Advertisement

Antimicrobial resistance in Cambodia: a review

Open AccessPublished:June 05, 2019DOI:https://doi.org/10.1016/j.ijid.2019.05.036

      Highlights

      • Antimicrobial resistance data for Cambodia is limited, but improving, with 24 articles included in this review.
      • Resistance rates for appear to be similar to those of other countries in the region.
      • High resistance rates are seen to many first-line antibiotics, especially among Enterobacteriaceae.
      • National human and food-animal surveillance will improve understanding of antimicrobial resistance epidemiology in Cambodia.

      Abstract

      Objectives

      Following the launch of the Global Antimicrobial Resistance Surveillance System (GLASS), antimicrobial resistance (AMR) rates in many countries remain poorly described. This review provides an overview of published AMR data from Cambodia in the context of recently initiated national human and food-animal surveillance.

      Methods

      PubMed and the Cochrane Database of Systematic Reviews were searched for articles published from 2000 to 2018, which reported antimicrobial susceptibility testing (AST) data for GLASS specific organisms isolated from Cambodia. Articles were screened using strict inclusion/exclusion criteria. AST data was extracted, with medians and ranges of resistance rates calculated for specific bug-drug combinations.

      Results

      Twenty-four papers were included for final analysis, with 20 describing isolates from human populations. Escherichia coli was the most commonly described organism, with median resistance rates from human isolates of 92.8% (n = 6 articles), 46.4% (n = 4), 55.4% (n = 8), and 46.4% (n = 5) to ampicillin, 3rd generation cephalosporins, fluoroquinolones, and gentamicin respectively.

      Conclusions

      Whilst resistance rates are high for several GLASS organisms, there were insufficient data to draw robust conclusions about the AMR situation in Cambodia. The recently implemented national AMR surveillance systems will begin to address this data gap.

      Keywords

      Introduction

      Antimicrobial resistance (AMR) has emerged as a major threat to human health (). Global mortality and the economic burden caused by AMR are anticipated to continue increasing if it is left unchecked, and a “post-antibiotic era” has been predicted (). Southeast (SE) Asia has been identified as a region of great importance in the development and spread of AMR (
      • Chereau F.
      • Opatowski L.
      • Tourdjman M.
      • Vong S.
      Risk assessment for antibiotic resistance in South East Asia.
      ). In Thailand, it has been estimated that 43% of deaths resulting from hospital-acquired bacteraemia were excess mortality due to multi drug resistance (
      • Lim C.
      • Takahashi E.
      • Hongsuwan M.
      • Wuthiekanun V.
      • Thamlikitkul V.
      • Hinjoy S.
      • et al.
      Epidemiology and burden of multidrug-resistant bacterial infection in a developing country.
      ). Similarly, in Cambodia, community-acquired drug-resistant bacteraemia in children is associated with increased mortality, and results in a doubling of hospital admission costs (
      • Fox-Lewis A.
      • Takata J.
      • Miliya T.
      • Lubell Y.
      • Soeng S.
      • Sar P.
      • et al.
      Antimicrobial resistance in invasive bacterial infections in hospitalized children, Cambodia, 2007-2016.
      ).
      Poor hygiene and infection control, lack of sanitation, weak or unenforced medicines regulation, and sub-standard quality drugs have been suggested as some of the main drivers of AMR in SE Asia (
      • Zellweger R.M.
      • Carrique-Mas J.
      • Limmathurotsakul D.
      • Day N.P.J.
      • Thwaites G.E.
      • Baker S.
      • et al.
      A current perspective on antimicrobial resistance in Southeast Asia.
      ). In addition, intensification of agriculture and aquaculture may contribute to AMR owing to increased and unregulated use of antibiotics in these sectors as therapeutic, prophylactic, metaphylactic, and growth promotion agents (
      • Zellweger R.M.
      • Carrique-Mas J.
      • Limmathurotsakul D.
      • Day N.P.J.
      • Thwaites G.E.
      • Baker S.
      • et al.
      A current perspective on antimicrobial resistance in Southeast Asia.
      ). Acknowledging the diversity of these drivers, a One Health approach to tackling AMR has been encouraged (
      • Robinson T.P.
      • Bu D.P.
      • Carrique-Mas J.
      • Fevre E.M.
      • Gilbert M.
      • Grace D.
      • et al.
      Antibiotic resistance is the quintessential One Health issue.
      ), and there is much work to be done to understand clearly the links between agriculture, humans, and the environment in the development and spread of AMR.
      In October 2015 the World Health Organisation (WHO) launched the Global Antimicrobial Resistance Surveillance System (GLASS), a necessary contribution to the global action plan against AMR. The surveillance system currently includes eight organisms: Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Staphylococcus aureus, Streptococcus pneumoniae, Salmonella spp., Shigella spp., and Neisseria gonorrhoeae (
      • WHO
      Manual for early implementation: global antimicrobial resistance surveillance system.
      ). Key drug classes for antimicrobial susceptibility testing (AST) include penicillins, third- and fourth-generation cephalosporins (3GC and 4GC), carbapenems, fluoroquinolones, aminoglycosides, tetracyclines, polymyxins, macrolides, and co-trimoxazole.
      Similar to many other low- and middle-income countries, Cambodia has only relatively recently begun to develop diagnostic microbiological facilities, and, as capacity expands, collaboration has led to sharing of AMR data, revision of clinical practice guidelines, and development of infection control policies (
      • Vlieghe E.R.
      • Sary S.
      • Lim K.
      • Sivuthy C.
      • Phe T.
      • Parry C.
      • et al.
      First national workshop on antibiotic resistance in Cambodia: Phnom Penh, Cambodia, 16-18 November 2011.
      ). In addition, there have been early reports of retrospective and prospective AMR surveillance from non-governmental hospitals (
      • Fox-Lewis A.
      • Takata J.
      • Miliya T.
      • Lubell Y.
      • Soeng S.
      • Sar P.
      • et al.
      Antimicrobial resistance in invasive bacterial infections in hospitalized children, Cambodia, 2007-2016.
      ,
      • Vlieghe E.R.
      • Phe T.
      • De Smet B.
      • Veng H.C.
      • Kham C.
      • Lim K.
      • et al.
      Bloodstream infection among adults in Phnom Penh, Cambodia: key pathogens and resistance patterns.
      ), and a handful of studies on animals and/or meat products (
      • Lay K.S.
      • Vuthy Y.
      • Song P.
      • Phol K.
      • Sarthou J.L.
      Prevalence, numbers and antimicrobial susceptibilities of Salmonella serovars and Campylobacter spp. in retail poultry in Phnom Penh, Cambodia.
      ,
      • Nadimpalli M.
      • Fabre L.
      • Yith V.
      • Sem N.
      • Gouali M.
      • Delarocque-Astagneau E.
      • et al.
      CTX-M-55-type ESBL-producing Salmonella enterica are emerging among retail meats in Phnom Penh, Cambodia.
      ,
      • Strom G.
      • Boqvist S.
      • Albihn A.
      • Fernstrom L.L.
      • Andersson Djurfeldt A.
      • Sokerya S.
      • et al.
      Antimicrobials in small-scale urban pig farming in a lower middle-income country-arbitrary use and high resistance levels.
      ,
      • Trongjit S.
      • Angkititrakul S.
      • Tuttle R.E.
      • Poungseree J.
      • Padungtod P.
      • Chuanchuen R.
      Prevalence and antimicrobial resistance in Salmonella enterica isolated from broiler chickens, pigs and meat products in Thailand-Cambodia border provinces.
      ). To date, however, these data have not been brought together to provide a country level perspective. A national GLASS-compatible AMR surveillance system has been recently implemented in eight sentinel sites (
      • Ministry of Health - Cambodia
      National policy to combat antimicrobial resistance.
      ), and food animal AMR surveillance has also been initiated nationally (K. Osbjer, Personal Communication). This review aims to describe the recent published AMR data from Cambodia and gives a summary of key AMR patterns in the country. By focusing on the organisms identified by GLASS, and incorporating a One Health approach, the review will provide context to national AMR surveillance systems, and to similar regional initiatives.

      Methods

      Literature search

      Searches were made of PubMed and the Cochrane Database for Systematic Reviews for articles published since 1st January 2000, and until 31st December 2018, in English language (final search date: 6th February 2019). The search query used for the Cochrane database was “Cambodia AND (antibiotic resistance OR antimicrobial resistance OR antibiotic susceptibility OR antimicrobial susceptibility)”. The full PubMed search query is included in the Supplementary Methods. Additional articles were identified through manual searches of the reference lists from relevant published papers.

      Study selection

      The titles and abstracts of all articles retrieved by the search queries were screened by one author (TR). Articles were included for review if they reported bacterial AST on isolates from specimens collected in Cambodia, regardless of source population (e.g. human, animal, food, or environment), or context (i.e. illness or carriage). Articles were excluded if they: (1) addressed only drug resistance in non-GLASS organisms; (2) did not report phenotypic AST data; (3) reported only AST data with a specific resistance phenotype as the denominator; (4) were written as reviews or individual case reports; (5) addressed isolates from travellers or exported food products. Where the fulfilment of inclusion or exclusion criteria was not entirely clear, the paper was included for full text review and excluded at that stage if indicated.
      All titles that were not excluded through title and abstract review underwent full text review by the same author (TR), with the same inclusion and exclusion criteria applied. Further exclusions were made if the AST data reported was not specific to GLASS bug-drug combinations. Articles that were written by the same research groups were assessed for the likelihood of overlapping or duplicate data sets. These groups were contacted to confirm overlaps and agree on exclusion of papers or ways to prevent duplication bias. Outstanding queries regarding paper selection were resolved by discussion with a second author (PT).

      Data extraction and analysis

      Data from all remaining papers were entered into a Microsoft Excel 2016 spreadsheet, including general article information (PubMed identification (PMID), first author, year of publication, and duration of data collection), isolate metadata where applicable (specimen type, population type (e.g. human), age group, community acquired infection (CAI) vs. hospital acquired infection (HAI), inpatient vs. outpatient, syndrome, and live or slaughtered animal status) and laboratory methodological information (pathogen identification, AST and breakpoints used, and laboratory accreditation). Further tables were created for the individual GLASS organisms, with resistance data entered from each paper for the GLASS specific antibiotics and antibiotic classes (see Supplementary Table S1). Intermediate susceptibility, where reported, was considered as resistant. Where susceptibility rates were reported, without resistance rates, the resistance rates were calculated as the inverse of the susceptibility rates. For E. coli and K. pneumoniae, both gentamicin and amikacin resistance data were also captured, where available. Resistance rates for Salmonella Typhi, S. Paratyphi A, and non-typhoidal serovars of Salmonella enterica (NTS) were reported separately given differences in epidemiology and resistance profiles. Resistance rates of S. aureus to cefoxitin and/or oxacillin, and rates of methicillin-resistant S. aureus (MRSA), were entered together as “MRSA”. Where AST results were given for more than one GLASS specific antibiotic of the same class (e.g. fluoroquinolones, 3GC, carbapenems), the rate that reflected the highest level of resistance was selected to represent the rate for that respective class. The exception to this was with regard to the aminoglycosides, which were reported individually, since gentamicin and amikacin show markedly different resistance rates. Amikacin, a semisynthetic aminoglycoside, has structural differences that render it refractory to most aminoglycoside modifying enzymes (
      • Ramirez M.S.
      • Tolmasky M.E.
      Amikacin: uses, resistance, and prospects for inhibition.
      ). Where articles quoted rates for an antibiotic class, without stating the specific antimicrobial(s) tested, this rate was accepted. As a result of paucity and heterogeneity of data, only the median and range of resistance proportions for each organism-drug combination were reported, as calculated by Excel. Meta-analysis to calculate summary estimates and test for heterogeneity was not feasible, nor was testing for reporting bias.

