Use of colistin in adult patients: A cross-sectional study

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Short

Communication

Use

of

colistin

in

adult

patients:

A

cross-sectional

study

Daniele

Roberto

Giacobbe

a,

*,

Carolina

Saf

ﬁoti

a,b

,

Angela

Raffaella

Losito

c

,

Matteo

Rinaldi

d

_,

_Caterina

_Aurilio

e

_,

_Cesare

_Bolla

f

_,

_Silvia

_Boni

g

_,

_Guglielmo

_Borgia

h

_,

Novella

Carannante

i

,

Giovanni

Cassola

j

,

Giancarlo

Ceccarelli

k

,

Silvia

Corcione

l

,

Daniela

Dalla

Gasperina

m

,

Francesco

Giuseppe

De

Rosa

l

,

Chiara

Dentone

n

,

Stefano

Di

Bella

o

,

Nicoletta

Di

Lauria

p

,

Marcello

Feasi

j

,

Marco

Fiore

q

,

Sara

Fossati

o

,

Erica

Franceschini

r

,

Andrea

Gori

s

,

Guido

Granata

t

,

Sara

Grignolo

g

,

Paolo

Antonio

Grossi

m

,

Giuliana

Guadagnino

u

,

Filippo

Lagi

k

,

Alberto

Enrico

Maraolo

h

,

Valeria

Marinò

v

,

Maria

Mazzitelli

w

,

Alessandra

Mularoni

u

,

Alessandra

Oliva

k,v

,

Maria

Caterina

Pace

q

_,

_Andrea

_Parisini

f

_,

_Francesca

_Patti

n

_,

_Nicola

_Petrosillo

t

_,

Vincenzo

Pota

e

,

Francesca

Raffaelli

c

,

Marianna

Rossi

x

,

Antonella

Santoro

r

,

Carlo

Tascini

i

,

Carlo

Torti

w

,

Enrico

Maria

Trecarichi

w

,

Mario

Venditti

k

,

Pierluigi

Viale

d

,

Alessio

Signori

a

,

Matteo

Bassetti

y

,

Valerio

Del

Bono

z

,

Maddalena

Giannella

d

,

Malgorzata

Mikulska

a,b

,

Mario

Tumbarello

c

,

Claudio

Viscoli

a,b

,

on

behalf

of

SITA

GIOVANI

(Young

Investigators

Group

of

the

Società

Italiana

Terapia

Antinfettiva)

and

the

COLI-CROSS

Study

Group

1

a

DepartmentofHealthSciences,UniversityofGenoa,Genoa,Italy b

OspedalePoliclinicoSanMartino–IRCCS,Genoa,Italy c

FondazionePoliclinicoUniversitarioA.GemelliIRCCS,UniversitàCattolicadelSacroCuore,Rome,Italy d

DepartmentofMedicalandSurgicalSciences,InfectiousDiseasesUnit,AlmaMaterStudiorum–UniversityofBologna,Bologna,Italy e

AnaesthesiaandIntensiveCareUnit,DepartmentofWomen,Children,GeneralandSpecialisticSurgery,L.VanvitelliUniversityofCampania,Naples,Italy f_SC_Malattie_Infettive,_ASO_SS._Antonio_e_Biagio_e_Cesare_Arrigo,_Alessandria,_Italy

g

DivisionediMalattieInfettive,OspedaleSant’Andrea,LaSpezia,Italy h

SectionofInfectiousDiseases,DepartmentofClinicalMedicineandSurgery,UniversityofNaplesFedericoII,Naples,Italy i

FirstDivisionofInfectiousDiseases,CotugnoHospital,AORNdeiColli,Naples,Italy j

DepartmentofInfectiousDiseases,GallieraHospital,Genoa,Italy k

DepartmentofPublicHealthandInfectiousDiseases,SapienzaUniversityofRome,PoliclinicoUmbertoI,Rome,Italy l_Department_of_Medical_Sciences,_Infectious_Diseases,_University_of_Turin,_Turin,_Italy

m_Infectious_and_Tropical_Diseases_Unit,_Department_of_Medicine_and_Surgery,_University_of_Insubria,_Varese,_Italy n

