (concentration dependent vs. time dependent Pharmacodynamics of the drug (concentration dependent vs. time dependent

killing)killing)

Site of infection (BBB, vegetations in IE)Site of infection (BBB, vegetations in IE)

Toxicity of the agentToxicity of the agent

Interactions with other drugsInteractions with other drugs

Bactericidal or bacteriostaticBactericidal or bacteriostatic

Resistance patterns Resistance patterns

Antibiotic therapyAntibiotic therapy

Empirical therapy.Empirical therapy.

-Based on best guess guided by knowledge of likely pathogen in that site or clinical -Based on best guess guided by knowledge of likely pathogen in that site or clinical setting.setting.

-appropriate in life threatening infections, justified for by the hope that early -appropriate in life threatening infections, justified for by the hope that early intervention will improve the outcome intervention will improve the outcome

Rx comm. Acquired infections e.g. CAP, UTIRx comm. Acquired infections e.g. CAP, UTI

-Once MCS results out change to specific agent -Once MCS results out change to specific agent

-Adv: immediate. Rx, short hosp. stay-Adv: immediate. Rx, short hosp. stay

-Disadv: use of many drugs, unnecessary S/E, good clinical acumen needed.-Disadv: use of many drugs, unnecessary S/E, good clinical acumen needed.

Empirical therapy: ApproachEmpirical therapy: Approach

Formulate a clinical diagnosis of microbial infectionFormulate a clinical diagnosis of microbial infection

Obtain specimen for laboratory examinationObtain specimen for laboratory examination

Formulate a microbiologic diagnosisFormulate a microbiologic diagnosis

Determine the necessity for empirical therapyDetermine the necessity for empirical therapy

Institute treatmentInstitute treatment

Examples of empiric antibiotic therapy based on Examples of empiric antibiotic therapy based on microbiological aetiologymicrobiological aetiology

Suspected org.Suspected org. 11stst choice choice Alternative drugAlternative drugN. GonorrheaN. Gonorrhea CeftriaxoneCeftriaxone SpectinomycinSpectinomycin

N.MeningitidisN.Meningitidis Pen GPen G CeftriaxoneCeftriaxone

E.coli, klebsiellaE.coli, klebsiella Septirin, Ceph,Septirin, Ceph, Quinolone, AGQuinolone, AG

PseudomonasPseudomonas Antips+AGAntips+AG Antips+QN,CPHAntips+QN,CPH

S. PneuS. Pneu PenPen Cphl,macrldes,qnlnsCphl,macrldes,qnlns

V.StrepV.Strep PenPen Cphl, vancoCphl, vanco

EnterococcusEnterococcus Pen+AGPen+AG Vanc+AGVanc+AG

ClostrdmClostrdm MetrndzleMetrndzle Vanc, bacitracinVanc, bacitracin

Definitive therapyDefinitive therapy

-depend on susceptibility & sensitivity tests.-depend on susceptibility & sensitivity tests.

-requires isolation of the pathogen.-requires isolation of the pathogen.

-requires knowledge of the MIC and MBC.-requires knowledge of the MIC and MBC.

-Advantage: accuracy, cheaper-Advantage: accuracy, cheaper

-Disadvantage: delay treatment, specimen may be difficult to get, varying -Disadvantage: delay treatment, specimen may be difficult to get, varying sensitivity patterns in different hospitals.sensitivity patterns in different hospitals.

Methods of susceptibility testsMethods of susceptibility tests

Broth microdilutionBroth microdilution

MicrodilutionMicrodilution

Agar dilution methodAgar dilution method

Disk diffusion test (Bauer Kurby procedure)Disk diffusion test (Bauer Kurby procedure) SusceptibleSusceptible IntermediateIntermediate ResistantResistant

Duration of therapyDuration of therapy

Depends on: Depends on:

the pathogen; the pathogen;

site of infection and site of infection and

host factors.host factors.

