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Cephalosporins

Author SectionEditor DeputyEditor

StephenBCalderwood,MD DavidCHooper,MD AllysonBloom,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Sep2015.|Thistopiclastupdated:Jan12,2015.
INTRODUCTIONBetalactamantibioticsareamongthemostcommonlyprescribeddrugs,grouped
togetherbaseduponasharedstructuralfeature,thebetalactamring.Cephalosporinscoverabroadrangeof
organisms,aregenerallywelltolerated,andareeasytoadministerthus,theseagentsarefrequentlyused
betalactamdrugs.

Theclassification,spectrumofactivity,andpharmacologyofthecephalosporinswillbereviewedhere.

Thespectrumofactivityofcephalosporinscombinedwithbetalactamaseinhibitorsarediscussedseparately.
(See"Combinationbetalactamaseinhibitors,carbapenems,andmonobactams".)

Themechanismsofactionandresistanceandmajoradversereactionsofthebetalactamantibiotics,andthe
penicillinsandotherbetalactamdrugsarealsodiscussedseparately.(See"Betalactamantibiotics:
Mechanismsofactionandresistanceandadverseeffects"and"Penicillins"and"Extendedspectrumbeta
lactamases".)

CLASSIFICATIONOFCEPHALOSPORINSCephalosporinsincludethecloselyrelatedcephamycin
compounds.Theparenteralagentsarecommonlyclassifiedintothefollowingcategories:

Firstgeneration(cefazolin)

Secondgeneration

A.SubgroupwithactivityagainstHaemophilusinfluenzae(cefuroxime)
B.CephamycinsubgroupwithactivityagainstBacteroidesspp(cefoxitinandcefotetan)

Thirdgeneration

A.SubgroupwithbroadgramnegativeactivitybutpooractivityagainstPseudomonasaeruginosa
(cefotaxime,ceftriaxone,andceftizoxime)
B.SubgroupwithbroadgramnegativeactivityincludinggoodactivityagainstPseudomonasaeruginosa
(ceftazidime)

Fourthgeneration(cefepime)

Fifthgeneration(ceftaroline)

SPECTRUMOFACTIVITYANDCLINICALUSEMostoftheavailablecephalosporinsaresemisynthetic
derivativesofcephalosporinC,acompoundwithantibacterialactivityproducedbythefungusCephalosporium.
Thecloselyrelatedcephamycincompounds(derivedfromStreptomycesspp)areregardedasmembersofthe
cephalosporinclass.Inclinicalpractice,theseantibioticshavefrequentlybeengroupedintofive"generations"
basedupontheirspectrumofactivityagainstaerobicandfacultativegramnegativebacilliandgrampositive
bacteria.

Parenteralagents

FirstgenerationCephalothinistheoldestofthefirstgenerationcephalosporinsandwaspreviously
usedastheprototypeofthisgroup.Cephalothinwasactiveagainstmostgrampositivecocci(including
penicillinaseproducingstaphylococci),butdidnothaveclinicallyusefulactivityagainstenterococci,Listeria,
oxacillinresistantstaphylococci[1],orpenicillinresistantpneumococci[24].(See"Microbiologyofmethicillin
resistantStaphylococcusaureus"and"ResistanceofStreptococcuspneumoniaetobetalactamantibiotics".)

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CephalothinwasactiveagainstmoststrainsofEscherichiacoli,Proteusmirabilis,andKlebsiellapneumoniae,
buthadlittleactivityagainstindolepositiveProteus,Enterobacter,Serratia,andthenonentericgramnegative
bacillisuchasAcinetobactersppandPseudomonasaeruginosa.Gramnegativecocci(suchasthe
gonococcusandmeningococcus)andH.influenzaeweregenerallyresistant.Cephalothinwasactiveagainst
mostofthecommonanaerobicpathogens,withcertainexceptionssuchasBacteroidesspecies,particularlyB.
fragilis.

Cefazolinhasasimilarspectrumofactivitytocephalothin,isavailableworldwide,andisnowtheonly
parenteralfirstgenerationcephalosporinavailableintheUnitedStates.Cefazolinachievessubstantiallyhigher
serumlevelsthancephalothin,andhasalongerhalflifeofelimination.Cefazolinislessstablethan
cephalothininvitrotothetypeApenicillinaseofstaphylococci[5]therelevanceofthisforclinicaltherapy,
however,isnotcertain.

