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1、Antibiotics Part 1Dr P Gayo MunthaliConsultant Microbiologist UHCWHonorary Associate Clinical ProfessorUniversity of Warwick ObjectivesBy the end of this lecture you should be able to:1)Explain the mode of action of beta lactams,aminoglycosides,fluoroquinolones,macrolides,tetracyclines and glycopept
2、ides2)Mention the major side effects of the antibiotic groups in(1)3)Appreciate different types of resistance and in simple terms,explain the mechanisms of resistance to beta lactams4)Explain some limitations in the use of antibiotics in(1)5)Understand the general spectrum of activity of antibiotics
3、 in(1)Antibiotics,Point of ActionCell membranePolymixin,bacitracin,colistinFolic acid MetabolismTrimethoprim,SulphonamidesCell wall SynthesisBeta-lactams,GlycopeptidesDaptomycinFosfomycin DNA ReplicationQuinolonesDNA Dependent RNA Pol.RifampicinProtein Synthesis 30S Tetracyclines,Aminoglycosides50S
4、Chloramphenicol,Clindamycin,Erythromycin,Linezolid,Streptogramin50S30SImportant mechanisms of resistance to antibioticsMechanism Typical exampleAntibiotics affectedInactivation-Lactamases-Lactams Aminoglycoside modifying enzymesAminoglycosidesChanges in target bindingChanges in PBPs/Peptide Terminal
5、-Lactams/GlycopeptidesRibosomal methylationMacrolidesDNA gyrase mutationFluoroquinolonesEfflux and permeability changesEfflux pumpsPump specificPorin protein lossMost except polymyxins and aminoglycosidePenicillins and CephalosporinssoR-CONHNCOOHsNoR-CONHCOOHRPenicillins 1940-Cephalosporins 1948-Car
6、bapenems and OthersSRCOOHNoCHHOoNoHOCOOHCarbapenems 1976-Clavulanic acid 1976MobactamsNoRRR-CONHMonobactam 1981-Beta Lactams Against Bacterial Cell Wall Cell wallOsmotic PressureAntibiotic against cell wallOsmotic PressureCell membraneRaptureCell MembraneSpectrum of ActivityVery wideGram positive an
7、d negative bacteriaAnaerobesSpectrum of activity depends on the agent and/or its groupAztreonam only active against gram negatives Adverse EffectsPenicillin hypersensitivity 0.4%to 10%Mild:rash Severe:anaphylaxis&deathThere is cross-reactivity among all PenicillinsPenicillins and cephalosporins 5-15
8、%Penicillins and carbapenems1%(may be higher)Desensitization is possible for mild hypersensitivityAztreonam does not display cross-reactivity with Penicillins and can be used in penicillin-allergic patientsPBP over expression Acquisition of Foreign PBPs genesMutation by recombination with foreign DN
9、APoint mutationPenicillin-Binding Protein(PBP)mediated ResistancePBP over expressionRareThe more PBPs are expressed,the more an organism becomes resistantS.aureus increased resistance to methicillin by over expression of PBP4E.faecium strains that over express PBP5 have increased resistance to penic
10、illin.AAC 39:2415-2422,AAC 38:1980-1983,AAC 45:1480-1486ResultAll PBPs in S.aureus become redundantMRSA is resistant to all-lactamsMutation by Recombination with Foreign DNAStreptococcus pneumoniae and Neisseria are capable of picking up foreign DNA and integrating it with their own DNAForm mosaic g
11、enePneumococcus picks up resistant genes from alpha haemolytic strepsReduced affinity to beta lactamsSeen as penicillin resistant Pneumococci JAC 1992,30(3);279-288MIC for meningitisIsolateBSACMICsEfflux pumps/Loss of PorinsImportant type of resistance in PseudomonasA combination of-Lactamase produc
12、tion and porin loss can lead to complex resistance patternCan lead to carbapenem resistance without carbapenemase productionOverexpressed Efflux pumpsPorinsPorins and PumpsAdapted from Journal of Bacteriology,April 2006,p.2297-2299,Vol.188,No.7-Lactamase-pleated sheet-5-helicesAAC 39:2593-2601Bound-
13、lactam by-Lactamase-Lactamases-actionsoR-CONHNCOOHNoR-CONHCOOHCH3CH3Enzyme-Ser-OHCC OSersCH3CH3HEnzymeHOHAnnu.Rev.Microbiol.45:37-67Simple-Lactamases Many Based on genes called TEM-1 and SHV-1 found on mobile DNA elementsTEM-1 and SHV-1 are simple penicillinases in EnterobacteriaceaeInactive against
14、 cephalosporinsConfer resistance to Penicillins such as Benzylpenicillin and amoxicillinOn mobile elements and therefore transmissibleStaphylococci also produce simple beta lactamases not based on TEM-1 and SHV-1Flucloxacillin designed to resist betalactamases in Staphylococcus aureus AAC 33:1131-11