MedicalDepartment,InfectiousDiseasesUnit,SanremoHospital,Imperia,Italy o

InfectiousDiseasesDepartment,AziendaSanitariaUniversitariaIntegratadiTrieste,Trieste,Italy p

DepartmentofExperimentalandClinicalMedicine,UniversityofFlorence,Florence,Italy q

DepartmentofAnaesthesiological,SurgicalandEmergencySciences,UniversityofCampania‘LuigiVanvitelli’,Naples,Italy r

ClinicofInfectiousDiseases,UniversityofModenaandReggioEmilia,Modena,Italy

s_University_of_Milan_and_Infectious_Diseases_Unit,_Department_of_Internal_Medicine,_Fondazione_IRCCS_Ca'_Granda_Ospedale_Maggiore_Policlinico,_Milan,_Italy t

ClinicalandResearchDepartmentforInfectiousDiseases,SevereandImmunedepression-AssociatedInfectionsUnit,NationalInstituteforInfectiousDiseases L.Spallanzani,IRCCS,Rome,Italy

u

InfectiousDiseasesISMETTIRCCS,Palermo,Italy v

IRCCSINMNeuromed,Pozzilli,Italy w

DepartmentofMedicalandSurgicalSciences,InfectiousandTropicalDiseasesUnit,‘MagnaGraecia’UniversityofCatanzaro,Catanzaro,Italy x

ClinicofInfectiousDiseases,SanGerardoHospital,UniversityofMilano–Bicocca,Monza,Italy y_Department_of_Medicine,_University_of_Udine_and_Azienda_Sanitaria_{Universitaria}_Integrata,_Udine,_Italy z

InfectiousDiseasesUnit,AziendaOspedalieraS.CroceeCarle,Cuneo,Italy

* Correspondingauthor.Presentaddress:UniversityofGenoa,DipartimentodiScienzedellaSalute(DISSAL),ViaAntonioPastore1,16132Genoa,Italy. E-mailaddress:daniele.roberto.giacobbe@gmail.com(D.R.Giacobbe).

1

COLI-CROSSStudyGroupcollaborators:F.Alessandri,A.Alﬁeri,R.M.Antonello,S.Argentero,S.Artioli,M.Bartoletti,A.Bartoloni,S.Beltramini,D.Bianchi,I.Bisso,E.Blasi Vacca,S.Buono,A.R.Buonomo,M.Canepa,A.Capone,G.Chichino,G.DeBenedectis,G.DiCaprio,Z.DiRosa,F.DiZazzo,I.Gentile,G.Greco,T.Lupia,R.Luzzati,A.Milano,S. MornesePinna,C.Mussini,M.B.Passavanti,C.Rogati,A.Russo,P.Sansone,G.Sarteschi,F.Serapide,M.Spaziante,F.Taglietti,S.TedeschiandR.F.Tobaldi.

https://doi.org/10.1016/j.jgar.2019.06.009

ContentslistsavailableatScienceDirect

Journal

of

Global

Antimicrobial

Resistance

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ARTICLE INFO Articlehistory: Received1April2019

Receivedinrevisedform3June2019 Accepted8June2019

Availableonline15June2019 Keywords: Colistin Colistimethate Acinetobacter Pseudomonas Klebsiella Antimicrobialresistance ABSTRACT

Objectives:Theaimofthisstudywastoassesscolistinuseinacountryendemicformultidrug-resistant Gram-negativebacteria(MDR-GNB).

Methods:Colistinprescriptionpatternswereevaluatedin22Italiancentres.Factorsassociatedwithuse ofcolistinincombinationwithotheranti-MDR-GNBagentswerealsoassessed.

