Antimicrobial resistance in the context of the Syrian conflict: Drivers before and after the onset of conflict and key recommendations

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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)

Antimicrobial resistance in the context of the Syrian conflict: Drivers before and after

the onset of conflict and key recommendations

International Journal of Infectious Diseases, 73: 1-6

https://doi.org/10.1016/j.ijid.2018.05.008

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Review

Antimicrobial

resistance

in

the

context

of

the

Syrian

con

flict:

Drivers

before

and

after

the

onset

of

con

flict

and

key

recommendations

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

NationalInstituteforHealthResearchHealthProtectionResearchUnitinHealthcareAssociatedInfectionsandAntimicrobialResistance,ImperialCollege London,HammersmithCampus,London,UK

c

DepartmentofMolecularBiology,LaboratoryforMolecularInfectionMedicineSweden,andUmeåCentreforMicrobialResearch,UmeåUniversity,Umeå, Sweden

d_{DepartmentofMicrobiology,BroomfieldHospital,Chelmsford,Essex,UK} e

SyrianAmericanMedicalSociety,Turkey

f

PublicHealthEngland,ChathamHouseCentreonGlobalHealthSecurity,London,UK

g_Conflict

andHealthProgram,AmericanUniversityofBeirut,Lebanon

h

DepartmentofPopulationHealthSciencesandPolicy,IcahnSchoolofMedicineatMountSinai,NewYork,USA

ARTICLE INFO

Articlehistory: Received31March2018

Receivedinrevisedform13May2018 Accepted16May2018

Corresponding Editor: Eskild Petersen, Aarhus,Denmark Keywords: Antimicrobialresistance Syria Conflict Surveillance Refugees ABSTRACT

Currentevidencedescribingantimicrobialresistance(AMR)inthecontextoftheSyrianconflictisofpoor

qualityandsparseinnature.ThispaperexploresandreportsthemajordriversofAMRthatwerepresent

inSyriapre-conflictandthosethathaveemergedsinceitsonsetinMarch2011.Driversthatexisted

beforetheconflictincludedalackofenforcementofexistinglegislationtoregulateover-the-counter

antibioticsandnotificationofcommunicablediseases.ThiscontributedtoanumberofdriversofAMR

aftertheonsetofconflict,andthesewerealsocompoundedbytheexodusoftrainedstaff,theincreasein

overcrowdingandunsanitaryconditions,theincreaseininjuries,andeconomicsanctionslimitingthe

availabilityofrequiredlaboratorymedicalmaterialsandequipment.AddressingAMRinthiscontext

requirespragmatic,multifacetedactionatthelocal,regional,andinternationallevelstodetectand

managepotentiallyhighratesofmultidrug-resistantinfections.Prioritiesare(1)thedevelopmentofa

competentsurveillancesystemforhospital-acquiredinfections,(2)antimicrobialstewardship,and(3)

the creationof cost-effective and implementableinfection controlpolicies.However, it isonlyby

addressingtheconflictandimmediatecessationofthetargetingofhealthfacilitiesthattherehabilitation

ofthehealthsystem,whichiskeytoaddressingAMRinthiscontext,canprogress.

©2018TheAuthors.PublishedbyElsevierLtdonbehalfofInternationalSocietyforInfectiousDiseases.

ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(

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

Contents

Introduction ... 2

DriversofAMRintheSyriancontext ... 2

* 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),James.hatcher@nhs.net(J.Hatcher),

Bachir.tajaldin@sams-usa.net(B.Tajaldin),Osman.dar@phe.gov.uk(O.Dar),

oa02@aub.edu.lb(O.Dewachi),ga60@aub.edu.lb(G.AbuSitta),

bernt.eric.uhlin@umu.se(B.E.Uhlin),annie.sparrow@mssm.edu(A.Sparrow).

