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asamphotericinB,cyclosporine,andvancomycin.Bloodureanitrogenandserum creatininevaluesare
monitoredinadditiontoserumlevelstoensuresafeandeffectivetherapy.Table6.11providesoptimal
serumconcentrationsforaminoglycosides.
Two forms of ototoxicity—auditory and vestibular—may occur alone or simultaneously. Auditory
toxicitypresentsas
hearinglossandtinnitus;vestibulartoxicityismanifestedbynausea,vomiting,andvertigo.Ototoxicity
may be irreversible and has been associated with high serum trough levels. The risk of ototoxicity
increaseswhentheaminoglycosidesareadministeredincombinationwithhigh-doseloopdiuretics,highdose macrolide antibiotics, or vancomycin. Long courses of aminoglycosides warrant baseline and
periodicauditorymonitoring.
TABLE6.11
AminoglycosideConcentrationMonitoring
Aminoglycoside TargetPeak TargetTrough
MultipleDailyDosing*
Gentamicin,tobramycin 4–10mcg/mL <2mcg/mL
Netilmicin 4–10mcg/mL 12mcg/mL
Amikacin,kanamycin 20–30mcg/mL <8mcg/mL
Streptomycin 20–30mcg/mL <8mcg/mL
Once–DailyDosing*
Gentamicin,tobramycin >15mcg/mL 01mcg/mL
Netilmicin >15mcg/mL 01mcg/mL
Amikacin >50mcg/mL <5mcg/mL
Plazomicin <3ug/mL
*Serumconcentrationsbaseduponsteadystateformultipledailydosing.Peakconcentrationsshouldbeobtained30–60minutesafterinfusion
andtroughconcentrations30minutesbeforenextinfusion.
†Randomconcentrationsroutinelymeasuredforonce-dailydosinginlieuofpeakandtroughserumconcentrationsanddosageadjustments
basedupondosingnomograms.
DrugInteractions
The aminoglycosides have the potential to cause or prolong neuromuscular blockade, although this is
uncommon.Itisrecommendedthatparenteralaminoglycosidesbeadministeredovera30-minuteinterval.
Theriskofneuromuscular blockadeincreases inpatientsreceivingconcurrentneuromuscularblockers,
generalanesthetics,orcalciumchannelblockersandinthosewithmyastheniagravis.Administrationof
calciumgluconateusuallyreversestheneuromuscularblockade.
TETRACYCLINES
Thetetracyclinespossessactivityagainstgram-positive,gram-negative,andatypicalorganisms,including
rickettsia,chlamydia,mycobacteria,andspirochetes.Theclassictetracyclinesareseparatedintoshort-,
intermediate-, andlong-actingagents(suchasdoxycyclineandminocycline).Thetetracyclinesbecame
thefirstclassofantimicrobialstobelabeledbroadspectrum,andtheyremainafrequentlyusedclassof
antimicrobials.Alterationstothetetracyclinestructurehavealsoyielded anewergenerationofagents.
Tigecycline(Tygacil),eravacycline(Xerava), andomadacycline(Nuzyra)have recentlybeenadded to
thetetracyclinearmamentarium.
PharmacokineticsandPharmacodynamics
AbsorptionfromtheGItractalongwithproteinbindingvariesamongagents.Thelong-actingagentshave
thehighestabsorptionandareproteinboundtothegreatestextent.Withtheexceptionofthelong-acting
agents,absorptionisimprovedwithadministrationonanemptystomach.Thetetracyclineshaveexcellent
tissuedistribution.Theprimaryrouteofeliminationisthroughthekidneybyglomerularfiltration,with
theexceptionofdoxycyclineandthenewer generationagents.Ingeneral,theshort-acting agentshavea
half-lifeof8hoursandthelong-actingagents16to18hours.Thetetracyclinesareremovedtoasmall
degreebyhemodialysis.Table6.12providesdosinginformation.
