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

Open AccessPublished:June 21, 2018DOI:https://doi.org/10.1016/j.ijid.2018.06.010

      Abstract

      Antimicrobial resistance (AMR) in populations experiencing war has yet to be addressed, despite the abundance of contemporary conflicts and the protracted nature of twenty-first century wars, in combination with growing global concern over conflict-associated bacterial pathogens. The example of the Syrian conflict is used to explore the feasibility of using existing global policies on AMR in conditions of extreme conflict. The available literature on AMR and prescribing behaviour in Syria before and since the onset of the conflict in March 2011 was identified. Overall, there is a paucity of rigorous data before and since the onset of conflict in Syria to contextualize the burden of AMR. However, post onset of the conflict, an increasing number of studies conducted in neighbouring countries and Europe have reported AMR in Syrian refugees. High rates of multidrug resistance, particularly Gram-negative organisms, have been noted amongst Syrian refugees when compared with local populations. Conflict impedes many of the safeguards against AMR, creates new drivers, and exacerbates existing ones. Given the apparently high rates of AMR in Syria, in neighbouring countries hosting refugees, and in European countries providing asylum, this requires the World Health Organization and other global health institutions to address the causes, costs, and future considerations of conflict-related AMR as an issue of global governance.

      Keywords

      Introduction

      Despite the proliferation of contemporary conflicts, the emergence of antimicrobial resistance (AMR) in settings of war and distressed migration has been neglected. This has been of particular concern in Syria where the protracted and increasingly destructive conflict has also been a driver of large-scale population movements both regionally and in Europe. Since 2012, the conflict has become the leading cause of death and injury in Syria. In the absence of accurate recent figures, it is estimated, as of the end of 2015, that 470 000 have been killed and 1.9 million injured (
      • Syrian Center for Policy Research
      Population status & analysis.
      ). With high rates of injury, the potential for infection is exacerbated by the crowded and often unsanitary conditions in health facilities, combined with the nature of injuries produced by heavy weaponry.
      The destruction of health facilities, the exodus or death of healthcare workers, and the increasing fragmentation of Syria’s health system have all contributed to the myriad of challenges in addressing AMR (
      • Fouad F.M.
      • Sparrow A.
      • Tarakji A.
      • et al.
      Health workers and the weaponisation of health care in Syria: a preliminary inquiry for The Lancet—American University of Beirut Commission on Syria.
      ). By April 2017, only 56 out of 111 public hospitals were still offering services (
      • WHO
      HeRAMS Syria: Snapshot for Public Hospitals.
      ), while it has been estimated that over 70% of all health professionals have 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), more than one million live in unhygienic conditions in overcrowded camps and collective shelters, at increased risk of typhoid, hepatitis, cholera, polio, and cutaneous leishmaniasis, among other infectious diseases (
      • Ismail S.A.
      • Abbara A.
      • Collin S.M.
      • et al.
      Communicable disease surveillance and control in the context of conflict and mass displacement in Syria.
      ).
      Under conditions of conflict, many of the safeguards against AMR are broken and drivers are accentuated; these include damaged health and sanitation infrastructure, disrupted medical supplies, the exodus of expert and trained health professionals, and increasing exposure in compromised healthcare settings. War further disrupts the political and regulatory bodies that often lead, monitor, and enforce policies that tackle the drivers of AMR. This first part of a two-part series presents a review and analysis of the literature on what is known about AMR in the Syrian conflict. The second part explores the pre-existing drivers of AMR in Syria and those that have occurred since the onset of conflict; recommendations on how these can be addressed are also made.