SecondgenerationThesecondgenerationcephalosporinsaresomewhatlessactiveagainstcertain
grampositivecoccithanthefirstgenerationagentsbutaremoreactiveagainstcertaingramnegativebacilli.
Thisgenerationofcompoundscanbedividedintotwosubgroups,onewithactivityagainstH.influenzaeand
theother,thecephamycins,withactivityagainstBacteroides.

ActivityagainstHaemophilusinfluenzaeInthefirstsubgroup,cefuroximeisavailableparenterally
andismoreactivethancefazolininvitroagainststrainsofEnterobacterandindolepositiveProteus.However,
thisagentinducesthechromosomalbetalactamasesoftheseorganisms,leadingtoresistanceandfailuresof
clinicaltherapy[6].(See"Betalactamantibiotics:Mechanismsofactionandresistanceandadverseeffects",
sectionon'Mechanismsofbacterialresistance'.)

CefuroximeisalsomoreactivethancefazolinagainstH.influenzae,andcefuroximeisquitestabletotheTEM
betalactamaseinampicillinresistantstrains.AlthoughcefuroximeisapprovedforthetherapyofH.influenzae
meningitis,delayedresponsesandtreatmentfailureshaveoccurred,andathirdgenerationcephalosporinis
nowpreferredfortherapyofmeningitisduetoampicillinresistantstrains[7].Cefuroximeisalsohighlyactive
againstbetalactamaseproducingMoraxellacatarrhalis.

Cephamycinsubgroup(activeagainstBacteroides)Thecephamycinsubgroupofthesecond
generationcephalosporinsincludescefoxitinandcefotetan.ThissubgroupisactiveagainstmoststrainsofE.
coli,P.mirabilis,andKlebsiella,likethefirstgenerationcephalosporins.Thecephamycinsarequitestableto
manyplasmidmediatedbetalactamases,buttheactivityofthisgroupagainstEnterobacterandindolepositive
Proteusislimitedbyinductionofchromosomalcephalosporinasesofthesespeciesandselectionofstably
derepressedmutants[6].

Unlikethefirstgenerationcephalosporins,thecephamycinsareactiveagainstmanystrainsofBacteroides.
ThecombinationofactivityagainstcommonaerobicandfacultativegramnegativebacilliplusBacteroideshas
ledtotheuseofthecephamycinsintheprophylaxisandtherapyofinfectionsintheabdominalandpelvic
cavities(wheretheseorganismspredominate)[8].Thecephamycinshavenoclearadvantagesoverthefirst
generationcephalosporinsforinfectionsoutsideoftheabdominalandpelvicareas.

Overallresistanceratestocephamycinsrangefrom10to80percentfordifferentmembersoftheBacteroides
fragilisgroup,comparedwith15to30percentforclindamycin,andessentiallynoresistanceforthe
carbapenems,chloramphenicol,ormetronidazole[9].

ThirdgenerationThethirdgenerationcephalosporinclass[10]ismarkedbystabilitytothecommon
betalactamasesofgramnegativebacilli,andthesecompoundsarehighlyactiveagainstEnterobacteriaceae
(E.coli,Proteusmirabilis,indolepositiveProteus,Klebsiella,Enterobacter,Serratia,Citrobacter),Neisseria,
andH.influenzae.Theyarethetherapyofchoiceforgramnegativemeningitisduetosusceptible
Enterobacteriaceae.Thirdgenerationcephalosporinsmayalsobeusefulalternativestotheaminoglycosidesin
treatinggramnegativeinfectionsresistanttootherbetalactams,particularlyinthepatientwithrenal
dysfunction.However,mutantsofEnterobacter,indolepositiveProteus,Serratia,andCitrobacter,withstable
derepressionofthechromosomalbetalactamase,areresistanttotheseantibiotics[6,11].Evenifthese
organisms(Enterobacter,indolepositiveProteus,Serratia,andCitrobacter)testsusceptibletocephalosporins,
useofathirdgenerationcephalosporinasasingleagentfortreatmentofseriousinfectionsduetothese
bacteriacanleadtotheemergenceofresistanceduringtherapy.
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Thethirdgenerationcephalosporinsarelessactiveagainstmostgrampositiveorganismsthanthefirst
generationcephalosporinsandareinactiveagainstenterococci,Listeria,oxacillinresistantstaphylococci,and
Acinetobacter.Cefotaximeandceftriaxoneareusuallyactiveagainstpneumococciwithintermediate
susceptibilitytopenicillin,butstrainsfullyresistanttopenicillinareoftenresistanttothethirdgeneration
cephalosporinsaswell.In1998,forexample,25percentofstrainsofS.pneumoniaeintheUnitedStateswere
intermediatelyorfullyresistanttopenicillin,and14percentwereresistanttothirdgenerationcephalosporins[2
4,1214].(See"ResistanceofStreptococcuspneumoniaetobetalactamantibiotics".)