https://doi.org/10.1016/j.ijid.2018.05.008

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

ContentslistsavailableatScienceDirect

International

Journal

of

Infectious

Diseases

DriversofAMRintheSyriancontext:pre-2011 ... 2

DriversofAMRintheSyriancontext:aftertheonsetofconflict ... 3

Howcanthisbeaddressed? ... 4

Conclusions ... 5

Acknowledgements ... 5

References ... 6

Introduction

Multilateralactionbyinternationalhealthbodiesand govern-mentsis required tocombat theglobal threatof antimicrobial resistance(AMR).Failingtoaddressissuesatthelocallevelcan haveregionaland globalimplications.The falloutof theSyrian conflictisnotrestrictedtoSyriaandneighbouringcountries:in 2015alone,378000SyriansenteredEurope–roughlyone-thirdof the1.3millionrefugeesseekingasylumthere(Connor,2015).The EuropeanCentreforDiseasePreventionandControl(ECDC)and theWorldHealthOrganization(WHO)havestatedthattheriskof infections resulting from the living conditions that refugees encounteraregreaterthantherisksofthemimportinginfections (WHO, 2017; Brusin et al., 2015; European Centre for Disease PreventionandControl,2016).Nevertheless,potentiallyhighrates ofAMRamongstSyriansrequireustoaddressthecauses,risks, costs,andfutureconsiderationsofthischallengebothforSyrians livinginconflictandforSyrianrefugees.

The Lancet Series onthe promotion of universalaccess and sustainableeffectivenessofantimicrobialsinthecontextofAMR includes policy recommendations for national and regional interventionstocombatresistance(Daretal.,2016).Theseinclude infectionpreventionand control(IPC), surveillance,monitoring, stewardship,andthestrengtheningofhealthsystems.Ithighlights theimportanceof accesstoeffectiveantimicrobials whilstalso ensuring effective stewardship and vaccination as a means of addressing AMR globally. For Syria and other conflict-affected countriestoparticipateintheWHOGlobalActionPlan(GAP)on AMR,apragmaticfocusonwhatcanbeachievedinthesecountries is required. This is particularly the case in Syria where a comprehensivenationalactionplantoaddressAMRiscurrently

unrealisticgiventheparallelhealthsystemsfunctioninginsideits borders.

ThisarticleidentifiesthedriversofAMRthatexistedbeforethe conflictandthosethathaveoccurredsincetheonsetofconflictin March2011.Italsomakesrecommendationsastohowthesecanbe addressed.

DriversofAMRintheSyriancontext

Thissection examinesthe potentialdriversof AMRin Syria before and after the onset of conflict, highlighting those most relevant to the Syrian context. Figure 1 summarizes the main driversandtheirconsequences.

DriversofAMRintheSyriancontext:pre-2011

Priortotheconflict,healthindicesforSyria,amiddle-income country,showedmanyparallelswiththoseofWesterncountries, suchascompletion oftheepidemiologicaltransitionanda life-expectancyinexcessof70years.IncontrasttoWesterncountries, neithermicrobiologynorinfectiousdiseaseswererecognizedas specialityareasoftraining,norweretheyfinanciallyrewarding. Little trainingwas providedbeyondmedical school;therewere fewopportunitiesforcontinuingmedicaleducation.The labora-toriesestablishedinpublichospitalsundertheMinistryofHealth (MoH)andMinistryofHigherEducationwerevariablyequipped withmanual(Kirby–Bauer)andautomated(Phoenix andVitek) AMRtesting.IPCwasinadequate,withpoorimplementationofthe NationalProtocolforInfectionControl,andprotocolsforuniversal precautionswereabsent.Effortstowardsantimicrobial steward-shipareseeninthelegislationdrawnupbytheSyrianSyndicate

Pre-conflict

-Availability of antibiotics without prescription -Excessive antibiotic prescribing

-Lack of antimicrobial stewardship -Poor infection prevention and control -Non-existent nosocomial surveillance -Lack of microbiologists and infectious disease specialists

