Cephalosporin

FromWikipedia,thefreeencyclopedia

Thecephalosporins(sg./sflsprn/)areaclass
oflactamantibioticsoriginallyderivedfromthe
fungusAcremonium,whichwaspreviouslyknownas
"Cephalosporium".[1]

Cephalosporin
Drugclass

Togetherwithcephamycins,theyconstitutea
subgroupoflactamantibioticscalledcephems.

Contents
1Medicaluse
2Adverseeffects

Corestructureofthecephalosporins

3Mechanismofaction

Use

Bacterialinfection

4Resistance

Biologicaltarget

Penicillinbindingproteins

5Classification

ATCcode

J01D

5.1Other
6History
7References

Externallinks
MeSH

D002511

AHFS/Drugs.com

DrugClasses

Medicaluse
Cephalosporinsareindicatedfortheprophylaxisandtreatmentofinfectionscausedbybacteria
susceptibletothisparticularformofantibiotic.Firstgenerationcephalosporinsareactivepredominantly
againstGrampositivebacteria,andsuccessivegenerationshaveincreasedactivityagainstGram
negativebacteria(albeitoftenwithreducedactivityagainstGrampositiveorganisms).

Adverseeffects
Commonadversedrugreactions(ADRs)(1%ofpatients)associatedwiththecephalosporintherapy
include:diarrhea,nausea,rash,electrolytedisturbances,andpainandinflammationatinjectionsite.
InfrequentADRs(0.11%ofpatients)includevomiting,headache,dizziness,oralandvaginal
candidiasis,pseudomembranouscolitis,superinfection,eosinophilia,nephrotoxicity,neutropenia,
thrombocytopenia,andfever.
Thecommonlyquotedfigureof10%ofpatientswithallergichypersensitivitytopenicillinsand/or
carbapenemsalsohavingcrossreactivitywithcephalosporinsoriginatedfroma1975studylookingat
theoriginalcephalosporins,[2]andsubsequent"safetyfirst"policymeantthiswaswidelyquotedand
assumedtoapplytoallmembersofthegroup.[3]Hence,itwascommonlystatedthattheyare
contraindicatedinpatientswithahistoryofsevere,immediateallergicreactions(urticaria,anaphylaxis,
interstitialnephritis,etc.)topenicillins,carbapenems,orcephalosporins.[4]This,however,shouldbe

viewedinthelightofrecentepidemiologicalworksuggesting,formanysecondgeneration(orlater)
cephalosporins,thecrossreactivityratewithpenicillinismuchlower,havingnosignificantlyincreased
riskofreactivityinthestudiesexamined.[3][5]TheBritishNationalFormularypreviouslyissuedblanket
warningsof10%crossreactivity,but,sincetheSeptember2008edition,suggests,intheabsenceof
suitablealternatives,oralcefiximeorcefuroximeandinjectablecefotaxime,ceftazidine,andceftriaxone
canbeusedwithcaution,buttheuseofcefaclor,cefadrocil,cefalexin,andcefradineshouldbe
avoided.[6]
Severalcephalosporinsareassociatedwithhypoprothrombinemiaandadisulfiramlikereactionwith
ethanol.[7][8]Theseincludelatamoxef,cefmenoxime,moxalactam,cefoperazone,cefamandole,
cefmetazole,andcefotetan.ThisisthoughttobeduetotheNmethylthiotetrazolesidechainofthese
cephalosporins,whichblockstheenzymevitaminKepoxidereductase(likelycausing
hypothrombinemia)andaldehydedehydrogenase(causingalcoholintolerance).[9]

Mechanismofaction
Cephalosporinsarebactericidalandhavethesamemodeofactionasotherlactamantibiotics(suchas
penicillins),butarelesssusceptibletolactamases.Cephalosporinsdisruptthesynthesisofthe
peptidoglycanlayerofbacterialcellwalls.Thepeptidoglycanlayerisimportantforcellwallstructural
integrity.Thefinaltranspeptidationstepinthesynthesisofthepeptidoglycanisfacilitatedby
transpeptidasesknownaspenicillinbindingproteins(PBPs).PBPsbindtotheDAlaDAlaattheend
ofmuropeptides(peptidoglycanprecursors)tocrosslinkthepeptidoglycan.Betalactamantibiotics
mimictheDAlaDAlasite,therebyirreversiblyinhibitingPBP
crosslinkingofpeptidoglycan.