MechanismofActionandSpectrumofActivity
Thetetracyclinesinhibitbacterialproteinsynthesisbybindingtothe30Ssubunitoftheribosomeandare
typicallybacteriostatic.Thetetracyclinesareactiveagainstgram-positiveandgram-negativebacteriaand
atypicalorganisms,includingspirochetes,rickettsia,chlamydia,mycoplasma,andlegionella.Thenewer
generationagentspossessenhancedactivityagainstMRSA,vancomycin-resistantenterococci(VRE),and
extended-spectrumbeta-lactamase-producingorganisms.
TABLE6.12
TetracyclineDosages
Drug AdultDosages
Doxycycline
(Vibramycin)
100mgIVorPOq12h
Eravacycline(Xerava) 1mg/kgIVq12h
Minocycline(Minocin) 100–200mgPOq12h
Tetracycline(Sumycin) 250–500mgPOq6h
Omadacycline
(Nuzyra)
200mgIVonday1,then100mgIVq24hor450mgPOdailyondays1–2,then300mg
POdaily
Tigecycline(Tygacil) 50mgIVq12h
Note:Dosageadjustmentnecessaryfordemeclocyline,minocycline,andtetracyclineinpatientswithrenalimpairment.Thetetracyclinesare
notrecommendedforuseinchildrenlessthanage8orduringpregnancyandbreast-feeding.
IV,intravenous.
ClinicalUses
Becauseoftheirbroadspectrumofactivity,thetetracyclinesareusedextensivelyinmanysettings.They
aretypicallyusedasalternativeswhenbeta-lactamsarenotanoption.Theyarefrequentlyusedintreating
rickettsial,chlamydial,andgramnegativeinfections,inadditiontoacnevulgarisandpelvicinflammatory
disease(PID).DoxycyclineisthedrugofchoiceforthetreatmentofearlyLyme diseaseandisusedin
treatingcommunity-acquiredpneumonia.Doxycyclineandminocyclineareusedassclerosingagentsfor
pleurodesis. Additionally, minocycline and doxycycline have gained popularity as a treatment for
community-acquiredMRSAinfections.Thoughatetracycline,demeclocycline(Declomycin)isprimarily
used to treat thesyndromeof inappropriate antidiuretic hormone and not as an antibiotic. The newer
generationagentsmaybeusedtotreatcomplicatedskinandskinstructureinfectionsandintra-abdominal
infectionsandmayproveusefulinthetreatmentoftetracycline-resistantorganisms.Giventheirspectrum
ofactivity,theymayalsobeusedforgram-negativeorganismsresistanttoalternativeagents.
AdverseEvents
The most frequent side effects associated with the tetracyclines are anorexia, nausea, vomiting, and
epigastric distress. These are typically lessened if the agents are administered with food.
Thrombophlebitis is associated with IV administration, and it is recommended that doxycycline be
administeredinalargevolumeandinfusedslowly.Hepatotoxicityisararebutpotentiallyfataltoxicity.
Theriskofhepatotoxicityincreasesifthepatientisconcurrentlyreceivingotherhepatotoxicagents.Graybrown discoloration of the teeth canbe a permanent effect of the tetracyclines. It results from stable
tetracycline–calcium complexes in bone and teeth and is related to dose and duration of therapy.
Therefore,childrenyoungerthanage8shouldnotreceivetetracyclines.Patientsreceivingtetracyclines
aremoresensitivetotheeffectsofthesunbecauseofaccumulationofthedrugintheskin.Minocycline
has been associated with dose-related vertigo. Tigecycline has been reported to cause asymptomatic
hyperbilirubinemia.
DrugInteractions
There are multiple druginteractions involving the tetracyclines. Theabsorption ofthetetracyclines is
affectedbyseveral agents.Tetracyclinesformchelatingcomplexes withdivalentandtrivalentcations,
decreasing tetracycline absorption. It is recommended that the administration of tetracyclines and
antacids,iron,cholestyramine,andsucralfatebeseparatedbyatleast1hour.Likewise,fooddecreases
the absorption of most tetracyclines, with the exception of doxycycline. Milk anddairy productsalso
impair their absorption. Phenytoin and carbamazepine, CYP (cytochrome P-450) enzyme inducers,
decrease the half-life of doxycycline. Concomitant administration of the tetracyclines and oral
contraceptives results in decreased levels of the oral contraceptive, so an additional form of
contraception is recommended. The tetracyclines also potentiate the effect of warfarin by impairing
vitaminKproductionbyintestinalflora.