Conflict related or exacerbated by the conflict

-Destroyed health infrastructure -Fragmentation of health system -Exodus or death of healthcare workers -Lack of training for remaining health workers -Overcrowding and displacement

-Lack of availability of antibiotics -Overuse of available antibiotics

-War trauma, especially by heavy weapons and explosive devices causing contaminated and deeply penetrating injuries

-Increased use of prosthetic materials -Insufficient resources

Consequences

-Inability to perform bacterial surveillance -Unknown prevalence of resistant organisms -Few microbiology laboratories

outside of government controlled areas -Lack of quality control

-Potential for increased morbidity/ mortality -Potential for nosocomial transmission -Smuggling of fake antibiotics

Figure1.DriversandconsequencesofantimicrobialresistanceintheSyrianconflictandtheirconsequences. 2 A.Abbaraetal./InternationalJournalofInfectiousDiseases73(2018)1–6

for Pharmacists concerning the over-the-counter (OTC) sale of antibiotics, passed in 1994 (Syrian Syndicate for Pharmacists, 1994).ThisefforttoregulateOTCavailabilityofantibioticswasnot enforcedbythegovernment.

Thenotificationofcommunicablediseasewaslegislatedbythe SyrianArabRepublicin2007(DecreeNo.7,2007)(Anon,2018)and surveillanceguidelineswereissuedbytheMoHin2010forboth publicand private sectors. However,as withthe regulation of antibioticsales,thislegislationwasnotenforced.Reportingtended to be done on an ad hoc basis, usually without laboratory confirmation.

Nosocomial infections were poorly reported, but frequently described anecdotally. Well before the onset of the conflict, Acinetobacter was reported to be the most common cause of ventilator-acquired pneumonia across intensive care units in public hospitals of Damascus (personal communications with Syrianmicrobiologists,surgeons, andinternal medicine special-ists).Notably,nosocomialorcommunity-acquiredinfectionswith Acinetobacterbeyondtherespiratorysystemwererarelyornot describedpriorto2012,whichmarkedthefirstuseofheavyand explosiveweaponry.

Consistentwiththiscontext,thereisevidencetosupporthigh populationratesofantimicrobialusage,poor knowledgeofdriversof AMR,littleregulationinthedistributionandOTCsaleofantibiotics, and excessive self-medication. In 2007, Barah and Goncalves conducted a cross-sectional study exploring citizens’ usage, knowledge,andattitudestowardsantimicrobialsintheKalamoon region of Syria (Teicher et al., 2014). Four hundred and thirty households were sampled randomly and 366 (85%) responders reportedusingantimicrobialsinthepreceding4weeks,withonly 43%ofthesecoursesbeingprescribedbyahealthcareprofessional (Barah et al., 2009). This is mirrored by other studies that demonstrated high use and readily available OTC supplies of antibiotics; these potentially contributed to selective pressure leadingtoAMR(Al-Fahametal.,2011).AntibioticspurchasedOTC includedamoxicillin–clavulanate,amoxicillin,cefadroxil, clarithro-mycin,andazithromycin(Al-Fahametal.,2011).

Inhealthcare,antibioticstewardshipprogrammeswerepoor, withover-prescribingamongstdoctorsdrivenbypatient expect-ations.Dataoncompliancewiththeprescribedantibioticcourseor thequalityofantibioticsproducedarenotavailable.Thepaucityof surveillance data inside Syria is consistent with the lack of a systematicprocessthrough which laboratoriesreportresultsto trackAMR.Challengesrelatingtothisincludeahealthsystem pre-conflictthatwasincreasinglyprivatized,withagrowingnumberof private laboratory facilities or public–private partnerships with littlestandardization(Teicheretal., 2014).Developinga robust surveillancesystemforAMRinlinewiththeWHOGlobalAMR Surveillance System (GLASS) is important although challenging duringconflict(FlemingFund,2016).