15、36 Extended Spectrum-lactamasesBased on TEM-1 and SHV-1Amino acid mutations in active site progressively increase their activity against cephalosporinsWhen they hydrolyze extended-spectrum cephalosporinsThey are then called ESBLsAlso attack a monobactam Aztreonam-On mobile elements thus transmissibl
16、eCarry other resistance genes,Gentamicin,CiprofloxacinCharacteristics of ESBLsMay appear sensitive to some cephalosporins and combinations of piperacillin and tazobactam as well as amoxicillin and clavulanic acidHowever,use of these-lactam agents will lead to microbiological and clinical failureOnly
17、 carbapenems among the-lactams can be used successfully AmpC-LactamasesProduced by almost all gram-negative bacteriaChrosomally encoded versions important in Citrobacter freundii,Enterobacter aerogenes,Enterobacter cloacae,Morganella morganii,Pseudomonas aeruginosa and Serratia marcescens(not found
18、in Salmonella and Klebsiella)AmpC-Lactamase genes have been found on transferable plasmidsClass C-LactamasesAll-lactams induce AmpC-lactamase productionOnly carbapenems are resistant to AmpC-lactamases If there is loss of porins as well,this will lead to carbapenem resistanceOther-lactams will be hy
19、drolysedMetallo-LactamasesRequire Zinc or other heavy metal for activityHydrolyse all-Lactams including carbapenemsMost will be associated with resistance to many antibiotic classesCurrently New Delhi Metallo-Lactamase(NDM-1)is a new flavour in the UKAssociated with IndiaResistant to almost all anti
20、biotics in use in the UKAminoglycosidesHighly positively charged compounds,concentration dependent activity Inhibit bacterial protein synthesis by irreversibly binding to 30S ribosomal unit Naturally occurring:StreptomycinNeomycinKanamycinTobramycinGentamicinSemisynthetic derivatives:Amikacin(from K
21、anamycin)Netilmicin(from Sisomicin)30S Ribosomal Unit Blockage by AminoglycosidesCauses mRNA decoding errorsBlock mRNA and transfer RNA translocationInhibit ribosome recyclingRibosome recycling follows the termination of protein synthesis Spectrum of ActivityGram-Negative AerobesEnterobacteriaceae;E
22、.coli,K.pneumoniae,Proteus sp.Citrobacter,Enterobacter sp.Morganella,Providencia,SerratiaPseudomonas aeruginosaAcinetobacterGram-Positive Aerobes(Usually in combination with-lactams)S.aureus and coagulase-negative staphylococciViridans streptococciEnterococcus sp.(gentamicin)Mechanisms of Resistance
23、Ribosome changesPrevents bindingLoss of cell permeabilityExpulsion by efflux pumpsEnzyme inactivation by Aminoglycoside modifying enzymesThis is the most important mechanismPharmacokineticsAll have similar pharmacologic propertiesGastrointestinal absorption:unpredictable but always negligibleDistrib
24、utionHydrophilic:widely distributes into body fluids but very poorly into;CSFVitreous fluid of the eyeBiliary tractProstate Tracheobronchial secretionsAdipose tissueElimination85-95%eliminated unchanged via kidneyt1/2 dependent on renal functionIn normal renal function t1/2 is 2-3 hours Adverse Effe
25、ctsNephrotoxicityDirect proximal tubular damage-reversible if caught earlyRisk factors:High troughs,prolonged duration of therapy,underlying renal dysfunction,concomitant nephrotoxinsOtotoxicity8th cranial nerve damage irreversible vestibular and auditory toxicityVestibular:dizziness,vertigo,ataxiaA
26、uditory:tinnitus,decreased hearingRisk factors:as for nephrotoxicityNeuromuscular paralysisCan occur after rapid IV infusion especially with;Myasthenia gravisConcurrent use of succinylcholine during anaesthesiaMacrolidesErythromycin is the prototype antibiotic for this groupBacteriostatic-usuallyInh
27、ibit bacterial RNA-dependent protein synthesis Bind reversibly to the 23S ribosomal RNA of the 50S ribosomal subunitsBlock translocation reaction of the polypeptide chain elongationMacrolides ErythromycinTelithromycinClarithromycinLactone RingAzithromycin15141414Mechanisms of ResistanceAltered targe
28、t sitesMethylation of ribosomes preventing antibiotic bindingResistance to macrolides,lincosamides(Clindamycin)and streptogramin BCan be induced by macrolidesEfflux pumpsResistance to macrolides onlyCross-resistance occurs between all macrolidesSpectrum of ActivityGram-Positive Aerobes:Activity:Clar
29、ithromycinErythromycinAzithromycinMSSAS.pneumoniaeBeta haemolytic streptococci and viridans streptococci Gram-Negative Aerobes:Activity:AzithromycinClarithromycinErythromycinH.influenzae,M.catarrhalis,Neisseria sp.NO activity against any EnterobacteriaceaeAnaerobes:upper airway anaerobesAtypical Bac
