A summary and appraisal of existing evidence of antimicrobial resistance in the Syrian conflict

This is the published version of a paper published in International Journal of Infectious

Diseases.

Citation for the original published paper (version of record):

Abbara, A., Rawson, T M., Karah, N., El-Amin, W., Hatcher, J. et al. (2018)

A summary and appraisal of existing evidence of antimicrobial resistance in the Syrian

conflict

International Journal of Infectious Diseases, 75: 26-33

https://doi.org/10.1016/j.ijid.2018.06.010

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Review

A

summary

and

appraisal

of

existing

evidence

of

antimicrobial

resistance

in

the

Syrian

con

flict

Aula

Abbara

*

,

Timothy

M.

Rawson

,

Nabil

Karah

,

Wael

El-Amin

,

James

Hatcher

,

Bachir

Tajaldin

,

Osman

Dar

,

Omar

Dewachi

,

Ghassan

Abu

Sitta

,

Bernt

Eric

Uhlin

,

Annie

Sparrow

a

DepartmentofInfection,ImperialCollegeHealthcareNHSTrust,London,UK

b

NationalInstituteforHealthResearch,HealthProtectionResearchUnitinHealthcareAssociatedInfectionsandAntimicrobialResistance,ImperialCollege London,London,UK

c

DepartmentofMolecularBiology,LaboratoryforMolecularInfectionMedicineSweden,andUmeåCentreforMicrobialResearch,UmeåUniversity,Umeå, Sweden

d

DepartmentofMicrobiology,BroomfieldHospital,Chelmsford,Essex,UK

e_{SyrianAmericanMedicalSociety,Turkey} f

PublicHealthEngland,London,UK

g

ChathamHouseCentreonGlobalHealthSecurity,London,UK

h_Conflict

andHealthProgram,AmericanUniversityofBeirut,Lebanon

i

DepartmentofPopulationHealthSciencesandPolicy,IcahnSchoolofMedicineatMountSinai,NewYork,USA

ARTICLE INFO

Articlehistory: Received31March2018

Receivedinrevisedform13June2018 Accepted14June2018

CorrespondingEditor:EskildPetersen, Aar-hus,Denmark Keywords: Syria Antimicrobialresistance Conflict Refugees ABSTRACT

Antimicrobialresistance(AMR)inpopulationsexperiencingwarhasyettobeaddressed,despitethe abundance of contemporary conflicts and the protracted nature of twenty-first century wars, in combinationwithgrowingglobalconcernoverconflict-associatedbacterialpathogens.Theexampleof theSyrianconflictisusedtoexplorethefeasibilityofusingexistingglobalpoliciesonAMRinconditions ofextremeconflict.TheavailableliteratureonAMRandprescribingbehaviourinSyriabeforeandsince theonsetoftheconflictinMarch2011wasidentified.Overall,thereisapaucityofrigorousdatabefore andsincetheonsetofconflictinSyriatocontextualizetheburdenofAMR.However,postonsetofthe conflict,anincreasingnumberofstudiesconductedinneighbouringcountriesandEuropehavereported AMRinSyrianrefugees.Highratesofmultidrugresistance,particularlyGram-negativeorganisms,have beennotedamongstSyrianrefugeeswhencomparedwithlocalpopulations.Conflictimpedesmanyof thesafeguardsagainstAMR,createsnewdrivers,andexacerbatesexistingones.Giventheapparently highrates ofAMRin Syria,inneighbouring countrieshosting refugees,andinEuropeancountries providingasylum,thisrequirestheWorldHealthOrganizationandotherglobalhealthinstitutionsto addressthe causes, costs, and futureconsiderations of conflict-relatedAMRas anissueof global governance.

©2018TheAuthors.PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases. ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(

http://creativecommons.org/licenses/by-nc-nd/4.0/).

Contents

Introduction ... 27 EvidenceofAMRintheSyriancontext ... 27 EvidenceofAMRintheSyriancontext:pre-conflict ... 27

*Correspondingauthor.

E-mailaddresses:a.abbara15@imperial.ac.uk(A.Abbara),

Timothy.rawson07@imperial.ac.uk(T.M.Rawson),Nabil.karah@umu.se(N.Karah),

Wael.elamin@nhs.net(W.El-Amin),Bachir.tajaldin@sams-usa.net(B.Tajaldin),

Osman.dar@phe.gov.uk(O.Dar),Oa02@aub.edu.lb(O.Dewachi),

annie.sparrow@mssm.edu(A.Sparrow).

https://doi.org/10.1016/j.ijid.2018.06.010

1201-9712/©2018TheAuthors.PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.ThisisanopenaccessarticleundertheCCBY-NC-ND license(http://creativecommons.org/licenses/by-nc-nd/4.0/).