Results:Atotalof221adultsreceivingcolistinwereincludedinthestudy.Theirmedianagewas64years (interquartile range 52–73 years) and 134 (61%) were male. Colistin was mostly administered intravenously (203/221; 92%) and mainly fortargeted therapy (168/221;76%). The most frequent indications for colistin therapy were bloodstream infection and lower respiratory tract infection. Intravenouscolistinwasadministeredincombinationwithatleastanotheranti-MDR-GNBagentin80% ofcases(163/203).Aloadingdoseof9MUofcolistimethatewasadministeredin79%ofpatientsreceiving i.v.colistinandadequatemaintenancedosesin85%.Inmultivariableanalysis,empiricaltherapy[odds ratio(OR)=3.25,95%conﬁdenceinterval(CI)1.24–8.53;P=0.017]andtargetedtherapyfor carbapenem-resistantEnterobacteralesinfection(OR=4.76,95%CI1.69–13.43;P=0.003)wereassociatedwithuseof colistinincombinationwithotheragents,whilstchronicrenalfailure(OR=0.39,95%CI0.17–0.88;P= 0.024)wasassociatedwithuseofcolistinmonotherapy.

Conclusion:ColistinremainsanimportantoptionforsevereMDR-GNBinfectionswhenothertreatments arenotavailable.Despiteinherentdifﬁcultiesinoptimisingitsuseowingtopeculiarpharmacokinetic/ pharmacodynamiccharacteristics,colistinwasmostlyusedappropriatelyinacountryendemicfor MDR-GNB.

1.Introduction

Colistin, a polymyxin antibiotic, is a last-resort treatment

option for multidrug-resistant Gram-negative bacteria

(MDR-GNB), especially carbapenem-resistant Enterobacterales (CRE)

andnon-fermenters[1–3].

Despite the fact that a reduction in its use will likely be

observed in the near future owing to the recent marketing of

several novel agents, colistin still remains among the few

potentially active treatment options for carbapenem-resistant

Acinetobacterbaumannii(CRAB)andforotherMDR-GNBresistant

tonovelcompounds [1,2,4–6].Veryimportantly, useofcolistin shouldbereservedfortheseindicationsandshouldbeavoidedin thepresenceofdependablealternatives,sinceitseffectivenessand safetycanbeimpaired byseveralfactors, including:(i)narrow

therapeutic index, which may result in either suboptimal

concentrationsornephrotoxicity[7]; (ii)suboptimal concentra-tions in lung tissue [8]; (iii) frequent unavailability of colistin therapeuticdrugmonitoringoutsideofresearchlaboratories;and (iv)unintendedtreatmentofcolistin-resistantinfectionsowingto

possible limitations of some classical susceptibility testing

methods[9].Therefore,usingcolistinappropriately(e.g.correct indication,correctdosage,reservingitforinfectionscausedby,or stronglysuspectedtobecausedby,MDR-GNB)iscertainlydifﬁcult

butisofparamountimportanceforimprovingpatientoutcomes

and relieving selective pressure due to suboptimaldosages on

thosestrainsforwhichcolistinremains,ormayremain,theonly activetherapeuticoption.

Although several studies evaluating the use of colistinfor

selectedMDR-GNBinfectionshavebeenconductedoverthelast

decades[3,6,10,11],littleisknownabouttheoverall character-isticsofcolistinuseincountriesendemicforMDR-GNB.Inlight ofthis,assessingcolistinprescriptionpatternsisafundamental

step for ultimately tailoring antimicrobial stewardship

inter-ventionsinorderbothtooptimisecolistinuseandtopreserve

its activity in the long-term. In this cross-sectional study,

prescription patterns of colistin in adult patients in Italy, a

countryendemicforMDR-GNB,especiallyCREandCRAB[12],

wereassessed.

2.Materialsandmethods

2.1.Studydesignandobjectives

Thisobservational,cross-sectionalstudywasconductedin22 Italiancentres[20hospitalsplus2intensivecareunits(ICUs)].The completelistofparticipatingcentresisavailableinSupplementary TableS1,whilsttheirgeographicaldistributionisshowninFig.1.

ThestudywasﬁrstapprovedbytheEthicsCommitteeofthe

co-ordinatingcentre(OspedalePoliclinicoSanMartino–IRCCS,Genoa, Italy)andsubsequentlybytheEthicsCommitteesoftheother21 participatingcentres.Afterreceivingapprovalfromthepertinent

local ethics committee, all adult patients starting colistin

treatmentduring a consecutive 3-monthperiod were

prospec-tivelyincludedinthestudy.The3-monthenrolmentperiodstarted

in March 2018 in the ﬁrst activated centre and ﬁnished in

September2018inthelastactivatedcentre.Datawerecollectedat thetimeofcolistininitiationwithnofollow-up,inlinewiththe

cross-sectional design and the objectives of the study. All

consciouspatientssigned aninformedconsenttoparticipatein

thestudy.Awaiverofinformedconsentforpatientsunconsciousat thetimeofcolistininitiationwasobtainedinmostparticipating centres(onlyﬁveunconsciouspatientswerenotenrolled).