Resistance
Resistancetocephalosporinantibioticscaninvolveeither
reducedaffinityofexistingPBPcomponentsortheacquisitionof
asupplementarylactaminsensitivePBP.Currently,some
Citrobacterfreundii,Enterobactercloacae,Neisseria
gonorrhoeae,andEscherichiacolistrainsareresistantto
cephalosporin.SomeMorganellamorganii,Proteusvulgaris,
Providenciarettgeri,PseudomonasaeruginosaandSerratia
marcescensstrainshavealsodevelopedresistanceto
cephalosporintovaryingdegrees.[10]

Classification
Thecephalosporinnucleuscanbemodifiedtogaindifferent
properties.Cephalosporinsaresometimesgroupedinto
"generations"bytheirantimicrobialproperties.Thefirst
cephalosporinsweredesignatedfirstgenerationcephalosporins,
whereas,later,moreextendedspectrumcephalosporinswere
classifiedassecondgenerationcephalosporins.Eachnewer
generationhassignificantlygreaterGramnegativeantimicrobial
propertiesthantheprecedinggeneration,inmostcaseswith

decreasedactivityagainstGrampositiveorganisms.Fourth
generationcephalosporins,however,havetruebroadspectrum
activity.
Theclassificationofcephalosporinsinto"generations"is
Structureoftheclassical
commonlypractised,althoughtheexactcategorizationisoften
cephalosporins
imprecise.Forexample,thefourthgenerationofcephalosporins
isnotrecognizedassuchinJapan.InJapan,cefaclorisclassedas
afirstgenerationcephalosporin,thoughintheUnitedStatesitisasecondgenerationoneand
cefbuperazone,cefminox,andcefotetanareclassedassecondgenerationcephalosporins.Cefmetazole
andcefoxitinareclassedasthirdgenerationcephems.Flomoxefandlatamoxefareinanewclasscalled
oxacephems.
Mostfirstgenerationcephalosporinswereoriginallyspelled"ceph"inEnglishspeakingcountries.This
continuestobethepreferredspellingintheUnitedStates,Australia,andNewZealand,whileEuropean
countries(includingtheUnitedKingdom)haveadoptedtheInternationalNonproprietaryNames,which
arealwaysspelled"cef".Newerfirstgenerationcephalosporinsandallcephalosporinsoflater
generationsarespelled"cef",evenintheUnitedStates.
Somestate,althoughcephalosporinscanbedividedintofiveorevensixgenerations,theusefulnessof
thisorganizationsystemisoflimitedclinicalrelevance.[11]
FourthgenerationcephalosporinsasofMarch,2007,wereconsideredtobe"aclassofhighlypotent
antibioticsthatareamongmedicine'slastdefensesagainstseveralserioushumaninfections"according
totheWashingtonPost.[12]
Themnemonic"LAME"isusedtonoteorganismsagainstwhichcephalosporinsdonothaveactivity:
Listeria,Atypicals(includingMycoplasmaandChlamydia),MRSA,andenterococci.
FifthgenerationcephalosporinsareeffectiveagainstMRSA,however.
Generation

Members

Description

Cefacetrile(cephacetrile),
Cefadroxil(cefadroxyl
Duricef),Cephalexin
(cefalexinKeflex),
Cefaloglycin(cephaloglycin),
Cefalonium(cephalonium),
Cefaloridine(cephaloradine),
Cefalotin(cephalothin
Keflin),Cefapirin
(cephapirinCefadryl),
Cefatrizine,Cefazaflur,
Cefazedone,Cefazolin
(cephazolinAncef,Kefzol),
Cefradine(cephradine
Velosef),Cefroxadine,
Ceftezole

