多粘菌素重新出现的抗多药耐药革兰阴性细菌的抗生素.docx

多粘菌素重新出现的抗多药耐药革兰阴性细菌的抗生素.docx

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多粘菌素重新出现的抗多药耐药革兰阴性细菌的抗生素

LancetInfectDis. 2006Sep;6（9）:

589-601.

Colistin:

there-emergingantibioticformultidrug-resistantGram-negativebacterialinfections.

LiJ1, NationRL, TurnidgeJD, MilneRW, CoulthardK, RaynerCR, PatersonDL.

Authorinformation

Abstract

IncreasingmultidrugresistanceinGram-negativebacteria,inparticularPseudomonasaeruginosa,Acinetobacterbaumannii,andKlebsiella pneumoniae,presentsacriticalproblem.Limitedtherapeuticoptionshaveforcedinfectiousdiseasecliniciansandmicrobiologiststoreappraisetheclinicalapplicationof colistin,apolymyxinantibioticdiscoveredmorethan50yearsago.Wesummariserecentprogressinunderstandingthecomplexchemistry,pharmacokinetics,andpharmacodynamicsof colistin,theinterplaybetweenthesethreeaspects,andtheireffectontheclinicaluseofthisimportantantibiotic.Recentclinicalfindingsarereviewed,focusingonevaluationofefficacy,emergingresistance,potentialtoxicities,andcombination therapy.Inthebattleagainstrapidlyemergingbacterialresistancewecannolongerrelyentirelyonthediscoveryofnewantibiotics;wemustalsopursuerationalapproachestotheuseofolderantibioticssuchas colistin.

Introduction

Oneofthegreatestaccomplishmentsofmodernmedicinehasbeenthedevelopmentofantibioticsforthetreatmentofpotentiallyfatalinfections.However,thishasinevitablybeenfollowedbytheacquisitionofresistancetowardstheirantimicrobialactivity.Unfortunately,thepasttwodecadeshaveseenamarkeddeclineinthediscoveryanddevelopmentofnovelantibioticsandaremarkableincreaseinresistancetothosecurrentlyavailable.1Inparticular,thereissubstantialconcernworldwidewiththemountingprevalenceofinfectionscausedbymultidrug-resistantGram-negativebacteria,inparticularPseudomonasaeruginosa,Acinetobacterbaumannii,andKlebsiellapneumoniae;forthesespecies,polymyxinsaresometimestheonlyavailableactiveantibiotics.2–8SincetherehavebeennopromisingnewchemicalentitiesforGram-negativeinfectionsinthedrugdevelopmentpipeline,1,4,5cliniciansandmicrobiologistshavebeenforcedtoreappraisetheclinicalvalueofcolistin,arelativelyoldpolymyxinantibiotic.Incriticallyillpatientswithsuchinfections,colistin（polymyxinE）isincreasinglybeingusedassalvagetherapy.2,4,7AlthoughthenovelagenttigecyclinehassignificantactivityagainstmultidrugresistantAbaumannii,9itisnotactiveagainstPaeruginosaduetoeffluxbyMexXY-OprM.10

Colistinisamulticomponentpolypeptideantibiotic,comprisedmainlyofcolistinAandB,thatbecameavailableforclinicaluseinthe1960s,butwasreplacedinthe1970sbyantibioticsconsideredlesstoxic.2,7,11Therearetwoformsofcolistincommerciallyavailable:

colistinsulfatefororalandtopicaluse,andcolistimethatesodium（sodiumcolistinmethanesulphonate,colistinsulfomethatesodium）forparenteraluse（figure1）;bothcanbedeliveredbyinhalation.Althoughtherehavebeenasubstantialnumberofclinicalreportsonthesuccessfuluseofcolistin6,12–24orpolymyxinB25–27（whichdiffersbyonlyoneaminoacidfromcolistin）againstinfectionscausedbymultidrug-resistantPaeruginosa,Abaumannii,andKpneumoniae,thereisadearthofinformationontheclinicalpharmacokinetics,pharmacodynamics,andtoxicodynamicsofcolistin;suchdataareessentialforestablishingoptimaldoseregimens.2Asaspecificexample,therearenodosingregimenslistedintheproductinformationforthedrugappropriateforcriticallyillpatientsrequiringhaemodialysisorcontinuousrenalreplacementtherapy.28–30Mostknowledgeonthepharmacokineticsofcolistinwasobtainedatleasttwodecadesagowhennon-specificmicrobiologicalassayswereusedtomeasuretheconcentrationsof“colistin”inbiologicalfluids.2

Becauseitisapproximately50yearssinceitsdiscoveryandintroductionintoclinicaluse,colistinwasneversubjectedtothedrugdevelopmentprocessesrequiredforcompliancewithcontemporaryregulatoryrequirements.Asaresult,thepharmacokineticandpharmacodynamicinformationrequiredtounderpinprescribingrecommendationsintheproductinformationislacking.Thisreviewwillfocusonthepharmacologyofcolistinandnewclinicalfindingsfromthepast10yearsthatreflectrenewedinterestinitsuse.Thescarceandheterogeneousdataontheuseofcolistinintheliteraturepreventsthequantitativesynthesisoftheimpactofthistreatment.Forthemechanismsofactivityandresistance,spectrumofactivityandanti-endotoxineffectofcolistin,pleaserefertoourrecentreview.2