Duration of Therapy for Bacterial InfectionsDuration of Therapy for Bacterial Infections

Duration of Duration of therapytherapy

InfectionsInfections

Single doseSingle dose GU, Strep pharyngitis, prim and secondary syphilisGU, Strep pharyngitis, prim and secondary syphilis

3 days3 days Cystitis in young women, community/travel acquired dirrheaCystitis in young women, community/travel acquired dirrhea

3-10 days3-10 days CAP(3-5days);CAM(pnemo or meningo);Antbtc assctd CAP(3-5days);CAM(pnemo or meningo);Antbtc assctd diarrhea(10 days);cellulitis ;epididymitisdiarrhea(10 days);cellulitis ;epididymitis

2 weeks2 weeks H.Pylori assctd PUD; neurosyphilis; disseminated gon infctns; H.Pylori assctd PUD; neurosyphilis; disseminated gon infctns; acute pyelonephritis; Pen-suscptble VSEacute pyelonephritis; Pen-suscptble VSE

3 weeks3 weeks Lyme disease; septic arthritis (NG)Lyme disease; septic arthritis (NG)

4 weeks4 weeks Acut and chronic prostitis; IE (Pen resistant)Acut and chronic prostitis; IE (Pen resistant)

>4 weeks>4 weeks A and C ostemyltis; S.aureaus endocarditis; FB infectionsA and C ostemyltis; S.aureaus endocarditis; FB infections

Combination of antibioticsCombination of antibiotics

USEDUSED

Provide broad-spectrum empiric therapy in seriously ill patients.Provide broad-spectrum empiric therapy in seriously ill patients.

Treat polymicrobial infection such as intraabdominal abscess. Treat polymicrobial infection such as intraabdominal abscess.

To decrease emergence of resistance strains. To decrease emergence of resistance strains.

To enhance antibacterial activity (synergy)To enhance antibacterial activity (synergy)

To use lower doses of a toxic drugTo use lower doses of a toxic drug

Antibiotic prophylaxisAntibiotic prophylaxis

Risk of infection must be greater than S/E of drugsRisk of infection must be greater than S/E of drugs

Shortest time possibleShortest time possible

Primary or secondary prophylaxisPrimary or secondary prophylaxis

Surgical or nonsurgical prophylaxisSurgical or nonsurgical prophylaxis

Antibiotic prophylaxisAntibiotic prophylaxis

SurgicalSurgical Contaminated and clean contaminated proceduresContaminated and clean contaminated procedures Operations in which postop infections may be catastrophic eg open heart Operations in which postop infections may be catastrophic eg open heart

surgerysurgery Placement of prosthetic materialsPlacement of prosthetic materials Procedures in imunocompromised pts.Procedures in imunocompromised pts.

NonsurgicalNonsurgical Individuals at high risk for temporary exposure to selected virulant org.Individuals at high risk for temporary exposure to selected virulant org. Patients at increased risk for developing infection because of underlying Patients at increased risk for developing infection because of underlying

disease e.g immunocompromised ptsdisease e.g immunocompromised pts

MISUSE OF ANTIBIOTICSMISUSE OF ANTIBIOTICS

Treating FUOTreating FUO

Improper dosingImproper dosing

Inappropriate reliance on chemotherapy aloneInappropriate reliance on chemotherapy alone

Lack of adequate bacteriological informationLack of adequate bacteriological information

Resistance to antibioticsResistance to antibiotics

RESISTANCE TO ANTIBIOTICSRESISTANCE TO ANTIBIOTICS

Genetic determinants of resistanceGenetic determinants of resistance

Biochemical mechanisms of resistanceBiochemical mechanisms of resistance

Current status of antibiotic resistanceCurrent status of antibiotic resistance

Limiting resistance to antibioticsLimiting resistance to antibiotics

Genetic determinant of ResistanceGenetic determinant of Resistance

Chromosomal determinantChromosomal determinant

Spontaneous mutation rate in bacteria popn. For any particular gene very low Spontaneous mutation rate in bacteria popn. For any particular gene very low (1: 1000000)(1: 1000000)

In most org., resistance from chromosomal mutation not of great significance In most org., resistance from chromosomal mutation not of great significance coz mutants have decreased pathogenecitycoz mutants have decreased pathogenecity

Impo. in MRSA and mycobacterium infections - TBImpo. in MRSA and mycobacterium infections - TB

Genetic determinant of ResistanceGenetic determinant of Resistance

Extrachromosomal determinantsExtrachromosomal determinants Plasmids: extra chromosomal genetic elements called plasmids that exist Plasmids: extra chromosomal genetic elements called plasmids that exist

free in the cytoplasm. These genetic elements can replicate on their own. free in the cytoplasm. These genetic elements can replicate on their own. They are closed loops of DNA that consist of single gene or many genes. They are closed loops of DNA that consist of single gene or many genes. Plasmids that carry genes for resistance for antibiotics (Plasmids that carry genes for resistance for antibiotics (r r genes) are called genes) are called R plasmids. Much drug resistance in clinical medicine is plasmid R plasmids. Much drug resistance in clinical medicine is plasmid mediated.mediated.

