26/10/2015 Aminoglycosides

OfficialreprintfromUpToDate
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Aminoglycosides

Author SectionEditor DeputyEditor

RichardHDrew,PharmD,MS, DavidCHooper,MD AllysonBloom,MD
FCCP

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Sep2015.|Thistopiclastupdated:Jul16,2014.
INTRODUCTIONTheaminoglycosideclassofantibioticsconsistsofmanydifferentagents.Gentamicin,
tobramycin,amikacin,streptomycin,neomycin,andparomomycinareapprovedbytheUSFoodandDrug
Administration(FDA)andavailableforclinicaluseintheUnitedStates.Ofthese,gentamicin,tobramycin,and
amikacinarethemostfrequentlyprescribed.

Themostcommonclinicalapplication(eitheraloneoraspartofcombinationtherapy)oftheaminoglycosidesis
inthetreatmentofseriousinfectionscausedbyaerobicgramnegativebacilli[1,2].Whilelesscommon,
aminoglycosides(incombinationwithotheragents)havealsobeenusedforthetreatmentofselectgram
positiveinfections.Inaddition,certainaminoglycosideshavedemonstratedclinicallyrelevantactivityagainst
protozoa(paromomycin),Neisseriagonorrhoeae(spectinomycin,notavailableintheUnitedStates),and
mycobacterialinfections(tobramycin,streptomycin,andamikacin).

Thistopicwillreviewbasicissuesrelatedtotheclinicaluseofaminoglycosides,includingmechanismof
action,spectrumofactivity,andadverseeffects.Dosingandmonitoringofaminoglycosidesandadministration
incertainpatientspopulationsarediscussedelsewhere.(See"Dosingandadministrationofparenteral
aminoglycosides"and"Cysticfibrosis:Antibiotictherapyforlungdisease",sectionon'Aminoglycosides'.)

Themultipleclinicalsettingsinwhichtheaminoglycosidesmaybeusedarealsodiscussedseparatelyinthe
appropriatetopicreviews.(See"Gramnegativebacillarybacteremiainadults",sectionon'Indicationsand
rationaleforcombinationtherapy'and"PrinciplesofantimicrobialtherapyofPseudomonasaeruginosa
infections",sectionon'Intravenousantibiotics'and"Antimicrobialtherapyofnativevalveendocarditis",section
on'ViridansstreptococciandStreptococcusbovis'.)

MECHANISMOFACTIONTheaminoglycosidesprimarilyactbybindingtotheaminoacylsiteof16S
ribosomalRNAwithinthe30Sribosomalsubunit,leadingtomisreadingofthegeneticcodeandinhibitionof
translocation[3,4].Theinitialstepsrequiredforpeptidesynthesis,suchasbindingofmRNAandthe
associationofthe50Sribosomalsubunit,areuninterrupted,butelongationfailstooccurduetodisruptionofthe
mechanismsforensuringtranslationalaccuracy[4].Theensuingantimicrobialactivityisusuallybactericidal
againstsusceptibleaerobicgramnegativebacilli.

Aminoglycosidesinitiallypenetratetheorganismbydisruptingthemagnesiumandcalciumbridgesbetween
lipopolysaccharidemoieties.Theyaretransportedacrossthecytoplasmicmembraneinanenergydependent
manner.Thisstepcanbeinhibitedinvitrobydivalentcations,increasedosmolality,acidicpH,andan
anaerobicenvironment[4].

ThemicrobiologicactivityofaminoglycosidesispHdependent.Asaresult,theantimicrobialeffectmaybe
reducedatthelowpHfoundinlungandbronchialsecretions.Inaninvitrostudy,forexample,theminimum
inhibitoryconcentration(MIC)ofaminoglycosideswasincreasedalmostfivefoldatapH<6.5[5].

SPECTRUMOFACTIVITYIngeneral,aminoglycosidesareactiveacrossabroadspectrumofaerobic
gramnegativeandgrampositiveorganismsaswellasmycobacteria.Ofnote,anaerobicbacteriaare
intrinsicallyresistanttoaminoglycosides.