      Results

      One-hundred-and-seventy-six articles were identified from the initial literature search. This was reduced to 42 after screening, and then 31 after full text review (Figure 1). After assessment for overlapping or duplicate data sets, seven articles were excluded (
      • Chheng K.
      • Carter M.J.
      • Emary K.
      • Chanpheaktra N.
      • Moore C.E.
      • Stoesser N.
      • et al.
      A prospective study of the causes of febrile illness requiring hospitalization in children in Cambodia.
      ,
      • Emary K.
      • Moore C.E.
      • Chanpheaktra N.
      • An K.P.
      • Chheng K.
      • Sona S.
      • et al.
      Enteric fever in Cambodian children is dominated by multidrug-resistant H58 Salmonella enterica serovar typhi with intermediate susceptibility to ciprofloxacin.
      ,
      • Moore C.E.
      • Giess A.
      • Soeng S.
      • Sar P.
      • Kumar V.
      • Nhoung P.
      • et al.
      Characterisation of invasive Streptococcus pneumoniae isolated from Cambodian children between 2007-2012.
      ,
      • Stoesser N.
      • Moore C.E.
      • Pocock J.M.
      • An K.P.
      • Emary K.
      • Carter M.
      • et al.
      Pediatric bloodstream infections in Cambodia, 2007 to 2011.
      ,
      • Vlieghe E.R.
      • Huang T.D.
      • Phe T.
      • Bogaerts P.
      • Berhin C.
      • De Smet B.
      • et al.
      Prevalence and distribution of beta-lactamase coding genes in third-generation cephalosporin-resistant Enterobacteriaceae from bloodstream infections in Cambodia.
      ,
      • Vlieghe E.R.
      • Phe T.
      • De Smet B.
      • Veng C.H.
      • Kham C.
      • Sar D.
      • et al.
      Increase in Salmonella enterica serovar paratyphi A infections in Phnom Penh, Cambodia, January 2011 to August 2013.
      ,
      • Wijedoru L.P.
      • Kumar V.
      • Chanpheaktra N.
      • Chheng K.
      • Smits H.L.
      • Pastoor R.
      • et al.
      Typhoid fever among hospitalized febrile children in Siem Reap, Cambodia.
      ), leaving a final count of 24 papers. Details of these papers are summarised in Table 1, and Supplementary Table S2. Among these, 20 reported isolates from human populations and four reported isolates from animals and/or meat products. Of the human population papers, nine reported isolates from children only, and seven reported isolates from sterile sites only (e.g. blood, cerebrospinal fluid). Three articles described isolates associated with both CAI and HAI, however, only in one article was it possible to separate these isolates (
      • Fox-Lewis A.
      • Takata J.
      • Miliya T.
      • Lubell Y.
      • Soeng S.
      • Sar P.
      • et al.
      Antimicrobial resistance in invasive bacterial infections in hospitalized children, Cambodia, 2007-2016.
      ). Three articles described isolates from CAI only, and no articles stated that their isolates were associated with HAI only. Assessment of study methodology showed that 11 articles either did not state, or did not explain in detail, organism identification methods used. AST was done by disk diffusion method in 18 studies, with 14 studies determining minimum inhibitory concentration (MIC) in addition to susceptibility by disk diffusion. MIC testing was largely done by the E-test method (n = 11). Four studies did not state which AST interpretative criteria were used (e.g. Clinical and Laboratory Standards Institute breakpoints). Of the remaining papers that did, all but one stated the specific edition used.
      Figure 1
      Figure 1PRISMA diagram of article selection procedure.
      Table 1Summary of individual papers included in review.
      ReferenceDuration of data collectionPopulationSpecimensAge groupHAI vs CAISyndromeGLASS Organism(s) included
      • Augustin A.
      • Shahum A.
      • Taziar M.
      • Benca J.
      • Koleno B.
      • Bukovino P.
      • et al.
      Resistance in uropathogens among HIV-positive Kenyan and Cambodian children in comparison to an HIV-negative population in south Sudan.
      Not statedHumanUrineChildNot statedNot statedE. coli, K. pneumoniae
      • Caron Y.
      • Chheang R.
      • Puthea N.
      • Soda M.
      • Boyer S.
      • Tarantola A.
      • et al.
      Beta-lactam resistance among Enterobacteriaceae in Cambodia: the four-year itch.
      Jan 2012– Dec 2015HumanBlood, pulmonary, urine, genital, stool, otherAllBothNot statedE. coli, K. pneumoniae
      • Fox-Lewis A.
      • Takata J.
      • Miliya T.
      • Lubell Y.
      • Soeng S.
      • Sar P.
      • et al.
      Antimicrobial resistance in invasive bacterial infections in hospitalized children, Cambodia, 2007-2016.
      2007–2016HumanBlood, CSFChildBothFebrileE. coli, K. pneumoniae, A. baumannii, S. aureus, S. pneumoniae, Salmonella spp.
      • Hout B.
      • Oum C.
      • Men P.
      • Vanny V.
      • Supaprom C.
      • Heang V.
      • et al.
      Drug resistance in bacteria isolated from patients presenting with wounds at a non-profit Surgical Center in Phnom Penh, Cambodia from 2011-2013.
      2011–2013HumanWound swabChildNot statedWound exudateE. coli, K. pneumoniae, A. baumannii, S. aureus
      • Inghammar M.
      • By Y.
      • Farris C.
      • Phe T.
      • Borand L.
      • Kerleguer A.
      • et al.
      Serotype distribution of clinical Streptococcus pneumoniae isolates before the introduction of the 13-valent pneumococcal conjugate vaccine in Cambodia.
      2005–2014HumanBlood, CSF, BAL, pleural fluid, sputumAllNot statedNot statedS. pneumoniae
      • Kasper M.R.
      • Sokhal B.
      • Blair P.J.
      • Wierzba T.F.
      • Putnam S.D.
      Emergence of multidrug-resistant Salmonella enterica serovar Typhi with reduced susceptibility to fluoroquinolones in Cambodia.
      Dec 2006–Apr 2009HumanBloodAllNot statedFeverSalmonella spp.
      • Khauv P.
      • Turner P.
      • Soeng C.
      • Soeng S.
      • Moore C.E.
      • Bousfield R.
      • et al.
      Ophthalmic infections in children presenting to Angkor Hospital for Children, Siem Reap, Cambodia.
      Mar 2012– Oct 2012HumanOphthalmicChildNot statedOphthalmic infectionS. aureus, S. pneumoniae, N. gonorrhoeae
      • Kuijpers L.M.F.
      • Phe T.
      • Veng C.H.
      • Lim K.
      • Ieng S.
      • Kham C.
      • et al.
      The clinical and microbiological characteristics of enteric fever in Cambodia, 2008-2015.
      2008–2015HumanBloodAllNot statedEnteric feverSalmonella spp.
      • Lay K.S.
      • Vuthy Y.
      • Song P.
      • Phol K.
      • Sarthou J.L.
      Prevalence, numbers and antimicrobial susceptibilities of Salmonella serovars and Campylobacter spp. in retail poultry in Phnom Penh, Cambodia.
      Mar 2006– Feb 2007Poultry carcassPoultry skinN/AN/AN/ASalmonella spp.
      • Meng C.Y.
      • Smith B.L.
      • Bodhidatta L.
      • Richard S.A.
      • Vansith K.
      • Thy B.
      • et al.
      Etiology of diarrhea in young children and patterns of antibiotic resistance in Cambodia.
      Nov 2004– Oct 2006HumanStoolChildNot statedDiarrhoeaE. coli, Salmonella spp., Shigella spp.
      • Moore C.E.
      • Sona S.
      • Poda S.
      • Putchhat H.
      • Kumar V.
      • Sopheary S.
      • et al.
      Antimicrobial susceptibility of uropathogens isolated from Cambodian children.
      Jan 2007– Dec 2011HumanUrineChildNot statedNot statedE. coli, K. pneumoniae
      • Phe T.
      • Vlieghe E.
      • Reid T.
      • Harries A.D.
      • Lim K.
      • Thai S.
      • et al.
      Does HIV status affect the aetiology, bacterial resistance patterns and recommended empiric antibiotic treatment in adult patients with bloodstream infection in Cambodia?.
      Jan 2009– Dec 2011HumanBloodAdultCAISystemic inflammatory responseE. coli, S. aureus
      • Rammaert B.
      • Goyet S.
      • Beaute J.
      • Hem S.
      • Te V.
      • Try P.L.
      • et al.
      Klebsiella pneumoniae related community-acquired acute lower respiratory infections in Cambodia: clinical characteristics and treatment.
      Apr 2007– Dec 2009HumanBlood, sputum, nasopharyngeal swabAllCAIAcute lower respiratory infectionK. pneumoniae
      • Ruppe E.
      • Hem S.
      • Lath S.
      • Gautier V.
      • Ariey F.
      • Sarthou J.L.
      • et al.
      CTX-M beta-lactamases in Escherichia coli from community-acquired urinary tract infections, Cambodia.
      Jan 2004– Dec 2005HumanUrineAllCAIUTIE. coli
      • Srun S.
      • Sinath Y.
      • Seng A.T.
      • Chea M.
      • Borin M.
      • Nhem S.
      • et al.
      Surveillance of post-caesarean surgical site infections in a hospital with limited resources, Cambodia.
      Oct 2010– Feb 2011HumanWound swabAdultNot statedSurgical wound infectionS. aureus
      • Stoesser N.
      • Emary K.
      • Soklin S.
      • Peng An K.
      • Sophal S.
      • Chhomrath S.
      • et al.
      The value of intermittent point-prevalence surveys of healthcare-associated infections for evaluating infection control interventions at Angkor Hospital for Children, Siem Reap, Cambodia.
      2011HumanNasal swabChildN/ACarriageS. aureus
      • Stoesser N.
      • Pocock J.
      • Moore C.E.
      • Soeng S.
      • Hor P.
      • Sar P.
      • et al.
      The epidemiology of pediatric bone and joint infections in Cambodia, 2007-11.
      Jan 2007– Jul 2011HumanSynovial fluidChildNot statedBone/joint infectionS. aureus
      • Strom G.
      • Boqvist S.
      • Albihn A.
      • Fernstrom L.L.
      • Andersson Djurfeldt A.
      • Sokerya S.
      • et al.
      Antimicrobials in small-scale urban pig farming in a lower middle-income country-arbitrary use and high resistance levels.
      Jan 2017– Feb 2017PigsStool, rectal swabN/AN/AN/A
      • Trongjit S.
      • Angkittitrakul S.
      • Chuanchuen R.
      Occurrence and molecular characteristics of antimicrobial resistance of Escherichia coli from broilers, pigs and meat products in Thailand and Cambodia provinces.
      Jul 2014– Jan 2015Pigs, poultry, meat productsStool, rectal swab, carcass swabN/AN/AN/AE. coli
      • Trongjit S.
      • Angkititrakul S.
      • Tuttle R.E.
      • Poungseree J.
      • Padungtod P.
      • Chuanchuen R.
      Prevalence and antimicrobial resistance in Salmonella enterica isolated from broiler chickens, pigs and meat products in Thailand-Cambodia border provinces.
      Jul 2014– Jan 2015Pigs, poultry, meat productsStool, rectal swab, carcass swabN/AN/AN/ASalmonella spp.
      • Turner P.
      • Turner C.
      • Suy K.
      • Soeng S.
      • Ly S.
      • Miliya T.
      • et al.
      Pneumococcal infection among children before introduction of 13-valent pneumococcal conjugate vaccine, Cambodia.
      Aug 2013– Jul 2014HumanNasopharyngeal swabs, bloodChildN/AAdmission or minor illnessS. pneumoniae
      • Vernel-Pauillac F.
      • Ratsima E.H.
      • Guillard B.
      • Goursaud R.
      • Lethezer C.
      • Hem S.
      • et al.
      Correlation between antibiotic susceptibilities and genotypes in Neisseria gonorrhoeae from different geographical origins: determinants monitoring by real-time PCR as a complementary tool for surveillance.
      Oct 2006– Oct 2007HumanCervical/urethral swabNot statedNot statedNot statedN. gonorrhoeae
      • Vlieghe E.R.
      • Phe T.
      • De Smet B.
      • Veng C.H.
      • Kham C.
      • Bertrand S.
      • et al.
      Azithromycin and ciprofloxacin resistance in Salmonella bloodstream infections in Cambodian adults.
      Jul 2007– Jun 2011HumanBloodAdultNot statedSystemic inflammatory responseSalmonella spp.
      Vlieghe et al. (2013)Jul 2007– Dec 2010HumanBloodAdultBothSystemic inflammatory responseE. coli, K. pneumoniae, A. baumannii
      The earliest published article identified was from 2007 (
      • Augustin A.
      • Shahum A.
      • Taziar M.
      • Benca J.
      • Koleno B.
      • Bukovino P.
      • et al.
      Resistance in uropathogens among HIV-positive Kenyan and Cambodian children in comparison to an HIV-negative population in south Sudan.
      ). The most commonly reported organism was E. coli, with AST data reported by 11 papers. In contrast, AST data was reported by one paper for Shigella spp. (
      • Meng C.Y.
      • Smith B.L.
      • Bodhidatta L.
      • Richard S.A.
      • Vansith K.
      • Thy B.
      • et al.
      Etiology of diarrhea in young children and patterns of antibiotic resistance in Cambodia.
      ), and two papers for N. gonorrhoeae (
      • Khauv P.
      • Turner P.
      • Soeng C.
      • Soeng S.
      • Moore C.E.
      • Bousfield R.
      • et al.
      Ophthalmic infections in children presenting to Angkor Hospital for Children, Siem Reap, Cambodia.
      ,
      • Vernel-Pauillac F.
      • Ratsima E.H.
      • Guillard B.
      • Goursaud R.
      • Lethezer C.
      • Hem S.
      • et al.
      Correlation between antibiotic susceptibilities and genotypes in Neisseria gonorrhoeae from different geographical origins: determinants monitoring by real-time PCR as a complementary tool for surveillance.
      ). Four studies reported isolates from non-human populations, specifically, E. coli and NTS.

