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6
PrinciplesofAntimicrobialTherapy
StevenP.Gelone,StaciPacetti,andJudithA.O’Donnell
LearningObjective
1.Discussfactorsthatmayinfluencetheselectionofanappropriateantimicrobialregimen.
2.Givenaclinicalscenario,recommendasafe,effectiveandpatient-specificantimicrobialtreatment
option.
3. Identify common mechanisms of antimicrobial resistance and the antimicrobial stewardship
strategiesthatmaybeutilized.
INTRODUCTION
Theselectionofanappropriateantimicrobialagenttotreataninfectionisguidedbyanumberoffactors.
Typically, empiric antimicrobialtherapyisbasedontheepidemiologyofthesuspectedinfection,with
therapydirectedtowardthemostlikelyorganisms.Laboratorystudies, includingGramstainaswellas
culture and sensitivity testing, help to identify the pathogen and its susceptibility to a variety of
antimicrobials. Althoughthere may be several options, efficacy, toxicity,pharmacokinetic profile, and
costultimatelydeterminetheagentofchoice.Theoptimaldoseanddurationoftheantimicrobialtherapy
arethendeterminedbypatientfactorssuchasage,weight,andconcurrentdiseasestatesaswell asthe
siteandseverityofinfection.
FACTORSINVOLVEDINSELECTINGANANTIMICROBIALREGIMEN
Beforeinitiatingantibiotictherapy,asystematicapproachtoidentifythesourceandsiteofinfectionmust
beundertaken.Acompletemedicalhistoryandphysicalexaminationshouldbeconductedtoidentifysigns
and symptoms consistent with the presence of infection. Identifying underlying medical or social
conditionssuchasdiabetes,immunosuppression(cancer,humanimmunodeficiencyvirus[HIV]infection),
pastmedications,orintravenous(IV)drugusemayhelpinidentifyingapredispositiontowardinfection
orthemostlikelypathogencausingdisease.Inaddition,determiningwheretheinfectionwasacquired(in
the community vs. a nursing home or hospital setting) may also help to limit the list of most likely
pathogens. Health care–acquired pathogens may necessitate broad-spectrum empiric therapy to cover
multidrug-resistant(MDR)pathogens.
Identifyingthecausativepathogenistheultimategoalbecauseitallowsforoptimalantibioticselection
andpatientoutcome.UpdatedrecommendationsfromtheInfectiousDiseasesSocietyofAmerica(IDSA)
and the American Society of Microbiology on the appropriate utilization of microbiologic laboratory
testingmayguidehealthcareprovidersintheirdiagnosticapproach.Specimensfromthemostlikelybody
sitesshouldbeproperlycollectedandsenttothemicrobiologylaboratory. Dependingonthebodysite
involved,specimenswillbestained(e.g.,Gram stain)todeterminemorphologyandcellwallstructure
(coccivs.bacilliandgrampositivevs. gram-negative)andanalyzedtodetectwhitebloodcells(which
indicateinflammationandinfection).Thegoldstandardofdiagnosisininfectiousdiseasesistobeableto
grow thecausative organismincultureandperformantibiotic susceptibilitytestingtodeterminewhich
agentsaremostlikelytobeeffectiveineradicatingthepathogen.Susceptibilityresultsoftentake48to72
hoursafterculturesareobtained.Newermethodsoftestingcanhelpidentifyspecificpathogens(suchas
methicillin-resistantStaphylococcusaureus[MRSA]andCandida)morequickly.
TABLE6.1
InfectionandMostLikelyInfectingOrganism
BodySite(Infection) MostLikelyOrganism
Heart(Endocarditis)
Subacute Streptococcusviridans
Acute Staphylococcusaureus
Injectiondruguser Staphylococcusaureus,gram-negativeaerobicbacilli,Enterococcusspp.