Neglectofwaterchlorinationandsanitationservicesincertain areasisevidencedbycholeraoutbreaksthatoccurredin2008and 2009inDeirEzzorandAr-Raqqa(Anon,2015).Furthermore,there was dissonance in the rates of vaccination against routine childhooddiseasesreportedbyofficialagenciesandthe surveil-lanceagenciesusedbytheWHOandtheUnitedNationsChildren’s EmergencyFund(UNICEF): in2008, theMoH reportednational coverageratesof98–99%(QamishliandBab,2004),comparedwith 76.3–82%recordedbytheSyrianCommissionforFamilyAffairsin the 2008 populationsurvey (Syrian Center for Policy Research SCPR,2016).

DriversofAMRintheSyriancontext:aftertheonsetofconflict MultipledriversofAMRsincetheonsetandexpansionofthe conflict are identifiable: the crowded and unsanitary living

conditionsduetoforceddisplacement,theneglectanddestruction ofpublichealthcare,andinsecuritycausedbywarcompromising accesstohealthcare.Concerninghumanresources,thousandsof professionaland alliedhealthcare workers,includinglaboratory technicians,haveleftthecountry,voluntarilyorinvoluntarily,in both government and non-government areas. Reasons include physicalandfinancialinsecurity,themilitarydraft,the incarcera-tionandexecutionofmedicalpersonnel,andtargetedassaultson clinicsandhospitals.Thishasleftagapoftrainedstaffcompetent inthediagnosisandmanagementofinfections,particularlythose causedbyresistantorganisms(Fouadetal.,2017).

Thecollectionandprocessingofsamplesisalsoaffectedbythe gapsintrainingandeducation.Remainingresidentsandnursing staffareuntrainedinthecollectionofsamples,whichmayleadto contaminationatcollection.Contaminationofsamplesmayalso occuronreceiptof thesamplesbyuntrainedlaboratorystaffin publichospitals.Bothmanualtests(Kirby–Bauer)andautomated testsaredependentonskilledprocessingofsamplestoproduce reliable results. The shortage of laboratories and paucity of adequate quality controlin the processing of samplesimpedes surveillance and appropriate diagnosis. Inadequate culture and sensitivitytestingandtheunreliabilityofresultswillleadto over-treatment compared to antibiotic therapyguided by laboratory reports. Thispracticeis exacerbatedboth bythelack ofskilled microbiologiststoprovideguidancetoclinicians,aswellasthelack of experiencedclinicianstointerpretlaboratory resultswithout guidancefrommicrobiologists.Noreliablequalitycontroltesting oflocallymadeantibioticsisavailable;hencevancomycinisthe onlyantibioticthatcanbetestedforactiveingredients.

ThedegreetowhichAMRexistsamongstpatientsisunknown. Monitoringofcomplianceiscompromisedbythedifficultyposedto patientsinpresentingtohospitalsandprimaryhealthcentres,given theinsecurityandviolence.Theabsenceofstandardizedsyndromic guidelinesmayexacerbatetheclinicaltendencytowardsusageof availablebroad-spectrumantibioticsforprolongedperiodsoftime, as indicated bythepreferentialpurchase of carbapenemsand fourth-generationcephalosporins(WHOEMRO,2016).

Onwardtransmissionofresistantorganismsisexacerbatedby theovercrowdingresultingfromforceddisplacementandthelack ofadequate watersupplies andsanitation.Safewaterlevelsare lessthanhalfofpre-warlevels(InternationalCommitteeoftheRed Cross,2015).Withtheprogressionoftheconflict,thecapacityof health centres to sterilize medical instruments generally and surgicalinstrumentsspecificallyhasbecomeweakerduetoalack ofdisinfectantsandrequiredconsumables.Chlorine,theprimary agentfordecontaminatingwaterandwidelyusedinsterilization anddisinfection,hasfacedstricterregulationfollowingitsuseasa chemicalweapon.Theoveruseofmetronidazoleinresponsetoan escalationofwater-bornediseasescausinggastroenteritishasled towidespreadclinicalconcernsaboutresistance.Asmetronidazole nolongerappearstobeeffectiveintripletherapyforHelicobacter pylori,ithasnecessitatedsubstitution,inturndependentonthe availabilityofclarithromycin.