      Escherichia coli

      There were nine papers that reported E. coli among human populations (Table 2). Fluoroquinolone and co-trimoxazole AST were reported in all these studies. Median resistances were calculated as 92.8% (n = 6, IQR 86.1–94.3), 46.4% (n = 4, IQR 44.8–53.8), 55.4% (n = 8, IQR 40.2–69.8), 79.9% (n = 8, IQR 72.6–83.3), 46.4% (n = 5, IQR 44.7–51.7), for ampicillin, 3GC, fluoroquinolones, co-trimoxazole, and gentamicin respectively. No carbapenem resistance was found in the three studies that reported AST data for this antibiotic class. 4GC (cefepime) resistance was reported as 22.2%–46.2% by two studies (
      • Hout B.
      • Oum C.
      • Men P.
      • Vanny V.
      • Supaprom C.
      • Heang V.
      • et al.
      Drug resistance in bacteria isolated from patients presenting with wounds at a non-profit Surgical Center in Phnom Penh, Cambodia from 2011-2013.
      ,
      • Vlieghe E.R.
      • Phe T.
      • De Smet B.
      • Veng H.C.
      • Kham C.
      • Lim K.
      • et al.
      Bloodstream infection among adults in Phnom Penh, Cambodia: key pathogens and resistance patterns.
      ), and colistin resistance was reported as 0.8%, (n = 1/130) in one study (
      • Vlieghe E.R.
      • Phe T.
      • De Smet B.
      • Veng H.C.
      • Kham C.
      • Lim K.
      • et al.
      Bloodstream infection among adults in Phnom Penh, Cambodia: key pathogens and resistance patterns.
      ).
      Table 2Resistance rates for E. coli and K. pneumoniae isolates from humans.
      Specimen type(s)Ampicillin3GC
      3GC, third generation cephalosporin: ceftriaxone, ceftazidime.
      4GC
      4GC, fourth generation cephalosporin: cefepime.
      Carbapenem
      Carbapenems: meropenem.
      Fluoroquinolone
      Fluoroquinolones: ciprofloxacin.
      Co-trimoxazoleGentamicinAmikacinColistin
      n%n%n%n%n%n%n%n%n%
      E. coli
      • Fox-Lewis A.
      • Takata J.
      • Miliya T.
      • Lubell Y.
      • Soeng S.
      • Sar P.
      • et al.
      Antimicrobial resistance in invasive bacterial infections in hospitalized children, Cambodia, 2007-2016.
      Blood & CSF101/10794.453/10749.5--0/980.048/10545.789/10584.851/10648.1----
      • Caron Y.
      • Chheang R.
      • Puthea N.
      • Soda M.
      • Boyer S.
      • Tarantola A.
      • et al.
      Beta-lactam resistance among Enterobacteriaceae in Cambodia: the four-year itch.
      Multiple types
      Specimens include blood, stool, pulmonary, pus, genito-urinary, and other body fluid samples.
      --------560/78971.0g580/78973.5--206/78926.0--
      • Hout B.
      • Oum C.
      • Men P.
      • Vanny V.
      • Supaprom C.
      • Heang V.
      • et al.
      Drug resistance in bacteria isolated from patients presenting with wounds at a non-profit Surgical Center in Phnom Penh, Cambodia from 2011-2013.
      Wound swab33/3691.724/3666.78/3622.20/360.025/3669.428/3677.822/3661.11/362.8--
      • Moore C.E.
      • Sona S.
      • Poda S.
      • Putchhat H.
      • Kumar V.
      • Sopheary S.
      • et al.
      Antimicrobial susceptibility of uropathogens isolated from Cambodian children.
      Urine164/17096.568/17040.0----77/17045.3147/17086.576/17044.7----
      • Vlieghe E.R.
      • Phe T.
      • De Smet B.
      • Veng H.C.
      • Kham C.
      • Lim K.
      • et al.
      Bloodstream infection among adults in Phnom Penh, Cambodia: key pathogens and resistance patterns.
      Papers with overlapping datasets: Ampicillin, 4GC, and Colistin resistance rates taken from Vlieghe et al., 2013. All other resistance rates taken from Phe et al., 2013, as larger numbers of isolates.
      Blood122/13093.8--60/13046.2----------1/1300.8
      • Phe T.
      • Vlieghe E.
      • Reid T.
      • Harries A.D.
      • Lim K.
      • Thai S.
      • et al.
      Does HIV status affect the aetiology, bacterial resistance patterns and recommended empiric antibiotic treatment in adult patients with bloodstream infection in Cambodia?.
      Papers with overlapping datasets: Ampicillin, 4GC, and Colistin resistance rates taken from Vlieghe et al., 2013. All other resistance rates taken from Phe et al., 2013, as larger numbers of isolates.
      Blood--70/15146.4--0/1510.0113/15174.8125/15182.878/15151.73/1512.0--
      • Meng C.Y.
      • Smith B.L.
      • Bodhidatta L.
      • Richard S.A.
      • Vansith K.
      • Thy B.
      • et al.
      Etiology of diarrhea in young children and patterns of antibiotic resistance in Cambodia.
      Stool295/32391.3------6/ 3231.9288/32389.240/32312.4----
      • Ruppe E.
      • Hem S.
      • Lath S.
      • Gautier V.
      • Ariey F.
      • Sarthou J.L.
      • et al.
      CTX-M beta-lactamases in Escherichia coli from community-acquired urinary tract infections, Cambodia.
      Urine--------68/9363.075/9370.0------
      • Augustin A.
      • Shahum A.
      • Taziar M.
      • Benca J.
      • Koleno B.
      • Bukovino P.
      • et al.
      Resistance in uropathogens among HIV-positive Kenyan and Cambodian children in comparison to an HIV-negative population in south Sudan.
      Urine12/1675.0------4/1625.06/1637.5------
      K. pneumoniae
      • Fox-Lewis A.
      • Takata J.
      • Miliya T.
      • Lubell Y.
      • Soeng S.
      • Sar P.
      • et al.
      Antimicrobial resistance in invasive bacterial infections in hospitalized children, Cambodia, 2007-2016.
      Blood & CSFN/A115/14678.8--1/1420.786/14260.6111/14377.690/14562.1----
      • Caron Y.
      • Chheang R.
      • Puthea N.
      • Soda M.
      • Boyer S.
      • Tarantola A.
      • et al.
      Beta-lactam resistance among Enterobacteriaceae in Cambodia: the four-year itch.
      Multiple types
      Specimens include blood, stool, pulmonary, pus, genito-urinary, and other body fluid samples.
      N/A------71/24329.0
      Resistance rate stated for antibiotic class only, without stating specific antibiotic.
      118/24348.5--47/24319.5--
      • Hout B.
      • Oum C.
      • Men P.
      • Vanny V.
      • Supaprom C.
      • Heang V.
      • et al.
      Drug resistance in bacteria isolated from patients presenting with wounds at a non-profit Surgical Center in Phnom Penh, Cambodia from 2011-2013.
      Wound swabN/A5/1050.02/1020.00/100.02/1020.05/1050.04/1040.00.00.0--
      • Moore C.E.
      • Sona S.
      • Poda S.
      • Putchhat H.
      • Kumar V.
      • Sopheary S.
      • et al.
      Antimicrobial susceptibility of uropathogens isolated from Cambodian children.
      UrineN/A16/1984.2----12/1963.218/1994.715/1978.9----
      • Vlieghe E.R.
      • Phe T.
      • De Smet B.
      • Veng H.C.
      • Kham C.
      • Lim K.
      • et al.
      Bloodstream infection among adults in Phnom Penh, Cambodia: key pathogens and resistance patterns.
      BloodN/A15/3246.99/3228.10/320.07/3221.924/3275.09/3228.10.00.01/323.1
      • Augustin A.
      • Shahum A.
      • Taziar M.
      • Benca J.
      • Koleno B.
      • Bukovino P.
      • et al.
      Resistance in uropathogens among HIV-positive Kenyan and Cambodian children in comparison to an HIV-negative population in south Sudan.
      UrineN/A------1/303.39/3030.0------
      • Rammaert B.
      • Goyet S.
      • Beaute J.
      • Hem S.
      • Te V.
      • Try P.L.
      • et al.
      Klebsiella pneumoniae related community-acquired acute lower respiratory infections in Cambodia: clinical characteristics and treatment.
      Blood & respiratoryN/A------1/462.210/4632.3------
      CSF, cerebrospinal fluid.
      a Papers with overlapping datasets: Ampicillin, 4GC, and Colistin resistance rates taken from Vlieghe et al., 2013. All other resistance rates taken from
      • Phe T.
      • Vlieghe E.
      • Reid T.
      • Harries A.D.
      • Lim K.
      • Thai S.
      • et al.
      Does HIV status affect the aetiology, bacterial resistance patterns and recommended empiric antibiotic treatment in adult patients with bloodstream infection in Cambodia?.
      , as larger numbers of isolates.
      b Specimens include blood, stool, pulmonary, pus, genito-urinary, and other body fluid samples.
      c 3GC, third generation cephalosporin: ceftriaxone, ceftazidime.
      d 4GC, fourth generation cephalosporin: cefepime.
      e Carbapenems: meropenem.
      f Fluoroquinolones: ciprofloxacin.
      g Resistance rate stated for antibiotic class only, without stating specific antibiotic.
      Two studies describing E. coli isolates from pigs and chickens were identified (
      • Strom G.
      • Boqvist S.
      • Albihn A.
      • Fernstrom L.L.
      • Andersson Djurfeldt A.
      • Sokerya S.
      • et al.
      Antimicrobials in small-scale urban pig farming in a lower middle-income country-arbitrary use and high resistance levels.
      ,
      • Trongjit S.
      • Angkittitrakul S.
      • Chuanchuen R.
      Occurrence and molecular characteristics of antimicrobial resistance of Escherichia coli from broilers, pigs and meat products in Thailand and Cambodia provinces.
      ). Both reported resistance rates to ampicillin (75.0%–86.0%), 3GC (2.0%–8.4%), fluoroquinolones (0.7%–59.0%), and gentamicin (6.6%–25.0%) (Supplementary Table S3). One study reported resistance rates from 261 isolates to colistin (20.0%,) and to carbapenems (0.0%) (
      • Strom G.
      • Boqvist S.
      • Albihn A.
      • Fernstrom L.L.
      • Andersson Djurfeldt A.
      • Sokerya S.
      • et al.
      Antimicrobials in small-scale urban pig farming in a lower middle-income country-arbitrary use and high resistance levels.
      ). Neither of these papers reported AST data for co-trimoxazole, amikacin, or 4GC.