SULFONAMIDES
In 1932, the dye prontosil rubrum was found to be effective in treating streptococcal infections.
Subsequently,itwasdeterminedthatoneoftheby-productswassulfanilimide.Manipulationofthisbyproductcreatedtheclassofantimicrobialsknownasthesulfonamides.
PharmacokineticsandPharmacodynamics
Oralsulfonamidesarereadilyabsorbedfrom theGItract.Theyaredistributedthroughallbodytissues
andenter the CSF, pleural fluid, andsynovial fluid. Theyareeliminatedfromthe bodybyglomerular
filtrationandhepaticmetabolism.Thehalf-livesofthesulfonamidesvaryfromhourstodays;sulfadoxine
(Fansidar)(nolongeravailableintheUnitedStates),at5to10days,hasthelongesthalf-life.Table6.13
givesdosinginformation.
MechanismofActionandSpectrumofActivity
The sulfonamides work by inhibiting the incorporation of para-aminobenzoic acid, the basic building
blockusedbybacteriatosynthesizedihydrofolicacid.Makingdihydrofolicacidisthefirststepleading
to folic acid synthesis, which is required for bacterial cell growth. Sulfamethoxazole (SMX)
competitivelyinhibitsthebacterialenzymedihydropteroatesynthetase.
Trimethoprim (TMP), combined with SMX, inhibits the enzyme dihydrofolate reductase,
synergistically inhibiting folic acid formation at another step in the pathway. Because bacterial
dihydrofolatereductaseisinhibitedmuchmorethanthemammalianenzymeandbecausehumansobtain
exogenousdietaryfolate,inhibitionoffolatesynthesisbySMX–TMPinhumansisnotamajorproblem.
TABLE6.13
SulfonamideDosages
Drug AdultDosages PediatricDosages
Sulfadiazine 4–8gPOindivideddosesq6–12h 100–150mg/kg/dPOdivided
q6h
Sulfisoxazole 4–8gPOindivideddosesq4–6h 120–150mg/kg/dPOdivided
q4–6h
Trimethoprim 100mgPOq12hor200mgPOq24h 4–6mg/kg/dPOdividedq12h
Trimethoprim–
sulfamethoxazole*
160/800mgPOq12hor10–20mg/kg/dIVin
divideddoses
6–20mg/kg/dPO/IVdivided
q6–12h
Note:Dosageadjustmentnecessaryinpatientswithrenalimpairment.
*Dosingrecommendationsarebasedonthetrimethoprimcomponent.IV,intravenous.
Thesulfonamidesareactiveagainstawiderangeofgram-positiveandgram-negativeorganisms,with
the exception of Pseudomonas species and group A streptococci. In combination with other folate
antagonists,theyalsodemonstrateactivityagainstP.jiroveciandToxoplasmagondii.
ClinicalUses
The sulfonamides are frequently used in treating many infections. Sulfasalazine (Azulfidine), a
sulfonamide derivativelackingsignificantantimicrobialactivity, ispoorlyabsorbedandis usedinthe
managementofulcerativecolitis.Becauseoftheirlimitedspectrumofactivityandincreasingresistance,
the sulfonamides are typically used in combination with other agents to increase efficacy or expand
coverage. TMP–SMX (Bactrim) is the combination of choice in treating urinary tract infections, P.
jiroveci pneumonia (PCP), toxoplasmosis, and some resistant gram-negative infections. Mafenide
(Sulfamylon)andsilversulfadiazine(Silvadene)aretopicalagentsfrequentlyusedintreatingburns.
AdverseEvents
Severalsideeffectsarereportedforsulfonamides.Themostcommonarerash,fever,andGIsideeffects.
Therashoccurswithin1to2weeksofinitiatingtherapy.Severedermatologicreactions,suchasStevensJohnsonsyndromeand vasculitis, are uncommonandassociated more withlonger-actingpreparations.
Hemolyticanemiacanoccurinpatientswithglucose-6-phosphatedehydrogenasedeficiency.
