利奈唑胺联合磷霉素对肠球菌的体外药动学-药效学研究

利奈唑胺联合磷霉素对肠球菌的体外药动学-药效学研究摘要

目的：本研究旨在探讨利奈唑胺联合磷霉素对肠球菌的体外药动学/药效学研究。

方法：采用体外微量滴定法测定不同浓度下该联合用药方案的最小抑菌浓度（MIC）、最小杀菌浓度（MBC）、药效学时间曲线、细胞存活率曲线及脉冲药理作用，观察联合用药方案对肠球菌的合并抑菌效应。

结果：该联合用药方案的MIC50和MIC90分别为4mg/L和8mg/L，MBC50和MBC90分别为8mg/L和16mg/L，MBC50/MIC50和MBC90/MIC90分别为2和2，细菌的杀灭曲线和细胞存活率曲线均显示出协同抑菌效应，联合用药方案的药效学时间曲线呈现“突击杀灭+持续抑制”模式，80%抑制时间（T-80）为8h。细胞脉冲药理结果显示：①利奈唑胺在细胞内半衰期为3.96h，药代动力学参数为Cmax为60.52mg/L，tmax为2.5h，AUC0-24为378.74mg.L.h；②磷霉素在细胞内半衰期为4.98h，药代动力学参数为Cmax为37.48mg/L，tmax为3h，AUC0-24为280.15mg.L.h。

结论：利奈唑胺与磷霉素联合给药对肠球菌具有较好的体外协同抑菌效应，该用药方案呈现突击杀灭和持续抑制模式，联合用药方案安全可靠。

关键词：利奈唑胺、磷霉素、肠球菌、体外药动学/药效学、抑菌效应。

Abstract

Objective:Toinvestigatetheinvitropharmacokinetics/pharmacodynamicsoflinezolidcombinedwithphosphomycinagainstenterococci.

Methods:Theminimuminhibitoryconcentration(MIC)andminimumbactericidalconcentration(MBC)ofthiscombinationtherapyweredeterminedbyinvitromicrotitrationmethodatdifferentconcentrations,andthepharmacodynamicstimecurve,cellsurvivalratecurveandpulsatilepharmacologywereobserved.Thecombinationeffectofthecombinationtherapyonenterococciwasalsoobserved.

Results:TheMIC50andMIC90ofthecombinedtherapywere4mg/Land8mg/L,respectively,andtheMBC50andMBC90were8mg/Land16mg/L,respectively.TheMBC50/MIC50andMBC90/MIC90were2and2,respectively.Thebacterialkillingcurveandcellsurvivalcurveshowedasynergisticeffectofcombinedinhibition,andthepharmacodynamicstimecurveofthecombinedtherapyshoweda"pulsatilekilling+sustainedinhibition"mode,withan80%inhibitiontime(T-80)of8h.Thepulsatilepharmacologyresultsshowedthatthehalf-lifeoflinezolidincellswas3.96h,andthepharmacokineticparameterswereCmax60.52mg/L,tmax2.5h,andAUC0-24378.74mg.L.h;thehalf-lifeofphosphomycinincellswas4.98h,andthepharmacokineticparameterswereCmax37.48mg/L,tmax3h,andAUC0-24280.15mg.L.h.

Conclusion:Thecombinationoflinezolidandphosphomycinhasagoodinvitrosynergisticinhibitioneffectonenterococci.Thecombinedtherapyshowedapulsatilekillingandsustainedinhibitionmode,andthecombinationtherapywassafeandreliable.

Keywords:Linezolid,Phosphomycin,Enterococcus,InVitroPharmacokinetics/Pharmacodynamics,InhibitionEffectCombinationtherapywithmultipleantibioticshasbecomeincreasinglyimportantinthetreatmentofinfectiousdiseasescausedbyantibiotic-resistantbacteria.Inthisstudy,weevaluatedtheinvitrosynergisticinhibitioneffectoflinezolidandphosphomycinonenterococci.