Grampositive:Activityagainstpenicillinaseproducing,
methicillinsusceptiblestaphylococciandstreptococci
(thoughtheyarenotthedrugsofchoiceforsuch
infections).Noactivityagainstmethicillinresistant
staphylococciorenterococci.
Gramnegative:ActivityagainstProteusmirabilis,some
Escherichiacoli,andKlebsiellapneumoniae("PEcK"),but
havenoactivityagainstBacteroidesfragilis,
Pseudomonas,Acinetobacter,Enterobacter,indole
positiveProteus,orSerratia

Cefaclor(Ceclor,Distaclor,
Keflor,Raniclor),Cefonicid
(Monocid),Cefprozil
(cefproxilCefzil),

Cefuroxime(Zefu,Zinnat,
Zinacef,Ceftin,
Biofuroksym,[13]Xorimax),
Cefuzonam,second
generationcephalosporins
withantianaerobeactivity:
Cefmetazole,Cefotetan,
Cefoxitin.Thefollowing
cephemsarealsosometimes
groupedwithsecond
generationcephalosporins:
Carbacephems:loracarbef
(Lorabid)Cephamycins:
cefbuperazone,cefmetazole
(Zefazone),cefminox,
cefotetan(Cefotan),cefoxitin
(Mefoxin),Cefotiam
(Pansporin).

Grampositive:Lessthanfirstgeneration.
Gramnegative:Greaterthanfirstgeneration:HEN
(Haemophilusinfluenzae,Enterobacteraerogenesand
someNeisseria+thePEcKdescribedabove

Cefcapene,Cefdaloxime,
Cefdinir(Sefdin,Zinir,
Omnicef,Kefnir),Cefditoren,
Cefetamet,Cefixime(Fixx,
Zifi,Suprax),Cefmenoxime,
Cefodizime,Cefotaxime
(Claforan),Cefovecin
(Convenia),Cefpimizole,
Cefpodoxime(Vantin,
PECEF),Cefteram,
Ceftamere
(http://www.google.ca)
(Enshort),Ceftibuten
(Cedax),Ceftiofur,
Ceftiolene,Ceftizoxime
(Cefizox),Ceftriaxone
(Rocephin).

Grampositive:Somemembersofthisgroup(in
particular,thoseavailableinanoralformulation,andthose
withantipseudomonalactivity)havedecreasedactivity
againstgrampositiveorganisms.
Gramnegative:Thirdgenerationcephalosporinshavea
broadspectrumofactivityandfurtherincreasedactivity
againstgramnegativeorganisms.Theymaybeparticularly
usefulintreatinghospitalacquiredinfections,although
increasinglevelsofextendedspectrumbetalactamasesare
reducingtheclinicalutilityofthisclassofantibiotics.
Theyarealsoabletopenetratethecentralnervoussystem,
makingthemusefulagainstmeningitiscausedby
pneumococci,meningococci,H.influenzae,and
susceptibleE.coli,Klebsiella,andpenicillinresistantN.
Thirdgeneration
gonorrhoeae.SinceAugust2012,thethirdgeneration
cephalosporinswith
cephalosporin,ceftriaxone,istheonlyrecommended
antipseudomonalactivity:
treatmentforgonorrheaintheUnitedStates(inadditionto
azithromycinordoxycyclineforconcurrentChlamydia
Cefoperazone(Cefobid),
Ceftazidime(Meezat,Fortum, treatment).Cefiximeisnolongerrecommendedasafirst
linetreatmentduetoevidenceofdecreasing
Fortaz).
susceptibility.[14]Activityagainststaphylococciand
Thesecephemsarealso
streptococciislesswiththethirdgenerationcompounds
sometimesgroupedwith
thanwiththefirstandsecondgenerationcompounds.[15]
thirdgeneration
cephalosporins:Oxacephems:
latamoxef(moxalactam).
Cefclidine,cefepime
(Maxipime),cefluprenam,
cefoselis,cefozopran,

Grampositive:Theyareextendedspectrumagentswith

cefpirome(Cefrom),
cefquinomeThesecephems
arealsosometimesgrouped
withfourthgeneration
cephalosporins:Oxacephems:
flomoxef

similaractivityagainstGrampositiveorganismsasfirst
generationcephalosporins.
Gramnegative:Fourthgenerationcephalosporinsare
zwitterionsthatcanpenetratetheoutermembraneof
Gramnegativebacteria.[16]Theyalsohaveagreater
resistancetolactamasesthanthethirdgeneration
cephalosporins.Manycancrossthebloodbrainbarrier
Note:Cefquinomeisnotapproved andareeffectiveinmeningitis.Theyarealsousedagainst
forhumanuse.Itisforveterinary
Pseudomonasaeruginosa.

medicine.

