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penicillinsinthecombinationshasbeenassociatedwiththeinactivationofaminoglycosidesinvitro.The
clinicalsignificanceofthisinteractionisunknown.
CEPHALOSPORINS
Thecephalosporins,abeta-lactamgroup,arestructurallysimilartothepenicillins.Substitutionsonthe
parent compound, 7-aminocephalosporanic acid, produce compounds with different pharmacokinetic
properties and spectra of activity. The cephalosporins are divided into generations based on their
antimicrobialspectrumofactivity.Theprogressionfromfirsttofourthgenerationingeneralreflectsan
increase in gram-negative coverage and a loss of gram-positive activity. The fifth generation cephalosporinsareconsideredMRSA-activeagents.Thesiderophorecephalosporinsrepresentanovelclass
ofcephalosporinswithactivityagainstdrug-resistantgram-negativeorganisms.
PharmacokineticsandPharmacodynamics
ThecephalosporinsarewellabsorbedfromtheGItract.Insomecases,foodenhancesabsorption.They
penetrate well into tissues and body fluids and achieve high concentrations in the urinary tract.
Noncephamycinsecond-generationagentsandallthird- andfourth-generationagentspenetratetheCSF
and play a role in treating bacterial meningitis. Most of the oral and parenteral cephalosporins are
excretedbythekidney,withtheexceptionofceftriaxone(Rocephin)andcefoperazone(notavailablein
the United States), which are eliminated by the liver. The cephalosporins exhibit a time-dependent
bactericidaleffectandaprolongedPAEagainststaphylococci.Table6.5providesdosinginformation.
TABLE6.5
CephalosporinDosages
Drug AdultDosages PediatricDosages
FirstGeneration
Cefazolin 500mg–1gIVq8h 50–100mg/kg/dIVdividedq8h
Cephalexin 250–1,000mgPOq6h 25–100mg/kg/dPOdividedq6h
Cefadroxil 500mg–1gPOq12h 30mg/kg/dPOdividedq12h
SecondGeneration
Cefotetan 1–2gIVq12h 40–80mg/kg/dIVdividedq12h
Cefoxitin 1–2gIVq6–8h 80–160mg/kg/dIVdividedq4–8h
Cefuroxime 750–1.5gIVq8h 75–150mg/kg/dIVdividedq8h
Cefuroximeaxetil 250–500mgPOq12h 20–30mg/kg/dPOdividedq12h
Cefaclor 250–500mgPOq8h 20–40mg/kg/dPOdividedq8–12h
ThirdGeneration
Cefotaxime 1–2gIVq8h 100–300mg/kg/dIVdividedq6–8h
Ceftazidime 1–2gIVq8h 90–150mg/kg/dIVdividedq8h
Ceftriaxone* 1–2gIVq12–24h 50–100mg/kg/dIVdividedq12–24h
Ceftibuten 400mgPOq24h 9mg/kg/dPOdividedq24h
Cefpodoximeproxetil 100–400mgPOq12h 10mg/kg/dPOdividedq12h
Cefprozil 250–500mgPOq12h 15–30mg/kg/dPOdividedq12h
Cefdinir 300mgPOq12hor600mgPOq24h 7–14mg/kg/dPOdividedq12–24h
FourthGeneration
Cefepime 1–2gIVq8–12h 50mg/kg/dIVdividedq8h
Ceftaroline 600mgIVq8h
—
SiderophoreCephalosporins
Cefiderocol 2gIVq8h
—
Note:Dosageadjustmentnecessaryforallagentsinpatientswithrenalimpairmentexceptceftriaxone.
*Dosageadjustmentnecessaryinpatientswithliverdysfunction.
IV,intravenous.
MechanismofActionandSpectrumofActivity
Likeotherbeta-lactams,thecephalosporinsinterferewithbacterialcellwallsynthesisbybindingtoand
inactivatingthePBPs.Thesiderophorecephalosporinsutilizethesiderophore–ironcomplexpathwayto
penetratetheoutermembraneofgram-negativeorganismsinadditiontonormalpassivediffusionthrough
membraneporins.