DrugInteractions
Thesulfonamidespotentiatetheeffectsofwarfarin,phenytoin,hypoglycemicagents,andmethotrexateas
aresultofdrugdisplacementordecreasedlivermetabolism.
GLYCOPEPTIDES
Vancomycin,aglycopeptideantibiotic,wasintroducedin1958.Shortlyafteritsintroduction,vancomycin
becameknownasMississippiMudbecauseofthecolorandimpuritiesinthemanufacturingprocess.The
clinicaluseofvancomycinwasinitiallylimitedduetoitspotentialfordrug-relatedtoxicities,alternative
available agents, and concern for the development of resistance. However, since the early 1980s,
vancomycinhasbeenanimportantagentintreatinggram-positiveinfections.Morerecentadditionstothis
class include dalbavancin (Dalvance), oritavancin (Orbactiv), and telavancin (Vibativ). All of these
agentshaveanarrowspectrumofactivitydirectedtowardgram-positiveorganisms.Thenewestagents,
dalba-vancinandoritavancin,haveprolongedhalf-livesthatallowformuchlessfrequentdosing.
PharmacokineticsandPharmacodynamics
VancomycinispoorlyabsorbedfromtheGItract.Becauseofitspoorbioavailability,oraladministration
ofvancomycinprovidesconcentrationsinthestoolsufficienttotreatClostridiumdifficile colitis. The
volume of distribution for vancomycin and telavancin, respectively, is 0.6 to 0.9 L/kg and 0.1 L/kg.
Vancomycinisminimallyboundtoproteins;however,telavancinishighlyboundtoproteins(greaterthan
90%).Theyhaverelativelygoodpenetrationintomostbodyfluidsandtissues.Unpredictablelevelsare
attainedintheCSFandbone.Telavancinisdosed10mg/kgIVoncedaily.Vancomycinisdosed15to20
mg/kgIVwiththeintervalbasedonkidneyfunction.Table6.14providesanexampleofavancomycin-
dosing nomogram, and Table 6.15 provides the dosing of dalbavancin, oritavancin, and telavancin.
Monitoring renal function is important in determining proper dosing because dosage adjustments are
necessary in patients with renal insufficiency. Both vancomycin and telavancin are renally excreted,
primarilyasunchangeddrug.Vancomycin’shalf-lifeinadultswithnormalrenalfunctionis5to11hours.
Thehalf-lifeoftelavancinis approximately8hours.Neithertelavancinnorvancomycinisclearedtoa
significantextentbyhemodialysisorperitonealdialysis.
Serumdrugmonitoringhasbeenusedforvancomycininpatientswithunpredictablekidneyfunctionor
severe infections or those receiving therapy for more than 3 to 5 days. In general, the target trough
concentrationrangesfrom15to20mg/mLforpneumonia,osteomyelitis,meningitis,andendocarditisand
from10to15mg/mLforotherinfections.
However, recent evidence suggests that trough levels may not correlate well to area under the
concentration (AUC) values. An updated consensus guideline on the therapeutic monitoring of
vancomycinwasrecentlypublishedandnowrecommendsAUC-baseddosingthatincludesbothpeakand
troughlevels.Serummonitoringisnotrequiredfordalbavancin,oritavancin,ortelavancin.Allofthese
agentsexhibitbactericidalactivityandaPAEof1to4hours.
TABLE6.14
VancomycinDosages
Note: These recommendations represent one of several nomograms used in the empiric dosing of vancomycin. Some prescribers use
pharmacokineticcalculationsandmonitorserumtroughlevelstoevaluatetheefficacyandtoxicityofaparticularregimen.Therapeutictrough
levelsaretypicallymaintainedbetween10and20mcg/mL.
*Patient’sbodyweightandIVdoseofvancomycin.
TABLE6.15
GlycopeptideDosages
Drug AdultDosages PediatricDosages
Dalbavancin(Dalvance) 1,000mgIVfollowedby500mgIV1wklater —
Oritavancin(Orbactiv) 1,200mgIVasasingleinjection —
Telavancin(Vibativ) 10mg/kgIVq24h —
IV,intravenous.