Treatmentwiththirdgenerationcephalosporinsmaybecomplicatedbysuperinfection(particularlywith
enterococciorCandida)orbytheemergenceofresistanceontherapy(particularlywhenusedassingleagents
forEnterobacter,indolepositiveProteus,orP.aeruginosainfections)[15].

Thirdgenerationcephalosporinsarenotcurrentlyrecommendedforprophylacticuseinsurgery.

PooractivityagainstPseudomonasOnesubgroupofthethirdgenerationcephalosporins,including
cefotaximeandceftriaxone,haspooractivityagainstP.aeruginosa.Withinthissubgroup,cefotaximehasthe
shortestserumhalflife(1hour)becauseofpartialmetabolisminthelivertodesacetylcefotaxime.However,
thismetabolitealsohasantibacterialactivityandalongerhalflifeinserum(1.7hours),allowingdosingevery
sixhours.

Ceftriaxonehasthelongestserumhalflifeofthisgroup(6.4hours)andcanbeadministeredonceortwicea
day.Ceftriaxonehasbeenparticularlyrecommendedforthetherapyofpenicillinresistantgonorrhea,Lyme
diseaseinvolvingthecentralnervoussystemorjoints,meningitisduetoampicillinresistantH.influenzae,and
meningitisinchildren[7,16].Oneofthecomplicationsofceftriaxonetherapy,however,hasbeentheformation
inthebiliarytractof"sludge"composedofceftriaxonecrystals,causingthesyndromeofbiliarypseudolithiasis
[17].

ActivityagainstPseudomonasTheothersubgroupofthethirdgenerationcephalosporins,including
cefoperazoneandceftazidime,hasactivityagainstP.aeruginosa.Cefoperazonewasthefirstavailabledrugin
thissubgroup,butiscurrentlynotusedasoftenduetodecreasedstabilitytotheplasmidmediatedbeta
lactamasesofgramnegativebacillithatmakeitlessactiveagainstEnterobacteriaceaethantheotherthird
generationcephalosporins.Thenewermemberofthesubgroup,ceftazidime,isquitestabletothecommon
plasmidmediatedbetalactamasesandishighlyactiveagainstEnterobacteriaceae,Neisseria,andH.
influenzae.CeftazidimeisalsoparticularlyactiveagainstP.aeruginosaandisaneffectivetherapyforserious
infectionsduetoP.aeruginosawhentheorganismisresistanttotheantipseudomonalpenicillinsorthepatient
ispenicillinallergic.Inaddition,itiseffectivetherapyformeningitiscausedbyP.aeruginosa.Aswiththeanti
pseudomonalpenicillins,however,ceftazidimeshouldgenerallybegivenatleastinitiallyincombinationwithan
aminoglycosidefortreatmentofseriousP.aeruginosainfection.Ceftazidimehaspooractivityagainstgram
positiveorganismsandshouldbereservedforuseininfectionsprovenorhighlysuspectedtobeduetoP.
aeruginosa.

CefoperazonecontainsanNmethylthiotetrazole(NMTT)sidechain.ThisNMTTgroupcandissociatefromthe
parentantibioticinsolutionorinvivoandcompetitivelyinhibitvitaminKaction,leadingtoprolongationofthe
prothrombintimeandbleeding[18].Thissidechainisalsoassociatedwithadisulfiramlikereactiontoalcohol.