ClinicalUses
Thecephalosporinsareusedintreatingmanyinfections.Ingeneral, thefirst-generationcephalosporins
areusedintreatinggram-positiveskininfections,pneumococcalrespiratoryinfections,andurinarytract
infections and for surgical prophylaxis. The second-generation cephalosporins are used in treating
community-acquiredpneumonia,otherrespiratorytractinfections,andskininfections.Mixedaerobicand
anaerobicinfectionsmaybetreatedwiththesecond-generationcephamycins(cefotetanandcefoxitin).In
addition, treating community-acquired bacterial meningitis typically includes a third-generation
cephalosporinsuchasceftriaxoneorcefotaxime(Claforan).Nosocomialinfectionsarecommonlytreated
with ceftazidime (Fortaz) or cefepime (Maxipime), whose broad spectrum of activity includes gramnegativeorganisms,especiallyP.aeruginosa.Ceftarolinefosamil(Teflaro),anewIVcephalosporin,has
activitysimilartoceftriaxonebutistheonlycephalosporinthatcoversMRSA.Thespectrumofactivity
ofcefiderocol(Fetroja),thenovelsiderophorecephalosporin,encompassesbothlactose-fermentingand
non-lactose-fermentinggram-negativepathogens,includingcarbapenem-resistantEnterobacterales.
AdverseEvents
The cephalosporins are a safe class of antimicrobials with a favorable toxicity profile. With a few
exceptions,theadverse eventsaresimilar acrossthegenerations.Hypersensitivityreactions,notunlike
those withthe penicillins, are characterizedby maculopapular rash andurticaria. Thecross-reactivity
between penicillins and cephalosporins is 3% to 10%. Patients who experience allergic reactions to
penicillins (other thanatype1allergy[see Chapter46])canoftentolerate a cephalosporin.Themost
commonsideeffectswithoraladministrationare nausea,vomiting,anddiarrhea.GIeffectsareusually
transient.LesscommonreactionsincludeapositiveCoombstestandrarelyhemolyticreactions.
DrugInteractions
Druginteractionsinvolvingcephalosporinsarerare.Probenecidhasbeenshowntoincreasethehalf-life
ofsomecephalosporinsbyinhibitingtherenaltubularsecretion.
MONOBACTAMS
Themonobactamsareauniqueclassofbeta-lactamswithafour-memberedringbutlackingafifthorsixth
member,likeotherbeta-lactams.Becauseaztreonam(Azactam)istheonlyagentofitsclasscommercially
available,mostoftheinformationrelatesspecificallytothatagent.Withprimaryactivityagainstgramnegative organisms, including Pseudomonas, aztreonam is considered a safer alternative to the
aminoglyco-sides,withasimilarspectrumofactivity.
PharmacokineticsandPharmacodynamics
Aztreonamdistributeswellintomosttissues,withavolumeofdistributionof0.16L/kg.Penetrationinto
the CSF is increased in the presence of inflamed meninges. Aztreonam is not extensively bound to
proteins. The approximate half-life is 2 hours, and dosages are typically calculated according to the
severityofdisease(Table6.6). Aztreonamis excretedprimarilyunchangedbyglomerularfiltration,so
dosage adjustments are necessary in patients with renal insufficiency. Aztreonam is cleared by
hemodialysisandperitonealdialysis.
TABLE6.6
AztreonamDosages
Monobactams
Drug AdultDosages PediatricDosages
Aztreonam 1–2gIVq6–12h 90–120mg/kg/dIVdividedq6–8h
Note:Dosageadjustmentrequiredinpatientswithimpairedrenalfunction.
IV,intravenous.
MechanismofActionandSpectrumofActivity
Aztreonam, like other beta-lactams, interferes with bacterial cell wall synthesis by binding to and
inactivatingPBPs.Theprincipalactivityofaztreonamisagainstmostaerobicgram-negativeorganisms,
includingP.aeruginosa,Serratiamarcescens,andCitrobacterspecies.Ithasvirtuallynoactivityagainst
gram-positive organisms. Its gram-negative coverage issimilar tothat of the aminoglycosides andthe
third-generationcephalosporinceftazidime.Aztreonamisnotactiveagainstanaerobicorganisms.
ClinicalUses
Aztreonamiscommonlyusedintreatingcomplicatedanduncomplicatedurinarytractandrespiratorytract
infections such as pneumonia and bronchitis when aerobic gram-negative coverage is necessary. To
broadencoverage,itisusuallyusedincombinationwithanagentexhibitinggram-positiveactivity.Itisa
reasonablesubstitutefortheaminoglycosidesintreatinggram-negativeinfectionsinpatientsathighrisk
fortoxicity.
