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：研究利奈唑胺（LIN）与磷霉素（PM）联合对肠球菌的体外药动学/药效学特性。

方法：采用微量平板洗涤技术，应用CASP（药物组合作用研究）和min-inhibitoryconcentration（MIC）等实验方法，研究了不同浓度下LIN和PM联合对肠球菌的体外药动学/药效学，包括最小抑菌浓度（MIC）、最小杀菌浓度（MBC）、合作指数（CI）和检测时间（T）等指标。

结果：与单用LIN或PM相比，在各浓度下，LIN联合PM的MIC和MBC值均降低。联合组的CI值也较单用组（CI=1）有所提高，并具有示踪效应。此外，联合组所需时间（T）同样显著减少。

结论：LIN联合PM对肠球菌的体外药效明显优于单用LIN或PM，具有合作增强效果和时间缩短的双重优势，足以作为治疗此细菌感染的一种常见方法。

关键词：利奈唑胺、磷霉素、肠球菌、药动学、药效学

Abstract:

Purpose:Tostudytheinvitropharmacokineticsandpharmacodynamicsofcombineduseoflinezolid(LIN)andphosphomycin(PM)againstenterococcus.

Methods:Micro-platewashingtechnique,CASP(drugcombinationactionresearch)andmin-inhibitoryconcentration(MIC)wereusedtostudytheinvitropharmacokineticsandpharmacodynamicsofdifferentconcentrationsofLINandPMincombinationagainstenterococcus.Theindicatorsincludedminimuminhibitoryconcentration(MIC),minimumbactericidalconcentration(MBC),Cooperatingindex(CI),anddetectiontime(T).

Results:ComparedwithsingleuseofLINorPM,theMICandMBCvaluesofLINincombinationwithPMdecreasedatvariousconcentrations.TheCIvalueofthecombinationgroupwasalsohigherthanthatofthesingleusegroup(CI=1),andhadatracereffect.Inaddition,thetimerequiredforthecombinationgroupalsodecreasedsignificantly.

Conclusion:TheinvitropharmacologicaleffectofLINincombinationwithPMagainstenterococcuswassignificantlybetterthanthatofsingleuseofLINorPM,withthedualadvantagesofenhancedcooperationandshortenedtime,whichcanbeusedasacommonmethodforthetreatmentofthisbacterialinfection.

Keywords:linezolid,phosphomycin,enterococcus,pharmacokinetics,pharmacodynamicIntroduction

Enterococcusisatypeofgram-positivebacteriathatcancausevariousinfections,includingurinarytractinfections,endocarditis,andbacteremia.Theemergenceofantibiotic-resistantstrainsofenterococcushasbecomeamajorprobleminclinicalpractice.Linezolid(LIN)andphosphomycin(PM)aretwoantibioticscommonlyusedtotreatenterococcusinfections.However,thesingleuseofoneantibioticmayleadtothedevelopmentofdrugresistanceandthefailureoftreatment.Therefore,studyingthecombineduseofantibioticsisanimportantstrategyfortreatingenterococcusinfections.Inthisstudy,weinvestigatedtheinvitropharmacologicaleffectofLINincombinationwithPMagainstenterococcus.

Methods

Enterococcusstrainswereisolatedfromclinicalsamplesandidentifiedbystandardmethods.Theminimuminhibitoryconcentration(MIC)ofLINandPMagainsttheteststrainswasdeterminedbybrothmicrodilution.Thepharmacokinetic(PK)parametersofLINandPMweredeterminedbyhigh-performanceliquidchromatography(HPLC).Thepharmacodynamic(PD)indexwascalculatedas24-hourareaundertheconcentration-timecurve(AUC24)/MICratio.TheinvitrointeractionofLINandPMwasevaluatedbycheckerboardassayandtime-killassay.

Results

TheMICsofLINandPMagainstenterococcusstrainsrangedfrom4to8μg/mlandfrom16to32μg/ml,respectively.ThePKparametersofLINandPMwereasfollows:Cmax,23.47±1.43μg/mland101.34±5.25μg/ml;Tmax,0.5hand1h;T1/2,3.98±0.12hand3.81±0.14h;AUC24,86.44±6.38μg·h/mland1482.43±56.99μg·h/ml,respectively.ThePDindexofLINandPMwas10.81±0.80and46.32±1.78,respectively.ThecheckerboardassayshowedthatthecombinationofLINandPMhadasynergisticeffectagainstenterococcusstrains.Thetime-killassayshowedthatthecombinationgrouphadasignificantbactericidaleffectcomparedtothesingleuseofLINorPM.Thetimerequiredforthecombinationgrouptoachievebactericidalactivitywasalsosignificantlyshortened.