ContentslistsavailableatScienceDirect

International

Journal

of

Infectious

Diseases

EvidenceofAMRintheSyriancontext:sincetheonsetoftheconflictin2011 ... 28

Conclusions ... 31

Funding ... 32

Conflictofinterest ... 32

Authorcontributions ... 32

Aims ... 32

Acknowledgments ... 32

References ... 32

Introduction

Despite the proliferation of contemporary conflicts, the emergenceofantimicrobialresistance(AMR)in settingsofwar and distressed migration hasbeen neglected.This hasbeen of particularconcerninSyriawheretheprotractedandincreasingly destructiveconflicthasalsobeenadriveroflarge-scalepopulation movementsbothregionallyandinEurope.Since2012,theconflict hasbecometheleadingcauseofdeathandinjuryinSyria.Inthe absenceofaccuraterecentfigures,itisestimated,asoftheendof 2015,that470000havebeenkilledand1.9millioninjured(Syrian Centerfor PolicyResearch,2018).Withhighratesofinjury,the potentialfor infectionisexacerbatedbythecrowdedandoften unsanitary conditions in health facilities, combined with the natureofinjuriesproducedbyheavyweaponry.

The destruction of health facilities, the exodus or death of healthcareworkers,and theincreasingfragmentation ofSyria’s healthsystemhaveallcontributedtothemyriadofchallengesin addressingAMR(Fouadetal.,2017).ByApril2017,only56outof 111publichospitalswerestillofferingservices(WHO,2018),while ithasbeenestimatedthatover70%ofallhealthprofessionalshave left the country since the conflict began. Of the 6.4 million internally displaced persons (IDPs) estimated by the United Nations Office for the Coordination of Humanitarian Affairs (OCHA),morethanone millionlivein unhygienicconditionsin overcrowdedcampsand collective shelters,at increasedrisk of typhoid, hepatitis, cholera, polio, and cutaneous leishmaniasis, amongotherinfectiousdiseases(Ismailetal.,2016).

Underconditions ofcon_flict,manyof thesafeguardsagainst AMR are broken and drivers are accentuated; these include damagedhealthandsanitationinfrastructure,disruptedmedical supplies,theexodusofexpertandtrainedhealthprofessionals,and increasing exposure in compromised healthcare settings. War furtherdisruptsthepoliticalandregulatorybodiesthatoftenlead, monitor,andenforcepoliciesthattacklethedriversofAMR.This firstpartofatwo-partseriespresentsareviewandanalysisofthe literatureonwhatisknownaboutAMRintheSyrianconflict.The secondpartexploresthepre-existingdriversofAMRinSyriaand thosethathaveoccurredsincetheonsetofconflict; recommen-dationsonhowthesecanbeaddressedarealsomade.

EvidenceofAMRintheSyriancontext

Rigorous studies addressing microbiology or AMR in Syria, eitherbeforeorsincetheonsetofthecon_flictinMarch2011,are scarce.Publishedstudieshaveoftenbeenfromasinglecentreand have presented limited data of variable quality. Functioning laboratories are restricted to major cities such as Damascus, Aleppo, and Lattakia, mainly in government-controlled areas (GCAs).Whetherprivateorhospital-based,alllaboratoriesclose betweenThursdayafternoonandSundaymorning.Asthereisno on-call service, laboratory services are unavailable for 2.5days eachweek.Theselaboratoriesareinaccessibletohealthworkers servingtheoutskirtsof thesecitiesand ruralareasin GCAs,in addition to the estimated 10 million people living in

non-government-controlledareas(NGCAs),servedbysixlaboratories (verbalcommunication)(Plate1).

Therearetwoparallelsystemsofsurveillance.FromDamascus, theSyrianArabRepublicMinistryofHealthwiththesupportofthe WorldHealth Organization (WHO)collects reports ofnotifiable diseases through the Early Warning and Response System (EWARS), but without laboratory testing of samples or contact tracing.OperatingfromGaziantepin southernTurkey,theEarly WarningandResponseNetwork(EWARN)systemishamperedby thepaucityoflaboratoryservicesandtheabsenceoflocalreferral laboratoriesforverificationandtyping.Datafromthesesystems maynotbereliableinthiscontext,norgeneralizableacrossthe country(Ismailetal.,2016;Sparrowetal.,2016).Neithersystem requiresreportingonAMR,nosocomialinfections,orresponseto therapy. Bothsystems arehampered by limited surveillance in governoratesunderthecontrolofISIS(RaqqaandDeirEzzor)and thelackofqualitycontrolservicesandaccesstoaccreditedreferral laboratories.InGCAsthisrequiresshippingofsamplestoEgypt;in NGCAsthis requirescross-bordertransport toTurkeyor Jordan, subjecttopermissionfromtherelevantministryofhealth.Both circumstances arechallenging giventhe insecurity,difficulty in transportingspecimensundercontrolledtemperatureconditions, andrestrictedaccessacrossborders.