      Klebsiella pneumoniae

      Antimicrobial susceptibility data was reported for K. pneumoniae isolates in seven studies (Table 2), all of which were from humans. Fluoroquinolone and co-trimoxazole resistance data were reported in all papers, with 3GC resistance data reported in four papers. The median resistance rate was 64.4% (n = 4, IQR 49.2–80.2), 21.9% (n = 7, IQR 11.7–44.8), 50.0% (n = 7, IQR 40.4–76.3), and 51.1% (n = 4, IQR 37.0–66.3) for 3GC, fluoroquinolones, co-trimoxazole, and gentamicin respectively. 4GC (cefepime) resistance was reported as 22.0-28.1% by two papers (
      • Hout B.
      • Oum C.
      • Men P.
      • Vanny V.
      • Supaprom C.
      • Heang V.
      • et al.
      Drug resistance in bacteria isolated from patients presenting with wounds at a non-profit Surgical Center in Phnom Penh, Cambodia from 2011-2013.
      ,
      • Vlieghe E.R.
      • Phe T.
      • De Smet B.
      • Veng H.C.
      • Kham C.
      • Lim K.
      • et al.
      Bloodstream infection among adults in Phnom Penh, Cambodia: key pathogens and resistance patterns.
      ), and colistin resistance was reported as 3.1% (n = 1/32 isolates), by one paper (
      • Vlieghe E.R.
      • Phe T.
      • De Smet B.
      • Veng H.C.
      • Kham C.
      • Lim K.
      • et al.
      Bloodstream infection among adults in Phnom Penh, Cambodia: key pathogens and resistance patterns.
      ).

      Acinetobacter baumannii

      Three papers reported resistance data for A. baumannii in humans (
      • Fox-Lewis A.
      • Takata J.
      • Miliya T.
      • Lubell Y.
      • Soeng S.
      • Sar P.
      • et al.
      Antimicrobial resistance in invasive bacterial infections in hospitalized children, Cambodia, 2007-2016.
      ,
      • Hout B.
      • Oum C.
      • Men P.
      • Vanny V.
      • Supaprom C.
      • Heang V.
      • et al.
      Drug resistance in bacteria isolated from patients presenting with wounds at a non-profit Surgical Center in Phnom Penh, Cambodia from 2011-2013.
      ,
      • Vlieghe E.R.
      • Phe T.
      • De Smet B.
      • Veng H.C.
      • Kham C.
      • Lim K.
      • et al.
      Bloodstream infection among adults in Phnom Penh, Cambodia: key pathogens and resistance patterns.
      ) (Supplementary Table S4). All three reported resistance rates for carbapenems (median 13.5%, range 5.9%-33.3%). Gentamicin resistance was reported by two papers with rates of 66.7% (n = 2/3 isolates) (
      • Hout B.
      • Oum C.
      • Men P.
      • Vanny V.
      • Supaprom C.
      • Heang V.
      • et al.
      Drug resistance in bacteria isolated from patients presenting with wounds at a non-profit Surgical Center in Phnom Penh, Cambodia from 2011-2013.
      ), and 58.8% (n = 10/17 isolates) (
      • Vlieghe E.R.
      • Phe T.
      • De Smet B.
      • Veng H.C.
      • Kham C.
      • Lim K.
      • et al.
      Bloodstream infection among adults in Phnom Penh, Cambodia: key pathogens and resistance patterns.
      ). The same two papers also reported amikacin resistance as 66.7% (n = 2/3 isolates) (
      • Hout B.
      • Oum C.
      • Men P.
      • Vanny V.
      • Supaprom C.
      • Heang V.
      • et al.
      Drug resistance in bacteria isolated from patients presenting with wounds at a non-profit Surgical Center in Phnom Penh, Cambodia from 2011-2013.
      ), and 41.2% (n = 7/17 isolates) (
      • Vlieghe E.R.
      • Phe T.
      • De Smet B.
      • Veng H.C.
      • Kham C.
      • Lim K.
      • et al.
      Bloodstream infection among adults in Phnom Penh, Cambodia: key pathogens and resistance patterns.
      ). One paper reported rates for colistin (17.6%, n = 3/17 isolates) (
      • Vlieghe E.R.
      • Phe T.
      • De Smet B.
      • Veng H.C.
      • Kham C.
      • Lim K.
      • et al.
      Bloodstream infection among adults in Phnom Penh, Cambodia: key pathogens and resistance patterns.
      ). None of the studies tested GLASS-specific tetracyclines (minocycline or tigecycline), although one paper did report resistance rates of 66.6% (n = 2/3 isolates) to tetracycline (
      • Hout B.
      • Oum C.
      • Men P.
      • Vanny V.
      • Supaprom C.
      • Heang V.
      • et al.
      Drug resistance in bacteria isolated from patients presenting with wounds at a non-profit Surgical Center in Phnom Penh, Cambodia from 2011-2013.
      ).