      Evidence of AMR in the Syrian context

      Rigorous studies addressing microbiology or AMR in Syria, either before or since the onset of the conflict in March 2011, are scarce. Published studies have often been from a single centre and 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). Whether private or hospital-based, all laboratories close between Thursday afternoon and Sunday morning. As there is no on-call service, laboratory services are unavailable for 2.5 days each week. These laboratories are inaccessible to health workers serving the outskirts of these cities and rural areas in GCAs, in addition to the estimated 10 million people living in non-government-controlled areas (NGCAs), served by six laboratories (verbal communication) (Plate 1 ).
      Plate 1
      Plate 1This is a map of Syria which shows the location of the major cities, Damascus, Lattakia and Aleppo where the main functioning laboratories remain.
      There are two parallel systems of surveillance. From Damascus, the Syrian Arab Republic Ministry of Health with the support of the World Health Organization (WHO) collects reports of notifiable diseases through the Early Warning and Response System (EWARS), but without laboratory testing of samples or contact tracing. Operating from Gaziantep in southern Turkey, the Early Warning and Response Network (EWARN) system is hampered by the paucity of laboratory services and the absence of local referral laboratories for verification and typing. Data from these systems may not be reliable in this context, nor generalizable across the country (
      • Ismail S.A.
      • Abbara A.
      • Collin S.M.
      • et al.
      Communicable disease surveillance and control in the context of conflict and mass displacement in Syria.
      ,
      • Sparrow A.
      • Almilaji K.
      • Tajaldin B.
      • Teodoro N.
      • Langton P.
      Cholera in the time of war: implications of weak surveillance in Syria for the WHO’s preparedness—a comparison of two monitoring systems.
      ). Neither system requires reporting on AMR, nosocomial infections, or response to therapy. Both systems are hampered by limited surveillance in governorates under the control of ISIS (Raqqa and Deir Ezzor) and the lack of quality control services and access to accredited referral laboratories. In GCAs this requires shipping of samples to Egypt; in NGCAs this requires cross-border transport to Turkey or Jordan, subject to permission from the relevant ministry of health. Both circumstances are challenging given the insecurity, difficulty in transporting specimens under controlled temperature conditions, and restricted access across borders.
      A review of the scientific literature describing AMR amongst Syrians who remain in Syria and those who are refugees either in the region (Jordan, Lebanon, Turkey) or in Europe was performed to accurately describe the current literature on AMR in the Syrian conflict. The search methods are given in the Appendix A. Table 1 summarizes studies addressing AMR before and after the onset of the conflict, including all published articles relating to refugees or Syrians inside Syria.
      Table 1Characteristics of key studies: divided into pre and post onset of the conflict in Syria, regional studies including Syrian refugees, and other studies describing Syrian refugees.
      Group (year of publication)YearLocationStudy descriptionSampleKey findings
      Pre-conflict
      • Al-Omar A.S.
      Bacterial culture results and susceptibility test of uropathogens isolated from outpatients referred from clinics in community.
      2004Misiaf, SyriaProspective culture of urine samples from all patients in the community127 positive urine samples
      • 68.6% of isolates were Enterobacteriaceae
      • 30.6% were Gram-positive (22.8% S. aureus)
      • Overall resistance reported at: 69% ampicillin, 55% TMP–SMX, 37% amoxicillin–clavulanate, 35% ofloxacin
      • Obeid B.
      • Obeid M.
      Antibiotic resistance of streptococcus pneumoniae from meningitis children in Damascus.
      Sep 2003 to May 2004Damascus, SyriaS. pneumoniae from CSF samples; susceptibility of strains using disc diffusion methods (NCCLS breakpoints)25 isolates
      • Reported resistance: 64% were resistant to penicillin, 48% to TMP–SMX, 16% to erythromycin, and 16% to tetracycline
      • None resistant to ceftriaxone, cefotaxime, amoxicillin–clavulanate
      • Al-Qwaret B.
      • SN
      • A-AM
      Isolation the aerobic bacteria caused infection in diabetic foot ulcers and their susceptibility to antibiotics.
      2010Damascus, SyriaProspective cohort study of aerobic organisms isolated from diabetic foot ulcers and their reported antibiotic sensitivities100 specimens, 128 organisms
      • 61% of S. aureus isolates were MRSA
      • N CPE/CRO identified
      • Al-Qwaret B.
      • SN
      • A-AM
      Isolation the aerobic bacteria caused infection in diabetic foot ulcers and their susceptibility to antibiotics.
      2012Damascus, SyriaReview of all aerobic bacterial conjunctivitis with antibiotic susceptibilities51 patients
      • High levels of susceptibility to first- and second-line agents reported
      • Keddo A.
      • Al-Omari M.
      Isolation of aerobic bacteria from tonisilitis in children with recurrent tonsillitis and studies of antibiotic susceptibility.
      2012Damascus SyriaPaediatric recurrent tonsillitis cases that underwent tonsillectomy

      Review of aerobic isolates from tonsil core culture
      80 patients
      • 25% of the K. pneumoniae isolates were carbapenem-resistant
      • 15% of E. coli were also imipenem-resistant
      • Hamzeh A.R.
      • Al Najjar M.
      • Mahfoud M.
      Prevalence of antibiotic resistance among Acinetobacter baumannii isolates from Aleppo, Syria.
      2008–2011Aleppo, SyriaRetrospective review of A. baumannii isolates260 patients with 260 isolates tested
      • Resistance to specific antibiotics: 65% imipenem, 87% piperacillin–tazobactam, 78% amikacin, 81% ciprofloxacin, 74% co-trimoxazole, 7% colistin
      • Turkmani A.
      • Ioannidis A.
      • Christidou A.
      • Psaroulaki A.
      • Loukaides F.
      • Tselentis Y.
      In vitro susceptibilities of Brucella melitensis isolates to eleven antibiotics.
      1995–2005Eastern MediterraneanIsolates of B. melitensis from animals in Syria5 isolates
      • Highly susceptible to most tested antibiotics
      Post commencement of the conflict – Syria
      Al-Kadrou et al. (2013)2013Damascus, SyriaAerobic bacterial infections in burns patients managed within a Syrian government hospital109 isolates from 53 samples
      • No polymyxin resistance in Gram-negatives identified
      • Tabana Y.
      • Dahham S.
      • Al-Hindi B.
      • Al-Akkad A.
      • Khadeer Ahamed M.B.
      Prevalence of methicillin-resistant Staphylococcus aureus (MRSA) among medical staff in three Syrian provinces.
      2015Aleppo, SyriaLaboratory evaluation of prevalence of PMQR genes at Aleppo University123 ESBL-producing isolates of E. coli and K. pneumoniae
      • Al-Assil B.
      • Mahfoud M.
      • Hamzeh A.R.
      First report on class 1 integrons and Trimethoprim-resistance genes from dfrA group in uropathogenic E. coli (UPEC) from the Aleppo area in Syria.
      2011Aleppo, SyriaThree hospitals in Aleppo; 75 patients with UTIs75 patients with UTIs caused by trimethoprim-resistant E. coli; 104 unique isolates
      • 96% susceptible to nitrofurantoin
      • Reduced susceptibility to: amoxicillin–clavulanate 43%, 3/4 GNB to cephalosporins 50–60%, piperacillin–tazobactam 66%, tetracyclines 44%, TMP–SMX 20%
      • Alheib O.
      • Al Kayali R.
      • Abajy M.Y.
      Prevalence of plasmid-mediated quinolone resistance (PMQR) determinants among extended spectrum beta-lactamases (ESBL)-producing isolates of Escherichia coli and Klebsiella pneumoniae in Aleppo, Syria.
      2015Aleppo, SyriaPMQR genes among ESBL E. coli and K. pneumoniae123 isolates
      • 66% of ESBL-positive isolates were resistant to ciprofloxacin
      • 83% of E. coli compared to 87% of K. pneumoniae harboured PMQR genes, but this did not necessarily confer phenotypic resistance
      • Mahfoud M.
      • Al Najjar M.
      • Hamzeh A.R.
      Multidrug resistance in Pseudomonas aeruginosa isolated from nosocomial respiratory and urinary infections in Aleppo, Syria.
      2011–12Aleppo, SyriaThree major hospitals in Aleppo