Prostheticvalve Staphylococcusepidermidis
Intra-abdominal
tissues
Escherichiacoli,Enterococcusspp.,anaerobes(especiallyBacteroidesfragilis),other
gram-negativeaerobicbacilli
Brain(Meningitis)
Children<age2mo E.coli,groupBstreptococci,Listeriamonocytogenes
Childrenage2moto12yStreptococcuspneumoniae,Neisseriameningitidis,Haemophilusinfluenzae
Adults(community
acquired)
S.pneumoniae,N.meningitidis
Adults(hospital
acquired)
S.pneumoniae,N.meningitidis,gram-negativeaerobicbacilli
HIVcoinfected Cryptococcusneoformans,S.pneumoniae
RespiratoryTract
Uppertract,community
acquired
S.pneumoniae,H.influenzae,Moraxellacatarrhalis,groupAstreptococci
Lowertract,community
acquired
S.pneumoniae,H.influenzae,M.catarrhalis,Klebsiellapneumoniae,Mycoplasma
pneumoniae,C.pneumoniae,viruses
Aspirationpneumonia Mouthflora(anaerobicandaerobic)
Lowertract,hospital
acquired
S.aureus(includingMRSA),P.aeruginosa,othergram-negativeaerobicbacilli
HIVcoinfected Pneumocystisjiroveci,S.pneumoniae
SkinandSoftTissue
Diabeticulcer Staphylococcusspp.,Streptococcusspp.,gram-negativeaerobicbacilli,anaerobes
UrinaryTract
Communityacquired E.coli,othergram-negativeaerobicbacilli,Enterococcusspp.,Staphylococcus
saprophyticus
Hospitalacquired E.coli,othergram-negativeaerobicbacilli,Enterococcusspp.
HIV,humanimmunodeficiencyvirus;MRSA,methicillin-resistantS.aureus.
Often, antibiotic therapy is initiated before culture and sensitivity testing is complete. Empiric
antibiotic therapyis based onthepremise ofprovidingcoverageforthemostlikelypathogens (Table
6.1).Ingeneral,themostlikelyorganismisbasedonthesuspectedsiteoftheinfection.Table6.2outlines
keypathogensandspectraofactivityforthemostcommonlyprescribedantibiotics.
In most patients treated initially with a parenteral antibiotic who are clinically improving, therapy
shouldbeswitchedtotheoralroute.Thismaynotapplytocertaininfections,suchasosteomyelitisand
endocarditis,inwhichparenteralantibioticsareoftencontinuedtoensureadequateconcentrationsatthe
infectionsite.Thisoralconversionshouldbebasedonthefollowingcriteria:
• The patient is respondingto therapy,as evidenced bya return to normal or a trendtoward normal
valuesinthepatient’stemperatureandwhitebloodcellcount.
•Thepatientcantakeoralmedicationsandabsorbthemadequately.
•Anoral equivalenttotheparenteralregimenexists.Notallparenteralagentsare availableorally.In
choosingtheoralequivalent,thegoalistoselectanagent(oragents)thatprovidesasimilarspectrum
ofantimicrobialactivityandpossessesgoodoralbioavailability.Thismaynecessitatetheuseoforal
agentsthatarefromadifferentclassfromtheparenteralagent.
Thepatient’sresponsetotherapyshouldbemonitoredregularly.Thisincludesmonitoringbothefficacy
and toxicity. If the patient responds to the prescribed antibiotic regimen, the presenting signs and
symptomsoftheinfectionshouldresolve.Parameterstobeconsideredforresponseregardlessofthesite
ofinfectionincludevitalsigns,whiteblood cellcount,and,ifthecultureproved positive forbacteria,
subsequentnegativeculturesas clinicallyindicated.Othersignsandsymptomsare specifictothebody
siteinvolved.Monitoringforadverseeventsisspecifictotheagentsprescribed.Allpatientsshouldbe
taughthowtorecognizethemostcommonadverseevents,andtheyshouldbeadvisedtonotifytheirhealth
care provider if an adverse reaction occurs. The following sections highlight antimicrobials used in
practice and include pharmacokinetics, pharmacodynamics, mechanism of action (see Figure 6.1),
spectrum of activity, common clinical uses, adverse events, drug interactions, and antimicrobial
resistance.