AdverseEvents
Aztreonamhasarelativelysafetoxicityprofile.Mostoftheadverseeventsassociatedwithaztreonamare
localreactionsandGIsymptoms.Elevatedaminotransferaselevelshavealsobeendocumented.Patients
allergic to penicillins and cephalosporins usually do not manifest an allergic reaction to aztreonam,
despite its beta-lactam structure. A cross-allergy specifically with ceftazidime has been reported and
linkedtoanidenticalsidechainonbothcompounds.
DrugInteractions
Noclinicallysignificantdruginteractionshavebeendocumentedwithaztreonam.
CARBAPENEMS
The carbapenems, ertapenem (Invanz), doripenem (Doribax), imipenem (Primaxin), and meropenem
(Merrem), are bicyclical beta-lactams with a common carbapenem nucleus (Table 6.7). Imipenem is
extensivelymetabolizedbyrenaldehydropeptidases,yieldingonlylimitedactivityintheurine.Cilastatin,
acompetitiveinhibitorofthedehydropeptidases,wasintroducedtoovercomeimipenemdegradationand
iscommerciallyavailableincombinationwithimipeneminaone-to-oneratio.Subsequently,ertapenem,
meropenem,anddoripenemweredeveloped;theymaintainstabilityagainstdehydropeptidasemetabolism
withouttheadditionofacilastatin-likeagent.Imipenem-cilastatin-relebactam(Recarbrio)isthefirstofa
newtriplecombinationthatincludesabeta-lactamaseinhibitortoassistinthetreatmentofcomplicated
gram-negative infections of the urinary and abdominal tracts. The carbapenems are the most broadspectrumagentscommerciallyavailable.
PharmacokineticsandPharmacodynamics
Carbapenemsarenotabsorbedafteroraladministration.Theyexhibitlinearpharmacokinetics;thus,peak
serumlevels increase proportionately as thedose is increased. Theyarewidelydistributedinto most
tissues,withanapproximatevolumeofdistributionof0.25 L/kg.Withtheexceptionofertapenem,they
are minimallybound toplasmaproteins.PenetrationintotheCSFvariesanddependsonthedegreeof
meningeal inflammation.Thehalf-life ofthe carbapenemsisapproximately1 hour.Theyareprimarily
eliminatedbyurinaryexcretionofunchangeddrug.Imipenem,meropenem,anddoripenem areremoved
byhemodialysisandhemofiltration.
The carbapenems, like other beta-lactams, exhibit time-dependent bactericidal effects. Unlike other
beta-lactams,theyexhibitaPAEagainstgram-negativeaerobeslastingatleast1to2hours.
TABLE6.7
CarbapenemDosages
Drug AdultDosages PediatricDosages
Ertapenem 1gIV/IMdaily 30mg/kg/dIVdividedq12h
Doripenem 500mgIVq8h Notrecommended
Imipenem 250–1,000mgIVq6h 25–100mg/kg/dIVdividedq6h
Meropenem 500–1,000mgIVq8h 30–120mg/kg/dIVdividedq8h
Note:Dosageadjustmentrequiredforallabovedrugsadministeredtopatientswithrenalimpairment.
IM,intramuscular;IV,intravenous.
MechanismofActionandSpectrumofActivity
Similartothepenicillinsandcephalosporins,thecarbapenemsbindtoseveralPBPsonthecellwalland
interferewithbacterialcellwallsynthesis.
Imipenem,meropenem, and doripenempossessthebroadestspectrum of activityofanyofthe beta-
lactam compounds. They have excellent activity against aerobic grampositive organisms, including
staphylococciandstreptococci,andgram-negativeorganismssuchasEnterobacteriaceae,P.aeruginosa,
and Acinetobacter species. They are also active against most gram-negative anaerobic organisms,
includingB.fragilis.Ertapenem has a similar spectrum of activity as theothercarbapenems, withthe
noted exceptions of P. aeruginosa and Acinetobacter species, for which ertapenem has no clinically
significantactivity.
ClinicalUses
Their broadspectrumofactivityandstabilitytomanybeta-lactamasesmakethecarbapenemsusefulas
singleagentsintreatingpolymicrobial infections.Theyhavebeenusedextensivelyintreatingskinand
softtissue,boneandjoint,intraabdominal,andlowerrespiratorytractinfections.Inaddition,meropenem
isusedintreatingCNSinfectionsbecauseithasalowerriskthanimipenemofcausingseizures.
