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Penicillins

Author SectionEditor DeputyEditor

StephenBCalderwood,MD DavidCHooper,MD AllysonBloom,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Sep2015.|Thistopiclastupdated:May27,2015.
INTRODUCTIONBetalactamantibioticsareamongthemostcommonlyprescribeddrugs,grouped
togetherbaseduponasharedstructuralfeature,thebetalactamring.Theclassification,spectrumofactivity
andpharmacologyofonegroupofbetalactamantibiotics,thepenicillins,willbereviewedhere.The
mechanismsofactionandresistanceandmajoradversereactionsofthebetalactamantibioticsarediscussed
separately.(See"Betalactamantibiotics:Mechanismsofactionandresistanceandadverseeffects".)The
cephalosporinsandotherbetalactamdrugsarealsodiscussedseparately.(See"Cephalosporins"and
"Combinationbetalactamaseinhibitors,carbapenems,andmonobactams".)

CLASSIFICATIONPenicillinscanbeclassifiedintothefollowingcategories:

PenicillinG
Antistaphylococcalpenicillins(nafcillin,oxacillin,cloxacillinanddicloxacillin)
Broadspectrumpenicillins:secondgeneration(ampicillin,amoxicillinandrelatedagents),thirdgeneration
(carbenicillinandticarcillin)andfourthgeneration(piperacillin)

SPECTRUMOFACTIVITYOneofthemajordifferencesamongthepenicillinsistherangeofbacteria
againstwhichtheyareactive.

PenicillinGPenicillinGishighlyactiveagainst:

Grampositivecocci(exceptpenicillinaseproducingstaphylococci,penicillinresistantpneumococci[15],
enterococci,andoxacillinresistantstaphylococci)(see"ResistanceofStreptococcuspneumoniaeto
betalactamantibiotics")
GrampositiverodssuchasListeria
GramnegativecoccisuchasNeisseriaspp(exceptpenicillinaseproducingNeisseria)
Mostanaerobes(withcertainimportantexceptions,includingBacteroides)

PenicillinGisonlybacteriostaticforenterococcireportsdocumentstrainswithincreasingintrinsicresistance
topenicillinand,rarely,withhighlevelresistanceduetopenicillinaseproduction[6](see"Mechanismsof
antibioticresistanceinenterococci").Seriousinfectionswithenterococciaregenerallytreatedwithcombination
therapyofacellwallactiveantibioticsuchaspenicillin,ampicillin,orvancomycinplusgentamicinor
streptomycin(unlesshighlevelresistancetotheseaminoglycosidesispresent).PenicillinGisnotactive
againstgramnegativebacillibecauseofpoorpenetrationthroughtheporinchannel.(See"Betalactam
antibiotics:Mechanismsofactionandresistanceandadverseeffects",sectionon'Mechanismsofbacterial
resistance'.)

AntistaphylococcalpenicillinsAntistaphylococcalpenicillins(nafcillin,oxacillin,cloxacillinand
dicloxacillin)inhibitpenicillinaseproducingstaphylococcibutareinactiveagainstoxacillinresistant
staphylococci[7](see"MicrobiologyofmethicillinresistantStaphylococcusaureus").However,forstrainsof
S.aureussensitivetooxacillin,antistaphylococcalpenicillinsarepreferabletovancomycinbecause
vancomycinislessactiveagainstS.aureusthanbetalactamsininvitroandclinicalstudies[8].
AntistaphylococcalpenicillinshavelessintrinsicactivitythanpenicillinGforbacteriasusceptibletoboth,and
antistaphylococcalpenicillinsareineffectiveforenterococci,Listeria,andNeisseriaspp.

BroadspectrumpenicillinsThebroadspectrumpenicillinsaredistinguishedbytheiractivityagainstgram
negativebacilli.Theseagentshavebeenstratifiedintothesecondgenerationpenicillins(ampicillin,amoxicillin
andrelatedagents),thethirdgenerationpenicillins(carbenicillinandticarcillin),andthefourthgeneration
penicillinpiperacillin.Noneofthebroadspectrumpenicillinsiseffectiveagainstpenicillinaseproducing
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staphylococci.

SecondgenerationAmpicillin,amoxicillin,andcloselyrelatedantibioticsareabletopenetratetheporin
channelofgramnegativebacteriabutarenotstabletobetalactamases.Theseantibioticsareactiveagainst
themajorityofstrainsofEscherichiacoli,Proteusmirabilis,Salmonella,Shigella,andHaemophilusinfluenzae.
WhilealargepercentageofencapsulatedH.influenzaetypebfromthebloodandcerebrospinalfluid(CSF)of
childrenarebetalactamasepositive(andampicillinresistant),amuchlowerpercentofthenontypebisolates
fromadultpatientswithcommunityacquiredpneumoniaarebetalactamasepositive[9].

Amoxicillinandampicillinhaveanidenticalspectrumofactivity,butamoxicillinisbetterabsorbedfromthe
intestinewhenadministeredorallyandyieldshigherbloodandurinelevels.Amoxicillinisavailablegenerically
andispreferabletoampicillinfororaluseexceptinthetherapyofShigellainfectionssensitivetoampicillin.
(See"Shigellainfection:Treatmentandpreventioninadults".)