30、teriaOther Bacteria:Mycobacterium avium complexPharmacokinetics 1Erythromycin(Oral:absorption 15%-45%)Short t1/2(1.4 hr)Acid labileAbsorption(Oral)Erythromycin:variable absorption of 15%-45%Clarithromycin:55%Azithromycin:38%Half Life(T1/2)Erythromycin 1.4 HoursClarithromycin(250mg and 500mg 12hrly)3
31、-4&5-7 hours respectivelyAzithromycin 68hours Improved tolerabilityExcellent tissue and intracellular concentrationsTissue levels can be 10-100 times higher than those in serumPoor penetration into brain and CSFCross the placenta and excreted in breast milkPharmacokinetics 2Metabolism&EliminationCla
32、rithromycin partially eliminated by the kidneyALL hepatic eliminationAdverse EffectsGastrointestinal(up to 33%)(especially Erythromycin)NauseaVomitingDiarrhoeaDyspepsiaThrombophlebitis:IV Erythromycin&AzithromycinQTc prolongation,ventricular arrhythmiasOther:ototoxicity with high dose erythromycin i
33、n renal impairmentFluoroquinolonesQuinolone pharmacoreFluoroquinolonesSynthetic antibioticsConcentration-dependent bactericidal activityBroad spectrum of activityExcellent pharmacokineticsbioavailability,tissue penetration,prolonged half-livesIn common useCiprofloxacinLevofloxacin MoxifloxacinMechan
34、ism of ActionInhibit bacterial topoisomerases which is used by bacteria to;Relax supercoiled DNA before replicationDNA recombinationDNA repair DNA gyrase Primary target for gram-negatives Topoisomerase IV Primary target for gram-positivesResistanceAltered target sites due to point mutations.The more
35、 mutations,the higher the resistance to Fluoroquinolones Most important and most common Altered cell wall permeability Efflux pumps Cross-resistance occurs between fluoroquinolonesSpectrum of ActivityGram-positive(MSSA Streptococcus pneumoniae)Moxifloxacin is most active Gram-Negative(Enterobacteria
36、ceae H.influenzae,M.catarrhalis,Neisseria sp.Pseudomonas aeruginosa)Ciprofloxacin is most activeAtypical bacteria:all have excellent activityPharmacokineticsAbsorptionGood bioavailabilityOral bioavailability 60-95%Divalent and trivalent cations(Zinc,Iron,Calcium,Aluminum,Magnesium)and antacids reduc
37、e GI absorptionDistribution Extensive tissue distribution but poor CSF penetrationMetabolism and EliminationCombination of renal and hepatic routesAdverse EffectsCardiac Prolongation QTc intervalAssumed to be class effect Articular DamageCartilage damageInduced in animals with large dosesTetracyclin
38、esHydronaphthacene nucleus containing four fused ringsTetracyclineShort actingDoxycyclineLong actingMechanism of ActionInhibit protein synthesisBind reversibly to bacterial 30S ribosomal subunitsPrevents polypeptide synthesis BacteriostaticResistanceEffluxAlteration of ribosomal target siteProductio
39、n of drug modifying enzymes Spectrum of ActivityAll have similar activitiesGram positives aerobic cocci and rodsStaphylococciStreptococciGram negative aerobic bacteriaAtypical organismsMycoplasmasChlamydiaeRickettsiaeProtozoaPharmacokineticsIncompletely absorbed from GI,improved by fastingMetabolise
40、d by the liver and concentrated in bile(3-5X higher than serum levels)Excretion primarily in the urine except doxycycline(60%biliary tract into faeces,40%in urine)Tissue penetration is excellent but poor CSF penetrationIncorporate into foetal and children bone and teeth Avoid in pregnancy and childr
41、enAdverse EffectsOesophageal ulcerationPhotosensitivity reactionGlycopeptidesVancomycinTeicoplaninVancomycinMechanism of ActionInhibit peptidoglycan synthesis in the bacterial cell wallComplex with D-alanyl-D-alanine portion of the cell wall precursorResistanceModification of D-alanyl-D-alanine bind
42、ing site of peptidoglycanD-alanyl-D-alanine terminal then ends in D-alanyl-D-lactateLeads to lower glycopeptide affinityComplex reactions to achieve this Spectrum of ActivityGram positive bacteria only including MRSAPharmacokineticsAbsorptionoral is negligibleIV required therapy for systemic infecti
43、onsDistributionDistributes widely into body tissues and fluids,including adipose tissueVariable penetration into CSF,even with inflamed meningesEliminationPrimarily eliminated unchanged by the kidney Adverse EffectsRed-Man Syndrome Erythema multiforme-like reaction with intense pruritus,tachycardia,hypotension,rash involving face,neck,upper trunk,back and upper armsRelated to infusion rateResolves spontaneously after discontinuationLengthen infusion(over 2-3 hr)Hematological Neutropaenia Eosinophilia