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Antibiotics and ResistanceAntibiotics and Resistance1. Antibiotics and clinical microbiology2. Types of antibiotics3. Mechanisms of action4. Test for antibiotic sensitivity5. Antibiotic resistance6. SolutionsFigure References:• Walsh, C.. 2000. Molecular mechanisms that confer antibacterial drugresistance. Nature 406:775• Levy, S. and Marshall, B.. 2004. Antibacterial resistance worldwide:causes, challenges and responses. Nature Medicine 10(12):S122-S129TOPICSHospital andClinicalMicrobiology• Implement an infectioncontrol program• Perform hospitalsurveillance.– Nosocomial infections– Fomites• Report epidemiologicalfindings to physicians• Perform microbialepidemiology– Typing strains– Monitoring strain diversity– Culture collectionChemotherapeutic agents• Chemical agents used to treat disease• Destroy pathogenic microbes or inhibit theirgrowth within host• Most are antibiotics– microbial products or their derivatives that killsusceptible microbes or inhibit their growth• Distinct from antimicrobial agents– Not intended for therapeutic purposes– Naturally occurring and/or synthetic– Used to sterilize or inhibit microbial growthBefore “modern” antibioticsmetals solutions were used.• Arsenic– Used since antiquity– was one of the first antimicrobial compounds andwas effective against syphilis.– Arsenic is very toxic to the patient however.• Mercury– Very effective antimicrobial agent.– Used to sterilize surfaces and kill microbes– Still used as preservative in vaccines• Bacteria can develop really high levels ofresistance to metals (5-10 mM!).General effects of Ab on bacteriaDisruption of cellwall and/ormembranesInterferes withprotein/DNAsynthesisThe Development of Chemotherapy• Paul Ehrlich (1904)– Developed concept of selective toxicity– Identified dyes that effectively treated African sleepingsickness– One of the first is salvarsan (arsenic containing drug)• Alexander Fleming accidentally discovered penicillin(1928)– Observed penicillin activity on contaminated plate• Selman Waksman discovered streptomycin (1944)The original The original PenicillumPenicillum plateplateAlexander FlemingAlexander Flemingdrawings and notesdrawings and notesGeneral Characteristics ofAntimicrobial Drugs• Selective toxicity– ability of drug to kill or inhibit pathogen whiledamaging host as little as possible• Therapeutic dose– drug level required for clinical treatment• Toxic dose– drug level at which drug becomes too toxic forpatient (i.e., produces side effects)• Therapeutic index– ratio of toxic dose to therapeutic doseMechanism of Action ofAntimicrobial Agents• Can impact pathogen by targeting somefunction necessary for its reproduction orsurvival• Targeted function is very specific topathogen → higher therapeutic indexSummary of the effect ofantibiotics on cell functionsDifferent types of antibiotics (Ab)Different types of antibiotics (Ab)Broad vs. Narrow SpectrumBroad spectrum: affects many different types of bacteriaNarrow spectrum: specific to one particular group of bacteriaHow do we determine the level ofantimicrobial activity?• Effectiveness expressed in two ways– Minimal inhibitory concentration (MIC)• lowest concentration of drug that inhibits growth of pathogen– Minimal lethal concentration (MLC)• lowest concentration of drug that kills pathogen• Two techniques are routinely used to determine MICand MLC1. Dilution Susceptibility Tests• Inoculate media containingdifferent concentrations ofdrug.• Monitor growth by platecounts or OD 600 nm.• Plot the OD 600 nm vs.concentration• The lowest concentrationshowing no growth is MIC• The MLC:– if broth used, tubes showingno growth can be subculturedinto drug-free medium– broth from which microbecan’t be recovered is MLC01.00.50MIC+ + + - - -50300+++MLCHiLoII. Kirby-Bauer Disk Diffusion Tests• Disks impregnated withspecific drugs are placedon agar plates inoculatedwith test microbe• Drug diffuses from diskinto agar, establishingconcentration gradient• Observe clear zones (nogrowth) around disksSwabKirby-Bauer Disc Diffusion ResultsZoneofInhibitionZone of inhibition (diameter) used todetermine susceptibility or resistanceWhat factors influence the effectiveness ofantimicrobial drugs during treatment?• Ability of drug to reach site of infection• Susceptibility of pathogen to drug• Ability of drug to reach concentrations inbody that exceed MIC of pathogenFactors influencing the MIC in thebody during treatment• Amount administered• Route of administration• Pharmacokinetics– The fate of a substance in the body:• Rate of uptake• Rate of clearance (elimination) from bodyMicrobial drug resistance• Using antibiotics inevitably selects forresistance.• This is a good thing for microbe.• This is a big problem for public health.• Once resistance originates in a population itcan be transmitted to other bacteriaAppearance ofdrug-resistantbacteriaPost-therapeutic effects of antibiotic dispersiona) Individual taking antibiotics is a focalpoint for high concentration of Ab (red)and resistant bacteria (black dots).b) Over time, resistance bacteria spreadand antibiotics goes into theenvironment via waste water anddisposalc) If other people are treated this can leadto higher density of resistant microbeswithin the environmentd) Selective process continues during andafter therapy.ResistantInfectionSpread ofResistanceResistantPopulationIn effectiveantibioticHome, daycare, hospital, farmThe individual is an incubator forgrowing and spreading resistantbacteriaAntibiotic ResistanceAntibiotic resistance• Lack the structural target for an antibiotic– Eg. Mycoplasma & Archaea are resistant topenicillin because they lack peptidoglycan• Antibiotic does not reach target– E.g outer membrane of Gram- is impermeable toPenicillin GNaturalAcquired… from antibioticresistance genesAntibiotic Resistance Genes• Degrade antibiotic– Penicillinase• Alter antibiotic– Acetylation• Pump out antibiotic– Tetracycline• Mutate target gene– Transpeptidation enzymeOrigin and spread of resistance genes• Resistance genes can be chromosomal or on plasmids– Can exist separate from chromosome or integrated into it• Chromosomal genes– Mutations can arise• If mutation rate is of 1 in 107,• In 1010 cells you might have 1000 mutations– Mutations might occur in genes encoding proteins targetedby drug• R plasmids–


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