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Antimicrobial Medications,Chapter 21,Discovery of antibioticsAlexander FlemingDiscovered penicillin while working with StaphylococcusNoticed there were no Staph colonies growing near a mold contaminantThe colonies appeared to be meltingIdentified mold as Penicillium and was producing a bactericidal substance that was effective against a wide range of microbesFleming unable to purify compound,21.1 History and Development ofAntimicrobial Drugs,Discovery of antibioticsErnst Chain and Howard Florey successfully purified penicillinIn 1941 tested on human subject with life threaten Staphylococcus aureus infectionTreatment effective initiallySupply of penicillin ran out before disease under controlDrug tested again with adequate supplyPatients recovered fullyMass production of penicillin during WWIISelman Waksman isolated streptomycin from soil bacterium Streptomyces griseus,21.1 History and Development ofAntimicrobial Drugs,21.2 Features of Antimicrobial Drugs,Most modern antibiotics come from organisms living in the soilIncludes bacterial species Streptomyces and Bacillus as well as fungi Penicillium and CephalosporiumTo commercially produce antibioticsStrain is inoculated into broth mediumIncubated until maximum antibiotic concentration is reachedDrug is extracted from broth mediumAntibiotic extensively purifiedIn some cases drugs are chemically altered to impart new characteristicsTermed semi-synthetic,Selective toxicityAntibiotics cause greater harm to microorganisms than to human hostGenerally by interfering with biological structures or biochemical processes common to bacteria but not to humansToxicity of drug is expressed as therapeutic indexLowest dose toxic to patient divided by dose typically used for treatmentHigh therapeutic index = less toxic to patient,21.2 Features of Antimicrobial Drugs,Antimicrobial actionDrugs may kill or inhibit bacterial growthInhibit = bacteriostaticKill = bacteriocidalBacteriostatic drugs rely on host immunity to eliminate pathogenBacteriocidal drugs are useful in situations when host defenses cannot be relied upon to control pathogen,21.2 Features of Antimicrobial Drugs,Spectrum of activityAntimicrobials vary with respect to range of organisms controlledNarrow spectrumWork on narrow range of organismsGram positive only OR Gram negative onlyBroad spectrumWork on broad range of organismsGram positive AND Gram negativeDisadvantage of broad spectrum is disruption of normal flora,21.2 Features of Antimicrobial Drugs,Tissue distribution, metabolism and excretionDrugs differ in how they are distributed, metabolized and excretedImportant factor for consideration when prescribingRate of elimination of drug from body expressed in half-lifeTime it takes for the body to eliminate one half the original dose in serumHalf-life dictates frequency of dosagePatients with liver or kidney damage tend to excrete drugs more slowly,21.2 Features of Antimicrobial Drugs,Effects of combinations of antimicrobial drugsCombination some times used to treat infectionsWhen action of one drug enhances another, effect is synergisticWhen action of one drug interferes with another, effect is antagonisticWhen effect of combination is neither synergistic or antagonistic, effect said to be additive,21.2 Features of Antimicrobial Drugs,Adverse effectsAllergic reactionsAllergies to penicillinToxic effectsAplastic anemiaBody cannot make RBC or WBCSuppression of normal floraAntibiotic associated colitisAntimicrobial resistance,21.2 Features of Antimicrobial Drugs,21.3 Mechanisms of Action of Antibacterial Drugs,Mechanism of action include:Inhibition of cell wall synthesisInhibition of protein synthesisInhibition of nucleic acid synthesisInhibition of metabolic pathwaysInterference with cell membrane integrityInterference with essential processes of M. tuberculosis,Inhibition of Cell wall synthesisBacteria cell wall unique in constructionContains peptidoglycanAntimicrobials that interfere with the synthesis of cell wall do not interfere with eukaryotic cellThese drugs have very high therapeutic indexLow toxicity with high effectivenessAntimicrobials of this class include lactam drugs Vancomycin Bacitracin,21.3 Mechanisms of Action of Antibacterial Drugs,Penicillins and cephalosporins Part of group of drugs called lactamsCompetitively inhibits function of penicillin-binding proteinsInhibits peptide bridge formation between glycan moleculesDrugs vary in spectrumSome more active against Gram (+)Some more active against Gram (-)Some organisms resist effects through production