AdverseEvents
Neurotoxicity,awell-knowneffectofthecarbapenems,ischaracterizedbyseizureactivity.Imipenemhas
been reported to lower the seizure threshold more frequently than meropenem and doripenem. Risk
factorsforseizuresincludeimpaired renalfunction,improperdosing,age,previousCNSdisorder,and
concomitantagents thatlower the seizure threshold. Meropenemand more recently doripenemare the
carbapenemsofchoiceinpatientswithaseizuredisorderorunderlyingriskfactors.SuchGIsideeffects
asnausea,vomiting,anddiarrheahavealsobeenreported.Decreasingtheinfusionratemaylessentheir
severity.
DrugInteractions
Concomitantadministrationofprobenecidandmeropenemordoripenemresultsindecreasedclearanceof
theseagentsandasubstantialincreaseinhalf-life;therefore,theconcurrentadministrationofmeropenem
ordoripenemwithprobenecidisnotrecommended.Asimilarinteractionwithimipenemoccursbuttoa
lesserdegree.
FLUOROQUINOLONES
Since1990,thefluoroquinolones(FQs)havebecomeadominantclassofantimicrobialagents.Noother
class of antimicrobial agents has grown so rapidly or been developed with such interest by
pharmaceuticalresearchcompanies.Althoughmultiplemedicationsinthisclasshavebeenapprovedby
theU.S.FoodandDrugAdministration(FDA),severalFQshavebeenremovedfromtheU.S.marketdue
totheidentificationofpostmarketingadverse events.This emphasizestheimportanceofpostmarketing
research and adverse-event reporting. In 2016, the FDA issued a warning stating that adverse effects
associatedwithFQsoutweighthebenefitsincertaininfections(FDA,2016).Today, theroutineuseof
FQs to treat various types ofuncomplicated infections is no longer recommended. Table 6.8 lists the
availableFQs.Ciprofloxacin,levofloxacin,andmoxifloxacinaremostcommonlyprescribed.
TABLE6.8
FluoroquinoloneDosages
Drug AdultDosages
Ciprofloxacin 250–750mgPOq12h;200–400mgIVq12h;400mgIVq8h(severeinfections)
Delafloxacin 300mgIVq12hor450mgPOq12h
Gemifloxacin 320mgPOdaily
Levofloxacin 250–750mgPO/IVdaily
Moxifloxacin 400mgPO/IVdaily
Norfloxacin 400mgPOq12h
Ofloxacin 200–400mgPOq12h
Note:Withtheexceptionofciprofloxacinforthetreatmentofurinarytractinfectionsandanthrax,thesedrugsarenotrecommendedforusein
childrenyoungerthanage18.Dosageadjustmentisrequiredforalldrugs(exceptmoxifloxacin)administeredtopatientswithrenalimpairment.
IV,intravenous.
PharmacokineticsandPharmacodynamics
TheFQs are bactericidal antibiotics. Delafloxacinis uniqueinthatitis ananionicFQ,whereas other
FQs are zwitterionic. This basically means that delafloxacin has increased accumulation in bacteria,
allowingforenhancedbactericidalactivity.
The FQs display a concentration-dependent killing effect. All FQs have excellent bioavailability,
makingiteasytotransitionfromanIVtoanoralformulation.Theyhaveavolumeofdistributionranging
from1.5to6.1L/kganddistributewellintomosttissuesandfluidsexcepttheCNS.Thehalflifeforthe
FQsrangesfrom4to12hours,withlevofloxacin,gemifloxacin,andmoxifloxacinhavingthelongesthalflives.Thesethreeagentsaredosedoncedaily.AllFQsundergorenaleliminationwiththeexceptionof
moxifloxacin.TheFQs are removedbyhemodialysisandperitonealdialysis,withpercentagesvarying
between products. All FQs also exhibit a PAE, which also appears to be a concentration-dependent
parameter. Thenewer compounds havebeenreportedtohave PAEsof 1 to6 hours, dependingonthe
pathogenanddrug.
MechanismofActionandSpectrumofActivity
The quinolone antibiotics are strong inhibitors of deoxyribonucleic acid (DNA) gyrase and
topoisomeraseIV.TheseenzymesarecriticaltotheprocessofsupercoilingDNA.Withoutsuchenzymatic
activity,bacterialDNAcannotreplicate.
All FQs possess activity against aerobic gram-negative organisms. Ciprofloxacin and levofloxacin
haveactivityagainstP.aeruginosa,representingtheoralantibioticscommonlyusedtotreatthispathogen.
