利奈唑胺聯(lián)合磷霉素對腸球菌的體外藥動學-藥效學研究

利奈唑胺聯(lián)合磷霉素對腸球菌的體外藥動學-藥效學研究摘要

目的：本研究旨在探討利奈唑胺聯(lián)合磷霉素對腸球菌的體外藥動學/藥效學研究。

方法：采用體外微量滴定法測定不同濃度下該聯(lián)合用藥方案的最小抑菌濃度（MIC）、最小殺菌濃度（MBC）、藥效學時間曲線、細胞存活率曲線及脈沖藥理作用，觀察聯(lián)合用藥方案對腸球菌的合并抑菌效應。

結果：該聯(lián)合用藥方案的MIC50和MIC90分別為4mg/L和8mg/L，MBC50和MBC90分別為8mg/L和16mg/L，MBC50/MIC50和MBC90/MIC90分別為2和2，細菌的殺滅曲線和細胞存活率曲線均顯示出協(xié)同抑菌效應，聯(lián)合用藥方案的藥效學時間曲線呈現(xiàn)“突擊殺滅+持續(xù)抑制”模式，80%抑制時間（T-80）為8h。細胞脈沖藥理結果顯示：①利奈唑胺在細胞內半衰期為3.96h，藥代動力學參數(shù)為Cmax為60.52mg/L，tmax為2.5h，AUC0-24為378.74mg.L.h；②磷霉素在細胞內半衰期為4.98h，藥代動力學參數(shù)為Cmax為37.48mg/L，tmax為3h，AUC0-24為280.15mg.L.h。

結論：利奈唑胺與磷霉素聯(lián)合給藥對腸球菌具有較好的體外協(xié)同抑菌效應，該用藥方案呈現(xiàn)突擊殺滅和持續(xù)抑制模式，聯(lián)合用藥方案安全可靠。

關鍵詞：利奈唑胺、磷霉素、腸球菌、體外藥動學/藥效學、抑菌效應。

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