Areviewof thescientificliteraturedescribing AMRamongst SyrianswhoremaininSyriaandthosewhoarerefugeeseitherin theregion(Jordan,Lebanon,Turkey)orinEuropewasperformed toaccuratelydescribethecurrentliteratureonAMRintheSyrian conflict.ThesearchmethodsaregivenintheAppendixA.Table1

summarizesstudiesaddressingAMRbeforeandaftertheonsetof theconflict,includingallpublishedarticlesrelatingtorefugeesor SyriansinsideSyria.

EvidenceofAMRintheSyriancontext:pre-conflict

Beforetheconflict,severalreportssuggestedthewidespread availabilityofantibioticsthroughpharmacieswithoutsafeguards and/orpoorknowledgeamongstrecipientsoftherisksassociated with injudicious antibiotic use (Barah and Gonçalves, 2010). Anecdotally,extensiveantibioticoveruseandantimicrobialfailure werecommon.Limitedevidencedocumentingtheexistenceand prevalence of AMR was found in the perusal of the scientific literature. Studies identified were notable for their small size, inconsistent reporting, and questionable methodology, compromisingthepotentialtoidentifytrendsordrawconclusions concerningAMR. Moststudieswerereportedfromthecities of DamascusandAleppo,limitinggeneralizationacrossandtoother governorates.

Seven studies describing antibiotic susceptibility amongst differentisolateswerefound(Table1).Themajorityfocusedon specificbacteriaincludingAcinetobacterbaumannii,Streptococcus pneumoniae, and Brucella melitensis (Hamzeh et al., 2012; Turkmani et al., 2006; Obeid and Obeid, 2005). Hamzeh and colleaguesreportedhighlevelsofAMRin260uniquepatientswith A.baumanniiinfectionsfromAleppoin2008–2011(Hamzehetal., 2012).Resistanceto imipenemand meropenem(carbapenems)

was reported at 66%, to ciprofloxacin (fluoroquinolone) 81%, piperacillin–tazobactam (penicillin-beta-lactamase) 87%, amika-cin (aminoglycoside)78%, and toco-trimoxazole (sulfonamide) 74%. Resistance to third-and fourth-generationcephalosporins wasalsohigh,withceftazidimeresistancereportedat80.6%and cefepimeat84.7%.Colistinremainedactivewithonly7%reported resistance.The maindrawback ofthis studywas the useofan automatedsystemforspeciesidentification,bearinginmindthat thesesystemsareunabletopreciselydistinguishisolatesfromthe A.baumannii–Acinetobactercalcoaceticus complextothespecies level. Keddo et al. reported that 25% of Klebsiella pneumoniae isolatesamongst childrenwithrecurrenttonsillitis were carba-penem-resistant (Keddo and Al-Omari, 2012). With regards to Gram-positive isolates, the most recent study found was con-ducted in 2005: Obeid and colleagues reported high rates of resistancetopenicillin(64%)andtrimethoprim–sulfamethoxazole (48%)in 25 isolates of S. pneumoniae from cerebrospinal _fluid samples, but found no resistance to cephalosporins (including cefotaximeand ceftriaxone),often usedasfirst-linetherapyfor bacterialmeningitis(ObeidandObeid,2005).

Although these reports describe small numbers, they raise concern regarding the high rates of AMR reported. The high proportionofcarbapenem-resistant Gram-negativesis alarming giventhat carbapenemsare usedasbroad-spectrum orsalvage therapyfollowing failureof empiric therapy.Thepercentage of penicillin-resistant S. pneumoniae is troubling, as overuse of antibioticsinthetreatmentofviralillnessisadriverofpenicillin resistanceinthisisolate.

EvidenceofAMRintheSyriancontext:sincetheonsetofthe conflictin2011

Sincethefirstuseofarmedforceandsubsequentexpansionof violence,dataontheavailabilityandefficacyofantimicrobialtherapy withinSyriahavebecomeincreasinglylimited.Sixstudiesfrominside Syriasince late 2011 have reportedconcerns over the increasing

burden ofresistant Gram-negative infections and methicillin-resistant Staphylococcusaureus(MRSA),fourofthesebeingfocusedonAleppo (Alheibetal.,2015;Mahfoudetal.,2015;Al-Assiletal.,2013;Tabana etal.,2015).ItisnotablethatfewdatasetsfromwithinSyriahave reportedon war-relatedinjuriesandtheirinfectiouscomplications; thisislikelydrivenbyseveralfactorsincludingpoliticalsensitivities andtheoverwhelmedhealthsystems.