TABLE6.2
SensitivityofOrganismstoSpecificAgents
‘Providessynergisticactivityagainstgram-positiveorganismswhencombinedwithacellwall-activeagent.
†Applicableonlytoorganismsisolatedintheurine.
-=Noactivityornoinformationavailable.
+=Poortomoderateactivity;useonlywhenknowntobesusceptible.
++=Goodactivity;resistanceinsomestrainsandgeographicallocationmaylimituse.
+++=Excellentactivity;generallyreliablecoverageforempirictherapy.
Thesymbolnexttonitrofurantoin-Applicableonlytoorganismsisolatedintheurine.
MRSA,methicillin-resistantS.aureus;MSSA,methicillin-sensitiveS.aureus.
FIGURE6-1AntibioticSitesandMechanismofAction.Thisfigureidentifiesvariousclassesofagents,
where they act within the bacterial cell and the specific bacterial function they inhibit. Used with
permissionfromTornetta,P.,Ricci, W.,Court-Brown,C.M.,McQueen,M.M.,&McKee,M.(2019).
RockwoodandGreen’sfracturesinadults(9thed.).WoltersKluwer.
DHF,dihydrofolicacid;DNA,deoxyribonucleicacid;mRNA,messengerRNA;PABA,para-aminobenzoicacid;RNA,ribonucleicacid;THF,
tetrahydrofolicacid.
PENICILLINS
First isolatedin1928, thepenicillins wereusedsuccessfullytotreat streptococcal andstaphylococcal
infections.Sincethen,manysyntheticpenicillinshavebeendevelopedtoaddresstheemergingproblem
ofresistance. Despite resistance,thepenicillinsremainanimportantclass ofantimicrobials. Theyare
classifiedbasedontheirspectraofactivity.
PharmacokineticsandPharmacodynamics
Most of the penicillinsare unstable intheacid environment of the stomach andmustbe administered
parenterally. Those that areacid stable are givenorally. They are widelydistributed in the bodyand
penetratethecerebrospinalfluid(CSF)inthepresenceofinflammation.Mostpenicillinsareexcretedby
thekidneys,andrenalimpairmentnecessitatesdosageadjustment.Thehalf-lifeofthepenicillinsinadults
withnormalrenal functionis 30 to90 minutes.Thepenicillinsareremovedbyhemodialysis,withthe
exceptionof nafcillinandoxacillin. The penicillins exhibit time-dependent bactericidal activity anda
postantibioticeffect(PAE)againstmostgram-positive organisms.SeeBox6.1forinformationonPAE.
Also,seeTable6.3fordosinginformation.
MechanismofActionandSpectrumofActivity
Themechanismofactionofthepenicillinsistheinhibitionofbacterialcellgrowthbyinterferencewith
cellwallsynthesis.Penicillinsbindtoandinactivatethepenicillin-bindingproteins(PBPs).
Box6.1 PostantibioticEffect
ThePAEisdefinedas“persistentsuppressionofbacterialgrowthafterabriefexposure(1or2hours)
ofbacteriatoanantibioticevenintheabsenceofhostdefensemechanisms”(Craig&Vogelman,1987,
pp.900–902).Thisdelayedgrowthofbacteriaresultsinanincreasedefficacyofthedrugsandallows
forlessfrequentdosingofmedications,potentiallyloweringtoxicityandimprovingcompliance.The
durationofthePAEisaffectedbytheclassofantibiotic,therelevantexposuretime,andthespecific
bacterial species. Bacteriostatic agents, such as macrolides, clindamycin, streptogramins,
tetracyclines,andlinezolid, havelongPAEs,whereas drugswithrelativelyslow bactericidal action
(e.g.,penicillins)havemoderatePAE.