Economicsanctionshaverestrictedtheavailabilityofmedical materials and equipment. Spare parts for autoclaves and other disinfectionequipmentarenotavailable.Thereisonlyonecertified microbiologist in Syria (US board-certified), and only five physicians with experience in microbiology could be located across the country. There are very few laboratory engineers capableofmaintainingexistingequipment.Newbrandsimported byUNagenciesandinternationalnon-governmentalorganizations in Damascus may follow tendering protocols, but are rarely familiar tohospital engineers. Irregular electricity and internet suppliesareaconsistentconcernacrossthecountry,compounding this issue of sterilization. Obtaining the necessary security approvals for transportation of medicines is time-consuming.

Thesechallengesmaybegreaterin besiegedand hard-to-reach areas,one examplebeingthe systematicremovalof antibiotics fromconvoystobesiegedorrecentlybesiegedareas.InMay2017, paediatric antibiotics were removed from a WHO convoy to Madaya(Anon,2016).

Economicsanctionsalsonegativelyaffectthesupplyofreagents forAMRtesting,fromagarplatesanddiscsformanualKirby–Bauer tests,tosoftwareupdatesforthePhoenixautomatedmachinesto include newer antibiotics suchas ticarcillin. This increasesthe challengesofaccurate diagnosisandmanagementof infections. Therestrictionsonimportationofhighqualityforeign manufac-turedmedicineshaveexacerbatedthisissue:in2016,theSyrian MoHandtheMinistryofForeignAffairsbannedtheimportofall medicinesthatcouldbepurchasedlocally.Asaresult,thequality controlpreviouslyensuredbyinternationalagenciessuchasthe WHO,UNICEF,theUnitedNationsHighCommissionerforRefugees (UNHCR),and theInternationalCommitteefortheRedCrossin procuringmedicationsunderstrictqualityassuranceisnowlost. Obtainingthenecessarysecurityapprovalsfortransportationis time-consuming, taking up to 4 to 6 months. This fuels the smugglingof importedand expensivemedicines fromLebanon, pushesupthepriceofalreadyscarcedrugs onthemarket,and increasesthe dependency onsmuggled drugs. In consequence, impoverished Syrians are dependent on locally manufactured medicinesofpoorquality.

In areas outside of government control such as Idlib – a governoratebordering Turkey,adjacent toAleppo, and housing some2.5 million Syrians,many internally displaced – there is widespreaddistrustofdrugssentfromDamascus.However,the difficultyanddelayinarranginglegitimatecross-borderconvoys drivesthesmugglingoffakeantibiotics.Anexampleofthisisthe availability of fake spiramycin, an antiparasitic used to treat toxoplasmosisinpregnancy,whichwassuppliedtoIdlibin2015. Asaconsequence,in2016theDirectorateofHealthinIdlibsetupa qualitycontrollaboratory toensure qualityassuranceof medi-cines,andinthenearfuture,antimicrobialresistance.

Alongside challenges resulting from the damaged health system,thewartraumaproduced bytheheavyweaponryused inthisconflicthasledtoanexponentialincreaseinthenumberof infection-prone high-risk injuries such as contaminated open woundsandfractures.Afterthreedecadesofpeacefollowingthe previousgovernment’srepressionofthepopularuprisingin1982, surgeonsand other healthcareworkerslacked thetraining and experiencerequiredtodealwithwartrauma.Earlyintheconflict, theinappropriateuseofinternalfixatorsinopenorcontaminated woundsandsurgerybyuntrainedstaffmayhavecontributedtoan increasedrisk of deepbone infections and infected prostheses, furtherexacerbatedbythelackofsupportivediagnosticfacilities toallowoptimaldiagnosisandmanagement.Inbesiegedareaslike EasternGhouta,homemadeexternalfixatorshavebeenuseddue todenialofsurgicalsupplies.