Patientswereincludedinthestudyonlyonce,atthetimeof initiationoftheﬁrstcolistintreatmentduringthestudyperiod.

The primary objective of thestudy was to describethe useof

colistin in terms of dosages, indications and characteristics of

treated patients. The secondary objective was to assess factors

associatedwiththeuseofcolistinincombinationwithother

anti-MDR-GNB agents. Details regarding protocol registration and

deviations, sample size calculation and statistical analysis are

availableintheSupplementarymethods.

3.Results

During thestudyperiod,229adultpatientsreceivedcolistin

treatment, of whom 221 (97%) were included in the study

(Supplementary Fig. S1). Their median age was 64 years

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Table 1 reports the complete demographic and clinical characteristicsof theenrolledpatients. Of the221 patients, 32 (14%)hadreceivedapreviouscourseofcolistintherapy,mostlyin

combination with other anti-MDR-GNB agents (29/30; 97%).

Previous colonisation/infection with at least one

carbapenem-resistant organism [CRE, carbapenem-resistant Pseudomonas

aeruginosa (CRPA) or CRAB] was registered in 62% of patients

(138/221),witha12%(15/121)prevalenceofcolistinresistancein previousisolates.

Colistinwasmostlyadministeredintravenously(203/221;92%)

andmainlyfortargetedtherapy(168/221;76%).Among203cases

of intravenous (i.v.) administration, colistin was concomitantly administeredasinhaled(20/203;10%)orintrathecal(3/203;1%)

therapy(SupplementaryTableS2).Themostfrequentindications

forcolistinadministrationweresepsisandlowerrespiratorytract infection(LRTI)forempiricaltherapyand bloodstreaminfection

(BSI) and LTRI for targeted therapy (Supplementary Table S2).

Among53casesofempiricaltherapy, 48(91%)had ahistoryof

previouscolonisation/infectionbyacarbapenem-resistant organ-isminthepatientand/orinotherpatientshospitalisedinthesame ward. Afterstarting empiricalcolistin, anaetiological diagnosis

was achievedin30/53 patients(57%) andCRE, CRABand CRPA

wereisolatedin33%(10/30),30%(9/30),and7%(2/30)ofcases,

respectively. CRAB was the most frequent causative agent of

infections treated with targeted colistin, being involved as

monomicrobialorpolymicrobialinfectionsinasmanyas85/168

cases(51%).Thecompletelistofaetiologicalagentsisavailableas

SupplementaryTableS3.

Colistinsusceptibilitytestingwasperformedon183/198(92%) causativeisolatesobtainedeitherbeforeoraftercolistininitiation,

mostly using automated systems (145/183; 79%). Broth

micro-dilutionasﬁrstsusceptibilitytestmethodorasconﬁrmatorytest

was performed in 124/183 cases (68%). Gradients tests were

employedin4/183cases(2%),andinallofthemwithsubsequent brothmicrodilutionconﬁrmation.Colistinsusceptibilityin

causa-tive agents isolated after initiation of empirical colistin was

assessedin15cases,ofwhich4(27%)werecolistin-resistant.

Intravenouscolistinwasadministeredincombinationwithat

leastoneotheranti-MDR-GNBagentin80%ofcases(163/203).A

loading dose of 9 million units (MU) of colistimethate was

administered in 79% of patients receiving i.v. colistin, whereas

adherencetotheEuropeanMedicinesAgency(EMA)Committee

forMedicinalProductsforHumanUse(CHMP)recommendations

[13]forprescribedmaintenancedosageswas85%(Table2).

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Table1

Demographicandclinicalcharacteristicsofadultpatientstreatedwithcolistin.