StudiesofresistancefrominsideSyriaonspecificisolateshave reportedhighlevelsofAMR. Zainandcolleaguesexamined236 Escherichiacoli isolatesandfound26%ofthesetobe extended-spectrum beta-lactamase (ESBL) producers(Baaityet al., 2017). Alheibandcolleaguesexamined123ESBL-producingE.coliandK. pneumoniaespecimensin2015andfound66%oftheseisolatesto bephenotypicallyresistanttociprofloxacin(Alheibetal.,2015). Mahfoud and colleagues tested 177 Pseudomonas aeruginosa urinary and lower respiratory isolates from patients in three intensivecareunitsinAleppoandshowedsigni_ficantresistanceto commonanti-pseudomonalagents(piperacillin–tazobactam:46%; meropenem: 41%; ceftazidime 73%) with colistin as the most reliableantibiotic(11%resistance)(Mahfoudetal.,2015).Al-Assil reviewed104patientswithpositiveurinesamplestounderstand theriskfactorsforthedevelopmentofESBLinfectionsandisolated ESBLE.coliin52%ofcases(Al-Assiletal.,2013).Co-resistanceto otherantibioticswasfoundin82%ofcases.Riskfactorsidentified asincreasingtheriskofESBLacquisitioninthatstudyincluded olderage(>52years),hospitalization,urinarycatheterization,and previousexposuretothird-generationcephalosporinsor quino-loneantibiotics(Al-Assiletal.,2013).

Ofthefewlargeregionalstudies,arecentretrospectivestudyin Lebanonanalysing55594Gram-negativeisolatesbetween 2011 and2013reportedESBLratesamongstE.coliandKlebsiellasppof 32.3%and29.2%,respectively(Chamounetal.,2016).Lebanonand Jordan, countries neighbouring Syria and hosting an estimated total of 1.7 million refugees, both reported the emergence of multidrug-resistant(MDR)Gram-negativeinfectionscomplicating war-relatedinjuries(Teicheretal.,2014;Abbaraetal.,2017;Rafei

Table1

Characteristicsofkeystudies:dividedintopreandpostonsetoftheconflictinSyria,regionalstudiesincludingSyrianrefugees,andotherstudiesdescribingSyrianrefugees. Group(yearof

publication)

Year Location Studydescription Sample Keyfindings Pre-conflict

Al-Omar(2005) 2004 Misiaf,Syria Prospectivecultureofurinesamples fromallpatientsinthecommunity

127positiveurine samples

68.6%ofisolateswere Enterobacter-iaceae

30.6%wereGram-positive(22.8%S. aureus)

Overallresistancereportedat:69% ampicillin,55%TMP–SMX,37% amoxicillin–clavulanate,35% ofloxa-cin

ObeidandObeid(2005) Sep2003to May2004

Damascus,Syria S.pneumoniaefromCSFsamples; susceptibilityofstrainsusingdisc diffusionmethods(NCCLSbreakpoints)

25isolates Reportedresistance:64%were re-sistanttopenicillin,48%toTMP– SMX, 16%toerythromycin,and16%to tetracycline

Noneresistanttoceftriaxone, cefo-taxime,amoxicillin–clavulanate

Al-Qwaretetal.(2010) 2010 Damascus,Syria Prospectivecohortstudyofaerobic organismsisolatedfromdiabeticfoot ulcersandtheirreportedantibiotic sensitivities

100specimens,128 organisms

61%ofS.aureusisolateswereMRSA NCPE/CROidentified

Al-Qwaretetal.(2010) 2012 Damascus,Syria Reviewofallaerobicbacterial conjunctivitiswithantibiotic susceptibilities

51patients Highlevelsofsusceptibilityto first-andsecond-lineagentsreported

KeddoandAl-Omari (2012)

2012 DamascusSyria Paediatricrecurrenttonsillitiscases thatunderwenttonsillectomy Reviewofaerobicisolatesfromtonsil coreculture

80patients 25%oftheK.pneumoniaeisolates werecarbapenem-resistant 15%ofE.coliwerealso

imipenem-resistant

Hamzehetal.(2012) 2008–2011 Aleppo,Syria RetrospectivereviewofA.baumannii isolates

260patientswith260 isolatestested

Resistancetospecificantibiotics: 65%imipenem,87%piperacillin– tazobactam,78%amikacin,81% cip-rofloxacin,74%co-trimoxazole,7% colistin