GramnegativeorganismsAminoglycosidesexhibitpotentinvitroactivityagainstawiderangeofaerobic
gramnegativepathogens,includingEnterobacteriaceae,Pseudomonasspp,Acinetobacterspp,and
Haemophilusinfluenzae.However,invitroactivityagainstBurkholderiacepacia,Stenotrophomonas
maltophilia,andanaerobicbacteriaisusuallypoororabsent.

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Differencesmayexistamongtheinvitropotenciesofthevariousaminoglycosides.Asanexample,gentamicin
usuallydemonstratessuperiorinvitroactivitytotobramycinagainstSerratiaspp,whiletobramycinisusually
morepotentthangentamicinagainstP.aeruginosa[6].AmongtheEnterobacteriaceae,amikacingenerally
demonstratesthemostpotentactivityinvitro,followedcloselybygentamicin[7].Themagnitudeofthese
differencescanvarybetweendifferentstrainsacrossdifferentinstitutions.

GrampositiveorganismsAminoglycosidesalsodemonstrateactivityinvitroagainstgrampositive
organisms,suchasS.aureus.However,mostauthoritiesbelievethesedrugsarenotadequatetherapyas
monotherapyforseriousinfectionscausedbyS.aureus.Aminoglycosideactivityagainstpneumococciis
generallyconsideredinsufficientforclinicalapplicationagainsttheseorganisms.Aminoglycosidesarenot
activealoneagainststreptococciandenterococci,althoughmayhaveadditiveorsynergisticeffectsagainst
thesepathogenswhencombinedwithotheragentsandintheabsenceofhighlevelresistance.

MycobacteriaStreptomycin,tobramycin,andamikacindemonstratefavorableactivityinvitroagainst
mycobacteria[8,9].Specifically,streptomycinisparticularlyactiveagainstM.tuberculosis,andamikacinis
generallythemostactiveaminoglycosideagainstM.fortuitum,M.abscessus,andM.chelonae.

RESISTANCEComparedwithotherclassesofantibiotics,theaminoglycosideshavedemonstratedrelative
stabilityagainstthedevelopmentofresistance.However,bothintrinsicandacquiredmechanismsof
resistancetoaminoglycosideshavebeendescribed.Aminoglycosideresistanceamonggramnegative
organismscanoccurthroughacquisitionorupregulationofgenesthatencodeinactivatingenzymesorefflux
systems.Emergenceofresistanceingramnegativebacilliduringtreatmentwithaminoglycosidesoccurs
infrequently.Enterococcihaveintrinsicresistancetolowandmoderatelevelsofaminoglycosidesandcan
acquireresistancetohighlevels.

Whilecrossresistancebetweenthespecificaminoglycosideagentsdoesoccur,itisincomplete.Therefore,
individualagentsshouldbetestedforinvitrosusceptibilityagainsttheisolatedpathogenwheneverpossible.

GramnegativeorganismsResistanceofgramnegativeorganismstoaminoglycosidesoccursbytwo
majormechanisms[4]:

BacterialproductionofinactivatingenzymesThemostcommonmechanismhasbeeninactivationof
thedrugbyphosphorylation(mediatedbyaminoglycosidekinases),adenylation,oracetylation(mediated
bytransferases)[4,1012].

Anothermechanismofinactivationismethylationof16SribosomalRNA.Thiseffectismediatedbyan
enzymeencodedbythermtAgeneandhasbeenassociatedwithhighlevelresistancetoallparenteral
aminoglycosidesincurrentuse[13,14].Bindingtotheaminoacylsiteon16SribosomalRNAisthe
mechanismbywhichaminoglycosidesnormallyinterferewithproteinsynthesis[3,4].

Inactivatingenzymescanbeencodedbyplasmidsorassociatedwithtransposableelements[4,13].
Plasmidexchangeanddisseminationoftransposonsfacilitatetheacquisitionofdrugresistance.