TABLE6.3
PenicillinDosages
Drug AdultDosages PediatricDosages
Natural
PenicillinG 2–4millionunitsIVq4–6h 100,000–400,000units/kg/dIVdivided
q4–6h
PenicillinG
benzathine
1.2–2.4millionunitsIMatspecifiedintervals 300,000–2.4millionunitsIMat
specifiedintervals
PenicillinG
procaine
0.6–4.8millionunitsIMindivideddosesq12–24hat
specifiedintervals
25,000–50,000units/kg/dIMdivided
1–2times/d
PenicillinVK 250–500mgPOq6h 25–50mg/kg/dPOdividedq6–8h
Aminopenicillins
Ampicillin 1–2gIVq4–6h 100–400mg/kg/dIVdivided4–6h
Amoxicillin–
ampicillin
250–500mgPOq8hor875–1,000mgPOq12h 400–100mg/kg/dPOdividedq6–12h
Penicillinase
Resistant
Cloxacillin 250–500mgPOq6h 50–100mg/kg/dPOdividedq6h
Dicloxacillin 250–500mgPOq6h 12.5–100mg/kg/dPOdividedq6h
Nafcillin 500mg–1gIVq4–6h 50–200mg/kg/dIVdividedq4–6h
Oxacillin 500–2gIVq4–6h 100–200mg/kg/dIVdividedq4–6h
Ureidopenicillins
Piperacillin 3–4gIVq4–6h 200–300mg/kg/dIVdividedq4–6h
Note:Dosageadjustmentofalldrugsrequiredinpatientswithimpairedrenalfunction,withtheexceptionofpenicillinase-resistantpenicillins.
IM,intramuscular;IV,intravenous.
ClinicalUses
Although the use of penicillin itself is limited due to widespread resistance, the penicillin class is
effective in treating many infections, including those ofthe upper and lower respiratory tract, urinary
tract,andcentralnervoussystem(CNS)aswellassexuallytransmitteddiseases.Theyaretheagentsof
choicefor treatinggram-positive infectionssuchasendocarditis causedbysusceptibleorganisms. The
ureidopenicillinsmaybeusedtotreatinfectionscausedbyPseudomonasaeruginosa.
AdverseEvents
Thereisalowincidenceofadversereactionswithpenicillinadministration.Hypersensitivityreactions
characterizedbymaculopapular rashandurticariaaremostcommon.Gastrointestinal(GI)side effects
are most common with oral administration. In the presence of severe renal dysfunction, high-dose
penicillinshavebeenassociatedwithseizuresandencephalopathy.Thrombophlebitishasoccurredwith
IVadministration.TheJarisch-Herxheimerreaction,characterizedbyfever,chills,sweating,andflushing,
mayoccurwhenpenicillinisusedintreatingspirochetes,inparticularsyphilis.Releaseoftoxicparticles
fromtheorganismprecipitatesthereaction.Inrarecases, leukopenia,thrombocytopenia,andhemolytic
anemiacanoccurwithpenicillins.
DrugInteractions
Druginteractionsinvolvingpenicillinsarerare.Probenecidhasbeenshowntoincreasethehalf-lifeof
thepenicillinsbyinhibitingrenaltubularsecretion.Theureidopenicillinshavebeenshowntoinactivate
theaminoglycosides,andtheseagentsshouldnotbemixedinthesameIVsolution.