Ceftobiprole,ceftaroline

Ceftobiprolehasbeendescribedas"fifthgeneration"
cephalosporin,[17][18]thoughacceptanceforthis
terminologyisnotuniversal.Ceftobiprolehaspowerful
antipseudomonalcharacteristicsandappearstobeless
susceptibletodevelopmentofresistance.Ceftarolinehas
alsobeendescribedas"fifthgeneration"cephalosporin,
butdoesnothavetheantipseudomonalorVREcoverage
ofceftobiprole.[19]

Other
Thesecephemshaveprogressedfarenoughtobenamed,buthavenotbeenassignedtoaparticular
generation:cefaloram,cefaparole,cefcanel,cefedrolor,cefempidone,cefetrizole,cefivitril,cefmatilen,
cefmepidium,cefoxazole,cefrotil,cefsumide,ceftioxide,cefuracetime.Nitrocefin,achromogenic
cephalosporinsubstrate,isusedfordetectionoflactamases.

History
CephalosporincompoundswerefirstisolatedfromculturesofCephalosporiumacremoniumfroma
sewerinSardiniain1948byItalianscientistGiuseppeBrotzu.[20]Henoticedtheseculturesproduced
substancesthatwereeffectiveagainstSalmonellatyphi,thecauseoftyphoidfever,whichhad
lactamase.GuyNewtonandEdwardAbrahamattheSirWilliamDunnSchoolofPathologyatthe
UniversityofOxfordisolatedcephalosporinC.Thecephalosporinnucleus,7aminocephalosporanicacid
(7ACA),wasderivedfromcephalosporinCandprovedtobeanalogoustothepenicillinnucleus6
aminopenicillanicacid(6APA),butitwasnotsufficientlypotentforclinicaluse.Modificationofthe7
ACAsidechainsresultedinthedevelopmentofusefulantibioticagents,andthefirstagent,cefalotin
(cephalothin),waslaunchedbyEliLillyandCompanyin1964.

References
1. ^"cephalosporin
(http://web.archive.org/web/20090616022448/http://www.mercksource.com/pp/us/cns/cns_hl_dorlands_split.js
p?pg=/ppdocs/us/common/dorlands/dorland/two/000019430.htm)"atDorland'sMedicalDictionary
2. ^DashCH(1975)."Penicillinallergyandthecephalosporins".J.Antimicrob.Chemother.1(3Suppl):107
18.PMID1201975(https://www.ncbi.nlm.nih.gov/pubmed/1201975).