DecreasedintracellularaccumulationofthedrugAminoglycosideresistanceindependentof
inactivatingenzymeshasbeenknownforsometimeinPseudomonasaeruginosa[15].Thisresistanceis
characterizedbyresistancetoallaminoglycosidesandisduetoaneffluxsystemthatresultsinreduced
levelsofaminoglycosideaccumulation[16].

Unlikemostotherantimicrobialclasses,emergenceofaminoglycosideresistanceduringtreatmentis
infrequentlyencounteredduringmanagementofgramnegativeinfections.Additionally,certainaminoglycoside
agentsmayretainactivitydespiteresistancetootherdrugsintheclass,dependingonthemechanismsof
resistance.Asanexample,amikacinhasbeeneffectiveinsomeinstitutionsagainstselectedorganismswith
highratesofinvitromicrobialresistancetogentamicinandtobramycin.Ratesofsusceptibilitytogentamicin
andtobramycinhavealsobeenobservedtoimproveafteramikacinwasintroduced[17,18].

EnterococciEnterococciareintrinsicallyresistanttolowtomoderatelevelsofaminoglycosides.The
minimuminhibitoryconcentrations(MICs)ofgentamicinareusually8to64mcg/mLandthoseofstreptomycin
are64to512mcg/mL.However,thepotentialforsynergyexistswhenenterococciwithlowlevelresistanceto

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anaminoglycosideareexposedtoacombinationoftheaminoglycosidewithacellwallactiveagent,suchas
penicillinorvancomycin.

Thereareincreasingreportsofacquiredhighlevelenterococcalresistancetoaminoglycosides(MIC>2,000
mcg/mL).Thesignificanceofsuchhighlevelresistanceisthatiteliminatesthesynergismexpectedbetween
anaminoglycosideandacellwallactiveagent.Differentgeneticmutationsareresponsibleforhighlevel
resistancetodifferentaminoglycosides.(See"Mechanismsofantibioticresistanceinenterococci",sectionon
'Aminoglycosideresistance'.)

AnaturallyoccurringcharacteristicofE.faeciumismoderatelevelresistancetotobramycin(MICs64to1000
mcg/mL)andresistancetosynergism.Thisisduetothepresenceofanaminoglycosidemodifyingenzyme
thatmodifiestobramycinbutnotgentamicin[19].Thisenzymealsoeliminatessynergybetweencellwall
activeagentsandtobramycin,kanamycin,andnetilmicin.(See"Mechanismsofantibioticresistancein
enterococci".)

CLINICALUSEDespitetherelativelybroadspectrumofactivityofaminoglycosides,theirwidespread
clinicaluseisgenerallylimitedbecauseoftheavailabilityoflesstoxicagentswithcomparableefficacyand
withouttheneedforserumdrugconcentrationmonitoring.Aminoglycosidesremainimportantasasecond
agentintreatmentofseriousinfectionsduetoaerobicgramnegativebacilliandcertaingrampositive
organismsandaspartofamultidrugregimenforcertainmycobacterialinfections.Therearerareinstances
(especiallyoutsidetheurinarytract)inwhichmonotherapywithaminoglycosidesisadequatetreatment.

CombinationantibacterialtherapyThemostfrequentclinicaluseofaminoglycosides(mostcommonlyin
combinationwithotherantibacterialagents)isempirictherapyofseriousinfections,suchassepticemia,
nosocomialrespiratorytractinfections,complicatedurinarytractinfections,complicatedintraabdominal
infections,andosteomyelitiscausedbyaerobicgramnegativebacilli.Onceanorganismhasbeenidentified
anditssusceptibilitiesdeterminedtoalternateagents,aminoglycosidesareusuallydiscontinuedinfavorof
lesstoxicantibioticstocompleteatreatmentcourse.Combinationtherapyagainstgramnegativeorganismsis
discussedindetailelsewhere.(See"Gramnegativebacillarybacteremiainadults",sectionon'Indicationsand
rationaleforcombinationtherapy'and"PrinciplesofantimicrobialtherapyofPseudomonasaeruginosa
infections",sectionon'Combinationantimicrobialtherapy'.)