      Lower respiratory tract and urine samples with nosocomial infections from intensive care patients in whom P. aeruginosa was isolated
      177 samples (tested against CLSI guidelines)
      • 59 female/118 male
      • Samples: 138 lower respiratory tract and 39 urinary
      • Selected susceptibility: piperacillin–tazobactam 54.5%, amikacin 42.8%, ceftazidime 28.6%, meropenem 59.1%, imipenem 56.1%, colistin 89.1%
      Nofal (2016)2016Damascus, SyriaRetrospective review of species and sensitivities of otitis media cases87 patients, 49 isolates
      • 52% male, 48% female
      • K. pneumoniae (n = 3): 100% sensitive to imipenem and levofloxacin
      • S. aureus (n = 16): 100% sensitive to imipenem
      • Al-Assil B.
      • Mahfoud M.
      • Hamzeh A.R.
      First report on class 1 integrons and Trimethoprim-resistance genes from dfrA group in uropathogenic E. coli (UPEC) from the Aleppo area in Syria.
      2011Aleppo, SyriaThree hospitals in Aleppo

      Risk factors for ESBL infections assessed by multivariate regression analysis
      104 patients with positive urine samples
      • MDR E. coli ∼63%
      • ESBL E. coli ∼52%
      • Levels of co-resistance high in ESBLs (82%)
      • Age >52 years, hospitalization, urinary catheters, prior third-generation cephalosporin use, and previous quinolone therapy were all associated with ESBLs in this study
      • Baaity Zain
      • Almahmoud Iyad
      • Khamis Atiea
      Prevalence of extended spectrum β lactamases (ESBL) in E. coli at Al-Assad Teaching Hospital.
      Latakia, SyriaAl-Assad Teaching

      Antibiotic susceptibility and ESBL production by disc diffusion using CLSI/EUCAST
      236 E. coli isolates
      • 32% of the E. coli isolates were MDR and 26% were ESBL-producers
      Post commencement of the conflict – outside Syria
      • Teicher C.L.
      • Ronat J.B.
      • Fakhri R.M.
      • et al.
      Antimicrobial drug resistant bacteria isolated from Syrian war-injured patients, August 2011–March 2013.
      2011–13Amman JordanMédecins Sans Frontières surgical project managing

      MDR defined as: (1) ESBL-expressing Enterobacteriaceae; (2) P. aeruginosa and A. baumannii isolates resistant to at least one agent in three antimicrobial categories typically used for treatment; or (3) MRSA
      61 Syrian orthopaedic patients with suspected infections undergoing surgical sampling intraoperatively
      • Age 26 years (IQR 22–34 years); 98% male
      • Injury to admission approximately 5 months (IQR 1.2–8.1 months): gunshot wounds n = 31, explosion wounds n = 20
      • 45 of these patients had at least one organism, with 69% (31/45) MDR organisms: P. aeruginosa (10/31), E. coli (5/8), carbapenem-resistant A. baumannii (4/5), MRSA (7/17)
      • Kassem D.F.
      • Hoffmann Y.
      • Shahar N.
      • et al.
      Multidrug-resistant pathogens in hospitalized Syrian children.
      2013–2016IsraelMicrobiological surveillance screening of severely ill or injured Syrian children