Variable No.ofpatientsa

% 95%CI

Demographiccharacteristics

Age(years)[median(IQR)] 64(52–73) 62–67

Malesex 134/221 61 54–67

Medicalhistory

Previoushospitalisation(within6months) 124/221 56 49–63

Diabetesmellitus 55/221 25 19–31

Chronicrenalfailure 45/221 20 15–26

Solidneoplasm 40/221 18 13–24

Haematologicalmalignancy 16/221 7 4–11

Charlsoncomorbidityindex[median(IQR)] 2(1–3) 2–2

Previoustreatmentwithcolistinb

32/221 15 10–20

Anti-MDR-GNBmonotherapy 1/30 3 0–16

Anti-MDR-GNBcombinationtherapy 29/30 97 84–100

Unknownwhethermonotherapyorcombination 2/32

Hospitalstaybeforecolistininitiation(days)[median(IQR)] 21(10–43) 17–25

Microbiologicalhistory

Previouscolonisation/infectionbyCRE

Inthepatient 89/221 40 34–47

Colistin-resistant 8/77 10 5–19

(Colistinnottested) (12)

Inotherpatientsinthesamewardc _142/221 ₆₄ _58–70

Previouscolonisation/infectionbyCRPA

Inotherpatientsinthesamewardc _32/221 ₁₅ _10–20

Previouscolonisation/infectionbyCRAB

Inotherpatientsinthesamewardc

94/221 43 36–49

Previouscolonisation/infectionbyCRE,CRPAand/orCRAB

Inotherpatientsinthesamewardc

165/221 75 68–80

Baselinevariablesc Ward ICU 96/221 43 37–50 Medicalward 80/221 36 30–43 Surgicalward 33/221 15 11–20 Rehabilitationward 12/221 5 3–9 PresenceofCVC 165/221 75 68–80

Presenceofurinarycatheter 179/221 81 75–86

Mechanicalventilation 66/221 30 24–36

Septicshock 43/221 19 15–25

Neutropenia 14/221 6 4–10

Serumalbumin(g/dL)[median(IQR)]d

2.6(2.3–3.0) 2.6–2.8

Missing(serumalbuminnottested) 22/221

Serumcreatinine(mg/dL)[median(IQR)]d

0.8(0.6–1.3) 0.7–0.9

Haemodialysis 15/221 7 4–11

KDIGOstageofAKI

NoAKI 170/221 77 71–82

Stage1 24/221 11 7–16

Stage2 12/221 5 3–9

Stage3 15/221 7 4–11

AKI,acutekidneyinjury;CI,conﬁdenceinterval;CRAB,carbapenem-resistantAcinetobacterbaumannii;CRE,carbapenem-resistantEnterobacterales;CRPA, carbapenem-resistantPseudomonasaeruginosa;CVC,centralvenouscatheter;ICU,intensivecareunit;IQR,interquartilerange;KDIGO,KidneyDisease:ImprovingGlobalOutcomes; MDR-GNB,multidrug-resistantGram-negativebacteria.

a_Results_are_presented_as_no._of_{patients/total}_of_patients_unless_otherwise_stated. b

Previousanti-MDR-GNBcombinationwasdeﬁnedasprevioustreatmentwithcolistinincombinationwithatleastoneofthefollowingagents:carbapenems; aminoglycosides;fosfomycin;tigecycline;trimethoprim/sulfamethoxazole;rifampicin;ceftazidime/avibactam;andceftolozane/tazobactam.

c

Atthetimeofcolistininitiation. d

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Intheunivariableanalysis,mechanicalventilation,presenceof septicshock,empiricaltherapy,targetedtherapyforCREinfections andi.v.administrationshowedastatisticallysigniﬁcant associa-tionwiththeuseofcolistinincombination,whereaschronicrenal

failureandtargetedtherapyofCRABinfections wereassociated

withuseofcolistinmonotherapy(SupplementaryTableS4).Inthe

multivariable analysis(model A), only empirical therapy [odds

ratio(OR)=3.25,95%conﬁdenceinterval(CI)1.24–8.53;P=0.017], targetedtherapyforCREinfections(OR=4.76,95%CI1.69–13.43; P=0.003)andchronicrenalfailure(OR=0.39,95%CI0.17–0.88; P=0.024) retained statisticallysigniﬁcant associations (Supple-mentaryTableS5).SupplementaryTableS5alsoshowstheresults

of theadditionalmultivariable modelwithcentre as arandom

effect (model B), which largely conﬁrmed the associations

observedin modelA (althoughwithborderlinesigniﬁcancefor

chronicrenalfailure,possiblybecauseofreducedpower),butalso indicatedi.v.administrationasafurthervariableassociatedwith

combinationtherapy.