MechanismofActionandSpectrumofActivity
Glycopeptidesarecellwall–activeagents.TheyworkbyinhibitingthebindingoftheD-alanyl-D-alanine
portion of the cell wall precursor or by interfering with the polymerization and cross-linking of
peptidoglycan.Theneweragentshavemorerapidbactericidalactivitythanvancomycin.
Theprincipalactivityoftheglycopeptidesislimitedtogram-positiveaerobicandanaerobicbacteria
such as methicillin-sensitive and methicillin-resistant staphylococci, streptococci, enterococci, and
Clostridiumspecies.
ClinicalUses
Vancomycinisusedtotreatmanyinfections.Itisfrequentlyusedtotreatseriousgram-positiveinfections
inpatientsallergictoorunabletotoleratebeta-lactamantibiotics,anditisthedrugofchoiceforMRSA
and other resistant gram-positive infections. Neutropenic fever, endocarditis, and meningitis are
commonlytreatedwithvancomycin.Oralvancomycinisnowrecommendedas afirst-linetreatmentof
bothsevereandnon-severecasesofC.difficilecolitis.Theneweragentsarecurrentlyindicatedonlyfor
thetreatmentofskinandskinstructureinfections.
AdverseEvents
Themostcommonsideeffectsassociatedwithvancomycinadministrationarefeverandchills,phlebitis,
and red man syndrome, a histamine-mediated phenomenon associated with the rate of vancomycin
infusion.Thetypicalsyndromeconsistsofpruritus;flushingofthehead,neck,andface;andhypotension.
It usually resolves when the drug is discontinued. This reaction can also occur with telavancin.
Vancomycinandtelavancinshouldbeinfusedoveratleast1hour.
Nephrotoxicityasaresultofvancomycinaloneis uncommon.Typically,a combinationofvariables
andriskfactorsprecipitatesrenalinsufficiency.Riskfactorsincludeage,preexistingrenaldisease,and
theuseofothernephrotoxicagentssuchasaminoglycosides,amphotericinB,acyclovir,andcyclosporine.
In clinical trials evaluating telavancin and vancomycin, an increase in serum creatinine was more
commonwithtelavancin.Vancomycinhasbeenclassifiedasanototoxicagent.Althoughrare,ototoxicity
has occurred in patients receiving high-dose therapy or concurrent ototoxic agents (e.g.,
aminoglycosides).Hematologiceffectsfromvancomycinsuchasthrombocytopeniaandneutropeniaare
rare.Themostcommonlyreportedadverseeffectsoftelavancinaretastedisturbances,nausea,vomiting,
andfoamyurine.Duetotherisktothefetus,telavanciniscontraindicatedduringpregnancy.
DrugInteractions
Sincetheglycopeptidesdonotundergosignificanthepaticmetabolism,drug–druginteractionswiththese
agentsareunlikely.
OXAZOLIDINONES
The oxazolidinones are a totally synthetic antibiotic class first investigated in the late 1980s as
antidepressant agents. Serendipitously, these agents were discovered to have excellent antibacterial
activity.Themainreasonfortheirclinicaldevelopmenthasbeentheemergenceandspreadofresistance
ingram-positive pathogens.Linezolid(Zyvox)andtedizolid(Sivextro)aretheonlyagentsavailablein
thisclass.
PharmacokineticsandPharmacodynamics
LinezolidandtedizolidarewellabsorbedfromtheGItract.Peaklevelsareachievedwithin1to2hours,
and levels increase linearly as the dose is increased. The absolute bioavailability of these agents is
greaterthan90%.Theoralformulationmaybeadministeredwithoutregardtomeals.Oxazolidinonesare
predominantly eliminated by nonrenal mechanisms, and their metabolism does not involve the CYP
enzyme system. Linezolid is removed by hemodialysis and should be dosed following hemodialysis
sessions,whiletedizolidisnotsignificantlyaffected.Table6.16providesdosinginformation.
Oxazolidinones are considered bacteriostatic agents. Oxazolidinones exhibit a modest to prolonged
PAEagainststaphylococciandenterococci.
MechanismofActionandSpectrumofActivity
Oxazolidinonesbindtothe50Sribosomeatauniquebindingsiteanddisruptbacterialproteinsynthesis.