Combinationtherapywithgentamicinisfrequentlyusedforthetreatmentofinvasiveenterococcalinfections
notexhibitinghighlevelaminoglycosideresistance(suchasendocarditis)andsometimesforseriousinfections
duetocertainstreptococci.However,eveninsomeofthesecases(aswithenterococcalendocarditis)the
toxicityofprolongedaminoglycosideshasledtopreferreduseofothercombinationregimens.Theseusesare
discussedindetailelsewhere.(See"Antimicrobialtherapyofnativevalveendocarditis",sectionon'Viridans
streptococciandStreptococcusbovis'and"Antimicrobialtherapyofnativevalveendocarditis",sectionon
'Otherstreptococcalspecies'and"Antimicrobialtherapyofnativevalveendocarditis",sectionon'Enterococci'
and"Treatmentofenterococcalinfections",sectionon'Clinicalapproach'.)

Aminoglycosidesarealsousedfordefinitivecombinationtreatmentofsevereinfectionsduetoorganismssuch
asBrucellasppandListeriamonocytogenes.(See"Clinicalmanifestations,diagnosis,andtreatmentof
brucellosis",sectionon'Antibiotictherapy'and"Treatment,prognosis,andpreventionofListeria
monocytogenesinfection",sectionon'Antibioticregimens'.)

WhilecombinationtherapywithlowdoseaminoglycosideshaspreviouslybeenusedforS.aureusbacteremia,
thisisnolongerroutinepractice.(See"ClinicalapproachtoStaphylococcusaureusbacteremiainadults",
sectionon'Synergisticaminoglycosides'.)

Prophylacticuseofaminoglycosides(incombinationwitheitherclindamycinorvancomycin)isusually
restrictedtoselectsurgicalproceduresinvolvingthegastrointestinal,urinarytract,orfemalegenitaltractin
patientswithbetalactamallergies[20].(See"Antimicrobialprophylaxisforbacterialendocarditis"and
"Antibioticprophylaxisforgastrointestinalendoscopicprocedures".)

AntimycobacterialtherapyAminoglycosidesareusefulforthetreatmentofdrugresistanttuberculosisand
certainnontuberculousmycobacterialinfections(incombinationwithotherantimycobacterialagents).These
indicationsarediscussedindetailelsewhere.(See"Diagnosis,treatment,andpreventionofdrugresistant

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tuberculosis",sectionon'Injectableagents'and"Treatmentofnontuberculousmycobacterialinfectionsofthe
lunginHIVnegativepatients",sectionon'Recommendedregimen'and"Rapidlygrowingmycobacterial
infectionsinHIVnegativepatients",sectionon'Treatment'.)

MonotherapyTherearefewindicationsformonotherapywithsystemicaminoglycosides:

TularemiaStreptomycinandgentamicinarefirstlineagents,althoughotheroptionsmaybeusedin
lessseverecases.(See"Clinicalmanifestations,diagnosis,andtreatmentoftularemia",sectionon
'Treatment'.)

PlagueStreptomycinandgentamicinarefirstlineagents,althoughotheroptionsmaybeusedin
patientswhocannottolerateaminoglycosides.(See"Clinicalmanifestations,diagnosis,andtreatmentof
plague(Yersiniapestisinfection)",sectionon'Antibioticregimens'.)

UrinarytractinfectionsduetomultidrugresistantgramnegativeorganismsAminoglycosides
achievehighlevelsintheurinarytract,andinsomecases(particularlywithamikacin),retainactivity
againstgramnegativeorganismsresistanttomostotherclassesofantibiotics.However,susceptibility
shouldbeconfirmedasaminoglycosideresistanceisnotuncommonamongsuchorganisms[21].

NeisseriagonorrhoeaeSpectinomycinisanalternatetherapyfornonpharyngealgonococcal
infectionsinpatientswhohaveseverepenicillinallergy.However,itisnotavailableintheUnitedStates.
(See"Treatmentofuncomplicatedgonococcalinfections",sectionon'Spectinomycin'.)