Transfer of r genes between bacteria take place in one of these form:Transfer of r genes between bacteria take place in one of these form:1.1. Transposons: stretches of DNA that can be transferred (transposed) from Transposons: stretches of DNA that can be transferred (transposed) from

one plasmid to another or plasmid to chromosome.one plasmid to another or plasmid to chromosome.2.2. Conjugation: conjugate plasmids which cause bacteria to make a Conjugation: conjugate plasmids which cause bacteria to make a

connecting tube btn bacteria through which the plasmid or other plasmids connecting tube btn bacteria through which the plasmid or other plasmids can pass.can pass.

3.3. Transduction: transmission of r gene-carrying plasmid by bacteriophage Transduction: transmission of r gene-carrying plasmid by bacteriophage (bacteria virus)(bacteria virus)

BIOCHEMICAL MECHANISM OF RESISTANCE BIOCHEMICAL MECHANISM OF RESISTANCE TO ANTIBOITICSTO ANTIBOITICS

1.1. Production of enzymes that inactivate the drug:B lactamase –penicillins, Production of enzymes that inactivate the drug:B lactamase –penicillins, cephalosporins, acetyltransferase –CAFcephalosporins, acetyltransferase –CAF

2.2. Alteration of drug sensitive site or binding siteAlteration of drug sensitive site or binding site-plasmid mediated alt 50s binding site-erythromycin-plasmid mediated alt 50s binding site-erythromycin- alt of 30s subunit- amino glycoside (xsomal mutation)- alt of 30s subunit- amino glycoside (xsomal mutation)

3.3. Decreased drug accumulation in the bacteriaDecreased drug accumulation in the bacteria-active efflux of the drug: resistance to B lactams, amino glycosides, quinolones.-active efflux of the drug: resistance to B lactams, amino glycosides, quinolones.-plasmid mediated resistance to TCs through efflux of the TCs-plasmid mediated resistance to TCs through efflux of the TCs

4. 4. Alteration of enzyme pathwaysAlteration of enzyme pathways

-plasmid mediated synthesis of DHFR with low affinity for trimethoprim-plasmid mediated synthesis of DHFR with low affinity for trimethoprim ..

Examples of antibiotic resistanceExamples of antibiotic resistance

Enteroccocci:Enteroccocci:

B-lactam: b-lactamse enzymeB-lactam: b-lactamse enzyme

AG: enzymes that modify the drugsAG: enzymes that modify the drugs

Clindamycin:gene that effluxes the drugClindamycin:gene that effluxes the drug

Vancomycin: modified targets of vanco (low level and high level resistance)Vancomycin: modified targets of vanco (low level and high level resistance)

Examples..ctdExamples..ctd

MRSAMRSA

Many strains of staph now resistant to all currently available antibiotics.Many strains of staph now resistant to all currently available antibiotics.

Produce B-latamase –resist to B-lactamsProduce B-latamase –resist to B-lactams-B-lactam binding protein –resist to methicillin-B-lactam binding protein –resist to methicillin-staph also show resistance to other antibiotics:-staph also show resistance to other antibiotics:streptomycic(alt of target site)streptomycic(alt of target site)-CAF & macrolides, (change enzymes-CAF & macrolides, (change enzymes-trim/sulfo,(DHFR, incr PABA)-trim/sulfo,(DHFR, incr PABA)-amino glycosides (alt target site)-amino glycosides (alt target site)-quinolones( decr uptake.-quinolones( decr uptake.

SummarySummary

1.1. Make a diagnosisMake a diagnosisas precisely as possibleas precisely as possiblestate org. responsible and site of infectionstate org. responsible and site of infection

2.2. Decide if chemotherapy is necessary: if no symptomatic rx. If yes:Decide if chemotherapy is necessary: if no symptomatic rx. If yes:3.3. Select best drugSelect best drug4.4. Administer drug: best route, optimum dose , freq & duration.Administer drug: best route, optimum dose , freq & duration.5.5. Continue therapy until cured/improvement.Continue therapy until cured/improvement.6.6. Test for cure/improvement. (clinical & lab.)Test for cure/improvement. (clinical & lab.)7.7. ? Prophylaxis & how long? Prophylaxis & how long

EXAMPLE: IEEXAMPLE: IE

Referances:Referances:

Katzung pharmacologyKatzung pharmacology Harrisons internal med 17Harrisons internal med 17 thth ed ed Uptodate.comUptodate.com Hopkins-abxguide.comHopkins-abxguide.com Idsociety.orgIdsociety.org

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