Antagonismhasbeendescribedwithchloramphenicolandclindamycin.
The principal activity of the oxazolidinones is against gram-positive aerobic organisms, including
staphylococci,streptococci,andenterococci.Inparticular,activityagainstresistantpathogens,including
MRSA,penicillin-resistantstreptococci,andVRE,isexcellent.
ClinicalUses
Linezolid hasFDA approval forthetreatmentofcommunityandnosocomial pneumonia,skinandskin
structure infections, andvancomycin-resistant Enterococcusfaecium, while tedizolid is onlyapproved
forthetreatmentofskinandskinstructureinfections.
TABLE6.16
OxazolidinoneDosages
Drug AdultDosages PediatricDosages
Linezolid(Zyvox) 400–600mgPO/IVq12h 20mg/kg/dPO/IVdividedq12hor30mg/kg/dPO/IVdividedq8h
Tedizolid(Sivextro) 200mgPO/IVdaily –
IV,intravenous.
AdverseEvents
In general, oxazolidinones are well tolerated when used for short-course therapy. The most common
adverse events include diarrhea, nausea, taste perversion, and vomiting. Thrombocytopenia has been
reportedonaveragein3%to4%ofpatientsinstudiesoflinezolid.Additionally,anemia,leukopenia,and
pancytopeniahavebeenreported.Acompletebloodcountshouldbemonitoredinpatients,especiallyif
receivinglinezolidforlongerthan2weeks.
DrugInteractions
Asmentionedearlier,thisclassofagentswasinitiallyinvestigatedforitsantidepressantactivityandas
suchlinezolidandtedizolidpossessweakmonoamineoxidaseinhibitoryactivity.Thereisapotentialfor
druginteractions withsympathomimetic agents, such as pseudoephedrine, selective serotonin reuptake
inhibitorantidepressantslikecitalopram,someherbalproducts,andfoodsrichintyramine.
LIPOPEPTIDES
Daptomycin is an antibacterial agent belonging to the class known as the lipopeptides. This class of
agentshasbeenstudiedforitsantibacterialactivityforseveraldecades;however,daptomycinistheonly
agentavailable. Daptomycin(Cubicin)isa naturalproductdeveloped forthetreatmentofMDRgrampositivepathogens.
PharmacokineticsandPharmacodynamics
Daptomycin’s pharmacokinetics are nearly linear and time independent at doses of up to 6 mg/kg
administered once daily for 7 days. Its half-life is approximately 8 hours. The apparent volume of
distribution in healthy adults is approximately 0.1 L/kg. Daptomycin reversibly binds human plasma
proteins,primarilytoserumalbumin,withameanserumproteinbindingof90%.Becauserenalexcretion
is the primary route of elimination, dosage adjustments are necessary in patients with severe renal
insufficiency(creatinineclearancelessthan30mL/min).Thedoseforpatientswithnormalrenalfunction
is4to6mg/kgIVadministereddaily(Table6.17).Thereisverylimitedinformationtosupporttheuseof
daptomycin in pediatric patients. Daptomycin exhibits rapid, concentration-dependent bactericidal
activityagainstgram-positiveorganisms.
TABLE6.17
LipopeptideDosages
Drug AdultDosages PediatricDosages
Daptomycin(Cubicin) 4–6mg/kgIVq24h
Note:DosageadjustmentnecessaryforCrCl<30mL/min.
IV,intravenous.
MechanismofActionandSpectrumofActivity
Themechanismofactionofdaptomycinisdistinctfromthatofanyotherantibiotic.Itbindstobacterial
membranes and causes a rapiddepolarizationof membrane potential. The loss of membrane potential
leadstobacterialcelldeath.
Daptomycin covers most gram-positive pathogens such as S. aureus (including methicillin-resistant
strains),streptococcus,andenterococcus.ItisactiveagainstMRSAandVRE.