Becauseofpooractivityand/orpenetrationintolungs,abscesses,andthecentralnervoussystem,
aminoglycosidesshouldnotberelieduponasmonotherapyininfectionsthatinvolvethesesites.

OtheraminoglycosideformulationsParomomycinisanoral,poorlyabsorbedaminoglycosidethatis
mainlyusedastreatmentforintraintestinalamebicinfection.(See"IntestinalEntamoebahistolytica
amebiasis",sectionon'Clinicalapproach'.)

Aminoglycosidesarealsoavailableintopical,inhaled,intraventricular,intraperitoneal,andimpregnatedcement
formulationsforspecificindications.(See"Externalotitis:Treatment",sectionon'Antibiotics'and"Cystic
fibrosis:Antibiotictherapyforlungdisease",sectionon'Inhaled'and"Gramnegativebacillarymeningitis:
Treatment",sectionon'Intrathecalandintraventriculartherapy'and"Treatmentofprostheticjointinfections",
sectionon'Replacementarthroplasty'and"Microbiologyandtherapyofperitonitisincontinuousperitoneal
dialysis",sectionon'Administrationanddosing'.)

DOSINGDosingandmonitoringofparenteralaminoglycosidesarediscussedindetailelsewhere.(See
"Dosingandadministrationofparenteralaminoglycosides".)

PHARMACODYNAMICSANDKINETICSCertainpharmacodynamicandkineticpropertiesofthe
aminoglycosideareimportantfortheirclinicalapplication.Thepostantibioticeffect(PAE)andconcentration
dependentkillingcharacteristicsofaminoglycosidesallowforefficacywhendosedatanextendedintervalfor
certaininfections,andthesynergisticeffectwithcellwallactiveagentshasledtothefrequentuseof
aminoglycosidesincombinationwiththeseagentsforseriousinfections.Limitationsinthedistributionof
aminoglycosidesrestricttheiruseforinfectionsatcertainanatomicalsites,aspoorpenetrationisachievedin
theCSF,biliarytree,andbronchialsecretions.

PostantibioticeffectThepostantibioticeffect(PAE)referstothepersistentsuppressionofbacterial
growththatoccursafterthedrughasbeenremovedinvitroorclearedbydrugmetabolismandexcretionin
vivo.Initiallydescribedforgramnegativebacilli,aminoglycosidesalsoexhibitPAEagainstStaphylococcus
aureusbutnotagainstothergrampositivecocci.ThedurationofthePAE(approximately3hours[range1to
7.5hours])dependsuponthemethodofevaluationandtheorganismstudied[22].Ingeneral,thePAEislonger
forgramnegativeorganismsthangrampositiveorganisms.ThedurationofthePAEisreducedintheabsence
ofpolymorphonuclearleukocytes(PMNs)[23].

ConcentrationdependentkillingConcentrationdependentkillingreferstotheabilityofhigher
concentrationsofaminoglycosides(relativetotheorganism'sMIC)toinducemorerapid,andcomplete,killing
ofthepathogen[24].Aminoglycosidesexhibitconcentrationdependentmicrobiologicactivityinbothinvivo

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andinvitromodels.Achievingoptimalpeakconcentrationsofaminoglycosideswithstandarddosingregimens
canbedifficult,sinceeffortsmustbemadetoavoidsustainedelevatedtroughconcentrations(whichcan
predisposetonephrotoxicity).Relativetotraditionaldosingmethods,theconsolidateddosingapproachismore
likelytoachieveoptimalpeakconcentrationsthatresultinconcentrationdependentkilling[25].(See"Dosing
andadministrationofparenteralaminoglycosides".)

SynergisticeffectAsynergisticeffecthasbeendemonstratedinvitroforselectedorganismswhen
aminoglycosidesareusedincombinationwithotherantibiotics,mostoftenwithcellwallactiveagents(eg,
betalactamantibiotics)[26].

AbsorptionandtimetopeaklevelsPeakserumaminoglycosideconcentrationsaremeasured
approximately30to60minutesafterterminationofanintravenousinfusion,or30to90minutesafteran
intramuscularinjection.Theaminoglycosidesarenotabsorbedafteroraladministration.However,local
instillationintothepleuralspaceorperitonealcavitycanresultinsignificantserumconcentrations.