      Screened for: ESBL, CRE, MRSA, MDR A. baumannii, and VRE
      128 children
      • MDR carriage found in 83%, with NDM CRE most prevalent
      • 24/128 had MDR infections (90% were wounded): ESBL 66%, MDR A. baumannii 20%, CRE 15%
      • Angeletti S.
      • Ceccarelli G.
      • Vita S.
      • et al.
      Unusual microorganisms and antimicrobial resistances in a group of Syrian migrants: sentinel surveillance data from an asylum seekers centre in Italy.
      2016ItalyMicrobiological surveillance using rectal, pharyngeal, and nasal swabs48 refugees
      • High rates of Gram-negative non-lactose-fermenting organisms such as Pseudomonas and Aeromonas species, with 5 carbapenem-resistant isolates
      • No CRE
      • 24% (6/25) of S. aureus isolates were methicillin-resistant
      Bhalla et al. (2016)2016Amman, JordanObservational study at the Médecins sans Frontières surgical programme hospital managing chronic trauma-related infections colonized or infected with AMR organismsNANA
      • Abbara A.
      • Al-Harbat N.
      • Karah N.
      • et al.
      Antimicrobial drug resistance among refugees from Syria, Jordan.
      2015Amman, JordanMicrobiological samples from infected injuries (bone and soft tissue) amongst injured Syrian refugees75 patients
      • 20% had osteomyelitis, 53% had prosthetic material
      • 30 bacterial isolates of which 97% were GNB
      • 66% were MDR and 37% were carbapenem-resistant
      • Ravensbergen S.J.
      • Lokate M.
      • Cornish D.
      • et al.
      High prevalence of infectious diseases and drug-resistant microorganisms in asylum seekers admitted to hospital; no Carbapenemase producing Enterobacteriaceae until September 2015.
      2016Groningen, NetherlandsScreening of asylum seekers for MDROs upon admission to hospital130 asylum seekers; 36.5% Eritrean and 18.6% Syrian
      • 31% colonized with an MDRO: 7.7% with MRSA; 20% ESBL (20 E. coli, 4 K. pneumoniae, 1 M. morganii, and 1 E. cloacae)
      • 10% resistant to fluoroquinolones
      • No carbapenemases
      • Reinheimer C.
      • Kempf V.A.
      • Göttig S.
      • Hogardt M.
      • Wichelhaus T.A.
      • O’Rourke F.
      • et al.
      Multidrug-resistant organisms detected in refugee patients admitted to a University Hospital, Germany June-December 2015.
      2015GermanyMicrobiological surveillance screening of patients admitted to Frankfurt hospital for MDROs, for GNB (ESBL and A. baumannii), and MRSA143 refugees, including 47 (43%) from Syria, 29 from Afghanistan, 14 from Somalia
      • 60.8% colonized with MDR GNB in Refugee population compared to 16.8% in the general population
      • ESBL E. coli and K. pneumoniae were significantly more common (23.8% vs. 4.9% and 4.2% vs. 0.8%)
      • 1 CRE and 2 carbapenem-resistant A. baumannii
      • MRSA 5.6% vs. 1.2% in the general population
      • Heudorf U.
      • Krackhardt B.
      • Karathana M.
      • Kleinkauf N.
      • Zinn C.
      Multidrug-resistant bacteria in unaccompanied refugee minors arriving in Frankfurt am Main, Germany, October to November 2015.
      2015Frankfurt, Main, GermanyMicrobiological surveillance screening of unaccompanied minors (aged <18 years) screened for MDR Enterobacteriaceae in stool samples119 individuals, 7 Syrians
      • Total: 35% had ESBL Enterobacteriaceae, including 8% GNB resistant to three antibiotic groups
      • Syrians: 3 had ESBL Enterobacteriaceae; none had MDR
      • Tenenbaum T.
      • Becker K.-P.
      • Lange B.
      • et al.
      Prevalence of multidrug-resistant organisms in hospitalized pediatric refugees in an University Children’s Hospital in Germany 2015–2016.
      2015–2016GermanyRetrospective observational study of screening of paediatric refugee patients admitted to hospital325 patients
      • MDR detected in 33.8%
      • 110 of 113 samples GNB
      • 87 MDR GNB/ESBL
      • 22 MRSA
      • 1 VRE
      • Heydari F.
      • Mammina C.
      • Koksal F.
      NDM-1-producing Acinetobacter baumannii ST85 now in Turkey, including one isolate from a Syrian refugee.
      2014TurkeyMicrobiological surveillance screening of all A. baumannii resistant to carbapenems collected over the year period and screening for NDM-1-producing organisms2 Syrian refugees admitted to ICU· 1 isolate of 2 from a Syrian refugee admitted to ICU with acute renal failure and gastritis
      Peretz et al. (2014)2014Galilee Medical Centre, IsraelMicrobiological surveillance screening of Syrians admitted to hospital

      Screened for: ESBL, CRE, MRSA, MDR A. baumannii, and VRE
      27 children and 60 adults
      • Children: 21 isolates of MDROs in 19/27 patients; 20/21 ESBL Enterobacteriaceae; MRSA = 1/21
      • Adults: 28/60 carriers; 5 patients, CRE (2 × NDM); 11 patients, MRSA; 5 A. baumannii; 7 ESBL
      • Rafei R.
      • Dabboussi F.
      • Hamze M.
      • et al.
      First report of blaNDM-1-producing Acinetobacter baumannii isolated in Lebanon from civilians wounded during the Syrian war.
      2012LebanonSyrians admitted to Lebanese hospitals

