U of M PHAR 6124 - Bacterial Resistance of Respiratory Pathogens

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Bacterial Resistance of Bacterial Resistance of Respiratory PathogensRespiratory PathogensJohn C. Rotschafer, Pharm.D.John C. Rotschafer, Pharm.D.University of MinnesotaUniversity of MinnesotaAntibiotic Misuse Antibiotic Misuse ■■~150 million courses of antibiotic prescribed by ~150 million courses of antibiotic prescribed by office based office based prescribersprescribers■■Estimated 50Estimated 50--66% of prescriptions unnecessary66% of prescriptions unnecessary■■Represents 25% increase over 1980Represents 25% increase over 1980■■Use in children < 15 years 3X greater than other Use in children < 15 years 3X greater than other age groupsage groups■■Most commonMost commonDxDx■■Common respiratoryCommon respiratory■■URTIURTI■■BronchitisBronchitis■■SinusitisSinusitis■■PharyngitisPharyngitisAntibiotic MisuseAntibiotic Misuse■■Enormous problemEnormous problem■■Problem spans the farmers feedlot to children’s day Problem spans the farmers feedlot to children’s day care center to the physician’s office to the acute care care center to the physician’s office to the acute care hospitalhospital■■Problem for 3rd world countries & western Problem for 3rd world countries & western civilizationcivilization■■Pressure on clinician to prescribePressure on clinician to prescribe■■Issue that involves patient complianceIssue that involves patient compliance■■Solutions to this problem will require a Solutions to this problem will require a multidisciplinary approachmultidisciplinary approachIntroductionIntroduction■■Antibiotic resistance to standard therapy Antibiotic resistance to standard therapy with common bacteria is an ever with common bacteria is an ever increasing problemincreasing problem■■Bacteria have strategic advantagesBacteria have strategic advantages■■Naturally mutate Naturally mutate ■■Extraordinary rates of growth Extraordinary rates of growth ■■Produce a “new generation” of bacteria Produce a “new generation” of bacteria with genetic advantagewith genetic advantageResistant BacteriaResistant Bacteria■■AMPAMP--R R H.H.influenzaeinfluenzae■■PCNPCN--R R S.S.pneumoniaepneumoniae■■Multiple antibiotic resistantMultiple antibiotic resistantEnterococciEnterococci■■MethicillinMethicillinresistant staphylococci resistant staphylococci ■■Vancomycin resistant staphylococciVancomycin resistant staphylococci■■M. tuberculosisM. tuberculosis■■N.N.gonorrheaegonorrheae■■S.S.pyogenespyogenes■■Gram negative bacteriaGram negative bacteriaAntibiotic Therapeutic ApproachAntibiotic Therapeutic Approach■■Objective decision makingObjective decision making■■Use antibiotics only when neededUse antibiotics only when needed■■Be selective and use minimum number Be selective and use minimum number ■■Optimize pharmacodynamic outcome Optimize pharmacodynamic outcome parametersparameters■■Peak / MIC ratioPeak / MIC ratio■■AUC / MIC ratioAUC / MIC ratio■■Time > MICTime > MIC■■Optimize antibiotic dose & intervalOptimize antibiotic dose & intervalTherapeutic ApproachTherapeutic Approach■■URTI & LRTI DilemmaURTI & LRTI Dilemma■■Bacterial pathogen & antibiotic Bacterial pathogen & antibiotic susceptibility often unknownsusceptibility often unknown■■Gram stain often not doneGram stain often not done■■Sputum or sinus often not culturedSputum or sinus often not cultured■■++Chest XChest X--ray ray ■■Treatment guidelines may not be Treatment guidelines may not be current with level of bacterial current with level of bacterial resistance or incorporate new agentsresistance or incorporate new agentsAntibioticsAntibiotics■■Antibiotics kill bacteria:Antibiotics kill bacteria:■■Transport to the site of infectionTransport to the site of infection■■Transport into the bacteria (Influx)Transport into the bacteria (Influx)■■Binding to a strategic siteBinding to a strategic site■■PBPPBP■■RibosomeRibosome■■DNADNAGyraseGyrase■■Metabolically poisoning the bacteriaMetabolically poisoning the bacteria■■Time dependent Time dependent ■■Concentration dependentConcentration dependentCommon Mechanisms of Bacterial Common Mechanisms of Bacterial ResistanceResistance■■BetaBeta--lactamaseslactamases((PitoutPitoutet al Am J Med 103:51et al Am J Med 103:51--59,1997)59,1997)■■Enzyme is made up ofEnzyme is made up ofaminoacidsaminoacids■■AlteringAlteringaminoacidsaminoacidssequence changes sequence changes potency (ESBL)potency (ESBL)■■Result of betaResult of beta--lactamaselactamase■■Open antibiotic betaOpen antibiotic beta--lactamlactamringring■■Regenerate enzymeRegenerate enzyme■■Over 50 differentOver 50 differentplasmidplasmidenzymesenzymes■■Several chromosomally enzymesSeveral chromosomally enzymes■■Richmond Sykes or Bush Type I Richmond Sykes or Bush Type I enzymesenzymesAntibiotic DestructionAntibiotic Destruction■■MacrolidesMacrolides■■Enzyme alters the 50S ribosomeEnzyme alters the 50S ribosome■■Resistance to erythromycin means Resistance to erythromycin means resistance to all current resistance to all current macrolidesmacrolides■■EffluxEfflux■■Newer Newer macrolides macrolides still likely effectivestill likely effectiveAntibiotic DestructionAntibiotic Destruction■■Target alterationTarget alteration■■BetaBeta--lactamslactams■■Alteration of penicillin binding Alteration of penicillin binding proteins (proteins (PBP’sPBP’s))■■MethicillinMethicillinresistant resistant S. aureus S. aureus (MRSA) or (MRSA) or S.S.epidermidisepidermidis(MRSE) (MRSE) alteration of PBPalteration of PBP--22■■Penicillin Resistant Penicillin Resistant S.S.pneumoniae pneumoniae ■■EnterococcusEnterococcusStreptococcusStreptococcuspneumoniaepneumoniaePenicillin ResistantPenicillin ResistantPCNPCN--RRS.S.pneumoniaepneumoniae■■PneumococcalPneumococcalSentinel Surveillance System, Sentinel Surveillance System, November 1996)November 1996)■■SensitiveSensitive(PCN MIC ≤ 0.06 mg/L)(PCN MIC ≤ 0.06 mg/L)■■NonsusceptibleNonsusceptible(PCN MIC 0.12 (PCN MIC 0.12 --1.0 mg/L)1.0 mg/L)■■ResistantResistant(PCN MIC ≥ 2.0 mg/L)(PCN MIC ≥ 2.0 mg/L)S.S.pneumoniaepneumoniae■■Mechanism of resistanceMechanism of resistance■■Modification of penicillin binding Modification of penicillin binding proteins (proteins


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U of M PHAR 6124 - Bacterial Resistance of Respiratory Pathogens

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