Considerations for the optimal management of antibiotic therapy in elderly patients

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Review

Considerations for the optimal management of antibiotic therapy in elderly patients

MarcoFalcone^a,*,MicalPaul^b,GiusyTiseo^a,Dafna Yahav^c,VirginiePrendki^d,

Lena E.Friberg^e,RobertoGuerri^f,Gaetan Gavazzi^g,CristinaMussini^h,MarcoTinelliⁱ,for theESCMID StudyGroup forInfections intheElderly (ESGIE)

aDepartmentofClinicalandExperimentalMedicine,UniversityofPisa,ViaParadisa2,Pisa56124,Italy

bDivisionofInfectiousDiseases,RambamHealthCareCenterandTheRuthandBruceRappaportFacultyofMedicine,Technion–IsraelInstituteofTechnology, Haifa,Israel

cInfectiousDiseasesUnit,RabinMedicalCenter,BeilinsonHospital,PetahTikva,Israel

dDivisionofInternalMedicineoftheAged,DepartmentofRehabilitationandGeriatrics,GenevaUniversityHospitalsandUniversityofGeneva,Hôpitaldes Trois-Chêne,Geneva,Switzerland

eDepartmentofPharmaceuticalBiosciences,UppsalaUniversity,Uppsala,Sweden

fInfectiousDiseasesDepartment,HospitaldelMar,DepartmentofMedicine,UniversitatAutònomadeBarcelona,Barcelona,Spain

gUniversityClinicsofGeriatrics,UniversityHospitalofGrenoble-Alpes,GREPIEA7408UniversityofGrenobleAlpes,Grenoble,France

hClinicofInfectiousDiseases,UniversityofModenaandReggioEmilia,Modena,Italy

iDivisionofInfectiousandTropicalDiseases,HospitalofLodi,Lodi,Italy

ARTICLE INFO

Articlehistory:

Received2February2020

Receivedinrevisedform14February2020 Accepted26February2020

Availableonline9March2020

Keywords:

Elderly Pharmacokinetics Pharmacodynamics Antibiotics Dosage Adverseevents

ABSTRACT

Objectives:Tomaximiseefﬁcacyandminimisetoxicity,specialconsiderationsarerequiredforantibiotic prescriptionin elderlypatients. This review aimstoprovide practical suggestionsfor theoptimal managementofantibiotictherapyinelderlypatients.

Methods:Thiswasanarrativereview.Aliteraturesearchofpublishedarticlesinthelast15yearson antibiotics andelderlypatientswas performedusingtheCochrane Libraryand PubMedelectronic databases.Thethreepriorityareaswereidentiﬁed:(i)pharmacokinetics/pharmacodynamics(PK/PD)for optimising dosage regimens and route of administration; (ii) antibiotic dosages in some special subpopulations; and (iii) treatmentconsiderations relatingto differentantibiotic classesand their adverseevents.

Results:CliniciansshouldunderstandthealteredPK/PDofdrugsinthispopulationowingtoco-morbid conditionsandnormalphysiologicalchangesassociatedwithageing.Thebodyofevidencejustiﬁesthe needforindividualiseddoseselection,especiallyinpatientswithimpairedrenalandliverfunction.

Cliniciansshouldbeawareofthemajordrug–druginteractionscommonlyobservedintheelderlyaswell aspotentialsideeffects.

Conclusion:Antibiotictherapyintheelderlyrequiresacomprehensiveapproach,includingstrategiesto improveappropriateantibioticprescribing,limittheiruseforuncomplicatedinfectionsandensurethe attainmentofanoptimalPK/PDtarget.Tothispurpose,furtherstudiesinvolvingtheelderlyareneededto betterunderstandthePKofantibiotics.Moreover,itisnecessarytoassesstheroletherapeuticdrug monitoringinguidingantibiotictherapyinelderlypatientsinordertoevaluateitsimpactonclinical outcome.

4.0/).

* Correspondingauthor.