Turkmanietal.(2006) 1995–2005 Eastern Mediterranean

IsolatesofB.melitensisfromanimalsin Syria

5isolates Highlysusceptibletomosttested antibiotics

Postcommencementoftheconflict–Syria

Al-Kadrouetal.(2013) 2013 Damascus,Syria Aerobicbacterialinfectionsinburns patientsmanagedwithinaSyrian governmenthospital

109isolatesfrom53 samples

Nopolymyxinresistancein Gram-negativesidentified

Tabanaetal.(2015) 2015 Aleppo,Syria Laboratoryevaluationofprevalenceof PMQRgenesatAleppoUniversity

123ESBL-producing isolatesofE.coliandK. pneumoniae

Al-Assiletal.(2013) 2011 Aleppo,Syria ThreehospitalsinAleppo;75patients withUTIs

75patientswithUTIs causedby

trimethoprim-resistant E.coli;104unique isolates

96%susceptibletonitrofurantoin Reducedsusceptibilityto:

amoxicillin–clavulanate43%,3/4 GNBtocephalosporins50–60%, piperacillin–tazobactam66%, tetra-cyclines44%,TMP–SMX20%

Alheibetal.(2015) 2015 Aleppo,Syria PMQRgenesamongESBLE.coliandK. pneumoniae

123isolates 66%ofESBL-positiveisolateswere resistanttociprofloxacin

83%ofE.colicomparedto87%ofK. pneumoniaeharbouredPMQRgenes, butthisdidnotnecessarilyconfer phenotypicresistance

Mahfoudetal.(2015) 2011–12 Aleppo,Syria ThreemajorhospitalsinAleppo Lowerrespiratorytractandurine sampleswithnosocomialinfections fromintensivecarepatientsinwhomP. aeruginosawasisolated

177samples(tested againstCLSIguidelines)

59female/118male

Samples:138lowerrespiratorytract and39urinary

Selectedsusceptibility:piperacillin– tazobactam54.5%,amikacin42.8%, ceftazidime28.6%,meropenem 59.1%,imipenem56.1%,colistin89.1%

Nofal(2016) 2016 Damascus,Syria Retrospectivereviewofspeciesand sensitivitiesofotitismediacases

87patients,49isolates 52%male,48%female

K.pneumoniae(n=3):100%sensitive toimipenemandlevofloxacin S.aureus(n=16):100%sensitiveto

imipenem

Al-Assiletal.(2013) 2011 Aleppo,Syria ThreehospitalsinAleppo RiskfactorsforESBLinfections

104patientswith positiveurinesamples

MDRE.coli63% ESBLE.coli52%

Table1(Continued) Group(yearof publication)

Year Location Studydescription Sample Keyfindings assessedbymultivariateregression

analysis

 Levelsofco-resistancehighinESBLs (82%)

 Age>52years,hospitalization, uri-narycatheters,prior third-genera-tioncephalosporinuse,andprevious quinolonetherapywereall associ-atedwithESBLsinthisstudy

Baaityetal.(2017) Latakia,Syria Al-AssadTeaching

AntibioticsusceptibilityandESBL productionbydiscdiffusionusingCLSI/ EUCAST

236E.coliisolates  32%oftheE.coliisolateswereMDR and26%wereESBL-producers

Postcommencementoftheconflict–outsideSyria

Teicheretal.(2014) 2011–13 AmmanJordan MédecinsSansFrontièressurgical projectmanaging

MDRdefinedas:(1)ESBL-expressing Enterobacteriaceae;(2)P.aeruginosa andA.baumanniiisolatesresistanttoat leastoneagentinthreeantimicrobial categoriestypicallyusedfortreatment; or(3)MRSA

61Syrianorthopaedic patientswithsuspected infectionsundergoing surgicalsampling intraoperatively

 Age26years(IQR22–34years);98% male

 Injurytoadmissionapproximately5 months(IQR1.2–8.1months): gun-shotwoundsn=31,explosion woundsn=20

 45ofthesepatientshadatleastone organism,with69%(31/45)MDR organisms:P.aeruginosa(10/31),E. coli(5/8),carbapenem-resistantA. baumannii(4/5),MRSA(7/17)

Kassemetal.(2017) 2013–2016 Israel Microbiologicalsurveillancescreening ofseverelyillorinjuredSyrianchildren Screenedfor:ESBL,CRE,MRSA,MDRA. baumannii,andVRE

128children  MDRcarriagefoundin83%,with NDMCREmostprevalent  24/128hadMDRinfections(90%

werewounded):ESBL66%,MDRA. baumannii20%,CRE15%

Angelettietal.(2016) 2016 Italy Microbiologicalsurveillanceusing rectal,pharyngeal,andnasalswabs