      Salmonella spp

      In total, seven papers were identified for inclusion of AST data for Salmonella spp., including two studies of isolates from animals and/or their meat products (
      • Lay K.S.
      • Vuthy Y.
      • Song P.
      • Phol K.
      • Sarthou J.L.
      Prevalence, numbers and antimicrobial susceptibilities of Salmonella serovars and Campylobacter spp. in retail poultry in Phnom Penh, Cambodia.
      ,
      • Trongjit S.
      • Angkititrakul S.
      • Tuttle R.E.
      • Poungseree J.
      • Padungtod P.
      • Chuanchuen R.
      Prevalence and antimicrobial resistance in Salmonella enterica isolated from broiler chickens, pigs and meat products in Thailand-Cambodia border provinces.
      ). Data from the human papers are summarised in Table 3. Fluoroquinolone resistance was reported in all papers, with much higher rates seen in S. Typhi (range 88.0%–96.9%, n = 3) than in S. Paratyphi A (range 11.5%-22.7%, n = 2) or NTS (range 0.6%-63.4%, n = 3). Resistance to 3GC was uncommon in all Salmonella spp. isolates (0.0%-8.1%) and, in the three studies reporting data, carbapenem resistance was not detected.
      Table 3Resistance rates for Salmonella spp. isolates from humans.
      Specimen type(s)Fluoroquinolone
      Fluoroquinolones: ciprofloxacin.
      3GC
      3GC, third generation cephalosporin: ceftriaxone, cefotaxime.
      Carbapenem
      Carbapenems: meropenem. NTS, non-typhoidal salmonella. CSF, cerebrospinal fluid.
      n%n%n%
      S. Typhi
      • Fox-Lewis A.
      • Takata J.
      • Miliya T.
      • Lubell Y.
      • Soeng S.
      • Sar P.
      • et al.
      Antimicrobial resistance in invasive bacterial infections in hospitalized children, Cambodia, 2007-2016.
      Blood & CSF308/32295.71/1730.6--
      Papers with overlapping datasets: Data used from Kuijpers et al. 2017 for S. Typhi and S. Paratyphi due to higher number of isolates, and likewise for Vlieghe et al., 2012 for NTS.
      • Kuijpers L.M.F.
      • Phe T.
      • Veng C.H.
      • Lim K.
      • Ieng S.
      • Kham C.
      • et al.
      The clinical and microbiological characteristics of enteric fever in Cambodia, 2008-2015.
      Blood62/6496.90/640.00/640.0
      • Kasper M.R.
      • Sokhal B.
      • Blair P.J.
      • Wierzba T.F.
      • Putnam S.D.
      Emergence of multidrug-resistant Salmonella enterica serovar Typhi with reduced susceptibility to fluoroquinolones in Cambodia.
      Blood36/4188.00/410.0--
      S. Paratyphi A
      • Fox-Lewis A.
      • Takata J.
      • Miliya T.
      • Lubell Y.
      • Soeng S.
      • Sar P.
      • et al.
      Antimicrobial resistance in invasive bacterial infections in hospitalized children, Cambodia, 2007-2016.
      Blood & CSF10/4422.70/440.0--
      Papers with overlapping datasets: Data used from Kuijpers et al. 2017 for S. Typhi and S. Paratyphi due to higher number of isolates, and likewise for Vlieghe et al., 2012 for NTS.
      • Kuijpers L.M.F.
      • Phe T.
      • Veng C.H.
      • Lim K.
      • Ieng S.
      • Kham C.
      • et al.
      The clinical and microbiological characteristics of enteric fever in Cambodia, 2008-2015.
      Blood21/18311.50/1830.00/1830.0
      Non-typhoidal salmonellae (NTS)
      • Fox-Lewis A.
      • Takata J.
      • Miliya T.
      • Lubell Y.
      • Soeng S.
      • Sar P.
      • et al.
      Antimicrobial resistance in invasive bacterial infections in hospitalized children, Cambodia, 2007-2016.
      Blood & CSF26/4163.43/378.1--
      Papers with overlapping datasets: Data used from Kuijpers et al. 2017 for S. Typhi and S. Paratyphi due to higher number of isolates, and likewise for Vlieghe et al., 2012 for NTS.
      • Vlieghe E.R.
      • Phe T.
      • De Smet B.
      • Veng C.H.
      • Kham C.
      • Bertrand S.
      • et al.
      Azithromycin and ciprofloxacin resistance in Salmonella bloodstream infections in Cambodian adults.
      Blood12/3732.01/372.70/370.0
      • Meng C.Y.
      • Smith B.L.
      • Bodhidatta L.
      • Richard S.A.
      • Vansith K.
      • Thy B.
      • et al.
      Etiology of diarrhea in young children and patterns of antibiotic resistance in Cambodia.
      Stool1/1780.6----
      a Papers with overlapping datasets: Data used from
      • Kuijpers L.M.F.
      • Phe T.
      • Veng C.H.
      • Lim K.
      • Ieng S.
      • Kham C.
      • et al.
      The clinical and microbiological characteristics of enteric fever in Cambodia, 2008-2015.
      for S. Typhi and S. Paratyphi due to higher number of isolates, and likewise for
      • Vlieghe E.R.
      • Phe T.
      • De Smet B.
      • Veng C.H.
      • Kham C.
      • Bertrand S.
      • et al.
      Azithromycin and ciprofloxacin resistance in Salmonella bloodstream infections in Cambodian adults.
      for NTS.
      b Fluoroquinolones: ciprofloxacin.
      c 3GC, third generation cephalosporin: ceftriaxone, cefotaxime.
      d Carbapenems: meropenem. NTS, non-typhoidal salmonella. CSF, cerebrospinal fluid.
      The two non-human studies, describing NTS isolates from chickens and pigs, both reported AST data for fluoroquinolones (0.0%-2.5%), and 3GC (0.0%-6.0%) (
      • Lay K.S.
      • Vuthy Y.
      • Song P.
      • Phol K.
      • Sarthou J.L.
      Prevalence, numbers and antimicrobial susceptibilities of Salmonella serovars and Campylobacter spp. in retail poultry in Phnom Penh, Cambodia.
      ,
      • Trongjit S.
      • Angkititrakul S.
      • Tuttle R.E.
      • Poungseree J.
      • Padungtod P.
      • Chuanchuen R.
      Prevalence and antimicrobial resistance in Salmonella enterica isolated from broiler chickens, pigs and meat products in Thailand-Cambodia border provinces.
      ) (Supplementary Table S5). Neither study reported carbapenem resistance data.

      Shigella spp

      One study reported AST data for Shigella spp., with no resistance found to ciprofloxacin or azithromycin among 41 isolates (
      • Meng C.Y.
      • Smith B.L.
      • Bodhidatta L.
      • Richard S.A.
      • Vansith K.
      • Thy B.
      • et al.
      Etiology of diarrhea in young children and patterns of antibiotic resistance in Cambodia.
      ) (Supplementary Table S6). This paper did not report AST data for 3GC.

      Neisseria gonorrhoeae

      Two papers reported AST data for N. gonorrhoeae (Supplementary Table S7). One reported ciprofloxacin (93.3%) and penicillin (100%) resistance rates on 15 isolates from Cambodia, as part of a larger multi-country study (
      • Vernel-Pauillac F.
      • Ratsima E.H.
      • Guillard B.
      • Goursaud R.
      • Lethezer C.
      • Hem S.
      • et al.
      Correlation between antibiotic susceptibilities and genotypes in Neisseria gonorrhoeae from different geographical origins: determinants monitoring by real-time PCR as a complementary tool for surveillance.
      ). The other reported AST data for 3GC (0%) and ciprofloxacin (100%) from two isolates (
      • Khauv P.
      • Turner P.
      • Soeng C.
      • Soeng S.
      • Moore C.E.
      • Bousfield R.
      • et al.
      Ophthalmic infections in children presenting to Angkor Hospital for Children, Siem Reap, Cambodia.
      ). Resistance rates were not reported for azithromycin, spectinomycin, or gentamicin in either paper.

      Staphylococcus aureus

      MRSA rates ranged from 0% to 52.5%, with a median of 20.0% (n = 7, IQR 8.7%–35.8%) (Table 4). All S. aureus isolates were from studies of humans, with one study reporting isolates from hospital screening.
      Table 4Methicillin resistance rates for S. aureus isolates.
      Specimen type(s)MRSA
      n%
      S. aureus
      • Fox-Lewis A.
      • Takata J.
      • Miliya T.
      • Lubell Y.
      • Soeng S.
      • Sar P.
      • et al.
      Antimicrobial resistance in invasive bacterial infections in hospitalized children, Cambodia, 2007-2016.
      Blood & CSF24/18513.0
      • Hout B.
      • Oum C.
      • Men P.
      • Vanny V.
      • Supaprom C.
      • Heang V.
      • et al.
      Drug resistance in bacteria isolated from patients presenting with wounds at a non-profit Surgical Center in Phnom Penh, Cambodia from 2011-2013.
      Wound swab52/9952.5
      • Khauv P.
      • Turner P.
      • Soeng C.
      • Soeng S.
      • Moore C.E.
      • Bousfield R.
      • et al.
      Ophthalmic infections in children presenting to Angkor Hospital for Children, Siem Reap, Cambodia.
      Ophthalmic1/234.3
      • Stoesser N.
      • Emary K.
      • Soklin S.
      • Peng An K.
      • Sophal S.
      • Chhomrath S.
      • et al.
      The value of intermittent point-prevalence surveys of healthcare-associated infections for evaluating infection control interventions at Angkor Hospital for Children, Siem Reap, Cambodia.
      Nasal swab1/520.0
      • Phe T.
      • Vlieghe E.
      • Reid T.
      • Harries A.D.
      • Lim K.
      • Thai S.
      • et al.
      Does HIV status affect the aetiology, bacterial resistance patterns and recommended empiric antibiotic treatment in adult patients with bloodstream infection in Cambodia?.
      Blood11/5121.6
      • Srun S.
      • Sinath Y.
      • Seng A.T.
      • Chea M.
      • Borin M.
      • Nhem S.
      • et al.
      Surveillance of post-caesarean surgical site infections in a hospital with limited resources, Cambodia.
      Specific AST not stated.
      Wound swab1/250.0
      • Stoesser N.
      • Pocock J.
      • Moore C.E.
      • Soeng S.
      • Hor P.
      • Sar P.
      • et al.
      The epidemiology of pediatric bone and joint infections in Cambodia, 2007-11.
      Synovial fluid0/40.0
      MRSA, methicillin resistant Staphylococcus aureus: cefoxitin, oxacillin.
      a Specific AST not stated.

      Streptococcus pneumoniae

      Four papers reporting AST data for S. pneumoniae were included (Table 5). All papers reported resistance rates for penicillin (median 46.6%, IQR 31.8%–58.1%), co-trimoxazole (median 75.2%, IQR 74.5%–79.3%), and 3GC (median 4.8%, IQR 3.4%–8.0%). One of the papers reported isolates from a study of nasopharyngeal carriage of S. pneumoniae in children (
      • Turner P.
      • Turner C.
      • Suy K.
      • Soeng S.
      • Ly S.
      • Miliya T.
      • et al.
      Pneumococcal infection among children before introduction of 13-valent pneumococcal conjugate vaccine, Cambodia.
      ), whereas the others reported isolates from unwell patients.
      Table 5Papers reporting resistance rates for S. pneumoniae isolates.
      Specimen type(s)PenicillinCo-trimoxazole
      3GC, third generation cephalosporin: ceftriaxone.
      3GC
      n%n%n%
      S. pneumoniae
      • Fox-Lewis A.
      • Takata J.
      • Miliya T.
      • Lubell Y.
      • Soeng S.
      • Sar P.
      • et al.
      Antimicrobial resistance in invasive bacterial infections in hospitalized children, Cambodia, 2007-2016.
      Blood & CSF73/14450.7101/13475.46/1344.5
      • Inghammar M.
      • By Y.
      • Farris C.
      • Phe T.
      • Borand L.
      • Kerleguer A.
      • et al.
      Serotype distribution of clinical Streptococcus pneumoniae isolates before the introduction of the 13-valent pneumococcal conjugate vaccine in Cambodia.
      Multiple types
      Specimens include blood, pleural fluid, sputum, bronchoalveolar lavage, and cerebrospinal fluid (CSF).
      70/16542.4149/16490.98/1575.1
      • Turner P.
      • Turner C.
      • Suy K.
      • Soeng S.
      • Ly S.
      • Miliya T.
      • et al.
      Pneumococcal infection among children before introduction of 13-valent pneumococcal conjugate vaccine, Cambodia.
      Nasopharyngeal swab779/97280.1711/97273.1163/97216.8
      • Khauv P.
      • Turner P.
      • Soeng C.
      • Soeng S.
      • Moore C.E.
      • Bousfield R.
      • et al.
      Ophthalmic infections in children presenting to Angkor Hospital for Children, Siem Reap, Cambodia.
      Ophthalmic0/40.03/475.00/40.0
      a Specimens include blood, pleural fluid, sputum, bronchoalveolar lavage, and cerebrospinal fluid (CSF).
      b 3GC, third generation cephalosporin: ceftriaxone.