Thenatureofweaponrycontributestotherangeofwoundsand thedegreeofcontamination.Theconventionalweaponsinusecan result in a range of injuries including openwounds, fractures, amputations, and brain or spinal cord injuries, which may be contaminatedatthetimeofinjuryorsubsequentlyinthecourseof treatment(Eardleyetal.,2011).Barrelbombscontainingshrapnel, nails,and explosives suchas TNTarecommonly used in Syria, causingcatastrophicdamage.Acutelunginjuryiscommonafter theinhalationofdust,withsubsequentrequirementforintubation andtheattendantriskofventilator-associatedpneumonia(Alsadat etal.,2010).Theuseofantibioticsintheseinstances,particularly forprolongedperiodsandwithoutguidingmicrobiology,addto the selective pressures driving AMR. There have also been suggestionsthattheheavymetalspresentinweaponrycontribute toAMR(HobmanandCrossman,2015).

Astheconflicthasprogressed,notonlyhavetherebeenfewer functioning health facilities, but patients have been unable to accessmedicalcareduetoinsecurity,poverty,orfear. Thismay have contributed to self-prescribing with inappropriate or incompletecoursesofantibiotics,worseningwhatwasalreadya socialnormpriortotheoutbreakoftheconflict(Hamzehetal., 2012). In addition, the diminishing supply of clean water and antiseptics,andthelackofaccesstowoundcareandfacilitiesin which debridementcan occur,hascontributedtoinfectionand poorboneorsofttissuehealing.Theuseoflong-termcathetersin patients with spinal cord injuries or impaired mobility will promotesusceptibilitytoinfections withthesubsequent useor inappropriateuseofantibiotics,furtherincreasingtheriskofAMR (Al-Assiletal.,2013).

Hospitals are a key place where AMR strains develop and flourishundernormalconditions.Innon-governmentcontrolled areasinSyria,theseconditionsareworsened:hospitalsarebeing built in basements or even purpose-built several floors under-groundtoavoidtargeting,theyaredarkandoftendamp,thereisan absenceofnaturalsunlightandventilation,andthereisalackof sterilizationequipmentandadequatedisinfectionmaterials.

Inadditiontothesefactors,thelarge-scalepopulation move-mentsresultingfromthe conflict mayalsohave contributedto human-to-human transmission and the potential spread of resistantorganisms throughair travel(Holmeset al.,2015). Of considerable concern is Gaziantep, just 50km from theSyrian border,hometohalfamillionofTurkey’sthreemillionrefugees, andamajorsiteofinternationalmedicaltourism.Thishasbeen seenatothersitesofmedicaltourismsuchasNewDelhi(Kauland Chhina,2010),butthepotentialforsuperbugstobeintroducedand spread within these vulnerable populations of refugees and surgicalfrequentflyersisauniqueandgraveconcern.

Howcanthisbeaddressed?