Pharmacology

Chemistry—importantdifferencesbetweenchemicalentities

Althoughwidelyusedintheliterature,thetermscolistinandcolistimethatearenotinterchangeable.2,31–34Colistin（usuallyusedasthesulphatesalt）isapolycation,whereascolistimethate（usedasthesodiumsalt）isapolyanionatphysiologicalpH（figure1）.Colistimethateispreparedfromcolistinbyreactionofthefreeγ-aminogroupsofthefiveα,γ-diaminobutyricacidresidueswithformaldehydefollowedbysodiumbisulphite.35

Colistimethateisnotstableinvitro32orinvivo,31,33andishydrolysedtoaseriesofmethanesulphonatedderivativespluscolistin.Colistinismorestablethancolistimethateinhumanplasma.32Thedifferencesinchemistrybetweencolistimethateandcolistinalsotranslateintodifferencesinpharmacokineticsandpharmacodynamics.Whereascolistimethateiseliminatedmainlybythekidneyandtheurinaryexcretioninvolvesrenaltubularsecretion,colistiniseliminatedpredominantlybythenon-renalroutebecause,atleastinpart,thecompoundundergoesveryextensiverenaltubularreabsorption.33,36Afterintravenousadministrationofcolistimethate（sodium）,theplasmahalf-livesofcolistimethateareapproximatelyhalfofthoseofthecolistingeneratedfromitinvivoinbothrats（23・6[SD3・9]minvs55・7[19・3]min）33andpatientswithcysticfibrosis（124[52]minvs251[79]min）.31WithrespecttoantibacterialactivityagainstPaeruginosa,recentstudieshaveindicatedthatcolistimethateisanon-activeprodrugofcolistin.37Arecentreviewprovidesmoredetailsontheconsiderabledifferencesbetweencolistimethateandcolistinintheirchemistry,pharmacokinetics,andpharmacodynamics.2Giventhesedifferences,werecommendthattheformulationsofcolistinshouldbefullydescribedinallfuturereports,particularlyclinicalstudies,aseithercolistinsulfateorcolistimethatesodium,toavoidanyconfusionininterpretationofstudieswithoneorbothsubstances.

Inconsistentdoseregimensoftwomajorcolistimethate（sodium）products

Colistimethatesodiumisadministeredparenterallysinceitislesstoxicthancolistinsulfate.35ThetwomostcommoncommerciallyavailableparenteralformulationsofcolistimethatesodiumareColomycin（Dumex-AlpharmaA/S,Copenhagen,Denmark）andColy-MycinMParenteral（ParkedalePharmaceuticals,Rochester,USA;table1）.Thevialsofbothformulationscontaincolistimethatesodiumdrypowderforreconstitutionbeforeadministration.Unfortunately,thetwoproductsarelabelleddifferentlywithrespecttocontent.Colomycinislabelledininternationalunits（IU;500000IU,1millionIU,and2millionIUpervial）;30sincethereareapproximately12500unitspermilligramofcolistimethatesodium,38thereare40,80,and160mgofcolistimethatesodiumineachvialsize,respectively.30Therecommendeddoseforthisproductforapatientover60kgandwithnormalrenalfunctionis1–2millionIUthreetimesdaily,equivalentto240–480mgcolistimethatesodiumperday.Bycontrast,Coly-MycinMParenteralislabelledascontaining“150mgcolistinbaseactivitypervial”.28,29Actually,eachvialcontainsapproximately400mgcolistimethatesodium,whichisequivalenttoabout5millionIU.Therecommendeddosesforthisproductare2・5–5mg/kgcolistinbaseactivityperdayintwotofourdivideddoses;whichisequivalenttoabout6・67–13・3mg/kgofcolistimethatesodiumperday.28,29Hence,forapatientwithnormalrenalfunctionandbodyweightof60kg,therecommendeddailydoseofColy-Mycin（400–800mg）isalmostdoublethatofColomycin（240–480mg）.Unfortunately,despitethefactthatthisdifferencehasimportantimplicationsfortherapeuticdoses,itseemstohavebeenignoredinpublishedworks,andbrandorproducttypeisoftennotspecified.Tofurtherconfusematters,thereareseveralotherbrandsofcolistimethatesodiumdescribedinsomerecentclinicalreports（Bellon,France;39Norma,Greece;40LaboratoryBristol-MyersSquibb,Argentina13）;however,beinggenericproducts,itisverydifficulttoobtaintheirproductinformation.

Consideringthatcolistinisoneofthefewandmostimportantantibioticsagainstmultidrug-resistantGram-negativebacteria,itiscrucialthatoptimaldoseregimensbeusedtomaximiseefficacyandminimisethedevelopmentofresistance.2Acceptablesafetywasdemonstratedwith6–9mg/kgofcolistimethatesodiumperday（dividedintotwotothreedoses）ofColomycin41–44and2・5–5mg/kgperdaycolistinbaseactivitywithColy-Mycin,45thelattercorrespondingtoanactualdailydoseof6・67–13・3mgcolistimethatesodiumperkgperday.Therecommendedupperdailydoseforthetwoproducts（480mgcolistimethatesodiumperdayand800mgcolistimethatesodiumperdayforColomycinandColy-Mycin,respectively;table1）differsubstantially.Therefore,itispossiblethatthereispotential“under-dosing”whenColomycinisused.

Clearly,withthemultiplicityoftermsusedtoexpresscontentofvialsanddoseinformation,thereismajorpotentialtocreateconfusioninthemindsofclinicianswishingto