However,widespreaduseoftheFQssincethelate1990shaveledtoincreasedresistanceagainstgramnegativepathogensandlimiteduseinsomepartsoftheUnitedStates.NewerFQs,suchaslevofloxacin,
moxifloxacin,andgemifloxacin,have activityagainstgram-positiveorganismsincludingStreptococcus
species.Theseagentsaresometimesreferredtoastheanti-pneumococcalorrespiratoryFQsgiventheir
activity against Streptococcus pneumoniae and usefulness in treating community-acquired pneumonia.
Moxifloxacin(Avelox)hassomeactivityagainstanaerobicbacteria.Delafloxacin(Baxdela)possessesin
vitroactivityagainstMRSA,P.aeruginosa,andcertainanaerobicbacteriaincludingB.fragilis.
ClinicalUses
TheFQshavebeenshowntobeeffectiveintreatingmanyinfections,includingurinarytractinfections,
pneumonia,sexuallytransmitteddiseases, skinandsofttissueinfections,GIinfections(incombination
with an agent for anaerobic coverage), traveler’s diarrhea, and osteomyelitis. For hospital-acquired
infections such as nosocomial pneumonia, ciprofloxacin (Cipro) or levofloxacin (Levaquin) is the
preferred agent, as part of a drug combination, because these agents have the best activity against P.
aeruginosa.Ciprofloxacinisalsorecommendedformeningococcalprophylaxisasasingle500-mgoral
dose.
AdverseEvents
The most common side effects include nausea, diarrhea, dizziness, and confusion. QTc interval
prolongation remains a potentially serious effect as well. Enhanced warnings include disabling and
potentiallypermanentsideeffectsinvolvingtendons,muscles,joints,nerves,andtheCNS.
DrugInteractions
The FQs have several significant drug–drug interactions. Ciprofloxacin is a potent inhibitor of the
cytochrome P-450 (CYP) 1A2 isoenzymeandmay increase the effect of other medications, including
theophylline, warfarin (Coumadin), tizanidine, and propranolol. Antacids, sucralfate, and magnesium,
calcium,orironsaltswilldecreasetheabsorptionoftheFQsifgivenconcomitantly.Theseagentsshould
be separated when administered orally. Due to theriskofQTc prolongation and torsades de pointes,
medications that prolong the QTc interval should be used cautiously with the FQs. Prolonged
administration of FQs in combinationwith corticosteroids increases the risk of tendonitis andtendon
rupture.HyperglycemicandhypoglycemiceventshavebeenreportedwithFQswhenadministeredwith
insulinorotherantidiabeticagents.
MACROLIDES
Erythromycin(E-Mycin),theprototypicalmacrolide,hasbeenusedintreatingmanyinfectionsoverthe
years.However,itsusehasbeendiminishedbyitsGIsideeffects.Thistoxicityhasevenbeenusedasa
meansof treatingpatientswithdiabeticgastroparesis.Neweragents(clarithromycinandazithromycin)
havebeendevelopedwithimprovedGItoleranceandlongerhalf-lives.Telithromycin(Ketek),arelated
ketolidewithasimilarmechanismofactionandantibacterialcoverage,waswithdrawnfromthemarket
duetosafetyconcernsofacutehepaticfailure.Fidaxomicin(Dificid)isthefirstmacrolideantibioticwith
anarrowspectrumofactivitytargetedagainstClostridiumdifficile.
PharmacokineticsandPharmacodynamics
ThemacrolidesareusuallyadministeredorallyandareabsorbedfromtheGItractifnotinactivatedby
gastricacid.Fidaxomicinisnotsystemicallyabsorbedandactslocallyinthecolon.Themacrolideshave
good tissuepenetration,achieve highintracellular concentrations,andexhibitminimal proteinbinding.
Themacrolidesaremetabolized via theliver andexcretedinthe urine. Half-livesvarythroughout the
class,from2 hours forerythromycin,4 to5 hours for clarithromycin(Biaxin), and50 to60hours for
azithromycin(Zithromax).Thelonghalflifeandhighintracellular concentrationsofazithromycinpermit
once-dailydosingandshortcourses.Dosageadjustmentinpatientswithrenalfailureisnecessarywith
clarithromycin (Biaxin) and erythromycin (Table 6.9). The macrolides are minimally cleared via
hemodialysisandperitonealdialysis.