E-mailaddress:marco.falcone@unipi.it(M.Falcone).

http://dx.doi.org/10.1016/j.jgar.2020.02.022

JournalofGlobalAntimicrobialResistance22(2020)325–333

ContentslistsavailableatScienceDirect

Journal of Global Antimicrobial Resistance

j o u r n a lh o m e p ag e :w w w . e l s e vi e r . c o m / l o c a t e/ j g a r

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Contents

1. Introduction ...................................................................................................... 326

2. Methods ......................................................................................................... 326

3. Pharmacokinetics/pharmacodynamicsandrouteofadministrationofantibioticsintheelderly ................................... 327

3.1. β-Lactamantibiotics .......................................................................................... 327

3.2. Vancomycin ................................................................................................. 327

3.3. Linezolid ................................................................................................... 327

3.4. Daptomycin ................................................................................................. 327

3.5. Fluoroquinolones ............................................................................................ 329

3.6. Gentamicin ................................................................................................. 329

3.7. Colistin .................................................................................................... 329

3.8. Routeofantibioticadministration ............................................................................... 329

4. Antibioticdosagesinspecialpatientpopulations ........................................................................ 329

4.1. Elderlypatientswithchronickidneydisease(CKD)orhaemodialysis .................................................. 329

4.2. Elderlycirrhoticpatients ...................................................................................... 330

5. Adverseeffectsofantibioticsinelderlypatients ......................................................................... 330

6. Limitations ....................................................................................................... 332

7. Conclusions ...................................................................................................... 332

Conﬂictofinterests ................................................................................................ 332

Acknowledgment .................................................................................................. 332

References ....................................................................................................... 332

1.Introduction

The World Health Organization (WHO) predicts that the numberofpeopleaged60yearswillrisefrom900millionto 2billionbetween2015and2050(movingfrom12%to22%ofthe totalglobalpopulation)[1].Ageingisariskfactorfordeveloping infections. Antibiotics are among the most frequently newly- prescribeddrugsinelderlypatients,especiallyinthoseresidingin nursinghomesorlong-termcarefacilities(LTCFs)[2].Multipleco- morbidities,changesindrugpharmacokinetics(PK)andpharma- codynamics (PD), and the presence of polypharmacy with the inherentrisk ofadversedrugreactions anddrug–drugordrug– diseaseinteractionsmakethechoiceoftheoptimalantibioticvery challenging in elderly patients [3]. Appropriate antibiotic pre- scription,eitherintermsofdrugchoiceordosage,isofparamount importanceamongelderlypatients,butbalancingefficacy,safety, tolerabilityanddevelopmentofantimicrobialresistanceisdifficult inthispatientpopulation.Theobjectiveofthisreviewistodiscuss specialconsiderationsforantibiotictherapyinelderlypatients,in generalandforspecificantibiotics.

2.Methods

This review with recommendations for practice has been produced bya teamof experts belongingtotheESCMID Study GroupforInfectionsintheElderly (ESGIE).Thepaneldiscussed unmetneedsofantibiotictherapyinelderlypatientsandidentiﬁed the following three areas of interest: (i) PK considerations for optimisingdosageregimens and routeof administrationin the elderly; (ii) antibiotic dosages in special elderly populations (speciﬁcally patients withrenal disease,cirrhotic patients, and patientswithalteredfatandmusclebodycomposition);and(iii) adverse events and drug interactions of antibiotics in elderly adults.

Electronic databases including the Cochrane Library and PubMed were utilised for a comprehensive search using the following combinations of keywords for the identiﬁcation of relevantstudies:[(‘elderly’OR‘LTCF’OR‘nursinghomes’OR‘aged’) AND (‘pharmacokinetics’ OR ‘pharmacodynamics’) AND ‘antibiotics’], [‘elderly’ AND ‘antibiotics’AND (‘chronic renal failure’ OR‘hemodialysis’OR‘kidneydisease’OR‘dosageadjustment’)],

Fig.1.Mainpharmacokinetic/pharmacodynamic(PK/PD)alterationsofantibioticsinelderlypatients.Ofnote,theroleofproteinbindingondrugadjustmentisnotclear.