      Discussion

      This review provides a summary of all the published GLASS-organism AMR data for Cambodia over the last 19 years. To date, there are few published AMR datasets but the rate at which manuscripts are appearing has increased: only two publications were identified prior to 2010, compared with 10 from 2016–2018. The small number of isolates and lack of classification metadata (e.g. age groups, hospitalization status) make it difficult to draw firm conclusions from the data. However, resistance rates to several key clinically-important antibiotics were found to be alarmingly high.
      The best represented GLASS organisms in this review were Enterobacteriaceae, with E. coli, K. pneumoniae, or Salmonella spp. being described by two thirds of the papers (15/22). Shigella spp. were an exception to this, with only one paper. Another striking lack of data was with regard to N. gonorrhoeae, with only two papers, both describing small numbers of isolates, and with resistance rates reported to only two of the five GLASS specific antibiotics. The level of representation for each GLASS organism may partly be a reflection of their respective burdens on healthcare. A study at a tertiary hospital in Hanoi showed that K. pneumoniae and E. coli were responsible for 17.5% and 17.3% of blood stream infections (BSI) respectively (
      • Dat V.Q.
      • Vu H.N.
      • Nguyen The H.
      • Nguyen H.T.
      • Hoang L.B.
      • Vu Tien Viet D.
      • et al.
      Bacterial bloodstream infections in a tertiary infectious diseases hospital in Northern Vietnam: aetiology, drug resistance, and treatment outcome.
      ), and, in a paediatric setting in Cambodia, Salmonella spp. were shown to be responsible for 30.4% of BSI (
      • Fox-Lewis A.
      • Takata J.
      • Miliya T.
      • Lubell Y.
      • Soeng S.
      • Sar P.
      • et al.
      Antimicrobial resistance in invasive bacterial infections in hospitalized children, Cambodia, 2007-2016.
      ). Microbiology laboratories and clinical services prioritise much of their diagnostic capabilities on the most unwell patients who require management in hospital, rather than on infections based in the community setting, such as diarrhoeal illness and genito-urinary infection. Nevertheless, Shigella spp. account for 12.5% of diarrhoeal deaths globally (
      • GBD Diarrhoeal Diseases Collaborators
      Estimates of global, regional, and national morbidity, mortality, and aetiologies of diarrhoeal diseases: a systematic analysis for the Global Burden of Disease Study 2015.
      ), and N. gonorrhoeae causes high levels of morbidity in LMICs, with both known for rapid development of AMR (
      • Kotloff K.L.
      • Riddle M.S.
      • Platts-Mills J.A.
      • Pavlinac P.
      • Zaidi A.K.M.
      Shigellosis.
      ,
      • Unemo M.
      • Del Rio C.
      • Shafer W.M.
      Antimicrobial resistance expressed by Neisseria gonorrhoeae: a major global public health problem in the 21st century.
      ). Future surveillance and research outputs in Cambodia and SE Asia should not neglect these organisms.
      Our review has demonstrated the particularly high levels of resistance among Enterobacteriaceae to many of the most accessible and widely used antibiotics in Cambodia, including ampicillin, gentamicin, 3GC, fluoroquinolones, and co-trimoxazole. The rise in prevalence of ESBL producing organisms in Cambodia has been raised as a concern (
      • Caron Y.
      • Chheang R.
      • Puthea N.
      • Soda M.
      • Boyer S.
      • Tarantola A.
      • et al.
      Beta-lactam resistance among Enterobacteriaceae in Cambodia: the four-year itch.
      ). In Phnom Penh, among fish, pork, and chicken samples, bacterial plasmids carrying CTX-M type ESBL genes also carry resistance genes for multiple other classes of antibiotic, including aminoglycosides, fluoroquinolones, and co-trimoxazole (
      • Nadimpalli M.
      • Fabre L.
      • Yith V.
      • Sem N.
      • Gouali M.
      • Delarocque-Astagneau E.
      • et al.
      CTX-M-55-type ESBL-producing Salmonella enterica are emerging among retail meats in Phnom Penh, Cambodia.
      ). Furthermore, a link has been made between CTX-M type ESBL producing E. coli isolated from fish, pork, and chicken in markets from Phnom Penh, and isolates colonising humans (
      • Nadimpalli M.
      • Vuthy Y.
      • de Lauzanne A.
      • Fabre L.
      • Criscuolo A.
      • Gouali M.
      • et al.
      Meat and fish as sources of extended-spectrum beta-lactamase-producing Escherichia coli, Cambodia.
      ). A subsequent concern is that injudicious use of any of these classes of antibiotic will co-select for resistance genotypes against the others. If resistance rates among Enterobacteriaceae worsen, management of their associated infections will become increasingly dependent upon more expensive, and less readily available antibiotics.
      AMR rates in Cambodia appear to be in keeping with the limited number of reports of regional AMR rates. Surveillance of GLASS organisms in Thailand has shown high resistance rates among E. coli and K. pneumoniae to 3GC, and ciprofloxacin, with well-preserved sensitivity to meropenem and cefepime (
      • Sirijatuphat R.
      • Sripanidkulchai K.
      • Boonyasiri A.
      • Rattanaumpawan P.
      • Supapueng O.
      • Kiratisin P.
      • et al.
      Implementation of global antimicrobial resistance surveillance system (GLASS) in patients with bacteremia.
      ). A review of antibiotic susceptibilities in Africa and Asia also demonstrated high 3GC, co-trimoxazole, and gentamicin resistance among Asian E. coli and K. pneumoniae isolates (
      • Ashley E.A.
      • Lubell Y.
      • White N.J.
      • Turner P.
      Antimicrobial susceptibility of bacterial isolates from community acquired infections in Sub-Saharan Africa and Asian low and middle income countries.
      ). There are, however, some clear differences to elsewhere in the world. Increased ciprofloxacin resistance rates among Salmonella spp. are of particular concern, when compared to countries outside of Asia. A recent systematic review of antimicrobial resistance in Africa showed that 28 studies describing AST in S. Typhi had a median resistance to ciprofloxacin of 0% (
      • Tadesse B.T.
      • Ashley E.A.
      • Ongarello S.
      • Havumaki J.
      • Wijegoonewardena M.
      • Gonzalez I.J.
      • et al.
      Antimicrobial resistance in Africa: a systematic review.
      ). In contrast, our review shows high levels of fluoroquinolone resistance in S. Typhi in Cambodia, with a range of 88.0%–95.7%. This finding adds weight to the argument that the region is a “hotspot” for the development of AMR in enteric fever, particularly gyrA mediated fluoroquinolone resistance (
      • Vlieghe E.R.
      • Phe T.
      • De Smet B.
      • Veng C.H.
      • Kham C.
      • Bertrand S.
      • et al.
      Azithromycin and ciprofloxacin resistance in Salmonella bloodstream infections in Cambodian adults.
      ,
      • Wong V.K.
      • Baker S.
      • Pickard D.J.
      • Parkhill J.
      • Page A.J.
      • Feasey N.A.
      • et al.
      Phylogeographical analysis of the dominant multidrug-resistant H58 clade of Salmonella Typhi identifies inter- and intracontinental transmission events.
      ). Resistance to fluoroquinolones appears less prevalent among S. Paratyphi A isolates (11.5%–22.7%), however increasing rates of decreased-ciprofloxacin-sensitivity were reported in Phnom Penh throughout the recent outbreak (
      • Kuijpers L.M.F.
      • Phe T.
      • Veng C.H.
      • Lim K.
      • Ieng S.
      • Kham C.
      • et al.
      The clinical and microbiological characteristics of enteric fever in Cambodia, 2008-2015.
      ). Continuing use of ciprofloxacin as a first line treatment of uncomplicated enteric fever in Cambodia can reasonably be expected to lead to prolonged fever clearance times, treatment failures, and increased carriage rates of S. Typhi and S. Paratyphi A. Azithromycin may be considered an affordable and accessible alternative therapy for uncomplicated enteric fever, but AST reporting to this drug is not currently a GLASS requirement for Salmonella spp., a decision that may need to be revisited. Sensitivity to 3GC seems quite well preserved among Salmonella spp., and no resistance to carbapenems was reported in these papers. ESBL producing Salmonella spp. have been described in Cambodia (
      • Nadimpalli M.
      • Fabre L.
      • Yith V.
      • Sem N.
      • Gouali M.
      • Delarocque-Astagneau E.
      • et al.
      CTX-M-55-type ESBL-producing Salmonella enterica are emerging among retail meats in Phnom Penh, Cambodia.
      ,
      • Trongjit S.
      • Angkititrakul S.
      • Tuttle R.E.
      • Poungseree J.
      • Padungtod P.
      • Chuanchuen R.
      Prevalence and antimicrobial resistance in Salmonella enterica isolated from broiler chickens, pigs and meat products in Thailand-Cambodia border provinces.
      ), and the emergence of an extensively drug resistant dominant strain of S. Typhi or S. Paratyphi A, as recently seen in Pakistan (
      • Klemm E.J.
      • Shakoor S.
      • Page A.J.
      • Qamar F.N.
      • Judge K.
      • Saeed D.K.
      • et al.
      Emergence of an extensively drug-resistant Salmonella enterica serovar typhi clone harboring a promiscuous plasmid encoding resistance to fluoroquinolones and third-generation cephalosporins.
      ), could herald a regional disaster. Resistance to 3GC in Salmonella spp. should be monitored closely in the region.
      There are widely accepted differences in organisms and AMR patterns between hospital acquired infections (HAI) and community acquired infections (CAI) (
      • Cardoso T.
      • Almeida M.
      • Carratala J.
      • Aragao I.
      • Costa-Pereira A.
      • Sarmento A.E.
      • et al.
      Microbiology of healthcare-associated infections and the definition accuracy to predict infection by potentially drug resistant pathogens: a systematic review.
      ). One study from a paediatric hospital in Cambodia clearly demonstrated this difference, with higher rates of resistance seen amongst BSI isolates from HAI compared to those from CAI (
      • Fox-Lewis A.
      • Takata J.
      • Miliya T.
      • Lubell Y.
      • Soeng S.
      • Sar P.
      • et al.
      Antimicrobial resistance in invasive bacterial infections in hospitalized children, Cambodia, 2007-2016.
      ). In this study, rates of MRSA associated with HAI were 40.0% (n = 8/20), compared with 9.7% (n = 16/165) in those from CAI. Few other studies in this review clearly delineated between these different categories of infection, however this rate of MRSA associated with HAI correlates closely to the rate of MRSA from wound swabs in another paediatric inpatient population in Cambodia (52.5%, n = 52/99) (
      • Hout B.
      • Oum C.
      • Men P.
      • Vanny V.
      • Supaprom C.
      • Heang V.
      • et al.
      Drug resistance in bacteria isolated from patients presenting with wounds at a non-profit Surgical Center in Phnom Penh, Cambodia from 2011-2013.
      ). GLASS uses inpatient status as a proxy for hospital acquired infection, and while this is an imperfect method, inpatient and outpatient status was more widely reported, and this approach may provide at least some insight into the differences between HAI and CAI in Cambodia and elsewhere.
      Significant variation was observed in specific AST reported for each organism. Fluoroquinolone AST was reported universally for the Enterobacteriaceae, and the only papers that did not report co-trimoxazole AST, where indicated by GLASS, were non-human studies. On the other hand, both colistin and 4GC resistance rates were reported by only two of the twelve papers addressing E. coli, K. pneumoniae, or A. baumannii, and fewer than 50% (7/17) of papers reported carbapenem resistance, where indicated by GLASS. The fact that antimicrobial susceptibilities for colistin, 4GC, and carbapenems are under reported or not tested, may reflect the lack of availability of these drugs to clinicians. Nevertheless, they are considered “reserve” or “watch” antibiotics, and it is of great importance to know the resistance patterns of their target pathogens (
      • Sharland M.
      • Pulcini C.
      • Harbarth S.
      • Zeng M.
      • Gandra S.
      • Mathur S.
      • et al.
      Classifying antibiotics in the WHO essential medicines list for optimal use-be AWaRe.
      ).
      AMR in non-humans has been relatively neglected to date. Only four papers from this review addressed AMR in animals or meat products, and no studies were identified looking at environmental isolates. However, the fact that three of these were published within the last three years may represent the beginning of a shift towards a multi-sector approach to AMR research in Cambodia. Antibiotics, including colistin, are frequently used for prophylaxis and growth promotion in SE Asian agriculture (
      • Nhung N.T.
      • Cuong N.V.
      • Thwaites G.
      • Carrique-Mas J.
      Antimicrobial usage and antimicrobial resistance in animal production in Southeast Asia: a review.
      ). It is of concern that colistin resistance was found in 20% of porcine E. coli isolates from Phnom Penh (
      • Strom G.
      • Boqvist S.
      • Albihn A.
      • Fernstrom L.L.
      • Andersson Djurfeldt A.
      • Sokerya S.
      • et al.
      Antimicrobials in small-scale urban pig farming in a lower middle-income country-arbitrary use and high resistance levels.
      ). Genetic testing was not done in this study, but subsequent investigation has confirmed a link with the mcr-1 gene (
      • Strom Hallenberg G.
      • Borjesson S.
      • Sokerya S.
      • Sothyra T.
      • Magnusson U.
      Detection of mcr-mediated colistin resistance in Escherichia coli isolates from pigs in small-scale farms in Cambodia.
      ), and reflects similar regional rates of mcr-1 associated colistin resistance in food animals (
      • Nguyen N.T.
      • Nguyen H.M.
      • Nguyen C.V.
      • Nguyen T.V.
      • Nguyen M.T.
      • Thai H.Q.
      • et al.
      use of colistin and other critical antimicrobials on pig and chicken farms in Southern Vietnam and its association with resistance in commensal Escherichia coli bacteria.
      ). The mcr-1 gene has been reported in human isolates collected in Cambodia in as early as 2012 (
      • Stoesser N.
      • Mathers A.J.
      • Moore C.E.
      • Day N.P.
      • Crook D.W.
      Colistin resistance gene mcr-1 and pHNSHP45 plasmid in human isolates of Escherichia coli and Klebsiella pneumoniae.
      ) and has also been identified in Salmonella spp. and E. coli isolated from market food in Phnom Penh (
      • Nadimpalli M.
      • Fabre L.
      • Yith V.
      • Sem N.
      • Gouali M.
      • Delarocque-Astagneau E.
      • et al.
      CTX-M-55-type ESBL-producing Salmonella enterica are emerging among retail meats in Phnom Penh, Cambodia.
      ,
      • Nadimpalli M.
      • Vuthy Y.
      • de Lauzanne A.
      • Fabre L.
      • Criscuolo A.
      • Gouali M.
      • et al.
      Meat and fish as sources of extended-spectrum beta-lactamase-producing Escherichia coli, Cambodia.
      ). The transmission pathways have not yet been clarified, but the role of food and food animals in the human acquisition of mcr-1 carrying Enterobacteriaceae is believed to be significant, and raises fears for the future of one of our “last-resort” antibiotics (
      • Nhung N.T.
      • Cuong N.V.
      • Thwaites G.
      • Carrique-Mas J.
      Antimicrobial usage and antimicrobial resistance in animal production in Southeast Asia: a review.
      ).
      While providing a useful overview of AMR in Cambodia, this review had some limitations. Paper quality was not assessed, but clearly study methodology and presentation of AST data was highly variable. This has been noted elsewhere in previous similar reviews, and there are calls for better standardisation of AMR data presented in published manuscripts (
      • Ashley E.A.
      • Dance D.A.B.
      • Turner P.
      Grading antimicrobial susceptibility data quality: room for improvement.
      ). It should be hoped that, with the adoption of such tools as the Microbiology Investigation Criteria for Reporting Objectively (MICRO) checklist, high quality AMR data will be seen more consistently in future (
      • Turner P.
      • Fox-Lewis A.
      • Shrestha P.
      • Dance D.A.B.
      • Wangrangsimakul T.
      • Cusack T.P.
      • et al.
      Microbiology Investigation Criteria for Reporting Objectively (MICRO): a framework for the reporting and interpretation of clinical microbiology data.
      ). Some specific resistance mechanisms, including ESBL and methicillin resistance, may have been underrepresented, as several studies used laboratory methodology that selected for specific resistance phenotypes, and therefore had inappropriate denominators for inclusion. Other studies were also excluded as they presented only genotypic resistance data, without phenotypic description. The expansion of both clinical and research microbiological capacity in Cambodia will result in newer technologies being used, including whole genome sequencing, to determine and control AMR (
      • Koser C.U.
      • Ellington M.J.
      • Peacock S.J.
      Whole-genome sequencing to control antimicrobial resistance.
      ). Future reviews and surveillance should reflect these changes.
      Globally, important steps are being made to reduce further development and spread of AMR. Accurate reporting of AMR in clinical isolates from humans is one key step. In addition to harmonisation between national and global surveillance systems, efforts need to be made to standardise methodology data in published research outputs and embrace a broader One Health approach, including surveillance in plants and the environment. Capture of patient-level data will be critical to understand the impacts of AMR. In Cambodia, the fledgling national AMR surveillance systems for humans and food animals will contribute to the generation of multi-sectoral data, allowing a stronger One Health approach in tackling AMR. Furthermore, standardised microbiological and clinical data will be used by GLASS, and will inform public health policy at country, regional, and global levels.