TABLE6.9
Macrolide/KetolideAntibioticDosages
Drug AdultDosages PediatricDosages
Azithromycin 250–500mgIV/POdailyor2,000mg(ER)PO
singledose
5–12mg/kgIV/POdailyor30mg/kgPO
singledose
Clarithromycin* 250–500mgPOq12hor1,000mg(ER)PO
daily
15mg/kg/dPOdividedq12h
Erythromycinbase* 250mg–1gPOq6h 30–50mg/kg/dPOdividedq6–8h
Erythromycinethyl
succinate
400–800mgPOq6–12h 30–50mg/kg/dPOdividedq6–8h
Erythromycininjection 500–1,000mgIVq6–8h 15–50mg/kg/dIVdividedq6h
*Dosageadjustmentnecessaryinpatientswithrenalimpairment.
ER,extended-releaseproduct;IV,intravenous.
MechanismofActionandSpectrumofActivity
Themechanismofactionofthemacrolidesisinhibitionofbacterialproteinsynthesisbybindingtothe
50S ribosomal subunit. The spectrum of activity of the macrolides includes gram-positive and gramnegative aerobes and atypical organisms, including chlamydia, mycoplasma, legionella, rickettsia,
mycobacteria,andspirochetes.
ClinicalUses
The macrolides are used in several settings. Their broad spectrum of activity makes them useful in
treating respiratory tract, skin, and soft tissue infections, sexually transmitted diseases, HIV-related
Mycobacteriumavium–Mycobacteriumintracellularecomplexinfection,andotherinfectionscausedby
atypicalorganismssuchaschlamydia,rickettsia,andlegionella.Fidaxomicinissolelyusedtotreatboth
severeandnon-severecasesofC.difficileinfection.
AdverseEvents
Themacrolidesareingeneralconsideredsafeagents.Particularlywitherythromycin,GIeffectssuchas
abdominalpain,nausea,andvomitingaremostcommon.ThenewermacrolidescausefewerGIeffects.
Hepatotoxicityrelatedtothemacrolidesisrarebutserious;italsoislessfrequentwiththeneweragents.
ExtremelyhighdosesofIVerythromycinandoralclarithromycinhavebeenassociatedwithototoxicity.
PhlebitismayoccurwithIVerythromycinadministration.
DrugInteractions
Amongthemacrolides,erythromycinandclarithromycinarepotentinhibitorsoftheCYP3A4isoenzyme.
Whenadministered concomitantly,theyhavebeenshowntoprolongthehalf-lifeofanextensivelistof
agents, including cyclosporine, tacrolimus, carbamazepine, theophylline, warfarin, and most statins.
Azithromycin does notundergo significantcytochromeP-450metabolism, so the possibility ofsimilar
interactionsislow.MacrolideshavethepotentialtoincreasetheQTcinterval,socautionshouldbeused
inpatientsreceivingconcomitantmedicationsthatcanalsoprolongtheQTcinterval.
AMINOGLYCOSIDES
Despitetheadventofmanynewantibioticsoverthepastseveraldecades,theaminoglycosidesremainan
importanttherapeuticdrugclass.Theirmajordrawbackhasbeentheirpotentialfordrug-relatedtoxicities
(nephrotoxicityandototoxicity).Becauseofthese,theiruseorthelengthoftherapyhasbeenrestricted.
Theintroductionofamodifieddosingregimenthatusesonce-daily(orextended-interval)dosingofthese
agentsforseveralinfectionshasprovidedawayofmaximizingtheirtherapeuticeffectswhileminimizing
theriskoftoxicity.
PharmacokineticsandPharmacodynamics
TheaminoglycosidesarepoorlyabsorbedfromtheGItract,andparenteraladministrationisnecessaryto
treatsystemicinfections.Theyare weaklyboundtoserumproteins(10%)andfreelydistributeintothe
extracellular fluid. The approximate volume of distribution is 0.25 L/kg, which may be significantly
affectedin intensive carepatientsandin disease statessuchasmalnutrition, obesity, andascites. The
amino-glycosidesareexcretedunchangedviaglomerularfiltration.Thehalf-lifeofaminoglycosidesinan
adult with normal renal function is approximately 1 to 3 hours. Dosage adjustments are necessary in
patientswithrenalimpairmentbecausesubstantial increases inthehalf-lifeareseen.Aminoglycosides
canberemovedbyhemodialysis,peritonealdialysis,andcontinuoushemofiltration/dialysis.