ThirdgenerationCarbenicillinandticarcillinalsocanpenetratetheporinchannelofgramnegative
bacteriainhighdoses,buttheyarelessactivethanampicillinonaweightbasis.However,thecarboxygroup
onthesidechainoftheseantibioticsexpandsthespectrumofactivitybyrenderingthemmoreresistanttothe
chromosomalbetalactamasesofcertainorganisms,suchasindolepositiveProteusspecies,Enterobacter
species,andPseudomonasaeruginosa.Thirdandfourthgenerationpenicillinsaremostusefulininfections
causedbytheseorganisms.

Carbenicillinindanylsodiumisanorallyabsorbedformofcarbenicillinwhichmaybeindicatedfororaltherapy
ofresistanturinarytractinfectionstheusualdoseisoneortwotablets(382mgeach)fourtimesaday.Oral
carbenicillinisnoteffectivefortherapyofinfectionsoutsideoftheurinarytract.Carbenicillinisnotavailable
anymoreforparenteraluse.

Ticarcillinhasthesamespectrumofactivityascarbenicillinbutistwotofourtimesmoreactiveonaweight
basisagainstP.aeruginosathenormalmaximumparenteraldoseis18g/day.Ticarcillinisadisodiumsalt
(whichmaycauseaprobleminpatientswithvolumeoverload)andmaycauseableedingdiathesisby
inhibitionofplateletfunctionandprolongationofthebleedingtime.Ticarcillinisadministerednowin
combinationwithabetalactamaseinhibitor.(See"Combinationbetalactamaseinhibitors,carbapenems,and
monobactams",sectionon'Betalactamaseinhibitorcombinations'.)

FourthgenerationPiperacillinisaderivativeofampicillin[10].Itcoversmuchthesamespectrumas
carbenicillinandticarcillinbutismoreactiveinvitroonaweightbasis.Inaddition,ithassomeactivityagainst
strainsofKlebsiella,althoughcephalosporinsremainthepreferredagents.Itismoreactivethancarbenicillinor
ticarcillinagainstenterococciandBacteroidesfragilis,butotheragentsarepreferredforthetreatmentofthese
organismsaswell.

PiperacillinissomewhatmoreactiveagainstEnterobacteriaceaethancarbenicillinorticarcillinandmoreactive
thanticarcillinagainstP.aeruginosa.Aswithticarcillin,clinicalfailureshaveoccurredwhenpiperacillinisused
asasingleagenttotreatseriousPseudomonasinfections.Piperacillinisusuallyadministerednowin
combinationwithabetalactamaseinhibitor.(See"Combinationbetalactamaseinhibitors,carbapenems,and
monobactams",sectionon'Betalactamaseinhibitorcombinations'.)

ThethirdandfourthgenerationpenicillinsaregenerallyconsideredtogetherasantiPseudomonalpenicillins
[11]andonlyasinglerepresentativeemployedasstandardtherapyatagivenhospital.Severalfactorsenter
thedecisionoverwhichoftheseagentstochoose:

Piperacillinismoreactiveinvitroonaweightbasisininhibitingbacterialgrowthbutnotinbacterial
killingforP.aeruginosa,ticarcillinismorerapidlybactericidal

Piperacillinhaslittleenhancedstabilitytobetalactamasescomparedwithticarcillin

Piperacillinhaslesseffectthanticarcillinonplateletfunction

Noneofthesefactorsclearlyfavoroneofthesedrugsovertheothersthus,thechoiceofoneforstandard
therapyinaninstitutionmayprimarilybemadebaseduponcostconsiderations.

PHARMACOLOGYThehalflivesofthepenicillinsaresimilarandallachieveadequatelevelsinmost
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bodilyfluids,butdoseadjustmentwithrenalinsufficiencydependsuponthepresenceofnonrenalroutesof
excretionanddiffersamongthesedrugs.

HalflifeAlloftheavailablepenicillinshaverelativelyshorthalflives(generallyonehourorless)allofthe
parenteralagentsareusuallyadministeredonaneveryfourhourbasiswhentreatingserioussystemic
infectionsinpatientswithnormalrenalfunction.Piperacillinhasdosedependentpharmacokineticsandalonger
halflifewhenhigherdosesareadministered.

LevelsindifferentbodilyfluidsAllofthepenicillinsachievetherapeuticlevelsinpleural,pericardial,
peritonealandsynovialfluids,aswellasurine.Allachievelevelsinbilehigherthancorrespondingserumlevels
(assumingtheabsenceofobstruction)nafcillin,ampicillin,andpiperacillinachieveveryhighlevelsinbile.

ThepenicillinspenetratetheCSFpoorlyintheabsenceofinflammationbutachievetherapeuticlevelsin
patientswithmeningitiswhoaregivenmeningealdosesofparenteraltherapy(table1).(See"Initialtherapyand
prognosisofbacterialmeningitisinadults",sectionon'DrugentryintoCSF'.)