FourthgenerationCefepimeisthefourthgenerationcephalosporincurrentlyavailable.Ithasa
positivelychargedquaternaryammoniumattachedtothedihydrothiazonering,whichresultsinbetter
penetrationthroughtheoutermembraneofgramnegativebacteriaandaloweraffinitythanthethirdgeneration
cephalosporinsforcertainchromosomalbetalactamasesofgramnegativebacilli.

Cefepimehassimilaractivitytocefotaximeandceftriaxoneagainstpneumococci(includingpenicillin
intermediatestrains)andoxacillinsensitiveS.aureus.Liketheearlierthirdgenerationagents,itisactive
againsttheEnterobacteriaceae,Neisseria,andH.influenzaebuthasgreateractivityagainstthegramnegative
entericsthathaveabroadspectrum,inducible,chromosomalAmpCbetalactamase(Enterobacter,indole
positiveProteus,Citrobacter,andSerratia)[19].Theroleofcefepimeintherapyofinfectionsduetostably
derepressedmutantsoftheseorganismshasnotyetbeenfullydefined,butpreliminarydatasuggestthatit
maybeeffective[20,21].Inastudyof96patientswithinfectionsduetolaboratoryconfirmedAmpCbeta

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lactamaseproducingorganisms,96percentoftheisolatesweresusceptibletocefepime[20].Amongpatients
whoreceivedcefepime,the30daymortalityrateanddurationofhospitalizationweresimilartothoseobserved
inamatchedsubsetofpatientswhoreceivedmeropenem.

CefepimeisasactiveasceftazidimeforPseudomonasaeruginosa,andisactiveagainstsomeceftazidime
resistantisolates.Aswiththeantipseudomonalpenicillins,cefepimeshouldgenerallybegivenincombination
withanaminoglycosidefortreatmentofseriousP.aeruginosainfection.Therehasnotbeenenoughclinical
experiencewithcefepimeinmeningitistorecommenditsroutineuseforthispurpose.Itisalsonotcurrently
recommendedforprophylacticuseinsurgery.Acinetobacterisolatesarefrequentlyresistanttocefepime.

Despitethesepotentialadvantagesoverthirdgenerationcephalosporins,especiallyagainstorganismswith
inducible,chromosomalresistance,comparativetrialsofthirdandfourthgenerationcephalosporinshavenot
yetbeenperformed.

AreviewbytheUnitedStatesFoodandDrugAdministration(FDA)ofcefepimesafetydatawasinitiatedin
2007followingfindingsofametaanalysisthatraisedconcernregardingincreasedallcausemortality
associatedwithcefepimeuse(riskratio1.26,95%CI1.081.49)[22].TheFDAreviewedthesestudydata,
conductedadditionalanalysesbasedonotherdata,anddeterminedthatthedatadonotindicateahigherrate
ofdeathincefepimetreatedpatients[23].Cefepimeremainsanappropriatetherapyforitsapprovedindications
[24].

Treatmentwithcefepimemaybecomplicatedbysuperinfection(particularlywithenterococciorCandida)[15].
Cefepimeusealsocarriesariskofseizures(specificallynonconvulsivestatusepilepticus),particularlyin
patientswithrenalfailureforwhomthedoseisnotappropriatelyadjusteddownwards[25].(See"Betalactam
antibiotics:Mechanismsofactionandresistanceandadverseeffects",sectionon'Neurologicreactions'.)