      Carbapenem-resistant A. baumannii isolates investigated using PCR to identify OXA and NDM producing organisms
      4 patients with war wounds
      • All 4 had carbapenem-resistant A. baumannii identified as carrying the bla-NDM-1 gene
      • These organisms all had phenotypic susceptibility to aminoglycosides, colistin, and tigecycline
      • Rafei R.
      • Pailhoriès H.
      • Hamze M.
      • et al.
      Molecular epidemiology of Acinetobacter baumannii in different hospitals in Tripoli, Lebanon using bla OXA-51-like sequence based typing.
      2011–13LebanonReview of isolates from Lebanese and Syrian wounded; respiratory, wound, urine, catheters, and blood isolates116 isolates
      • 90 male, 26 female
      • 70/116 (60%) had carbapenem-resistant phenotype (including NDM-1 and OXA-23)
      • Syrian refugees had a greater number of carbapenem-resistant A. baumannii (74% vs. 47%)
      A. baumannii, Acinetobacter baumannii; AMR, antimicrobial-resistant; B. melitensis, Brucella melitensis; CLSI, Clinical and Laboratory Standards Institute; CPE, carbapenemase-producing Enterobacteriaceae; CRE, carbapenem-resistant Enterobacteriaceae; CRO, ; CSF, cerebrospinal fluid; E. coli, Escherichia coli; E. cloacae, Enterobacter cloacae; ESBL, extended-spectrum beta-lactamase; EUCAST, European Committee on Antimicrobial Susceptibility Testing; GNB, Gram-negative bacilli; ICU, intensive care unit; IQR, interquartile range; K. pneumoniae, Klebsiella pneumoniae; MDR, multidrug-resistant; MDRO, multidrug-resistant organism; M. morganii, Morganella morganii; MRSA, methicillin-resistant Staphylococcus aureus; NA, no; NCCLS, National Committee for Clinical Laboratory Standards; NDM, New Delhi metallo-beta-lactamase; OXA, ; P. aeruginosa, Pseudomonas aeruginosa; PMQR, plasmid-mediated quinolone resistance; S. aureus, Staphylococcus aureus; S. pneumoniae, Streptococcus pneumoniae; TMP–SMX, trimethoprim–sulfamethoxazole; UTI, urinary tract infection; VRE, vancomycin-resistant enterococci.

      Evidence of AMR in the Syrian context: pre-conflict

      Before the conflict, several reports suggested the widespread availability of antibiotics through pharmacies without safeguards and/or poor knowledge amongst recipients of the risks associated with injudicious antibiotic use (
      • Barah F.
      • Gonçalves V.
      Antibiotic use and knowledge in the community in Kalamoon, Syrian Arab Republic: a cross-sectional study.
      ). Anecdotally, extensive antibiotic overuse and antimicrobial failure were common. Limited evidence documenting the existence and 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, compromising the potential to identify trends or draw conclusions concerning AMR. Most studies were reported from the cities of Damascus and Aleppo, limiting generalization across and to other governorates.
      Seven studies describing antibiotic susceptibility amongst different isolates were found (Table 1). The majority focused on specific bacteria including Acinetobacter baumannii, Streptococcus pneumoniae, and Brucella melitensis (
      • Hamzeh A.R.
      • Al Najjar M.
      • Mahfoud M.
      Prevalence of antibiotic resistance among Acinetobacter baumannii isolates from Aleppo, Syria.
      ,
      • Turkmani A.
      • Ioannidis A.
      • Christidou A.
      • Psaroulaki A.
      • Loukaides F.
      • Tselentis Y.
      In vitro susceptibilities of Brucella melitensis isolates to eleven antibiotics.
      ,
      • Obeid B.
      • Obeid M.
      Antibiotic resistance of streptococcus pneumoniae from meningitis children in Damascus.
      ). Hamzeh and colleagues reported high levels of AMR in 260 unique patients with A. baumannii infections from Aleppo in 2008–2011 (
      • Hamzeh A.R.
      • Al Najjar M.
      • Mahfoud M.
      Prevalence of antibiotic resistance among Acinetobacter baumannii isolates from Aleppo, Syria.
      ). Resistance to imipenem and meropenem (carbapenems) was reported at 66%, to ciprofloxacin (fluoroquinolone) 81%, piperacillin–tazobactam (penicillin-beta-lactamase) 87%, amikacin (aminoglycoside) 78%, and to co-trimoxazole (sulfonamide) 74%. Resistance to third- and fourth-generation cephalosporins was also high, with ceftazidime resistance reported at 80.6% and cefepime at 84.7%. Colistin remained active with only 7% reported resistance. The main drawback of this study was the use of an automated system for species identification, bearing in mind that these systems are unable to precisely distinguish isolates from the A. baumanniiAcinetobacter calcoaceticus complex to the species level. Keddo et al. reported that 25% of Klebsiella pneumoniae isolates amongst children with recurrent tonsillitis were carbapenem-resistant (
      • Keddo A.
      • Al-Omari M.
      Isolation of aerobic bacteria from tonisilitis in children with recurrent tonsillitis and studies of antibiotic susceptibility.
      ). With regards to Gram-positive isolates, the most recent study found was conducted in 2005: Obeid and colleagues reported high rates of resistance to penicillin (64%) and trimethoprim–sulfamethoxazole (48%) in 25 isolates of S. pneumoniae from cerebrospinal fluid samples, but found no resistance to cephalosporins (including cefotaxime and ceftriaxone), often used as first-line therapy for bacterial meningitis (
      • Obeid B.
      • Obeid M.
      Antibiotic resistance of streptococcus pneumoniae from meningitis children in Damascus.
      ).
      Although these reports describe small numbers, they raise concern regarding the high rates of AMR reported. The high proportion of carbapenem-resistant Gram-negatives is alarming given that carbapenems are used as broad-spectrum or salvage therapy following failure of empiric therapy. The percentage of penicillin-resistant S. pneumoniae is troubling, as overuse of antibiotics in the treatment of viral illness is a driver of penicillin resistance in this isolate.