DoseadjustmentwithrenalinsufficiencyNafcillin,oxacillin,cloxacillin,anddicloxacillinhavemajornon
renalroutesofclearanceandneednodosemodificationeveninthepresenceofsevererenalfailure.Ampicillin
andthestructurallyrelatedantibioticpiperacillin,requiredosemodificationpredominantlywhentheGFRis
below10mL/min.TicarcillinrequiresdosemodificationwhentheGFRisbelow50mL/min.

Thedosing(table2)andadjustmentofdoseinthepatientwithrenaldysfunction(table3)ofthenewer
penicillinsareshownintheTables.

SUMMARY

PenicillinGishighlyactiveagainstmostGrampositivecocci,Grampositiverods,Gramnegativecocci,
andanaerobes.Exceptionsarebacteriafromtheseclassesthathaveacquiredresistancetopenicillinas
wellascertainanaerobesthatproduceabetalactamasesuchasBacteroides.Penicillinisonly
bacteriostaticagainstenterococci.(See'PenicillinG'above.)

ForstrainsofS.aureussensitivetooxacillin,antistaphylococcalpenicillinsarepreferabletovancomycin
becausetheyaremoreactiveinvitroandinclinicalstudies.(See'Antistaphylococcalpenicillins'above.)

BroadspectrumpenicillinshaveincreasedactivityoverpenicillinGagainstGramnegativebacillibutare
variablyinactivatedbybetalactamases.(See'Broadspectrumpenicillins'above.)

Allpenicillinshaverelativelyshorthalflivesandrequirefrequentadministrationwhengivenparenterally.
CSFpenetrationispoorexceptinthepresenceofinflammation.Theantistaphylococcalpenicillinsneed
nodosemodificationwhenusedinthesettingofrenalfailure.(See'Pharmacology'above.)

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REFERENCES

1. TomaszA.AntibioticresistanceinStreptococcuspneumoniae.ClinInfectDis199724Suppl1:S85.
2. FriedlandIR,McCrackenGHJr.ManagementofinfectionscausedbyantibioticresistantStreptococcus
pneumoniae.NEnglJMed1994331:377.
3. BradleyJS,ScheldWM.ThechallengeofpenicillinresistantStreptococcuspneumoniaemeningitis:
currentantibiotictherapyinthe1990s.ClinInfectDis199724Suppl2:S213.
4. PallaresR,LiaresJ,VadilloM,etal.Resistancetopenicillinandcephalosporinandmortalityfrom
severepneumococcalpneumoniainBarcelona,Spain.NEnglJMed1995333:474.
5. WhitneyCG,FarleyMM,HadlerJ,etal.IncreasingprevalenceofmultidrugresistantStreptococcus
pneumoniaeintheUnitedStates.NEnglJMed2000343:1917.
6. HermanDJ,GerdingDN.Antimicrobialresistanceamongenterococci.AntimicrobAgentsChemother
199135:1.
7. MulliganME,MurrayLeisureKA,RibnerBS,etal.MethicillinresistantStaphylococcusaureus:a
consensusreviewofthemicrobiology,pathogenesis,andepidemiologywithimplicationsforprevention

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andmanagement.AmJMed199394:313.
8. LowyFD.Staphylococcusaureusinfections.NEnglJMed1998339:520.
9. JorgensenJH,DoernGV,MaherLA,etal.Antimicrobialresistanceamongrespiratoryisolatesof
Haemophilusinfluenzae,Moraxellacatarrhalis,andStreptococcuspneumoniaeintheUnitedStates.
AntimicrobAgentsChemother199034:2075.
10. BushLM,JohnsonCC.Ureidopenicillinsandbetalactam/betalactamaseinhibitorcombinations.Infect
DisClinNorthAm200014:409.
11. TanJS,FileTMJr.Antipseudomonalpenicillins.MedClinNorthAm199579:679.

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GRAPHICS

PeakCSFconcentrationsofpenicillinsinbacterialmeningitis
PenicillinG 1.02.5g/mL

Nafcillin 9.5g/mL

Ampicillin 9.9g/mL

Ticarcillin 2633g/mL

Piperacillin 1335g/mL

Thedosesusedvariedfromstudytostudy,makingcomparisonsbetweendrugsunreliable.

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Dosingofnewerpenicillins

Dosingchanges
Normalunit Normaldose
Drug insevererenal
dose* interval
failure
Ticarcillin 3 Q4h Yes

Piperacillin 34 Q46h Yes

*Dosegivenateachnormaldoseinterval,ie,3gQ4hforticarcillin.
Thesedrugshavedosedependentpharmacokineticsandcanbegivenas4gQ6h.

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Adjustedmaximumdoseofnewerpenicillinsinrenaldisease

GFR(mL/min)
Drug Removalbydialysis
>50 1050 <10

Ticarcillin 3gQ4h 3gQ6h 2gQ12h Yes(H,P)

Piperacillin 4gQ6h 4gQ8h 4gQ12h Yes(H),No(P)

H:hemodialysisP:peritonealdialysis.

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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.
Conflictofinterestpolicy

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