Becauseofanarrowrangebetweenefficacyandtoxicity,renalfunctionandserumlevelsareusedto
monitortherapywithaminoglycosides.Table6.10givesdosageguidelines.
Pharmacodynamically,thebactericidaleffectoftheami-noglycosidesdependsondrugconcentration.
The number of organisms decreases more rapidly when a higher peak concentration is achieved. In
addition,theaminoglycosidesexhibitaPAEforbothgram-positiveandgram-negativeorganisms.
TABLE6.10
AminoglycosideDosages
Aminoglycoside AdultDosages PediatricDosages
MultipleDailyDosing
Gentamicin,tobramycin 1–1.7mg/kgIVq8h 6–7.5mg/kg/dIVdividedq8h
Netilmicin* 1.7–2mg/kgIVq8h
Amikacin,kanamycin* 5mg/kgIVq8hor7.5mg/kgIVq12h 15–22.5mg/kg/dIVdividedq8h
Streptomycin 0.5–2gIVq24h 20–40mg/kg/dIVdividedq6–12h
Once–DailyDosing*
Gentamicin,tobramycin 5–7mg/kgIVq24h 5–7.5mg/kgIVq24h
Netilmicin* 4–6mg/kgIVq24h
Amikacin 15–20mg/kgIVq24h 20mg/kgIVq24h
Plazomicin 15mg/kgIVq24h
Note:Dosageadjustmentrequiredforalldrugsadministeredtopatientswithrenalimpairment.
*NotroutinelyavailableforuseintheUnitedStates.
† Once-daily dosing of aminoglycosides is not recommended for enterococcal infections, during pregnancy, in instances of gram-positive
synergy,orforendocarditis,meningitis,orascites.
IV,intravenous.
MechanismofActionandSpectrumofActivity
Theaminoglycosidesareactivelytakenupbybacteriaandsubsequentlybindtothesmaller30Ssubunit
ofthebacterialribosome,thusinhibitingbacterialproteinsynthesis.
The principal activity of the aminoglycosides is against aerobic gram-negative bacilli such as
Escherichiacoli,Klebsiellaspecies, Proteus mirabilis, Enterobacter species, Acinetobacter species,
and P. aeruginosa. They are also generally active against gram-positive cocci, particularly
Staphylococcus, Enterococcus, and Streptococcus species, butthey mustbe used incombination (for
synergy)withacellwall–activeagentsuchasampicillin,nafcillin,orvancomycin.Streptomycinisalso
activeagainstFrancisellatularensisandMycobacteriumtuberculosis.Plazomicin(Zemdri) is a novel
aminoglycoside that has been modified to maintain stability against common mechanisms of
Enterobacteriaecaeresistance.
ClinicalUses
Theaminoglycosidesareprimarilyusedintreatinggramnegativeinfections.Theyhavelongbeenusedin
theempirictreatmentofneutropenicfeverandnosocomialinfectionsbecauseoftheirbroadcoverageof
P.aeruginosaandEnterobacteriaceae.Theyarealsofrequentlyusedwithcellwall–activeagentssuchas
penicillins, cephalosporins, and vancomycin to achieve synergy in treating gram-positive infections,
includingstaphylococcalandenterococcalinfections.Theyareroutinelyusedincombinationwithother
agents in treating pneumonia, bacteremia, and intra-abdominal and skin and soft tissue infections.
Monotherapy usually is not recommended, with the noted exception of patients with urinary tract
infections. The aminoglycosides havebeenused in treatingtuberculosis, withstreptomycin havingthe
greatestactivity againstM.tuberculosis. Streptomycin is also the treatment of choice for tularemia, a
potentialagentofbioterrorism.
AdverseEvents
Ingeneral, theaminoglycosideshave beenassociated with a varietyofadverse events(GIandCNS),
most of which are mild and transient. They rarely produce hypersensitivity reactions and are well
tolerated at the sites of administration. Nephrotoxicity and ototoxicity are also associated with
aminoglycosideuse.
Nephrotoxicityresultsfromaccumulationofthedrugintheproximaltubulecellsofthekidney,causing
nonoliguric renalfailure.Thisrenalfailureis usuallymild andreversibleandrarelyprogresses tothe
need for dialysis. Factors that increase the risk of toxicity to the kidney include increased age, renal
disease,increasedtroughlevels,dehydration,andconcomitantadministrationofnephrotoxicagentssuch
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