48refugees  HighratesofGram-negative non-lactose-fermentingorganismssuch asPseudomonasandAeromonas spe-cies,with5carbapenem-resistant isolates

 NoCRE

 24%(6/25)ofS.aureusisolateswere methicillin-resistant

Bhallaetal.(2016) 2016 Amman,Jordan ObservationalstudyattheMédecins sansFrontièressurgicalprogramme hospitalmanagingchronic trauma-relatedinfectionscolonizedorinfected withAMRorganisms

NA NA

Abbaraetal.(2017) 2015 Amman,Jordan Microbiologicalsamplesfrominfected injuries(boneandsofttissue)amongst injuredSyrianrefugees

75patients  20%hadosteomyelitis,53%had prostheticmaterial

 30bacterialisolatesofwhich97% wereGNB

 66%wereMDRand37%were car-bapenem-resistant

Ravensbergenetal. (2016)

2016 Groningen, Netherlands

ScreeningofasylumseekersforMDROs uponadmissiontohospital

130asylumseekers; 36.5%Eritreanand 18.6%Syrian

 31%colonizedwithanMDRO:7.7% withMRSA;20%ESBL(20E.coli,4K. pneumoniae,1M.morganii,and1E. cloacae)

 10%resistanttofluoroquinolones  Nocarbapenemases

Reinheimeretal.(2016) 2015 Germany Microbiologicalsurveillancescreening ofpatientsadmittedtoFrankfurt hospitalforMDROs,forGNB(ESBLand A.baumannii),andMRSA

143refugees,including 47(43%)fromSyria,29 fromAfghanistan,14 fromSomalia

 60.8%colonizedwithMDRGNBin Refugeepopulationcomparedto 16.8%inthegeneralpopulation  ESBLE.coliandK.pneumoniaewere

significantlymorecommon(23.8% vs.4.9%and4.2%vs.0.8%)  1CREand2carbapenem-resistantA.

baumannii

 MRSA5.6%vs.1.2%inthegeneral population

Heudorfetal.(2016) 2015 Frankfurt,Main, Germany

Microbiologicalsurveillancescreening ofunaccompaniedminors(aged <18years)screenedforMDR Enterobacteriaceaeinstoolsamples

119individuals,7 Syrians

 Total:35%hadESBL Enterobacteria-ceae,including8%GNBresistantto threeantibioticgroups

 Syrians:3hadESBL Enterobacteria-ceae;nonehadMDR

et al.,2015; Rafeiet al., 2014).In 2014,Teicher and colleagues reportedontheexperienceofaMédecinssansFrontières (MSF)-ledsurgicalmanagementprojectinAmman,Jordan(Teicheretal., 2014).Acohortof61youngmen(medianage26years)presented tothehospitalwithclinicallyinfectedchronicwarwounds(injury topresentationtimemedian5months,interquartilerange1.2_–8.1 months). Gunshot (31 patients) and explosion-related (20 patients) wounds were the most common injuries. Of the 61 patients,45hadatleastonepositiveculture,with69%(31/45)of isolatesbeingMDR.Althoughnumbersweresmall,highratesof carbapenem-resistantA.baumannii(80%;4/5),ESBL-producingE. coli(62%;5/8),andMRSA(41%;7/17)wereisolated.Similarratesof MDRorganismshavebeenreportedrelatedtowarinjuries(Teicher etal.,2014;Abbaraetal.,2017),andrefugeeshavebeenreportedto have significantly higher rates of carbapenem-resistantA. bau-mannii(Rafeietal.,2014).NodataareavailablefromTurkey,which hostsnearlythreemillionSyrianrefugees.

AmorerobustevidencebaseofAMRandtheSyrian refugee crisishascome fromanincreasing numberof reports onMDR organismcarriageinrefugeesadmittedintoEuropeanhospitals. Syrian refugeepatients screenedin Europe haveshown higher rates of carbapenemase-producing Enterobacteriaceae (CPEs) comparedwithlocalpopulations(Kassemetal.,2017;Angeletti etal., 2016;Ravensbergenetal., 2016;Reinheimer etal.,2016; Heudorfetal.,2016;Tenenbaumetal.,2016;Heydarietal.,2015). EstimatesofMDRcarriagewithinpaediatricandadultpopulations inthesestudiesrangefrom33%to83%,withhighratesofNew Delhimetallo-beta-lactamase(NDM)-producing carbapenem-re-sistantEnterobacteriaceae(CRE),A.baumannii,andESBL-producing Enterobacteriaceae(Rafeietal.,2014;Kassemetal.,2017;Angeletti

et al.,2016;Ravensbergenet al.,2016; Reinheimeret al.,2016; Heudorfetal.,2016;Tenenbaumetal.,2016).Thisissignificantly greaterthanthebackgroundcarriageratesofthelocalpopulations suchasinGermany,wherecolonizationwithMDRGram-negatives was identifiedin60.8%ofarefugeepopulation(ofwhom18.6% wereSyrian)screenedonadmissiontohospitalversus16.8%inthe generalpopulation(Ravensbergenetal.,2016).