      Evidence of AMR in the Syrian context: since the onset of the conflict in 2011

      Since the first use of armed force and subsequent expansion of violence, data on the availability and efficacy of antimicrobial therapy within Syria have become increasingly limited. Six studies from inside Syria since late 2011 have reported concerns over the increasing burden of resistant Gram-negative infections and methicillin-resistant Staphylococcus aureus (MRSA), four of these being focused on Aleppo (
      • Alheib O.
      • Al Kayali R.
      • Abajy M.Y.
      Prevalence of plasmid-mediated quinolone resistance (PMQR) determinants among extended spectrum beta-lactamases (ESBL)-producing isolates of Escherichia coli and Klebsiella pneumoniae in Aleppo, Syria.
      ,
      • Mahfoud M.
      • Al Najjar M.
      • Hamzeh A.R.
      Multidrug resistance in Pseudomonas aeruginosa isolated from nosocomial respiratory and urinary infections in Aleppo, Syria.
      ,
      • Al-Assil B.
      • Mahfoud M.
      • Hamzeh A.R.
      First report on class 1 integrons and Trimethoprim-resistance genes from dfrA group in uropathogenic E. coli (UPEC) from the Aleppo area in Syria.
      ,
      • Tabana Y.
      • Dahham S.
      • Al-Hindi B.
      • Al-Akkad A.
      • Khadeer Ahamed M.B.
      Prevalence of methicillin-resistant Staphylococcus aureus (MRSA) among medical staff in three Syrian provinces.
      ). It is notable that few datasets from within Syria have reported on war-related injuries and their infectious complications; this is likely driven by several factors including political sensitivities and the overwhelmed health systems.
      Studies of resistance from inside Syria on specific isolates have reported high levels of AMR. Zain and colleagues examined 236 Escherichia coli isolates and found 26% of these to be extended-spectrum beta-lactamase (ESBL) producers (
      • Baaity Zain
      • Almahmoud Iyad
      • Khamis Atiea
      Prevalence of extended spectrum β lactamases (ESBL) in E. coli at Al-Assad Teaching Hospital.
      ). Alheib and colleagues examined 123 ESBL-producing E. coli and K. pneumoniae specimens in 2015 and found 66% of these isolates to be phenotypically resistant to ciprofloxacin (
      • Alheib O.
      • Al Kayali R.
      • Abajy M.Y.
      Prevalence of plasmid-mediated quinolone resistance (PMQR) determinants among extended spectrum beta-lactamases (ESBL)-producing isolates of Escherichia coli and Klebsiella pneumoniae in Aleppo, Syria.
      ). Mahfoud and colleagues tested 177 Pseudomonas aeruginosa urinary and lower respiratory isolates from patients in three intensive care units in Aleppo and showed significant resistance to common anti-pseudomonal agents (piperacillin–tazobactam: 46%; meropenem: 41%; ceftazidime 73%) with colistin as the most reliable antibiotic (11% resistance) (
      • Mahfoud M.
      • Al Najjar M.
      • Hamzeh A.R.
      Multidrug resistance in Pseudomonas aeruginosa isolated from nosocomial respiratory and urinary infections in Aleppo, Syria.
      ). Al-Assil reviewed 104 patients with positive urine samples to understand the risk factors for the development of ESBL infections and isolated ESBL E. coli in 52% of cases (
      • Al-Assil B.
      • Mahfoud M.
      • Hamzeh A.R.
      First report on class 1 integrons and Trimethoprim-resistance genes from dfrA group in uropathogenic E. coli (UPEC) from the Aleppo area in Syria.
      ). Co-resistance to other antibiotics was found in 82% of cases. Risk factors identified as increasing the risk of ESBL acquisition in that study included older age (>52 years), hospitalization, urinary catheterization, and previous exposure to third-generation cephalosporins or quinolone antibiotics (
      • Al-Assil B.
      • Mahfoud M.
      • Hamzeh A.R.
      First report on class 1 integrons and Trimethoprim-resistance genes from dfrA group in uropathogenic E. coli (UPEC) from the Aleppo area in Syria.
      ).
      Of the few large regional studies, a recent retrospective study in Lebanon analysing 55 594 Gram-negative isolates between 2011 and 2013 reported ESBL rates amongst E. coli and Klebsiella spp of 32.3% and 29.2%, respectively (
      • Chamoun K.
      • Farah M.
      • Araj G.
      • et al.
      Surveillance of antimicrobial resistance in Lebanese hospitals: retrospective nationwide compiled data.
      ). Lebanon and Jordan, countries neighbouring Syria and hosting an estimated total of 1.7 million refugees, both reported the emergence of multidrug-resistant (MDR) Gram-negative infections complicating war-related injuries (
      • Teicher C.L.
      • Ronat J.B.
      • Fakhri R.M.
      • et al.
      Antimicrobial drug resistant bacteria isolated from Syrian war-injured patients, August 2011–March 2013.
      ,
      • Abbara A.
      • Al-Harbat N.
      • Karah N.
      • et al.
      Antimicrobial drug resistance among refugees from Syria, Jordan.
      ,
      • Rafei R.
      • Pailhoriès H.
      • Hamze M.
      • et al.
      Molecular epidemiology of Acinetobacter baumannii in different hospitals in Tripoli, Lebanon using bla OXA-51-like sequence based typing.
      ,
      • Rafei R.
      • Dabboussi F.
      • Hamze M.
      • et al.
      First report of blaNDM-1-producing Acinetobacter baumannii isolated in Lebanon from civilians wounded during the Syrian war.
      ). In 2014, Teicher and colleagues reported on the experience of a Médecins sans Frontières (MSF)-led surgical management project in Amman, Jordan (
      • Teicher C.L.
      • Ronat J.B.
      • Fakhri R.M.
      • et al.
      Antimicrobial drug resistant bacteria isolated from Syrian war-injured patients, August 2011–March 2013.
      ). A cohort of 61 young men (median age 26 years) presented to the hospital with clinically infected chronic war wounds (injury to presentation time median 5 months, interquartile range 1.2–8.1 months). Gunshot (31 patients) and explosion-related (20 patients) wounds were the most common injuries. Of the 61 patients, 45 had at least one positive culture, with 69% (31/45) of isolates being MDR. Although numbers were small, high rates of carbapenem-resistant A. baumannii (80%; 4/5), ESBL-producing E. coli (62%; 5/8), and MRSA (41%; 7/17) were isolated. Similar rates of MDR organisms have been reported related to war injuries (