DistributionThevolumeofdistributioninadultsrangesfrom0.2to0.4L/kg,andisincreasedinpatients
withascites,burns,pregnancy,andotherconditions(suchascysticfibrosis).Aminoglycosidesreach
concentrationsintheurine25to100foldthatofserum.Incontrast,theyshowpoorpenetrationintotheCSF,
biliarytree,andbronchialsecretions.

EliminationApproximately99percentoftheadministereddoseiseliminatedunchangedintheurine,
primarilybyglomerularfiltration.Theterminalhalfliferangesfrom1.5to3.5hoursinadultswithnormalrenal
function.Thehalflifeisprolongedinneonates,infants,andpatientswithdecreasedrenalfunction.

Aminoglycosidesareeffectivelyremovedbybothhemodialysis(continuousandintermittent)andperitoneal
dialysis.Asaresult,supplementaldosesafterhemodialysisaregenerallyrequired.(See"Dosingand
administrationofparenteralaminoglycosides",sectionon'Intermittenthemodialysis'.)

TOXICITYTheprimarytoxicitiesofaminoglycosidesarenephrotoxicityandototoxicity.Rarely,
neuromuscularblockadecanoccur.

NephrotoxicityThereportedincidenceofnephrotoxicityvarieswidelyduetovariationsinstudydesign,
toxicitydefinitions,patientpopulation,andconcomitantriskfactors.Areasonableestimate(dependingon
definition)maybe10to20percent,evenwhencarefulpatientselectionandclosemonitoringisperformed.In
mostcases,aminoglycosidetoxicityisreversible.

Aminoglycosideassociatednephrotoxicityisdiscussedingreaterdetailelsewhere.(See"Manifestationsofand
riskfactorsforaminoglycosidenephrotoxicity"and"Pathogenesisandpreventionofaminoglycoside
nephrotoxicityandototoxicity",sectionon'Nephrotoxicity'.)

OtotoxicityAminoglycosideinducedototoxicitymayresultineithervestibularorcochleardamage.
Manifestationsofvestibulartoxicityincludevertigo,disequilibrium,lightheadedness,nausea,vomiting,and
ataxia,whiletheusualsymptomsofcochleartoxicityaretinnitusandhearingloss.Inmanycases,ototoxicity
isirreversible.

Aminoglycosideassociatedototoxicityisdiscussedingreaterdetailelsewhere.(See"Pathogenesisand
preventionofaminoglycosidenephrotoxicityandototoxicity",sectionon'Ototoxicity'.)

NeuromuscularblockadeNeuromuscularblockadeisararebutseriousadverseeffectinducedby
aminoglycosidetherapy.Mostpatientsexperiencingsuchreactionshavediseasestatesand/orconcomitant
drugtherapythatinterferewithneuromusculartransmission.

Myastheniagravisisanabsolutecontraindicationtoaminoglycosideuse.

DRUGINTERACTIONSTheaminoglycosidescaninteractwithavarietyofotherdrugscausingincreased
toxicityand/ordecreasedefficacy.Specificinteractionsmaybereviewedusingthedruginteractionstool(Lexi
InteractOnline).ThistoolcanbeaccessedfromtheUpToDatesearchpageaswellasonindividualdrug
informationtopicsinthesectionentitled"Druginteractions."

SUMMARY

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Aminoglycosidesbindtotheaminoacylsiteof16SribosomalRNAanddisruptbacterialpeptide
elongation,whichisusuallybactericidalagainstsusceptibleaerobicgramnegativebacilli.Microbiologic
activityispHdependent,andacidicenvironments,likethosefoundinthelungandbronchialsecretions,
maydecreasetheantimicrobialeffect.(See'Mechanismofaction'above.)