4.Discussion

Inacohortof221patientsfrom22Italiancentres,colistinwas

mostlyused intravenouslyand in combinationwithother

anti-MDR-GNBagents,mainlyforthetargetedtherapyofLRTIsandBSIs

causedbycarbapenem-resistantorganisms.

Use of colistin in the USA and Europe has recently been

exploredbyWenzleretal.withanelectronicquestionnairesurvey

distributed to420physicians askingabout theirroutineuse of

colistin [14]. The respondents indicated that they administer

polymyxinsmainlyforpneumonia(63%)andforsuspected/proven

carbapenem-resistantinfections(85%)[14],whichisinlinewith thecurrentﬁndings.In addition,thecurrentstudyalsodirectly measuredtheactualproportionofempiricaluseofcolistin,which was24%versus76%fortargetedtherapy.Ofnote,thispreference towardsrestrictingtheuseofcolistinfortargetedtherapy,possibly

relying on the intention of avoiding nephrotoxic agents in

empiricaltherapy,couldtheoreticallyhelptodelaytheemergence ofcolistinresistance.Itisalsoworthnotingthatonnooccasion wascolistinusedforselectivedigestivedecontamination,possibly reﬂecting the intention to avoid further selective pressure for resistanceinacountryalreadyendemicforCRE[15–17].

Inthepresentstudy,thelevelofadequatenessofi.v.colistin

dosages was measured according to the EMACHMP review of

polymyxin-basedmedicines[13],observingahighproportionboth

of adequate loading doses (79%) and adequate maintenance

dosages (85%). These results are in line with the fact that

Table2

Characteristicsofintravenouscolistintherapies.

Variable No.ofpatientsa

% 95%CI

Typeoftherapy

Empiricaltherapy 49/203 24 19–30

Targetedtherapyb

154/203 76 70–81

Typeofanti-MDR-GNBtherapy

Colistinmonotherapy 40/203 20 15–26

Combinationtherapyc

163/203 80 74–85

TargetedtherapyforCREd

Combinationtherapye

36/40 90 77–97

TargetedtherapyforCRPAd

Combinationtherapye

15/22 68 45–85

TargetedtherapyforCRABd

Combinationtherapye

44/65 68 55–78

Dosage

Administrationofloadingdose 178/203 88 82–92

Administrationofloadingdoseof9MUofCMSf

160/203 79 73–84

AdequatedailymaintenancedosageofCMSaccording toestimatedCLCrg,h[20]

Allpatients 159/187 85 79–90

CLCr10to<30mL/min(4.50–5.50MU) 13/18 72 47–88

CLCr30to<50mL/min(5.50–7.50MU) 14/22 64 42–81

CLCr50mL/min(9.00MU) 132/147 90 84–94

CI,conﬁdenceinterval;CLCr,creatinineclearance;CMS,colistimethate;CRAB,carbapenem-resistantAcinetobacterbaumannii;CRE,carbapenem-resistantEnterobacterales; CRPA,carbapenem-resistantPseudomonasaeruginosa;EMACHMP,EuropeanMedicinesAgencyCommitteeforMedicinalProductsforHumanUse;IQR,interquartilerange; MDR-GNB,multidrug-resistantGram-negativebacteria;MU,millionunits.

a

Resultsarepresentedasno.ofpatients/totalofpatientsunlessotherwisestated.Thedenominator(n=203)includesintravenous(n=180),intravenousplusinhaled (n=20)andintravenousplusintrathecal(n=3)colistintherapies.

b _{Post-identiﬁcation}

ofthecausativeagent. c

Anti-MDR-GNBcombinationwasdeﬁnedastreatmentwithcolistinincombinationwithatleastoneofthefollowingagents:carbapenems;aminoglycosides;fosfomycin; tigecycline;trimethoprim/sulfamethoxazole; rifampicin;ceftazidime/avibactam;ceftolozane/tazobactam; and anyother anti-Gram-negativeagent administeredin combinationwithcolistinfortheintendedtreatmentofasuspectedorprovenMDR-GNBinfection.