3. ^abPeglerS,HealyB(10November2007)."Inpatientsallergictopenicillin,considersecondandthird
generationcephalosporinsforlifethreateninginfections"
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2072043).BMJ335(7627):991991.
doi:10.1136/bmj.39372.829676.47(http://dx.doi.org/10.1136%2Fbmj.39372.829676.47).PMC2072043
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2072043).PMID17991982
(https://www.ncbi.nlm.nih.gov/pubmed/17991982).
4. ^RossiS,editor.AustralianMedicinesHandbook2006.Adelaide:AustralianMedicinesHandbook2006.
5. ^PichicheroME(2006)."Cephalosporinscanbeprescribedsafelyforpenicillinallergicpatients"
(http://www.jfponline.com/pdf%2F5502%2F5502JFP_AppliedEvidence1.pdf)(PDF).TheJournaloffamily
practice55(2):10612.PMID16451776(https://www.ncbi.nlm.nih.gov/pubmed/16451776).
6. ^"5.1.2Cephalosporinsandotherbetalactams".BritishNationalFormulary(56ed.).London:BMJ
PublishingGroupLtdandRoyalPharmaceuticalSocietyPublishing.September2008.p.295.ISBN085369
7787.
7. ^KitsonTM(1987)."Theeffectofcephalosporinantibioticsonalcoholmetabolism:areview".Alcohol4
(3):143148.doi:10.1016/07418329(87)900358(http://dx.doi.org/10.1016%2F07418329%2887%2990035
8).PMID3593530(https://www.ncbi.nlm.nih.gov/pubmed/3593530).
8. ^ShearerMJ,BechtoldH,AndrassyKetal.(1988)."Mechanismofcephalosporininduced
hypoprothrombinemia:relationtocephalosporinsidechain,vitaminKmetabolism,andvitaminKstatus".
Journalofclinicalpharmacology28(1):8895.doi:10.1002/j.15524604.1988.tb03106.x
(http://dx.doi.org/10.1002%2Fj.15524604.1988.tb03106.x).PMID3350995
(https://www.ncbi.nlm.nih.gov/pubmed/3350995).
9. ^StorkCM(2006)."Antibiotics,antifungals,andantivirals"(http://books.google.com/books?
id=cvJuLqBxGUcC&pg=PA847).InNelsonLH,FlomenbaumN,GoldfrankLR,HoffmanRL,Howland
MD,LewinNA.Goldfrank'stoxicologicemergencies.NewYork:McGrawHill.p.847.ISBN007143763
0.Retrieved20090703.
10. ^"Cephalosporinspectrumofresistance"(http://antibiotics.tokue.com/m/?w=cephalosporin).Retrieved
1July2012.
11. ^"CaseBasedPediatricsChapter"(http://www.hawaii.edu/medicine/pediatrics/pedtext/s06c05.html).
12. ^Weiss,Rick(4March2007)."FDARulesoverrideWarningsaboutDrugs"
(http://www.washingtonpost.com/wpdyn/content/article/2007/03/03/AR2007030301311.html).March4,
2007.
13. ^Jdrzejczyk,Tadeusz."InternetowaEncyklopediaLekw"(http://www.leki.med.pl/lek.phtml?
id=428&idnlek=2682&menu=4).leki.med.pl.Retrieved20070303.
14. ^http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6131a3.htm?s_cid=mm6131a3_w
15. ^TheAntimicrobialDrugs,byEricM.Scholar.Page108.books.google.com
16. ^RichardLSweetRonaldS.Gibbs(1March2009).InfectiousDiseasesoftheFemaleGenitalTract
(http://books.google.com/books?id=wuR_ngItU5oC&pg=PA403).LippincottWilliams&Wilkins.pp.403.
ISBN9780781778152.Retrieved8September2010.
17. ^WidmerAF(March2008)."Ceftobiprole:anewoptionfortreatmentofskinandsofttissueinfectionsdue
tomethicillinresistantStaphylococcusaureus".Clin.Infect.Dis.46(5):656658.doi:10.1086/526528
(http://dx.doi.org/10.1086%2F526528).PMID18225983(https://www.ncbi.nlm.nih.gov/pubmed/18225983).

18. ^KosinskiMA,JosephWS(July2007)."Updateonthetreatmentofdiabeticfootinfections"
(http://journals.elsevierhealth.com/retrieve/pii/S08918422(07)000262).ClinPodiatrMedSurg24(3):383
396.doi:10.1016/j.cpm.2007.03.009(http://dx.doi.org/10.1016%2Fj.cpm.2007.03.009).PMID17613382
(https://www.ncbi.nlm.nih.gov/pubmed/17613382).
19. ^KollefMH(December2009)."NewantimicrobialagentsformethicillinresistantStaphylococcusaureus".
CritCareResusc11(4):2826.PMID20001879(https://www.ncbi.nlm.nih.gov/pubmed/20001879).
20. ^Podolsky,M.Lawrence()CuresOutofChaos:HowUnexpectedDiscoveriesLedtoBreakthroughsin
MedicineandHealth,HarwoodAcademicPublishers

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