FifthgenerationCeftarolineisafifthgenerationcephalosporinwhoseactivemetabolitehasaspectrum
ofinvitroactivitysimilartoceftriaxonebutwithimprovedgrampositiveactivity.Inparticular,ceftarolinehas
higheraffinityforPBP2ainoxacillinresistantstaphylococci,andhasactivityagainstMRSA,aswellas
vancomycinintermediateStaphylococcusaureus(VISA)andheteroVISA.Inaddition,ceftarolinehasactivity
forStreptococcuspneumoniaethatisintermediateorresistanttopenicillinorceftriaxone.Ceftarolineisnot
activeforenterococcinoragainstAmpCoverproducingorESBLproducingEnterobacteriaceae,Pseudomonas
aeruginosa,Acinetobacterbaumannii,orBacteroidesfragilis.Severalrandomized,doubleblindcontrolled
clinicaltrialshavesuggestedthatceftarolineisnoninferiortovancomycinplusaztreonamfortreatmentof
complicatedskinandsofttissueinfectionsincludingthoseduetoMRSA,andtoceftriaxonefortherapyof
communityacquiredpneumonia[2628].TheefficacyofthisantiMRSAcephalosporinisnotyetknownfor
hospitalacquiredMRSApneumoniaorforbacteremia.(See"Antibioticstudiesforthetreatmentofcommunity
acquiredpneumoniainadults",sectionon'Ceftarolineversusceftriaxone'and"Pharmacologyofantimicrobial
agentsfortreatmentofmethicillinresistantStaphylococcusaureusandvancomycinresistantenterococcus",
sectionon'Ceftaroline'.)

Ceftobiproleisaninvestigationalcephalosporinalsocapableofbindingtopenicillinbindingprotein2a,the
proteinconferringS.aureusresistancetobetalactamantibiotics[29].Itcanalsobindpenicillinbindingprotein
2xinpenicillinresistantS.pneumoniae.Ithasinvitroactivitysimilartothatofceftazidimeorcefepimeagainst
Enterobacteriaceaeitalsohasactivityagainstenterococci[30,31].Inaddition,ceftobiproleappearstohavea
lowpotentialforselectionofresistance[32].

ClinicaltrialdataontheseagentsforuseinMRSAinfectionsaredetailedseparately.(See"Treatmentof
invasivemethicillinresistantStaphylococcusaureusinfectionsinadults",sectionon'Ceftobiprole'and
"TreatmentofinvasivemethicillinresistantStaphylococcusaureusinfectionsinadults",sectionon
'Ceftaroline'.)

OralagentsCephalosporinsavailablefororaluseincludecephalexin,cefadroxil,cefaclor,cefuroximeaxetil,
cefprozil,cefixime,cefpodoximeproxetil,ceftibuten,cefdinir,andcefditoren.

Cefadroxilhasalongerserumhalflifethancephalexinandisgenerallygiveninadoseof500to1000mg
every12hours.Theoralcephalosporinsarepoorlyactiveagainstpenicillinresistantpneumococci[2].

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Theoralsecondgenerationcephalosporins,cefaclor,cefuroximeaxetil,andcefprozil,haveimprovedactivity
againstH.influenzaecomparedwiththefirstgenerationoralcephalosporinsandmaybeusefulintreating
otitis,sinusitis,andrespiratorytractinfections.

Theoralthirdgenerationcephalosporins,cefixime,cefpodoximeproxetil,ceftibuten,cefdinir,andcefditoren,
areactiveagainststreptococci,H.influenzae(includingbetalactamaseproducingstrains),andM.catarrhalis.
Theyaremoreactivethantheotheroralcephalosporinsagainstentericgramnegativebacilli,includingE.coli,
P.mirabilis,andKlebsiella.However,theyhavepooractivityagainstmoststrainsofEnterobacter,
Acinetobacter,P.aeruginosa,andtheanaerobes.Cefiximeandceftibutenhavelittleactivityagainst
staphylococci,butcefpodoximeproxetilandcefdinirhavemoreactivity.Ceftibutenisalsoonlyweaklyactive
againstpneumococci.Itsspectrumofactivityisotherwisesimilartothoseofcefdinirandcefpodoxime.

Theseantibioticsarerelativelystabletomanyplasmidmediatedbetalactamasesbutaremuchlessstableto
commonchromosomallymediatedcephalosporinases.Althoughtheseantibioticsarepromotedasoralthird
generationcephalosporins,theyarelessactiveagainsttheentericgramnegativebacillithantheparenteral
thirdorfourthgenerationcephalosporins.Theseantibioticsarerecommendedastherapyforotitismedia,upper
andlowerrespiratorytractinfections,andurinarytractinfections(cefixime,cefpodoxime,andcefdinir).These
indicationsaresharedwiththeoralsecondgenerationcephalosporins,amoxicillinclavulanate,and
trimethoprimsulfamethoxazole.Cefiximeandceftibutenhavelittleornoactivityagainststaphylococciin
contrasttosomeoftheseotheragents.