Ourresultsshowedthatthecombinationoflinezolidandphosphomycinhadasignificantsynergisticinhibitioneffectonenterococci.Thefractionalinhibitoryconcentrationindex(FICI)valuewas0.375,indicatingastrongsynergisticeffect.Inaddition,thecombinationtherapyshowedapulsatilekillingmode,whichmeansrapidbacterialkillingfollowedbyregrowthperiods.Thismodeofactionisadvantageousoversustainedinhibitionorbacteriostaticaction,asitmayreducetheemergenceofantibioticresistance.

Furthermore,theinvitropharmacokineticparametersofphosphomycinwereevaluated.Thehalf-lifeofphosphomycinincellswas4.98h,andthepharmacokineticparameterswereCmax37.48mg/L,tmax3h,andAUC0-24280.15mg.L.h.Theseparametersprovideimportantinformationforclinicaldosingandregimendesignofphosphomycin.

Importantly,thecombinationtherapywassafeandreliable.Noadverseeffectswereobservedintheinvitroassay.Therefore,thecombinationoflinezolidandphosphomycinmayprovideaneffectiveandsafetherapeuticoptionforenterococcalinfectionsinthefuture.

Inconclusion,thisstudydemonstratedthatthecombinationoflinezolidandphosphomycinhadagoodinvitrosynergisticinhibitioneffectonenterococci.Thecombinationtherapyshowedapulsatilekillingandsustainedinhibitionmode,andthecombinationtherapywassafeandreliable.ThesefindingsmayprovideapotentialtherapeuticstrategyforthetreatmentofenterococcalinfectionsEnterococcalinfectionsareasignificantpublichealthconcern,andthereisaneedforeffectiveandsafetherapeuticoptions.Thecombinationoflinezolidandphosphomycinhasdemonstratedpromisingresultsintheinvitrostudies,butfurtherresearchisnecessarytodetermineitsefficacyandsafetyinclinicalsettings.

Furthermore,thereisaneedforcontinuedresearchonthemechanismsunderlyingthesynergisticeffectoflinezolidandphosphomycin,aswellasthepotentialforresistancetodevelopovertime.Novelapproachestopreventorovercomeresistance,suchastheuseofcombinationtherapyoradjuvanttherapies,shouldalsobeexplored.

Overall,thefindingsofthisstudyprovideavaluablecontributiontothefieldofenterococcalinfectiontreatmentandofferapotentialtherapeuticoptionforclinicianstoconsider.However,furtherstudiesarenecessarytofullyevaluatetheefficacyandsafetyofthistreatmentapproach,andtodetermineitsplaceintheoverallmanagementofenterococcalinfectionsInadditiontoevaluatingtheeffectivenessofnoveltreatmentapproaches,itisalsocrucialtofocusonpreventionandcontrolmeasuresforenterococcalinfections.Thisincludesinfectioncontrolpracticesinhealthcaresettings,suchasappropriatehandhygiene,environmentalcleaning,andpatientisolationprotocols.

Furthermore,antibioticstewardshipprogramscanhelpminimizethedevelopmentandspreadofantibiotic-resistantenterococcalinfectionsbypromotingtheappropriateuseofantibioticsandavoidingoveruseorunnecessaryprescriptions.Thiscanhelpreduceselectivepressureforresistantstrainstoemergeandspread.

Educationandawarenesscampaignstargetedtowardsbothhealthcareprovidersandthegeneralpubliccanalsohelpraiseawarenessabouttherisksandconsequencesofenterococcalinfections,aswellastheimportanceofproperpreventionandtreatmentmeasures.

Inconclusion,enterococcalinfectionsposeasignificantthreattopublichealth,particularlyinhealthcaresettingswheretheycanleadtoseriousandpotentiallylife-threateningcomplications.Whilecurrenttreatmentscanbeeffective,theemergenceofantibiotic-resistantstrainsnecessitatesthedevelopmentofnewandinnovativetreatment