Aminoglycosidesexhibitpotentinvitroactivityagainstawiderangeofaerobicgramnegativepathogens
BurkholderiacepaciaandStenotrophomonasmaltophiliaareparticularexceptions.Gentamicinusually
demonstratessuperiorinvitroactivitytotobramycinagainstSerratiaspp,whiletobramycinisusually
morepotentthangentamicinagainstP.aeruginosa.Aminoglycosides(mostnotablyamikacinand
streptomycin)arealsoactiveagainstmycobacteria.(See'Spectrumofactivity'above.)

Emergenceofaminoglycosideresistanceduringtreatmentofgramnegativeinfectionsisinfrequentbut
canoccurthroughbacterialproductionofenzymesthatinactivatethedrugormethylatethetarget16S
ribosomalRNAandthroughaneffluxsystemthatdecreasesaminoglycosideaccumulation.Enterococci
areintrinsicallyresistanttomoderatelevelsofaminoglycosides.Thepotentialforsynergyincombination
withacellwallactiveagentremainsunlesstheenterococcushasacquiredhighlevelresistanceto
aminoglycosides.(See'Resistance'above.)

Aminoglycosidesaremostfrequentlyusedincombinationwithanotherantibacterialagentforempiric
therapyofsepticemia,nosocomialrespiratorytractinfections,complicatedurinarytractinfections,
complicatedintraabdominalinfections,andosteomyelitiscausedbyaerobicgramnegativebacilli.They
areoftendiscontinuedinfavoroflesstoxicantibioticsonceorganismidentityandsusceptibilityhasbeen
confirmed.(See'Clinicaluse'above.)

Combinationtherapywithgentamicinisfrequentlyusedforthetreatmentofinvasiveinfectionscausedby
enterococciintheabsenceofhighlevelresistance.(See'Clinicaluse'above.)

Parenteralaminoglycosidesarealsousedaspartofaregimenformycobacterialinfections,andasa
singleagentforthetreatmentoftularemia,plague,anduncomplicatedurinarytractinfectionscausedby
drugresistantgramnegativeorganisms.(See'Clinicaluse'above.)

Dosingandmonitoringofparenteralaminoglycosidesisdiscussedindetailelsewhere.(See"Dosingand
administrationofparenteralaminoglycosides".)

Aminoglycosidesdemonstratebothpostantibioticeffectandconcentrationdependentkilling.
Aminoglycosidesreachconcentrationsintheurine25to100foldthatofserumbuthavepoorpenetration
intotheCSF,biliarytree,andbronchialsecretions.Theyareeffectivelyremovedbybothhemodialysis
andperitonealdialysis.(See'Mechanismofaction'aboveand'Pharmacodynamicsandkinetics'above.)

Theprimarytoxicitiesofaminoglycosidesarenephrotoxicity,whichisgenerallyreversible,and
ototoxicity,bothvestibularandcochlear.Neuromuscularblockadeisararebutseriousadverseeffect,
andmyastheniagravisisanabsolutecontraindicationtoaminoglycosideuse.(See'Toxicity'aboveand
"Manifestationsofandriskfactorsforaminoglycosidenephrotoxicity"and"Pathogenesisandprevention
ofaminoglycosidenephrotoxicityandototoxicity".)

UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.

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Topic483Version10.0

Disclosures
Disclosures:RichardHDrew,PharmD,MS,FCCPSpeaker'sBureau:AmericanSocietyofMicrobiology[Antimicrobialstewardship,
multidrugresistantpathogens]CampbellUniversityVemCoMedicalEducation.OtherFinancialInterest:CustomID
(Software/website).DavidCHooper,MDConsultant/AdvisoryBoards:Bacterioscan[Antimicrobials(Urinediagnosticunder
development)]Cubist[Antimicrobials(Daptomycin,fidaxomycin,tedizolid,ceftolozanetazobactam)]Shionogi[Antimicrobials(Anti
gramnegativebetalactamunderdevelopment)]Melinta[Antimicrobials(Antimicrobialsunderdevelopment)]Cepheid[Antimicrobials
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(rapidgeneticdiagnostics)]FabPharma[Antimicrobials(Antimicrobialunderdevelopment)].AllysonBloom,MDNothingtodisclose.
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