      • Teicher C.L.
      • Ronat J.B.
      • Fakhri R.M.
      • et al.
      Antimicrobial drug resistant bacteria isolated from Syrian war-injured patients, August 2011–March 2013.
      ,
      • Abbara A.
      • Al-Harbat N.
      • Karah N.
      • et al.
      Antimicrobial drug resistance among refugees from Syria, Jordan.
      ), and refugees have been reported to have significantly higher rates of carbapenem-resistant A. baumannii (
      • Rafei R.
      • Dabboussi F.
      • Hamze M.
      • et al.
      First report of blaNDM-1-producing Acinetobacter baumannii isolated in Lebanon from civilians wounded during the Syrian war.
      ). No data are available from Turkey, which hosts nearly three million Syrian refugees.
      A more robust evidence base of AMR and the Syrian refugee crisis has come from an increasing number of reports on MDR organism carriage in refugees admitted into European hospitals. Syrian refugee patients screened in Europe have shown higher rates of carbapenemase-producing Enterobacteriaceae (CPEs) compared with local populations (
      • Kassem D.F.
      • Hoffmann Y.
      • Shahar N.
      • et al.
      Multidrug-resistant pathogens in hospitalized Syrian children.
      ,
      • Angeletti S.
      • Ceccarelli G.
      • Vita S.
      • et al.
      Unusual microorganisms and antimicrobial resistances in a group of Syrian migrants: sentinel surveillance data from an asylum seekers centre in Italy.
      ,
      • Ravensbergen S.J.
      • Lokate M.
      • Cornish D.
      • et al.
      High prevalence of infectious diseases and drug-resistant microorganisms in asylum seekers admitted to hospital; no Carbapenemase producing Enterobacteriaceae until September 2015.
      ,
      • Reinheimer C.
      • Kempf V.A.
      • Göttig S.
      • Hogardt M.
      • Wichelhaus T.A.
      • O’Rourke F.
      • et al.
      Multidrug-resistant organisms detected in refugee patients admitted to a University Hospital, Germany June-December 2015.
      ,
      • Heudorf U.
      • Krackhardt B.
      • Karathana M.
      • Kleinkauf N.
      • Zinn C.
      Multidrug-resistant bacteria in unaccompanied refugee minors arriving in Frankfurt am Main, Germany, October to November 2015.
      ,
      • Tenenbaum T.
      • Becker K.-P.
      • Lange B.
      • et al.
      Prevalence of multidrug-resistant organisms in hospitalized pediatric refugees in an University Children’s Hospital in Germany 2015–2016.
      ,
      • Heydari F.
      • Mammina C.
      • Koksal F.
      NDM-1-producing Acinetobacter baumannii ST85 now in Turkey, including one isolate from a Syrian refugee.
      ). Estimates of MDR carriage within paediatric and adult populations in these studies range from 33% to 83%, with high rates of New Delhi metallo-beta-lactamase (NDM)-producing carbapenem-resistant Enterobacteriaceae (CRE), A. baumannii, and ESBL-producing Enterobacteriaceae (
      • Rafei R.
      • Dabboussi F.
      • Hamze M.
      • et al.
      First report of blaNDM-1-producing Acinetobacter baumannii isolated in Lebanon from civilians wounded during the Syrian war.
      ,
      • Kassem D.F.
      • Hoffmann Y.
      • Shahar N.
      • et al.
      Multidrug-resistant pathogens in hospitalized Syrian children.
      ,
      • Angeletti S.
      • Ceccarelli G.
      • Vita S.
      • et al.
      Unusual microorganisms and antimicrobial resistances in a group of Syrian migrants: sentinel surveillance data from an asylum seekers centre in Italy.
      ,
      • Ravensbergen S.J.
      • Lokate M.
      • Cornish D.
      • et al.
      High prevalence of infectious diseases and drug-resistant microorganisms in asylum seekers admitted to hospital; no Carbapenemase producing Enterobacteriaceae until September 2015.
      ,
      • Reinheimer C.
      • Kempf V.A.
      • Göttig S.
      • Hogardt M.
      • Wichelhaus T.A.
      • O’Rourke F.
      • et al.
      Multidrug-resistant organisms detected in refugee patients admitted to a University Hospital, Germany June-December 2015.
      ,
      • Heudorf U.
      • Krackhardt B.
      • Karathana M.
      • Kleinkauf N.
      • Zinn C.
      Multidrug-resistant bacteria in unaccompanied refugee minors arriving in Frankfurt am Main, Germany, October to November 2015.
      ,
      • Tenenbaum T.
      • Becker K.-P.
      • Lange B.
      • et al.
      Prevalence of multidrug-resistant organisms in hospitalized pediatric refugees in an University Children’s Hospital in Germany 2015–2016.
      ). This is significantly greater than the background carriage rates of the local populations such as in Germany, where colonization with MDR Gram-negatives was identified in 60.8% of a refugee population (of whom 18.6% were Syrian) screened on admission to hospital versus 16.8% in the general population (
      • Ravensbergen S.J.
      • Lokate M.
      • Cornish D.
      • et al.
      High prevalence of infectious diseases and drug-resistant microorganisms in asylum seekers admitted to hospital; no Carbapenemase producing Enterobacteriaceae until September 2015.
      ).
      Comparative data from the European Antimicrobial Resistance Surveillance Network (EARS-Net) showed rates of resistance for seven specific pathogens in 2015.28 Penicillin non-susceptibility in S. pneumoniae ranged from 0.6% in Belgium to 39% in Romania. Carbapenem resistance was 0.1%, 8.1%, and 17.8% in E. coli, K. pneumoniae, and P. aeruginosa, respectively, with the highest rate of 93.5% seen in Acinetobacter sp in Greece. Polymyxin resistance was 0.8%, 4%, and 8.8% in P. aeruginosa, Acinetobacter sp, and K. pneumoniae, respectively. Most K. pneumoniae isolates with combined polymyxin and carbapenem resistance were reported from Greece and Italy. MRSA rates ranged from 0% in Iceland to 57% in Romania.