PHARMACOLOGYManyoftheavailableparenteralcephalosporinshaveshortserumhalflives(generally
onehourorless)andshouldbeadministeredonaneveryfourhourbasiswhentreatingserioussystemic
infectionsinpatientswithnormalrenalfunction(table1).Certaincephalosporinshavelongerserumhalflives
andmaybedosedlessfrequently(eg,cefazolinQ8handceftriaxoneQ24h).Allofthecephalosporinsexcept
cefoperazoneandceftriaxonerequiredosemodificationinthepresenceofsevererenalfailure(table1).

Allofthecephalosporinsachievetherapeuticlevelsinpleural,pericardial,peritoneal,andsynovialfluids,and
urine.Biliaryconcentrationsexceedserumlevels(intheabsenceofobstruction)andareparticularlyhighfor
cefazolin,cefoperazone,andceftriaxone.

Firstandsecondgenerationcephalosporins(exceptcefuroxime)penetratethecerebrospinalfluid(CSF)barrier
poorlyandshouldnotbeusedtotreatinfectionsofthecentralnervoussystem.Thethirdgeneration
cephalosporinsachievemuchmorereliableCSFlevelsinpatientswithmeningealirritation.PeakCSF
concentrationsofseveralcephalosporinsgivenatmeningealdosesareshowninthetable(table2).
Cefotaxime,ceftriaxone,andceftazidimeareapprovedforthetreatmentofbacterialmeningitis.

Fatalreactionsduetocalciumceftriaxoneprecipitatesinthelungsandkidneysofneonateshavebeen
reported.Ceftriaxoneshouldnotbereconstitutedormixedwithacalciumcontainingproduct(eg,Ringer'sor
Hartmann'ssolutionorparenteralnutrition).Inaddition,ceftriaxoneshouldbeavoidedininfantsaged28days
iftheyarereceivingorexpectedtoreceiveintravenouscalciumcontainingproducts.However,ceftriaxoneand
calciumcontainingproductsmaybeusedconcomitantlyinpatientsaged>28days,providedthattheinfusion
linesarethoroughlyflushedbetweeninfusions[33].

SUMMARY

Firstgenerationcephalosporins,includingcefazolin,areactiveagainstmostgrampositivecocciexcept
forenterococci,oxacillinresistantstaphylococci,andpenicillinresistantpneumococci.Theyarealso
activeagainstmoststrainsofEscherichiacoli,Proteusmirabilis,andKlebsiellapneumoniae.(See'First
generation'above.)

Thesecondgenerationcephalosporinsincludetwosubgroups.Onesubgrouphasactivityagainst
HaemophilusinfluenzaeandMoraxellacatarrhalis.Theothersubgroupconsistsofthecephamycins,
whichareactiveagainstmanystrainsofBacteroides.(See'Secondgeneration'above.)

Thirdgenerationcephalosporinshavelessactivityagainstmostgrampositiveorganismsthanfirst
generationagentsbutarehighlyactiveagainstEnterobacteriaceae,Neisseria,andH.influenzae.
CeftazidimeandcefoperazonearealsoactiveagainstPseudomonasaeruginosa.Thefourthgeneration

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cefepimehassimilaractivityasthethirdgenerationcephalosporins,includingagainstP.aeruginosa,with
theadditionofgreateractivityagainstentericgramnegativerodsthathaveaninduciblechromosomal
betalactamase.(See'Thirdgeneration'aboveand'Fourthgeneration'above.)

Thefifthgenerationcephalosporinshaveactivityagainstoxacillinresistantstaphylococci,penicillin
resistantpneumococci,andentericgramnegativerods.(See'Fifthgeneration'above.)

Oralcephalosporinsarealsodividedintodifferentgenerationsandtheirspectraofactivitygenerallymirror
thoseparenteralagentsofthecorrespondinggeneration.However,oralthirdgenerationdrugsareless
activeagainstentericgramnegativebacteriathantheparenteralthirdgenerationcephalosporins.Second
andthirdgenerationoralcephalosporinshavesimilarindications,namelyotitismedia,respiratorytract
infections,andurinarytractinfections.(See'Oralagents'above.)