ClinicalUses
DaptomycinisindicatedforthetreatmentofcomplicatedskinandskinstructureinfectionsandS.aureus
bloodstreaminfections (bacteremia), includingthose withright-sidedinfective endocarditis, causedby
methicillin-susceptible and methicillin-resistant isolates. Daptomycin is a useful alternative to other
agents (linezolid, quinupristin/dalfopristin) for treating infections caused by resistant gram-positive
pathogensbecausetherearefewoptionsatpresentfortreatingtheseinfections.Forcomplicatedskinand
skinstructureinfections,combinationtherapymaybeclinicallyindicatedifthedocumentedorpresumed
pathogensincludegram-negativeoranaerobicorganisms.Daptomycinisnotindicatedforthetreatmentof
pneumonia.
AdverseEvents
DaptomycinmaycauseGIreactionssuchas constipation,nausea,diarrhea,andvomiting.Injectionsite
reactionsandheadachemayoccur.Skeletalmuscletoxicitymanifestedasmusclepainhasbeenreported
withdaptomycin.Thisisaccompaniedbyanincreaseincreatininephosphokinase(CPK)levels.
DrugInteractions
CPKmonitoringshouldbedoneatleastweeklyforpatientsconcomitantlyreceivingastatinand/orthose
withrenalinsufficiency.Otherwise,daptomycindoesnothaveanysignificantdrug–druginteractions.
STREPTOGRAMINS
ThestreptograminantibioticsarenaturallyoccurringproductsthathavebeenusedclinicallyinEuropefor
more than 40 years. The semisynthetic derivative quinupristin/dalfopristin (Synercid) is the only
streptograminantibioticavailableintheUnitedStates.Itisacombinationoftwoantibiotics.
PharmacokineticsandPharmacodynamics
Quinupristin/dalfopristinisnotabsorbedfromtheGItract.AfterIVadministration,bothquinupristinand
dalfopristinhaveaserumhalf-lifeofapproximately1hour.Eachdrugismoderatelyproteinbound;the
volumeofdistributionis0.45and0.24L/kgforquinupristinanddalfopristin,respectively.Metabolismof
bothagentsisthroughtheliver.Thedrugisprimarilyexcretedinthefeces.
TABLE6.18
StreptograminDosages
Drug AdultDosages PediatricDosages
Quinupristin-dalfopristin(Synercid) 7.5mg/kgIVq8–12h 7.5mg/kgIVq8–12h
IV,intravenous.
Quinupristin/dalfopristinis a bactericidal agentagainstmostorganisms,withthenotedexceptionof
vancomycin-resistantE.faecium.Quinupristin/dalfopristinpossessesaPAErangingfrom8to18hours.
Thedosageforadultsandchildrenis7.5mg/kgevery8to12hours(Table6.18). Itis notsignificantly
removedbyhemodialysisorperitonealdialysis.
MechanismofActionandSpectrumofActivity
The streptogramins inhibit protein synthesis by binding to the 50S ribosome. The interaction of
quinupristin and dalfopristin is synergistic. Either compound alone is bacteriostatic, whereas the
combinationresultsinabactericidaleffect.
Theprincipalactivityofquinupristin/dalfopristinisagainstgram-positiveaerobicorganisms,including
staphylococci, streptococci, and enterococci. In particular, its activity against resistant pathogens,
includingmethicillin-resistantstaphylococci, penicillin-resistantstreptococci, andvancomycin-resistant
E.faecium,isexcellent.Quinupristin/dalfopristinisnotactiveagainstEnterococcusfaecalis.
ClinicalUses
Quinupristin/dalfopristin is approved by the FDA for treating skin and skin structure infections and
vancomycin-resistantE.faeciuminfections.Theuseofthisagentislimitedduetoadverseeffectsandthe
need for administration througha central venous line. It can be used totreat gram-positive infections
caused by methicillin-resistant staphylococci, penicillin-resistant S. pneumoniae, and vancomycinresistantE.faeciumwhenalternativeagentsarecontraindicated.
AdverseEvents
The most common adverse reactions are infusion related. Infusion site reactions, including pain,
inflammation,edema,andthrombophlebitis,havebeenreportedinasmanyas75%ofpatientsreceiving
quinupristin/dalfopristin through a peripheral IV catheter. Arthralgias and myalgias have also been
reported.Theymaybesevereandresultindiscontinuationoftherapy. Theyusuallyoccurafterseveral
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