BETA-LACTAM/BETA-LACTAMASEINHIBITORCOMBINATIONS
Resistancetobeta-lactamsdevelopswhenthedrugisinactivatedbytheenzymesknownaspenicillinases
or beta-lactamases produced by bacteria. After several attempts over the years to prevent penicillin
degradation by this enzyme, clavulanic acid became the first beta-lactamase inhibitor introduced and
combined with a beta-lactam. Other beta-lactamase inhibitors, avibactam, relebactam, sulbactam,
tazobactam, and vaborbactam, are also available in combination with ampicillin, ceftazidime,
ceftolozane,piperacillin,andthecarbapenemsimipenemandmeropenem.Theroleofthebeta-lactamase
inhibitoristopreventthebreakdownofthebeta-lactambyorganismsthatproducetheenzyme,thereby
enhancing antibacterial activity. These combinations are suitable alternatives for infections caused by
beta-lactamase-producing organisms such as S. aureus, Haemophilus influenzae, and Bacteroides
fragilis.
TABLE6.4
Beta-Lactam/Beta-LactamaseInhibitorDosages
Drug AdultDosages PediatricDosages
Amoxicillin–clavulanicacid(Augmentin) 250–500mgPOq8hor 20–40mg/kg/dPOdividedq8–12h
500–875mgPOq12hor
2gPOq12h*
80–90mg/kg/dPOdividedq12h
+
Ampicillin–sulbactam(Unasyn) 1.5–3gIVq6h 100–400mg/kg/dIVdividedq6h
Piperacillin–tazobactam(Zosyn) 4.5gIVq6–8hor3.375gIVq6h 240–300mg/kg/dIVdividedq8h
Ceftazidime–avibactam(Avycaz) 2.5gIVq8h
Ceftolozane–tazobactam(Zerbaxa) 750mgIVq8h
Meropenem–vaborbactam(Vabomere) 4gIVq8h
Imipenem–cilastatin–relebactam(Recarbrio) 1.25gIVq6h
Note:Dosageadjustmentrequiredforalldrugsadministeredtopatientswithrenalimpairment.
*Amoxicillin-clavulanicacid(AugmentinXR)extended-releaseformulation.
†Amoxicillin/clavulanicacid(AugmentinES-600)formulation.
IV,intravenous.
PharmacokineticsandPharmacodynamics
Thebeta-lactam/beta-lactamaseinhibitorsdiffuseintomostbodytissues,withtheexceptionofthebrain
andCSF. Thehalf-lifeofbothcomponentsineachcombinationisapproximately1hour.Becausethese
drugsareeliminatedbyglomerularfiltration,renaldysfunctionnecessitatesdosagechanges(Table 6.4).
Thecompoundsareremovedbyhemodialysisandperitonealdialysis.
MechanismofActionandSpectrumofActivity
The beta-lactam components of the combinations are cell wall–active agents. They interfere with
bacterial cell wall synthesis by binding to and inactivating PBPs. The beta-lactamase inhibitors
irreversibly bind to most beta-lactamase enzymes, protecting the beta-lactam from degradation and
improving their antibacterial activity. The beta-lactamase inhibitors by themselves lack significant
antibacterial activity. The spectrum of activity is similar to that of the beta-lactam derivative, with
broadercoverageagainstbeta-lactamase-producingorganisms.
ClinicalUses
Basedontheirbroadspectrumofactivity,thebeta-lactam/beta-lactamaseinhibitorsarefrequentlyusedin
treating polymicrobial infections. They are used extensively to treat intra-abdominal and gynecologic
infectionsandskinandsofttissueinfections,includinghumanandanimalbites,aswellasfootinfections
in diabetic patients. Respiratory tract infections, including aspiration pneumonia, sinusitis, and lung
abscesses,havebeensuccessfullytreatedwiththesecombinations.
AdverseEvents
Theadditionofthebeta-lactamaseinhibitortothevariousbeta-lactamshasnotresultedinanynew or
major adverse events. The major effects associated with the beta-lactam/beta-lactamase inhibitor
combinationsare hypersensitivityreactionsandGIsideeffectssuchas nauseaanddiarrheaassociated
withoraladministration.Elevatedaminotransferaselevelshavebeendocumentedforallagents.
DrugInteractions
Some of the combinations are physically incompatible with parenteral aminoglycosides. Each of the
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