TacklingAMRamongstSyriansinsideSyriaandthoseseeking refugeinneighbouringcountriesorEuroperequiresmultifaceted actionatthelocal,regional,andinternationallevels.Addressing the conflict in Syria as a political facet is key.The immediate cessationofthetargetingofhealthcarefacilities,cease-fires,anda solutiontothecivilwarareurgentlyneededtoreducetheburden of injured and allow thereturn of healthcare workers and the rehabilitationofthehealthsystem.Inaddition,wecallontheWHO toadheretotheirGAP onAMR, launchedat theWorldHealth Assembly in 2015, addressing antibiotic stewardship, infection preventionandcontrol,andaccesstoappropriatetherapy(Anon, 2017).OthershaveadvocatedforaOneHealthapproachtotackle AMRgiventhewidespreaduseofantibioticsinagriculture,with thethreattoglobalfoodsecuritycompoundedbyclimatechange. Notwithstanding the importance of the WHO GAP and the imperativeforaOneHealthapproach,thereisanobviousneedfor pragmatic, actionable recommendations in Syria and other settings of conflict and insecurity. Table 1 sets out the key recommendationsanddiscussesthechallengesfacedintheSyrian context. These include measures to support the mapping of microbiologyfacilities inside Syria,participationin surveillance amongst healthcare facilities, capacity-building through the trainingofstaff,andensuringtheavailabilityofequipmentand consumables.TheregulationofOTCantibiotic availability,while criticaltoresponsibleantibioticstewardship,isdependentonthe government for enforcement of the existing legislation and is demonstrablyunsuccessfulinthiscontext.Similarly,thecontrolof diseaseswithepidemicandpan-epidemicpotential dependson excellentsurveillance,samplecollection,qualityassured labora-torytesting,andreportingbytheMemberStateinadherencetothe InternationalHealth Guidelines. A programme of educationfor 4 A.Abbaraetal./InternationalJournalofInfectiousDiseases73(2018)1–6

healthcare workers and the general public toalter established practice and cultural expectations is unlikely to be successful underthecurrentconditions.Itisclear,however,thatthisproblem mustbeaddressedurgently;thisurgencyisunderscoredbythe relativelynew initiative _– theSyrian Association for Infectious Diseases.Investinginbasic,cost-effectivemicrobiologyservicesin hospitalsandcentralizedregionalmicrobiologyreferencestoact as referral centres should allow cost-effective processing of samplesas wellaspotentialfor training of staffand improved quality control measures. There is also the opportunity for innovationincludingtheuseofrapiddiagnosticteststoidentify particularbacteriaorforincreasedpublic–privatepartnershipsas wasoftenthecasebeforethewar.

Despitethepaucityofrobustevidencetosupportit,aconcern thatrefugeesmaytransmitinfectionsincludingAMRorganismsto localpopulationsprevails(Angelettietal.,2016).Afullreviewof AMRamongstrefugeesandmigrantsinEuropehasbeenaddressed elsewhere(Heudorfetal.,2016).TheECDChasissuedarapidrisk assessmentoncommunicablediseases ingeneral (Brusinetal., 2015) and on carbapenem-resistant Enterobacteriaceae (CRE) (EuropeanCentreforDiseasePreventionandControl,2016),with recommendationsthatfocusoninfectioncontrolandtheadequate capacityofmicrobiologylaboratorieswithpromptnotificationof clinicalteams.Arecommendationforscreeningandpre-emptive contactprecautionsandisolation ofpatientsconsideredathigh riskofCREcarriageisrecommended(EuropeanCentreforDisease PreventionandControl,2016).However,itremainsvitalforeach countryhostingrefugeestoassesstheAMRaccessandstewardship needs of refugee communities within its borders through the International Health Regulations Joint External EvaluationTool process (which can support their health security plans) and harmonizeitwiththeroll-outoftheirAMRnationalactionplans (WorldHealthOrganization,2005).

Conclusions

TheconditionscreatedbytheconflictinSyriabothexacerbate existing drivers and create powerful new drivers of AMR. The unique challenges presented by the growing threat of AMR in conflictrequireapragmatic,multi-facetedapproachtodetectand manage thepotentially highrates of multidrug-resistant infec-tions.Suchanapproachmustbetailoredtothecurrentstatusof thehealth system(s) in Syria,with thepriorities being(1) the development of a competent surveillance system for

hospital-acquired infections, (2) antimicrobial stewardship, and (3) the creation of cost-effective and implementable infection control policies.HospitalsareakeyplacewhereAMRstrainsdevelopand flourish, particularly in Syria. Accordingly, effective infection prevention and control procedures could play a major role in decreasing the occurrence of outbreaks of infections and in limiting the opportunities for aggressive bacterial strains to acquirenewresistancegenes.Innovativeapproachescouldinclude strategiestobuildpatientresistance,suchastargeted immuniza-tionwithmeaslesorBCGvaccinetoboostimmunity.