Changesinproteinbindingdonotrequireadjustmentsindosingregimensexceptincasesofintravenousdrugswithahighextractionratio(seetextformorecomments).

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[‘elderly’ AND‘antibiotics’AND(‘cirrhosis’OR‘hepaticfailure’)], and[‘elderly’AND‘antibiotics’AND‘adverseevents’].Articleswere selectedonthebasisofthefollowingcriteria:focusedonelderly patientsandpublishedinthelast15years.

Despitethelackofuniversallyacceptedagecriteriatoclassify agegroups,weagreedtoincludeinthisreviewallstudiesfocusing onpatientsaged65years.Casereportsandmini-caseserieswere excluded.

3.Pharmacokinetics/pharmacodynamicsandrouteof administrationofantibioticsintheelderly

AvarietyofpathophysiologicalchangesmayaffectthePKand PDofantibioticsinelderlypatients(Fig.1).

PKisaffectedbychangesinbodycomposition.Sarcopeniaand malnutrition can occur in elderly patients and substantially inﬂuencethePKofadministereddrugs.Decreasedfattissueand leanbodymassmayaffectdrugdistributiondependingontheir lipophilicity.Areducedmassofadiposetissueaccumulateslower amountsoflipophilicdrugs,whereaschangedmusclemassand redistributed body water affect the distribution of hydrophilic drugs. This could lead to greater ﬂuctuations of drug plasma concentrations and higher peak concentrations in the central compartment. Since malnutrition has been associated with reducedcontentofsomehepaticcytochromes,drugmetabolism maybereducedinpatientswithcachexia[4].

Drug distribution can be affected by oedema secondary to chronicheartfailureandbyascitessecondarytocirrhosis.Changes inplasmaproteinbindingdonotusuallyinﬂuencetheclinicaldrug exposure in a patient [5]. Of consequence, no adjustments in dosingregimensareneededexceptinrarecasesof intravenous drugswithahighextractionratioandnarrowtherapeuticindex thataregivenparenterally.

Morphologicalandfunctionalchangessuchasdelayedgastric emptying,reducedsplanchnicbloodﬂowandalteredgastricpH canaffectthebioavailabilityoforallyadministereddrugs[6].

Impairmentofrenalbloodﬂow,glomerularﬁltrationrateand capacityofrenaltubularsecretionincreasetheplasmahalf-lifeof drugseliminatedbythekidneys[6].Adescriptionoftheeffectsof ageingonthemetabolismandeliminationofseveralantibioticsis showninTable1.

PDfromthehost'sperspective(i.e.thehost'sclinicalresponse tothedrug)isaffectedbyimmunesenescence,thephysicalability todealwithcertaininfections(e.g.coughinginpneumonia)and, speciﬁcally,theabilitytodealwithsevereinfectionsfunctionally andcognitively(seeFig.1).Thesameantibioticlevelsatthesame siteof theinfection causedby thesamebacteriummighthave differentclinicaleffectsinyoungerandelderlypatients.

3.1.β-Lactamantibiotics

Regardingβ-lactams,itis wellknownthatthePDindexthat optimises efficacy is the percentage of time the unbound concentrationremainsabovetheminimuminhibitoryconcentra- tionofthetargetmicro-organism(%fT_>MIC).Thereisevidencethat ageaffectsthePKofβ-lactamsandtheeffectismainlymediatedby reduced renal clearancein the elderly.An increasein systemic exposuretoceftarolineof33%wasattributedtodecreasedrenal function in elderly subjects [8]. Nearly 70% of meropenem is excretedfromthebodyintheurine,andcreatinineclearance(CLCr) issignificantlycorrelatedwithmeropenemclearance[9–11].The PK of doripenem has been also specifically studied in elderly patientswithnosocomialpneumonia:theareaundertheplasma concentration–timecurve(AUC)washigherandtheelimination half-life (t1/2) was longer in elderly patients compared with younger healthy subjects [12]. However, there might be other

