High Protein Binding and Cidal Activity against Penicillin-Resistant S. pneumoniae A Cefditoren In Vitro Pharmacodynamic Simulation 英文参考文献.docVIP

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High Protein Binding and Cidal Activity against Penicillin-Resistant S. pneumoniae A Cefditoren In Vitro Pharmacodynamic Simulation 英文参考文献.doc

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High Protein Binding and Cidal Activity against Penicillin-Resistant S. pneumoniae A Cefditoren In Vitro Pharmacodynamic Simulation 英文参考文献

HighProteinBindingandCidalActivityagainst Penicillin-ResistantS.pneumoniae:ACefditorenInVitro PharmacodynamicSimulation DavidSevillano1,LorenzoAguilar1*,LuisAlou1,Mar?′a-Jose′ Gime′nez1,NataliaGonza′lez1 ,Martha Torrico1,FabioCafini1,Asuncio′nFenoll2,PilarCoronel3,Jose′ Prieto1 1Microbiology Department, School of Medicine, Universidad Complutense, Madrid, Spain, 2Spanish National Reference Pneumococcal Laboratory, Instituto de Salud CarlosIII,Madrid,Spain,3ScientificDepartment,Tedec-MeijiFarmaSA,Madrid,Spain Abstract Background:Althoughproteinbindingisareversiblephenomenon,itisassumedthatantibacterialactivityisexclusively exertedbythefree(unbound)fractionofantibiotics. Methodology/Principal Findings: Activity of cefditoren, a highly protein bound 3rd generation cephalosporin, over 24h afteranoral400mgcefditoren-pivoxilbidregimenwasstudiedagainstsixS.pneumoniaestrains(penicillin/cefditorenMICs; mg/ml): S1 (0.12/0.25), S2 (0.25/0.25), S3 and S4 (0.5/0.5), S5 (1/0.5) and S6 (4/0.5). A computerized pharmacodynamic simulation withmedia consisting in 75%human serum and25% broth (meanalbumin concentrations=4.8560.12g/dL) was performed. Protein binding was measured. The cumulative percentage of a 24h-period that drug concentrations exceededtheMICfortotal(T.MIC)andunboundconcentrations(fT.MIC),expressedaspercentageofthedosinginterval, weredetermined.Proteinbindingwas87.1%.Bactericidalactivity($99.9%initialinoculareduction)wasobtainedagainst strainsS1andS2at24h(T.MIC=77.6%,fT.MIC=23.7%).WithT.MICof61.6%(fT.MIC=1.7%),reductionsagainstS3 and S4 ranged from 90% to 97% at 12h and 24h; against S5, reduction was 45.1% at 12h and up to 85.0% at 24h; and against S6, reduction was 91.8% at 12h, but due to regrowth of 52.9% at 24h. Cefditoren physiological concentrations exertedantibacterialactivityagainststrainsexhibitingMICsof0.25and0.5mg/mlunderproteinbindingconditionssimilar tothoseinhumans. Conclusions/Significance:Theresultsofthisstudysuggestthat,fromthepharmacodynamicpe