d _Analyses_limited_to_{monomicrobial}_infections_due_to_CRE,_CRPA_or_CRAB. e

ColistincompanionagentsforCREinfections:meropenem(n=11);fosfomycin+meropenem(n=5);fosfomycin+tigecycline(n=4);meropenem+tigecycline(n=3); tigecycline(n=3);fosfomycin (n=2);gentamicin+meropenem(n=2);amikacin+ceftazidime/avibactam+tigecycline(n=1);ceftazidime/avibactam(n=1); ceftazi-dime+levoﬂoxacin(n=1);ceftazidime/avibactam+meropenem(n=1);ertapenem+meropenem(n=1);andgentamicin+tigecycline(n=1).Colistincompanionagentsfor CRPA infections: meropenem (n=6); ceftolozane/tazobactam (n=3); amikacin (n=1); amikacin+meropenem (n=1); ceftazidime/avibactam (n=1); ceftolozane/ tazobactam+meropenem (n=1); imipenem(n=1); piperacillin/tazobactam(n=1).Colistincompanion agents forCRAB infections:meropenem(n=15); merope-nem+tigecycline(n=5);rifampicin(n=5);tigecycline(n=4);ampicillin/sulbactam+meropenem(n=2);rifampicin+tigecycline(n=2);amikacin(n=1);ampicillin/ sulbactam(n=1);ampicillin/sulbactam+rifampicin(n=1);cefepime(n=1);ceftolozane/tazobactam+tigecycline(n=1);trimethoprim/sulfamethoxazole+tigecycline (n=1);fosfomycin+meropenem+rifampicin+tigecycline(n=1);gentamicin+meropenem(n=1);imipenem(n=1);andmeropenem+rifampicin(n=2).

f

AsrecommendedbytheEMACHMPbothinpatientswithandwithoutimpairedrenalfunction,includingthosereceivingrenalreplacementtherapy[13]. g

Inpatientsnotreceivinghaemodialysis(188/203).Maintenancedoseinformationmissingfor1patient(ﬁnaldenominator=187).Thelasttwoserumcreatininevalues beforecolistininitiationwerecollectedtoestimateCLCraccordingtotheJelliffeformula.

h

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antimicrobialstewardship interventionstoincrease theoptimal

useof this last-resort agenthavebeenalready implementedin

Italianhospitals[18],buttheyalsoclearlyidentifyspeciﬁcpoints

where further improvements are still needed, mainly tailored

interventionsfor reducing themissing21%of adequate loading

dosage.Inaddition,itshouldbenotedthatinternationalconsensus

guidelinesregarding the optimal use of polymyxins havebeen

publishedveryrecently(afterperformanceofthepresentstudy) thatindicatethepossibleneedforincreasedmaintenancedosages inpatientswithcreatinineclearance>80mL/min,inlinewiththe

mostrecentpharmacokinetic/pharmacodynamicevidence[19].If

validatedincon_ﬁrmatorystudies,thiswilllikelybecomecommon practiceinthefutureinordernottorisksuboptimalexposuresin patientswithoutrenalfunctionimpairments[19].

Most patients in this study received colistin as part of a

combinationforthetreatmentofasuspectedorproveninfection duetoMDR-GNB.Inthisregard,thepossiblesurvivalbeneﬁtof usingcombinationsfortreatingsevereCREinfections,previously

reported in observational studies [10], might contribute to

explaining the independent association found between use of

colistin in combination and both targeted therapy of CRE and

empiricaltherapy(needforCREcoverage).Nonetheless,although less frequently than for CRE infections, it is worth noting that

colistinwasalsomainlyusedincombinationsfortreatingCRPA

and CRAB (e.g. as i.v. treatment, combined regimens were

preferredtomonotherapyin90%ofmonomicrobialCREinfections

but also in 68% of monomicrobial CRPAinfections and 68% of

monomicrobial CRAB infections). On the one hand, the

non-negligibleproportionofpatientswithCRPAandCRABtreatedwith combinationsmaybeinlinewiththeintentionofclinicianstodeal

