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1、The Beta-Lactam AntibioticslCell wall active agentsPrevent the final step in the synthesis of the bacterial cell walllRange from very narrow spectrum to very broad spectrum-Lactams-lactam ringHow do they work?1.The-lactam binds to Penicillin Binding Protein(PBP)2.PBP is unable to crosslink peptidogl
2、ycan chains3.The bacteria is unable to synthesize a stable cell wall4.The bacteria is lysed“Penicillin binding protein”Peptidoglycan Synthesis“Time Dependant”H Derendorf“Time Dependant”WA CraigSo many choices which one to pick?lWhat is the likely organism?lWhats its major mode of resistance?lWheres
3、the infection?lWhats my local environment?the UNC Hospital antibiogramlWhat does the micro lab say?in vitro sensitivity testingClassificationlCephalosporins1st GenerationlCephalexin,Cefazolin2nd GenerationlCefoxitin,Cefuroxime,Cefotetan3rd GenerationlCefotaxime,Ceftriaxone,Ceftazidime4th Generationl
4、CefepimePenicillin GlAvailable PO,IM,IV(dosed in units)lDrug of Choice(DoC)2-4 MU IV q4hT.pallidum,N.meningitidis,Group A Strep,and ActinomycosislLong-acting formsProcaine PenG(12 hrs)Benzathine Pen(5 days)2.4 MU IM for syphilislAdverse Reactions other than skin rashPenicillin“serum sickness”/drug f
5、everJarisch-Herxheimer reaction(1 and 2 syphilis)Hemolytic anemia,pancytopenia,neutropeniaOxacillinlIVlDoC MSSA,MSSE 2g IV q4hActually less active against Pen susceptible isolates than PenMore active than Vanc vs.MSSAlSignificant hepatic metabolismNo need to dose adjust for renal impairmentlADRsHepa
6、totoxicity(cholestatic hepatitis)NeutropeniaKernicterus in neonatesPiperacillinlIVlDoC:PseudomonaslSpectrum:most Enterobacteriaceae(E.coli,Proteus,Klebsiella,Enterbacter,Serratia,Citrobacter,Salmonella and Shigella)lMost active penicillin vs.PseudomonaslOften used in combination with Aminoglycoside
7、or Cipro/LevofloxacinlADRsBleeding(platelet dysfunction)Neutropenia/Thrombocytopenia-Lactamase InhibitorslHow do you evade a-lactamase?1.Use a non-lactam agent2.Steric InhibitionPenicillins with large side chainsCephalosporins3.-lactam+-lactamase inhibitorsNot all-lactamases are inhibitable(!)Sulbac
8、tamlUnasyn(Amp/Sulbactam)lSpectrum:Amp+most anaerobes+many enteric Gm(-)rods,OSSAlDoC:for GNR mixed infection E.coli,Proteus,anaerobes when Pseudomonas is not implicatedDiabetic foot(once Pseudomonas ruled out)Wound infectionslSulbactam alone is very active against Acinetobacter spp.TazobactamlZosyn
9、(Pip/Tazo)lTHE most broad-spectrum penicillinlTazobactam may improve the activity of piperacillin vs.gram-negative rods,including anaerobesl4.5g IV q8h=3.375g IV q6hl4.5g IV q6h for PseudomonasThe Cephalosporins(generalized)1st GenerationGram(+)2nd GenerationDecreasing Gram(+)and Increasing Gram(-)3
10、rd GenerationGram(-),but also some GPC4th GenerationGram(+)and Gram(-)*Not effective vs.Enterococcus or ListeriaCephalexin/CefazolinlPO/IVlStable vs Staph penicillinaselSpectrum:MSSA,PSSP,most E.coli,and some KlebslCan be dose thrice weekly in HD pts1.5 grams IV TIWlDoC:surgical prophylaxis,bacteria
11、l peritonitis in CAPD pts 1 gm in the dwell baglADRsPositive Coombs test(though,hemolytic anemia is rare)CefuroximelIV/POlExtensive use in pediatricslSpectrum:Strep pneumo,Viridans Strep,most H.flu,N.meningitidislDoC:uncomplicated CAP(esp.H.flu),UTI/pyeloCeftriaxonelIVlOnce daily dosing(95%protein b
12、ound=long half-life)lSpectrum:Strep.pneumoniae,most Enterbacteriaceae,lExcretion:50%urine,50%bile=no need to adjust for renal insufficiencylCSF penetration:5-15%in meningitis,1.5%with out inflammationlDoC:bacterial meningitis,CAP,Strep.viridans endocarditis(+gent)lADRsCholestasisElevated bilirubin(d
13、isplacement)DiarrheaCeftazidimelIVlSpectrum:Enteric GNR(including Pseudomonas;some Acinetobacter)lNo anaerobic activity(same for cefotaxime and ceftriaxone)lDoC:Pseudomonas infxThird Generation Cephs:Issuesl-lactamase induction?ESBLsDe-repression of chromosomal-lactamaseslSelective pressure for VRE?
14、CarbapenemslImipenem,Meropenem,ErtapenemlBroad-spectrum coverage:Gram positive:PSSP,MSSA,VSEGram negative:most gram-negative organisms(Acinetobacter sp.,Pseudomonas sp.)lLack of coverage:Ertapenem:Pseudomonas sp.,Acinetobacter sp.All:Stenotrophomonas,Legionella sp.,MRSA,VRE CarbapenemslDistribution:
15、similar to penicillinslExcretion:renal clearancelAdverse reactions:Hypersensitivity:rash,urticaria,cross-reactivityImipenem:seizures(rare)lHigh doseslRenal dysfunctionlMost likely can occur with all carbapenems at high dosesMonobactamslMonobactams:AztreonamlSpectrum:ONLY Gram negative aerobic bacter
16、ia lLack of Coverage:Some resistant P.aeruginosa,E.cloacae,and C.freundii Acinetobacter sp.,Stenotrophomonas sp.lPharmacokinetics:Well distributed into tissues,esp.inflamed tissuesExcretion:renal clearancelAdverse reactions:Skin rash No cross-reactivity with Beta-Lactam classWhat about penicillin allergies?lLiterature reports a ceph/pen cross-reactivity of 1 10%lThe cross-reactivity of aztreonam/pen or ceph is essentially 0%lThe cross-reactivity of carbapenems/penicillins is also around 10%(similar to that of ceph/pen)lDecision making:Severity of reactionEos