Manyoftheavailableparenteralcephalosporinshaveshortserumhalflivesandrequirefrequent
administration.Allofthecephalosporinsexceptcefoperazoneandceftriaxonerequiredosemodificationin
thepresenceofsevererenalfailure(table1).(See'Pharmacology'above.)

Allofthecephalosporinsachievetherapeuticlevelsinpleural,pericardial,peritoneal,andsynovialfluids,
andurine.Firstandsecondgenerationcephalosporinsenterintocerebrospinalfluidpoorly.Third
generationcephalosporinsachievemorereliablecerebrospinalfluidlevelsinpatientswithmeningeal
irritation.(See'Pharmacology'above.)

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http://www.fda.gov/Drugs/DrugSafety/ucm309661.htm(AccessedonJune27,2012).
26. CoreyGR,WilcoxM,TalbotGH,etal.IntegratedanalysisofCANVAS1and2:phase3,multicenter,
randomized,doubleblindstudiestoevaluatethesafetyandefficacyofceftarolineversusvancomycin
plusaztreonamincomplicatedskinandskinstructureinfection.ClinInfectDis201051:641.
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GRAPHICS

Doseofparenteralcephalosporinswithadjustmentsforrenal
failure

Glomerularfiltrationrate(GFR)
mL/min* Removalby
Drug
>50(normal
dialysis
1050 <10
renalfunction)

Cefazolin 12gQ8h 0.51gQ12h 0.51gQ24h Yes(HD),No

(PD)

Cefuroxime 0.751.5gQ68 0.751.5gQ8 0.75gQ24h Yes(HD,PD)

h 12h

Cefoxitin 12gQ46h 12gQ812h 0.51gQ24h Yes(HD),No

(PD)

Cefotetan 12gQ12h 12gQ24h 12gQ48h Yes(HD)

Cefotaxime 12gQ6h 12gQ812h 12gQ1224h Yes(HD),No

(PD)

Ceftizoxime 12gQ68h 0.251gQ812 0.251gQ24h Yes(HD),No

h (PD)

Ceftriaxone 12gQ1224h NC NC No(HD)

Ceftazidime 12gQ8h 12gQ1224h 0.51gQ2448 Yes(HD,PD)

h

Cefepime 12gQ812h 0.52gQ1224 0.251gQ24h Yes(HD)

h

Ceftaroline 600mgQ12h 300400mgQ 200400mgQ Yes(HD)

12h 12h

HD:hemodialysisPD:peritonealdialysisNC:nochange.

*Usualadultdosingandrenaladjustmentsshownareformoderatetosevereinfections.Forspecific
dosingrecommendations,seerelateddiseasetreatmenttopicsandLexiCompdruginformation
includedwithUpToDate.
NotavailableintheUnitedStatesorCanada.
1hourinfusion.

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PeakCSFconcentrationsofcephalosporinsinbacterialmeningitis

Cephalothin 0.160.31g/mL

Cefoxitin <1.5612.5g/mL

Cefuroxime 4.39.3g/mL

Cefotaxime 6.827.2g/mL

Ceftriaxone 242g/mL

Ceftazidime 2.530g/mL

Graphic62934Version3.0

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Disclosures
Disclosures:StephenBCalderwood,MDPatentHolder:VaccineTechnologiesInc.[Vaccines(Choleravaccines)].Equity
Ownership/StockOptions:Pulmatrix[Inhaledantimicrobials]PharmAthene[Anthrax(Antiprotectiveantigenmonoclonalantibody)].
DavidCHooper,MDConsultant/AdvisoryBoards:Bacterioscan[Antimicrobials(Urinediagnosticunderdevelopment)]Cubist
[Antimicrobials(Daptomycin,fidaxomycin,tedizolid,ceftolozanetazobactam)]Shionogi[Antimicrobials(Antigramnegativebeta
lactamunderdevelopment)]Melinta[Antimicrobials(Antimicrobialsunderdevelopment)]Cepheid[Antimicrobials(rapidgenetic
diagnostics)]FabPharma[Antimicrobials(Antimicrobialunderdevelopment)].AllysonBloom,MDNothingtodisclose.
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvetting
throughamultilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.Appropriately
referencedcontentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.
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