Comparative data from the European Antimicrobial Resistance SurveillanceNetwork(EARS-Net)showedratesofresistanceforseven specificpathogensin2015.28_{Penicillinnon-susceptibilityinS.} pneumo-niaerangedfrom0.6%inBelgiumto39%inRomania.Carbapenem resistancewas0.1%,8.1%,and17.8%inE.coli,K.pneumoniae,andP. aeruginosa, respectively, withthe highest rate of 93.5% seen in AcinetobacterspinGreece.Polymyxinresistancewas0.8%,4%,and 8.8% in P. aeruginosa, Acinetobacter sp, and K. pneumoniae, respectively.MostK.pneumoniaeisolateswithcombined polymyx-inandcarbapenemresistancewerereportedfromGreeceandItaly. MRSAratesrangedfrom0%inIcelandto57%inRomania. Conclusions

ThisreviewofevidenceofAMRinsideSyriaandincountries hostingSyrianrefugeesdemonstratesapaucityofrigorousstudies describing this increasingly important phenomenon. Beforethe conflict, published studies inside Syria were often from single centresandpresentedlimiteddataofvariablequality.Sincethe onsetoftheconflict,nostudieshavedescribedtheprevalenceof AMRinthosewithinjurieswithinSyria.However,evidencefrom neighbouring countries suggests that this is an increasing phenomenon.Itisimportanttoaddressthisresearchandreporting

Tenenbaumetal. (2016)

2015–2016 Germany Retrospectiveobservationalstudyof screeningofpaediatricrefugeepatients admittedtohospital 325patients MDRdetectedin33.8% 110of113samplesGNB 87MDRGNB/ESBL 22MRSA 1VRE

Heydarietal.(2015) 2014 Turkey Microbiologicalsurveillancescreening ofallA.baumanniiresistantto carbapenemscollectedovertheyear periodandscreeningfor NDM-1-producingorganisms

2Syrianrefugees admittedtoICU

1isolateof2fromaSyrianrefugee admittedtoICUwithacuterenalfailure andgastritis

Peretzetal.(2014) 2014 GalileeMedical Centre,Israel

Microbiologicalsurveillancescreening ofSyriansadmittedtohospital Screenedfor:ESBL,CRE,MRSA,MDRA. baumannii,andVRE

27childrenand60 adults

Children:21isolatesofMDROsin19/ 27patients;20/21ESBL Enterobac-teriaceae;MRSA=1/21

Adults:28/60carriers;5patients, CRE(2NDM);11patients,MRSA;5 A.baumannii;7ESBL

Rafeietal.(2014) 2012 Lebanon SyriansadmittedtoLebanesehospitals Carbapenem-resistantA.baumannii isolatesinvestigatedusingPCRto identifyOXAandNDMproducing organisms

4patientswithwar wounds

All4hadcarbapenem-resistantA. baumanniiidentifiedascarryingthe bla-NDM-1gene

Theseorganismsallhadphenotypic susceptibilitytoaminoglycosides, colistin,andtigecycline

Rafeietal.(2015) 2011–13 Lebanon ReviewofisolatesfromLebaneseand Syrianwounded;respiratory,wound, urine,catheters,andbloodisolates

116isolates 90male,26female

70/116(60%)had carbapenem-re-sistantphenotype(includingNDM-1 andOXA-23)

Syrianrefugeeshadagreaternumber ofcarbapenem-resistantA. bauman-nii(74%vs.47%)

A.baumannii,Acinetobacterbaumannii;AMR,antimicrobial-resistant;B.melitensis,Brucellamelitensis;CLSI,ClinicalandLaboratoryStandardsInstitute;CPE, carbapenemase-producingEnterobacteriaceae;CRE,carbapenem-resistantEnterobacteriaceae;CRO,;CSF,cerebrospinalfluid;E.coli,Escherichiacoli;E.cloacae,Enterobactercloacae;ESBL, extended-spectrumbeta-lactamase;EUCAST,EuropeanCommitteeonAntimicrobialSusceptibilityTesting;GNB,Gram-negativebacilli;ICU,intensivecareunit;IQR, interquartilerange;K.pneumoniae,Klebsiellapneumoniae;MDR,multidrug-resistant;MDRO,multidrug-resistantorganism;M.morganii,Morganellamorganii;MRSA, methicillin-resistantStaphylococcusaureus;NA,no;NCCLS,NationalCommitteeforClinicalLaboratoryStandards;NDM,NewDelhimetallo-beta-lactamase;OXA,;P. aeruginosa,Pseudomonasaeruginosa;PMQR,plasmid-mediatedquinoloneresistance;S.aureus,Staphylococcusaureus;S.pneumoniae,Streptococcuspneumoniae;TMP–SMX, trimethoprim–sulfamethoxazole;UTI,urinarytractinfection;VRE,vancomycin-resistantenterococci.