with the possible suboptimal pharmacokinetics of colistin by

adding another agent, hoping for synergy or just for additive

effects.Ontheotherhand,thereduced useofcombinationsfor

CRPAandCRABincomparisonwithCREpossiblyreﬂectsthelackof

evidence for CRPA (only a few small observational studies

exploringtheuseofcolistin-based combinationsforCRPAhave

been conducted) and the results of the AIDA randomised

controlledtrialforCRAB[2].Inthislatterstudy,Pauletal.found thatadditionofmeropenemtocolistindidnotreducetherateof clinicalfailureinpatientswithsevereCRABinfections,thuscasting doubtsabouttheuseofcolistinplusmeropenemcombinationsfor CRAB[2].However,itisofnotethatcarbapenemswereemployed

inasmuchas61%ofcolistin-basedcombinationsusedforCRAB

infectionsinthecurrentstudy,possiblyreﬂectingthelackofother therapeuticoptions[20].

Withregardtootherfactorsassociatedwithuseofcolistinin

combination or as monotherapy in this study, the association

foundbetweenchronicrenalfailureandmonotherapymaypartly

depend on the unwillingness to combine colistin with other

nephrotoxicagents(i.e.aminoglycosides),evenwhentheyremain

theonly otherdependableoption. The associationbetween i.v.

administrationand usein combination found in theadditional

mixed multivariable model may reﬂect the preferential use of

combinationsfortreatingsevereinfections,whichusuallyrequire i.v.therapy.

Thepresentstudyhassomelimitations.Theﬁrstisthat follow-updatawerenotcollected,thusratesofclinicalresponsetocolistin

treatmentandsurvivalcouldnotbeassessed.However,themain

aimwas tofocus onthe characteristicsof colistin prescription

patterns and the study was thus designed to optimise the

collectionofcross-sectionaldescriptivedata(e.g.foradequately describingtheheterogeneityincolistintreatment)ratherthanfor

assessing the impact on outcome of colistin therapy (where

heterogeneityusuallyimpliesconsiderableconfoundingeffects). Anotherlimitationisthatwewereunabletoregisterdetaileddata

on the type of haemodialysis (e.g. intermittent haemodialysis,

sustained low-efﬁciency dialysis, continuous renal replacement

therapy).Consequently,theadequatenessofmaintenancedosages

inthe15patientswhoreceivedhaemodialytictreatmentcouldnot beevaluated.Itshouldalsobenotedthatdespitethelargesample size,peculiarcharacteristicsofsomeparticipatingcentres(e.g.two participatedonlyasICUs,onecentreisspecialisedinsolid-organ transplants,andanotheroneisspecialisedinneurorehabilitation) might partlylimit thegeneralisabilityoftheresults. Finally,no

phenotypicormolecularinformationregardingcarbapenemand

colistinresistancedeterminantswascollected.

Inconclusion,colistinremainsanimportantoptionforsevere MDR-GNBinfectionswhenotheroptionsarenotavailable.Colistin

was mostly used appropriately according to recommendations

availableatthetimeofthestudyinacountryendemicfor

MDR-GNB organisms,althoughtheresults alsoindicatethat targeted

efforts might be necessary for further increasing the rate of

adequateloadingdosages.Therecentavailabilityand

dissemina-tion of international consensus guidelines based on updated

informationmightfurtherimprovetheuseofthislast-resortdrug inthefuture.

Funding

Thiswork ispartiallysupportedbyagrant fromtheSocietà

ItalianadiTerapiaAntinfettiva(‘BorsadiStudioS.I.T.A.perricerche suinfezionibattericheefungine’).

Competinginterests

CV and DRG are among the authors of the International

ConsensusGuidelinesfortheoptimaluseofpolymyxins.Allother authorsdeclarenocompetinginterests.

Ethicalapproval

LiguriaRegionEthicsCommittee[registryno.321REG2017].

AppendixA.Supplementarydata

Supplementarymaterialrelatedtothisarticlecanbefound,inthe onlineversion,atdoi:https://doi.org/10.1016/j.jgar.2019.06.009. References

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