factors. For example, the 24-h AUC (AUC_0–24) for ampicillin/

sulbactamwassigniﬁcantlylowerinelderlypatients[13],likelyas aconsequenceofanincreaseoftheirvolumeofdistribution(Vd)in theacutephaseofpneumonia.Dataregardingnewdrugssuchas avibactamsuggest thatthemaximumconcentration(Cmax)was lowerandthet1/2waslongerinelderlymalesubjectscompared withyoungerones[14].

Dosagesforelderlysubjectsshouldbebasedatleastonrenal function (Table 1). Speciﬁc considerations for other newer antibioticinelderlypatientshaveyettobedeveloped.

3.2.Vancomycin

Advanced age is a recognised risk factor for vancomycin- induced nephrotoxicity [15]. Vancomycin clearance correlates with CLCr because up to 90% of administered vancomycin is excretedunchangedintheurinewhenrenalfunctionisnormal.

ThePK/PDindexthatbestpredictsvancomycinefﬁcacyistheAUC/

MICratio,andanAUC/MICratioof400hasbeenproposedasan efficacytargetforvancomycintherapy[11].Thelatestpublished guidelinesemphasisetheroleoftheAUCover24htoMICbybroth microdilution (AUC/MICBMD) of 400 as the primary PK/PD predictor of vancomycin activity ifthe MIC is 1mg/L, stating that trough-only monitoring may be insufficient to guide vancomycin dosing in all patients [16]. Some studies have evaluatedtheriskofnephrotoxicityinelderlypatientswithhigh (15mg/L) rather than low (<15mg/L) average vancomycin troughs levels [17]. Bourguignon et al. built and validated a vancomycinPKmodelforpatientsaged>80yearsusingBayesian approaches.Theauthorsfoundhighinterindividualvariabilityin PKparametersinthisspecificpopulation[18].

Unfortunately,therapeuticdrugmonitoring(TDM)ofvancomy- cininparticularsettingssuchasLTCFsisdifﬁculttoperform.Based onthecurrentbestavailableevidence,dailyAUCs(assuming an MICBMDof1mg/L)shouldbemaintainedbetween400and600mgh/

Ltomaximiseefﬁcacyandminimisethelikelihoodofnephrotoxicity [19].Toimplementmodel-basedTDM,software,accountingforthe dosinghistory,should bevalidatedinthis patientpopulationto achievetheoptimalPK/PDvancomycintarget(https://link.springer.

com/article/10.1007%2Fs40262-012-0020-y).

3.3.Linezolid

The AUC0–24of linezolidappearstobecorrelated withbody weightandage,showingatendencytoincreaseasbodyweight decreasesand/orasageincreases[20].ArecentPKstudyshowed that patients treated with the conventional linezolid dose of 600mg twice daily had a 20-fold interindividual variation in antibiotic trough concentrations, with a positive correlation betweenlinezolidtroughconcentrationsandpatientage[21].In a TDM analysis, very old patients(80years old)had concen- trationsthreetimeshighercomparedwithpatientsaged<40years [21]. Similarly, Tinelli et al. documented that elderly patients treatedwiththeconventionaldoseoflinezolidof600mgtwice daily havelinezolidtroughconcentrations exceeding theupper therapeutic threshold, set according to available literature, at 8.0mg/L[22].Baselineplateletcountandtherapydurationof10 days are the most important predictors of linezolid toxicity.

However,atthistime,thereisnoclearrecommendationofhowto adjustthelinezoliddosetoavoidoverexposureofthedruginthe elderly.

3.4.Daptomycin

AcomparisonofPKparametersofdaptomycininyoungadult (18–30years)and geriatric(75years)volunteersshowed that M.Falconeetal./JournalofGlobalAntimicrobialResistance22(2020)325–333 327