      Conclusions

      This review of evidence of AMR inside Syria and in countries hosting Syrian refugees demonstrates a paucity of rigorous studies describing this increasingly important phenomenon. Before the conflict, published studies inside Syria were often from single centres and presented limited data of variable quality. Since the onset of the conflict, no studies have described the prevalence of AMR in those with injuries within Syria. However, evidence from neighbouring countries suggests that this is an increasing phenomenon. It is important to address this research and reporting gap, as defining the current extent of AMR among Syrians will help to inform interventions that address the drivers of AMR in this population. This is particularly relevant given the population movements that have resulted from the conflict and the likelihood of ongoing challenges in addressing this issue which is of global importance. However, there are barriers to filling this evidence gap due to a combination of factors relating to the complex humanitarian situation inside Syria and the overwhelmed health systems in neighbouring countries. Collaboration and innovations are required to address this issue, which is of global importance.
      The second part of this two-part series addresses the drivers of AMR before and after the onset of conflict and makes recommendations as to how these can be addressed.

      Funding

      No funding received for this work.

      Conflict of interest

      No conflict of interest to declare.

      Author contributions

      AA conceived the idea, contributed to the literature review, the first draft and revisions of the manuscript. TMR, NK, WE-A, JH, contributed to the literature review, writing of the text and made significant contributions to revisions of the manuscript. BT, ODa, ODe, GAS, BEU made contributions to the text, literature review and revisions of the manuscript. AS contributed to the original text and subsequent revisions, the figures and tables and developed key concepts in the manuscript.

      Aims

      • 1.
        Compare what is known about antimicrobial resistance in Syria and neighbouring countries hosting Syrian refugees before and after the onset of the conflict.
      • 2.
        Identify geographical and population areas where there are evidence gaps.
      Compare what is known about antimicrobial resistance in Syria and neighbouring countries hosting Syrian refugees before and after the onset of the conflict.
      Identify geographical and population areas where there are evidence gaps.

      Acknowledgments

      We thank our Syrian colleagues working in Damascus, Quneitra, Homs, Aleppo, Idlib, Hama, Dara’a, Sweida, Lattakia, Tartous, Raqqa, Deir Ezzor, and Hasseke for providing data and sharing valuable insights; particularly surgical and microbiological colleagues at the AMR/Trauma training provided by the Syrian American Medical Society office in Gaziantep, Turkey, Professor Antony Keil from the Faculty of Medicine at the University of Western Australia, and Natalie Garland from the ISSMS.

      Appendix A

      Search methodology for the review of the literature on antimicrobial resistance in Syria pre and post the onset of conflict

      Drug-resistant bacteria were defined according to the US Centers for Disease Control and Prevention (CDC) definition as “microorganisms, predominantly bacteria, that are resistant to one or more classes of antimicrobial agents”; multidrug-resistant (MDR) bacteria were defined as microorganisms that are resistant to one or more agents in at least three separate classes, methicillin-resistant Staphylococcus aureus (MRSA), or an extended-spectrum beta-lactamase (ESBL)-producing organism.
      Information about antimicrobial resistance in Syria or amongst Syrian refugees was collected. A detailed scoping review was performed to summarize the available literature on AMR affecting Syrians pre and post conflict. This aimed to identify the key emerging themes and current concepts, and to highlight gaps in current evidence on AMR in Syria. MEDLINE, PubMed, Embase, and the World Health Organization (WHO) Global Health Library were searched using the terms ‘Syria’ and ‘antibiotic resistance’. The grey literature was searched using other search engines with the following additional terms: ‘Syria’, ‘refugee’, ‘antimicrobial resistance’, ‘screening’, ‘war-injury’. Only articles in English were included. The journal of the Syrian Clinical Laboratory Association was also searched. This was included to ensure that relevant literature was not missed; however the peer review process for this journal is unknown. Any identified references within the literature that were deemed relevant were also included in the final review.

      Appendix A. Supplementary data

      The following is Supplementary data to this article:

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