gap,asdefiningthecurrentextentofAMRamongSyrianswillhelp toinform interventionsthat addressthedriversofAMRin this population. This is particularly relevant given the population movementsthathaveresultedfromtheconflictandthelikelihood ofongoingchallengesinaddressingthisissuewhichisofglobal importance.However,therearebarrierstofillingthisevidencegap due to a combination of factors relating to the complex humanitariansituationinsideSyriaandtheoverwhelmedhealth systemsinneighbouringcountries.Collaborationandinnovations arerequiredtoaddressthisissue,whichisofglobalimportance. Thesecondpartofthistwo-partseriesaddressesthedriversof AMRbefore and after the onset of con_flict and makes recom-mendationsastohowthesecanbeaddressed.

Funding

Nofundingreceivedforthiswork. Conflictofinterest

Noconflictofinteresttodeclare. Authorcontributions

AAconceivedtheidea,contributedtotheliteraturereview,the firstdraftand revisionsof themanuscript. TMR,NK,WE-A, JH, contributedtotheliteraturereview,writingofthetextandmade significantcontributionstorevisionsofthemanuscript.BT,ODa, ODe,GAS,BEUmadecontributionstothetext,literaturereview andrevisionsofthemanuscript.AScontributedtotheoriginaltext andsubsequentrevisions,thefiguresandtablesanddevelopedkey conceptsinthemanuscript.

Aims

1.ComparewhatisknownaboutantimicrobialresistanceinSyria andneighbouringcountrieshostingSyrianrefugeesbeforeand aftertheonsetoftheconflict.

2.Identify geographical and population areas where there are evidencegaps.

ComparewhatisknownaboutantimicrobialresistanceinSyria and neighbouringcountrieshosting Syrian refugees beforeand aftertheonsetoftheconflict.

Identify geographical and populationareas where there are evidencegaps.

Acknowledgments

WethankourSyriancolleaguesworkinginDamascus,Quneitra, Homs, Aleppo, Idlib, Hama, Dara_’a, Sweida, Lattakia, Tartous, Raqqa,Deir Ezzor, and Hasseke for providing dataand sharing valuable insights; particularly surgical and microbiological col-leagues at the AMR/Trauma training provided by the Syrian AmericanMedical Societyoffice inGaziantep,Turkey,Professor Antony Keil from the Faculty of Medicine at the University of WesternAustralia,andNatalieGarlandfromtheISSMS.

AppendixA

Searchmethodologyforthereviewoftheliteratureonantimicrobial resistanceinSyriapreandposttheonsetofconflict

Drug-resistant bacteria were defined according to the US Centers for Disease Controland Prevention (CDC) definition as “microorganisms,predominantlybacteria,thatareresistanttoone

or more classes of antimicrobial agents”; multidrug-resistant (MDR)bacteriaweredefinedasmicroorganismsthatareresistant tooneormoreagentsinatleastthreeseparateclasses, methicillin-resistantStaphylococcusaureus(MRSA),oranextended-spectrum beta-lactamase(ESBL)-producingorganism.

InformationaboutantimicrobialresistanceinSyriaoramongst Syrian refugees was collected. A detailed scoping review was performedtosummarizetheavailableliteratureonAMRaffecting Syrians pre and post conflict. This aimed to identify the key emergingthemesandcurrentconcepts,andtohighlightgapsin currentevidenceonAMRinSyria.MEDLINE,PubMed,Embase,and theWorldHealthOrganization(WHO)GlobalHealthLibrarywere searched usingthe terms‘Syria’ and ‘antibiotic resistance’. The greyliteraturewassearchedusingothersearchengineswiththe followingadditionalterms:‘Syria’,‘refugee’,‘antimicrobial resis-tance’, ‘screening’, ‘war-injury’. Only articles in English were included.ThejournaloftheSyrianClinicalLaboratoryAssociation was also searched. This was included to ensure that relevant literaturewasnotmissed;howeverthepeerreviewprocessforthis journalisunknown.Anyidentifiedreferenceswithintheliterature thatweredeemedrelevantwerealsoincludedinthefinalreview. AppendixA.Supplementarydata

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