of -lactamase enzymeEnzyme breaks -lactam ring,21.3 Mechanisms of Action of Antibacterial Drugs,VancomycinInhibits formation of glycan chainsInhibits formation of PTG and cell wall constructionDoes not cross lipid membrane of Gram (-)Important in treating infections caused by penicillin resistant Gram (+) organismsMust be given intravenously due to poor absorption from intestinal tract,21.3 Mechanisms of Action of Antibacterial Drugs,Inhibition of protein synthesisStructure of prokaryotic ribosome acts as target for many antimicrobials of this classDifferences in prokaryotic and eukaryotic ribosomes responsible for selective toxicityDrugs of this class includeAminoglycosidesTetracyclinsMacrolidesChloramphenicolLincosamidesOxazolidinonesStreptogramins,21.3 Mechanisms of Action of Antibacterial Drugs,21.3 Mechanisms of Action of Antibacterial Drugs,TetracyclinsReversibly bind 30S ribosomal subunitBlocks attachment of tRNA to ribosomeEffective against certain Gram (+) and Gram (-)Newer tetracyclines such as doxycycline have longer half-lifeResistance due to decreased accumulation by bacterial cellsCan cause discoloration of teeth if taken as young child,21.3 Mechanisms of Action of Antibacterial Drugs,Inhibition of nucleic acid synthesisThese includeFluoroquinolonesRifamycins,21.3 Mechanisms of Action of Antibacterial Drugs,RifamycinsBlock prokaryotic RNA polymeraseBlock initiation of transcriptionRifampin most widely used rifamycinsEffective against many Gram (+) and some Gram (-) as well as members of genus MycobacteriumPrimarily used to treat tuberculosis as well as preventing meningitis after exposure to N. meningitidis Resistance due to mutation coding RNA polymeraseResistance develops rapidly,21.3 Mechanisms of Action of Antibacterial Drugs,21.4 Determining Susceptibility of Bacterial to Antimicrobial Drug,Susceptibility of organism to specific antimicrobials is unpredictableOften drug after drug tried until favorable response was observedIf serious infection, several drugs were prescribed at one time with hope that one was effectiveBetter approachdetermine susceptibilityPrescribe drug that acts against offending organismBest to choose one that affects as few others as possible,Determining MICMIC = Minimum Inhibitory ConcentrationQuantitative test to determine lowest concentration of specific antimicrobial drug needed to prevent growth of specific organismDetermined by examining strains ability to grow in broth containing different concentrations of test drug,21.4 Determining Susceptibility of Bacterial to Antimicrobial Drug,MIC is determined by producing serial dilutions with decreasing concentrations of test drugKnown concentrations of organism is added to each test tubeTubes are incubated and examined for growthGrowth determined by turbidity of growth mediumLowest concentration to prevent growth is MIC,21.4 Determining Susceptibility of Bacterial to Antimicrobial Drug,Conventional disc diffusion methodKirby-Bauer disc diffusion routinely used to qualitatively determine susceptibilityStandard concentration of strain uniformly spread of standard mediaDiscs impregnated with specific concentration of antibiotic placed on plate and incubated,Clear zone of inhibition around disc reflects susceptibilityBased on size of zone organism can be described as susceptible or resistant,21.4 Determining Susceptibility of Bacterial to Antimicrobial Drug,21.5 Resistance to Antimicrobial Drugs,Mechanisms of resistanceDrug inactivating enzymesSome organisms produce enzymes that chemically modify drugPenicillinase breaks -lactam ring of penicillin antibioticsAlteration of target moleculeMinor structural changes in antibiotic target can prevent bindingChanges in ribosomal RNA prevent macrolides from binding to ribosomal subunits,Acquisition of resistanceCan be due to spontaneous mutationAlteration of existing genesSpontaneous mutation called vertical evolutionOr acquisition of new genesResistance acquired by transfer of new genes called horizontal transfer,21.5 Resistance to Antimicrobial Drugs,Staphylococcus aureusCommon cause of nosocomial infectionsBecoming increasingly resistantIn past 50 years most strains acquired resistance to penicillinDue to acquisition of penicillinase genesUntil recently most infections could be treated with methicillin (penicillinase resistant penicillin)Many strains have become resistantMRSA methicillin resistant Staphylococcus aureusMany of these strains still susceptible to vancomycinSome hospitals identified VISAVISA vancomycin intermediate Staphylococcus aureus,21.5 Resistance to Antimicrobial D