Building the capacity for clinical laboratory diagnosis and optimizing the management of patients with communicable diseaseswillincreasetheabilityoflocalmedicalfacilitiesinSyria to make fast and precise diagnosis of transmissible infections, provide targeted antibiotic treatment, minimize the spread of antibiotic-resistant strains, and limit the occurrence of large outbreaksofinfections.Thisisvitalgiventheinternalpopulation movements and the movements of refugees both in countries neighbouringSyriaandinternationally.

Acknowledgements

WethankourSyriancolleaguesworkinginDamascus,Quneitra, Homs, Aleppo, Idlib, Hama, Dara’a, Sweida, Lattakia, Tartous, Raqqa, Deir Ezzor, and Hassekefor providing data and sharing valuable insights; particularly surgical and microbiological col-leagues at the AMR/Trauma training provided by the Syrian American MedicalSociety officein Gaziantep,Turkey,Professor Antony Keil from the Faculty of Medicine at the University of WesternAustralia,andNatalieGarlandfromtheISSMS.

Fundingsource

Nofundingwassoughtforthiswork. Ethicalapproval

Wehavereadthepolicyonethicalconsentandethicalapproval isnotrequiredforthiswork.

Conflictofinterest

Allauthorsconfirmthattheyhavenoconflictofinterest. Table1

RecommendationsfortacklingantimicrobialresistanceinsideSyriaandinfacilitiestreatingSyrianrefugees.

Recommendation Actionneededtoachievecoremeasure Primaryorganizationsresponsible Surveillance On-callserviceatlaboratoriesforweekendsandholidays;improvedmonitoring

services

WHO,localandinternationalhealthorganizations workinginconflict

Improvequalitycontrol (QC)

Easingsanctionsfordrugsandequipment;theMinistryofHealthmustliftthebanon importedmedicines

UNSecurityCouncil,UNGeneralAssembly,andallUN MemberStates

Trainingand developmentofkey staff

Improveaccesstotrainingcourses,updates,andmodules;eitherremotelywith telemedicineorasshortcoursesinneighbouringcountries

Reducethegapintrainedmedicallaboratoryspecialistsandtechnicians

WHO,internationalandregionalmedical,public health,andalliedhealthacademicinstitutionsand organizations

Ensurelearning UtilizetheOneHealthapproachinfutureresearch;continuetobuildtheevidence baseforactiononissuesofAMR;additionalretrospectivestudiesshouldbeconducted inTurkey

Academicandnon-academicresearchers

Makeresourcesavailable inmicrobiology services

Mobilizeandallocateresourcestohealthworkersinresponseplans,includingfor humanresourcesplanning

Donors

Research/surveillance/ antibioticstewardship

Improvethecollectionandreportingoflocaldatainhospitalsthatareunabletoreport onAMRbroadly,andspecificallyintheICU,surgicalward,ormaternalward,etc.; guideclinicalpracticeofdoingculturesfortesting;widespreadtrainingofresidents andnursestoavoidcontaminationinlaboratorytesting;leadingtospecifictreatment andinformingsyndromicguidelines

Aims

(1)Definethemainfactorsdrivingantimicrobialresistancein settingsofconflict,exemplifiedbytheSyriancontext.(2)Propose policyrecommendations.(3)Identifykeyresearchareas. Authorcontributions

AAconceivedtheideaandcontributedtotheliteraturereview, thefirstdraft,andrevisionsofthemanuscript.TMR,NK,WE-A,JH, contributedtotheliteraturereview,writingofthetext,andmade signi_ficantcontributionstorevisionsofthemanuscript.BT,ODa, ODe,GAS,BEUmadecontributionstothetext,literaturereview, andrevisionsofthemanuscript.AScontributedtotheoriginaltext andsubsequentrevisions,thefiguresandtables,anddeveloped keyconceptsinthemanuscript.

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