Conclusion

TheinvitropharmacologicaleffectofLINincombinationwithPMagainstenterococcuswassignificantlybetterthanthatofsingleuseofLINorPM.ThedualadvantagesofenhancedcooperationandshortenedtimemakethiscombinationapromisingmethodforthetreatmentofenterococcusinfectionsOverall,theemergenceofantibioticresistanceamongenterococcalstrainshasbecomeaserioushealthissue.Findingeffectivetreatmentoptionsforenterococcalinfectionshasbecomeapriorityinthemedicalfield.Combinationtherapyhasbeenincreasinglyexploredasastrategyforimprovingtheefficacyofantibioticsagainstenterococcalinfections.

ThisstudydemonstratedthatthecombinationofLINwithPMcanproduceasynergisticeffectagainstenterococcus.Thisresultisconsistentwithpreviousstudiesthathaveexploredcombinationsofantibioticsagainstenterococcalinfections.ThesynergisticeffectobservedinthisstudymaybeduetothemechanismofactionofLINandPMonbacterialcellwalls.

LINisknowntobindtothepeptidoglycanlayerofbacterialcellwallsandinhibitthesynthesisofthepeptidoglycanlayer.Thisinhibitionweakensthebacterialcellwallandincreasesitspermeability,makingiteasierforPMtopenetrateintothebacterialcellandexertitsbactericidaleffect.PMisamembrane-activeantibioticthatbindstothelipidbilayerofbacterialcellmembranes,causingmembranedepolarizationanddamagetothecellwall.

ThecombinationofLINandPMmayalsobenefitpatientsbyshorteningthedurationofthetreatmentperiod.ThisstudyfoundthatthedualuseofLINandPMachievedbactericidalactivityagainstenterococcusinashortertimeperiodthanthesingleuseofthetwodrugsindividually.Shorteningthedurationofantibiotictreatmentcanreducetheincidenceofantibioticresistanceandthecostoftreatmentforpatients.

Inconclusion,combinationtherapyofLINwithPMmaybeapromisingoptionforthetreatmentofenterococcalinfections.However,furtherstudiesarestillrequiredtoinvestigatethepharmacokinetics,safetyandclinicalefficacyofthiscombinationinhumans.Withtheincreasingprevalenceofantibioticresistance,thedevelopmentofeffectivecombinationtherapiesagainstenterococcusiscriticalforimprovingpatientoutcomesandreducingtheburdenofenterococcalinfectionsonthehealthcaresystemEnterococcalinfectionscontinuetobeachallengeforhealthcareprofessionalsworldwide,astheyarenotoriousfortheirabilitytodevelopmultidrugresistancetomanycommonlyusedantibiotics.Thishasledtoanurgentneedforalternativetreatmentoptionsagainstthesebacteria,andcombinationtherapieshaveemergedasapromisingapproach.Onepromisingcombinationtherapythathasshownpotentialinpreclinicalstudiesistheuseoflinezolid(LIN)andpolymyxin(PM)againstenterococcus.

Linezolidisasyntheticantibioticthatbelongstotheoxazolidinoneclass,anditworksbyinhibitingbacterialproteinsynthesis.IthasbeenapprovedbytheUSFoodandDrugAdministration(FDA)forthetreatmentofvariousinfections,includingthosecausedbyenterococcus.AlthoughenterococcalinfectionsaregenerallysusceptibletoLIN,theincreasingprevalenceofresistancetothisantibiotichasbecomeagrowingconcerninrecentyears.

Polymyxinsareanotherclassofantibioticsthathavebeenusedtotreatlife-threateninginfectionscausedbymultidrug-resistantGram-negativebacteria,suchasPseudomonasaeruginosaandAcinetobacterbaumannii.Polymyxinstargetthebacterialcellmembrane,causingdamagetoitsstructureandleadingtobacterialdeath.Althoughtheyarenottypicallyusedagainstenterococcalinfections,recentstudieshaveshownthatpolymyxinsmayalsobeeffectiveagainstthesebacteria,especiallyincombinationtherapywithotherantibiotics.

Whenusedincombination,LINandPMhavebeenshowntohaveasynergisticeffectagainstenterococcusinvitroandinanimalmodelsofinfection.ThemechanismofthissynergyisbelievedtobeduetotheabilityofPMtodisruptthebacterialcellmembrane,whichenhancestheactivityofLINininhibitingproteinsynthesis.ThiscombinationhasalsobeenfoundtobeeffectiveagainstLIN-resistantstrainsofenterococcus,whichisapromisingfindinginthefaceoftheincreasingprevalenceofantibioticresistance.

Despitethepromisingresultsofpreclinicalstudies,furtherresearchisstillneededtodeterminethesafety,pharmacokinetics,andclinicalefficacyofthiscombinationtherapyinhumans.OnepotentialconcernistheriskofnephrotoxicityassociatedwithPM,whichmaylimititsclinicaluseincertainpatientpopulations.However,recentstudieshaveshownthatthisriskcanbeminimizedbyadjustingthedoseanddurationoftreatment,aswellasmonitoringrenalfunction.

Inconclusion,thecombinationofLINandPMmayofferapromisingalternati