      Conclusion

      Availability of AMR data for Cambodia is limited but improving. From the data published to date, the AMR rates for GLASS organisms appear to be similar to those of other countries in the region. High resistance rates are seen to many first-line antibiotics, especially among Enterobacteriaceae. The recently commenced national AMR surveillance systems in humans and food animals will bring together data from across the country, in a uniform manner, to improve clarity of the AMR situation in Cambodia.

      Member organisations of the Cambodia Technical Working Group on Antimicrobial Resistance

      Ministry of Health — Department of Communicable Diseases Control; Ministry of Health – Department of Health Services / Bureau of Medical Laboratory Services; Ministry of Health – Department of Drugs and Food; Ministry of Agriculture, Forestry and Fisheries; Angkor Hospital for Children; Battambang Provincial Hospital; Calmette Hospital; Kampong Cham Provincial Hospital; National Paediatric Hospital; Siem Reap Provincial Hospital; Sihanouk Hospital Center of Hope; Takeo Provincial Hospital; Royal University of Agriculture; University of Health Sciences; Cambodia Oxford Medical Research Unit; Diagnostic Microbiology Development Program; Fondation Merieux; Institut Pasteur du Cambodge; National Institute of Public Health / National Public Health Laboratory; United States Centers for Disease Control and Prevention; United States Naval Medical Research Unit-2; Food and Agriculture Organization; World Health Organization.

      CDC and FAO disclaimer

      The findings and conclusions of this report are those of the authors and do not necessarily represent the official positions of the Food and Agriculture Organization of the United Nations (FAO), or the Centers for Disease Control and Prevention (CDC).

      Conflict of interest statement

      No competing interest declared.

      Funding source

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Ethical approval

      Not required.

      Appendix A. Supplementary data

      The following is Supplementary data to this article:

      References

        • Ashley E.A.
        • Dance D.A.B.
        • Turner P.
        Grading antimicrobial susceptibility data quality: room for improvement.
        Lancet Infect Dis. 2018; 18: 603-604
        • Ashley E.A.
        • Lubell Y.
        • White N.J.
        • Turner P.
        Antimicrobial susceptibility of bacterial isolates from community acquired infections in Sub-Saharan Africa and Asian low and middle income countries.
        Trop Med Int Health. 2011; 16: 1167-1179
        • Augustin A.
        • Shahum A.
        • Taziar M.
        • Benca J.
        • Koleno B.
        • Bukovino P.
        • et al.
        Resistance in uropathogens among HIV-positive Kenyan and Cambodian children in comparison to an HIV-negative population in south Sudan.
        Chemotherapy. 2007; 53: 383-384
        • Cardoso T.
        • Almeida M.
        • Carratala J.
        • Aragao I.
        • Costa-Pereira A.
        • Sarmento A.E.
        • et al.
        Microbiology of healthcare-associated infections and the definition accuracy to predict infection by potentially drug resistant pathogens: a systematic review.
        BMC Infect Dis. 2015; 15: 565
        • Caron Y.
        • Chheang R.
        • Puthea N.
        • Soda M.
        • Boyer S.
        • Tarantola A.
        • et al.
        Beta-lactam resistance among Enterobacteriaceae in Cambodia: the four-year itch.
        Int J Infect Dis. 2018; 66: 74-79
        • Chereau F.
        • Opatowski L.
        • Tourdjman M.
        • Vong S.
        Risk assessment for antibiotic resistance in South East Asia.
        BMJ. 2017; 358: j3393
        • Chheng K.
        • Carter M.J.
        • Emary K.
        • Chanpheaktra N.
        • Moore C.E.
        • Stoesser N.
        • et al.
        A prospective study of the causes of febrile illness requiring hospitalization in children in Cambodia.
        PLoS One. 2013; 8e60634
        • Dat V.Q.
        • Vu H.N.
        • Nguyen The H.
        • Nguyen H.T.
        • Hoang L.B.
        • Vu Tien Viet D.
        • et al.
        Bacterial bloodstream infections in a tertiary infectious diseases hospital in Northern Vietnam: aetiology, drug resistance, and treatment outcome.
        BMC Infect Dis. 2017; 17: 493
        • Emary K.
        • Moore C.E.
        • Chanpheaktra N.
        • An K.P.
        • Chheng K.
        • Sona S.
        • et al.
        Enteric fever in Cambodian children is dominated by multidrug-resistant H58 Salmonella enterica serovar typhi with intermediate susceptibility to ciprofloxacin.
        Trans R Soc Trop Med Hyg. 2012; 106: 718-724
        • Fox-Lewis A.
        • Takata J.
        • Miliya T.
        • Lubell Y.
        • Soeng S.
        • Sar P.
        • et al.
        Antimicrobial resistance in invasive bacterial infections in hospitalized children, Cambodia, 2007-2016.
        Emerg Infect Dis. 2018; 24: 841-851
        • GBD Diarrhoeal Diseases Collaborators
        Estimates of global, regional, and national morbidity, mortality, and aetiologies of diarrhoeal diseases: a systematic analysis for the Global Burden of Disease Study 2015.
        Lancet Infect Dis. 2017; 17: 909-948
        • Hout B.
        • Oum C.
        • Men P.
        • Vanny V.
        • Supaprom C.
        • Heang V.
        • et al.
        Drug resistance in bacteria isolated from patients presenting with wounds at a non-profit Surgical Center in Phnom Penh, Cambodia from 2011-2013.
        Trop Dis Travel Med Vaccines. 2015; 1: 4
        • Inghammar M.
        • By Y.
        • Farris C.
        • Phe T.
        • Borand L.
        • Kerleguer A.
        • et al.
        Serotype distribution of clinical Streptococcus pneumoniae isolates before the introduction of the 13-valent pneumococcal conjugate vaccine in Cambodia.
        Am J Trop Med Hyg. 2018; 98: 791-796
        • Kasper M.R.
        • Sokhal B.
        • Blair P.J.
        • Wierzba T.F.
        • Putnam S.D.
        Emergence of multidrug-resistant Salmonella enterica serovar Typhi with reduced susceptibility to fluoroquinolones in Cambodia.
        Diagn Microbiol Infect Dis. 2010; 66: 207-209
        • Khauv P.
        • Turner P.
        • Soeng C.
        • Soeng S.
        • Moore C.E.
        • Bousfield R.
        • et al.
        Ophthalmic infections in children presenting to Angkor Hospital for Children, Siem Reap, Cambodia.
        BMC Res Notes. 2014; 7: 784
        • Klemm E.J.
        • Shakoor S.
        • Page A.J.
        • Qamar F.N.
        • Judge K.
        • Saeed D.K.
        • et al.
        Emergence of an extensively drug-resistant Salmonella enterica serovar typhi clone harboring a promiscuous plasmid encoding resistance to fluoroquinolones and third-generation cephalosporins.
        mBio. 2018; 9
        • Koser C.U.
        • Ellington M.J.
        • Peacock S.J.
        Whole-genome sequencing to control antimicrobial resistance.
        Trends Genet. 2014; 30: 401-407
        • Kotloff K.L.
        • Riddle M.S.
        • Platts-Mills J.A.
        • Pavlinac P.
        • Zaidi A.K.M.
        Shigellosis.
        Lancet. 2018; 391: 801-812
        • Kuijpers L.M.F.
        • Phe T.
        • Veng C.H.
        • Lim K.
        • Ieng S.
        • Kham C.
        • et al.
        The clinical and microbiological characteristics of enteric fever in Cambodia, 2008-2015.
        PLoS Negl Trop Dis. 2017; 11e0005964
        • Lay K.S.
        • Vuthy Y.
        • Song P.
        • Phol K.
        • Sarthou J.L.
        Prevalence, numbers and antimicrobial susceptibilities of Salmonella serovars and Campylobacter spp. in retail poultry in Phnom Penh, Cambodia.
        J Vet Med Sci. 2011; 73: 325-329
        • Lim C.
        • Takahashi E.
        • Hongsuwan M.
        • Wuthiekanun V.
        • Thamlikitkul V.
        • Hinjoy S.
        • et al.
        Epidemiology and burden of multidrug-resistant bacterial infection in a developing country.
        eLife. 2016; 5
        • Meng C.Y.
        • Smith B.L.
        • Bodhidatta L.
        • Richard S.A.
        • Vansith K.
        • Thy B.
        • et al.
        Etiology of diarrhea in young children and patterns of antibiotic resistance in Cambodia.
        Pediatr Infect Dis J. 2011; 30: 331-335
        • Ministry of Health - Cambodia
        National policy to combat antimicrobial resistance.
        2014
        • Moore C.E.
        • Giess A.
        • Soeng S.
        • Sar P.
        • Kumar V.
        • Nhoung P.
        • et al.
        Characterisation of invasive Streptococcus pneumoniae isolated from Cambodian children between 2007-2012.
        PLoS One. 2016; 11e0159358
        • Moore C.E.
        • Sona S.
        • Poda S.
        • Putchhat H.
        • Kumar V.
        • Sopheary S.
        • et al.
        Antimicrobial susceptibility of uropathogens isolated from Cambodian children.
        Paediatr Int Child Health. 2016; 36: 113-117
        • Nadimpalli M.
        • Fabre L.
        • Yith V.
        • Sem N.
        • Gouali M.
        • Delarocque-Astagneau E.
        • et al.
        CTX-M-55-type ESBL-producing Salmonella enterica are emerging among retail meats in Phnom Penh, Cambodia.
        J Antimicrob Chemother. 2019; 74: 342-348
        • Nadimpalli M.
        • Vuthy Y.
        • de Lauzanne A.
        • Fabre L.
        • Criscuolo A.
        • Gouali M.
        • et al.
        Meat and fish as sources of extended-spectrum beta-lactamase-producing Escherichia coli, Cambodia.
        Emerg Infect Dis. 2019; 25
        • Nguyen N.T.
        • Nguyen H.M.
        • Nguyen C.V.
        • Nguyen T.V.
        • Nguyen M.T.
        • Thai H.Q.
        • et al.
        use of colistin and other critical antimicrobials on pig and chicken farms in Southern Vietnam and its association with resistance in commensal Escherichia coli bacteria.
        Appl Environ Microbiol. 2016; 82: 3727-3735
        • Nhung N.T.
        • Cuong N.V.
        • Thwaites G.
        • Carrique-Mas J.
        Antimicrobial usage and antimicrobial resistance in animal production in Southeast Asia: a review.
        Antibiotics (Basel). 2016; 5
        • Phe T.
        • Vlieghe E.
        • Reid T.
        • Harries A.D.
        • Lim K.
        • Thai S.
        • et al.
        Does HIV status affect the aetiology, bacterial resistance patterns and recommended empiric antibiotic treatment in adult patients with bloodstream infection in Cambodia?.
        Trop Med Int Health. 2013; 18: 485-494
        • Ramirez M.S.
        • Tolmasky M.E.
        Amikacin: uses, resistance, and prospects for inhibition.
        Molecules. 2017; 22
        • Rammaert B.
        • Goyet S.
        • Beaute J.
        • Hem S.
        • Te V.
        • Try P.L.
        • et al.
        Klebsiella pneumoniae related community-acquired acute lower respiratory infections in Cambodia: clinical characteristics and treatment.
        BMC Infect Dis. 2012; 12: 3
        • Robinson T.P.
        • Bu D.P.
        • Carrique-Mas J.
        • Fevre E.M.
        • Gilbert M.
        • Grace D.
        • et al.
        Antibiotic resistance is the quintessential One Health issue.
        Trans R Soc Trop Med Hyg. 2016; 110: 377-380
        • Ruppe E.
        • Hem S.
        • Lath S.
        • Gautier V.
        • Ariey F.
        • Sarthou J.L.
        • et al.
        CTX-M beta-lactamases in Escherichia coli from community-acquired urinary tract infections, Cambodia.
        Emerg Infect Dis. 2009; 15: 741-748
        • Sharland M.
        • Pulcini C.
        • Harbarth S.
        • Zeng M.
        • Gandra S.
        • Mathur S.
        • et al.
        Classifying antibiotics in the WHO essential medicines list for optimal use-be AWaRe.
        Lancet Infect Dis. 2018; 18: 18-20
        • Sirijatuphat R.
        • Sripanidkulchai K.
        • Boonyasiri A.
        • Rattanaumpawan P.
        • Supapueng O.
        • Kiratisin P.
        • et al.
        Implementation of global antimicrobial resistance surveillance system (GLASS) in patients with bacteremia.
        PLoS One. 2018; 13e0190132
        • Srun S.
        • Sinath Y.
        • Seng A.T.
        • Chea M.
        • Borin M.
        • Nhem S.
        • et al.
        Surveillance of post-caesarean surgical site infections in a hospital with limited resources, Cambodia.
        J Infect Dev Ctries. 2013; 7: 579-585
        • Stoesser N.
        • Emary K.
        • Soklin S.
        • Peng An K.
        • Sophal S.
        • Chhomrath S.
        • et al.
        The value of intermittent point-prevalence surveys of healthcare-associated infections for evaluating infection control interventions at Angkor Hospital for Children, Siem Reap, Cambodia.
        Trans R Soc Trop Med Hyg. 2013; 107: 248-253
        • Stoesser N.
        • Mathers A.J.
        • Moore C.E.
        • Day N.P.
        • Crook D.W.
        Colistin resistance gene mcr-1 and pHNSHP45 plasmid in human isolates of Escherichia coli and Klebsiella pneumoniae.
        Lancet Infect Dis. 2016; 16: 285-286
        • Stoesser N.
        • Moore C.E.
        • Pocock J.M.
        • An K.P.
        • Emary K.
        • Carter M.
        • et al.
        Pediatric bloodstream infections in Cambodia, 2007 to 2011.
        Pediatr Infect Dis J. 2013; 32: e272-6
        • Stoesser N.
        • Pocock J.
        • Moore C.E.
        • Soeng S.
        • Hor P.
        • Sar P.
        • et al.
        The epidemiology of pediatric bone and joint infections in Cambodia, 2007-11.
        J Trop Pediatr. 2013; 59: 36-42
        • Strom G.
        • Boqvist S.
        • Albihn A.
        • Fernstrom L.L.
        • Andersson Djurfeldt A.
        • Sokerya S.
        • et al.
        Antimicrobials in small-scale urban pig farming in a lower middle-income country-arbitrary use and high resistance levels.
        Antimicrob Resist Infect Control. 2018; 7: 35
        • Strom Hallenberg G.
        • Borjesson S.
        • Sokerya S.
        • Sothyra T.
        • Magnusson U.
        Detection of mcr-mediated colistin resistance in Escherichia coli isolates from pigs in small-scale farms in Cambodia.
        Antimicrob Agents Chemother. 2019; 63: e02241-18
        • Tadesse B.T.
        • Ashley E.A.
        • Ongarello S.
        • Havumaki J.
        • Wijegoonewardena M.
        • Gonzalez I.J.
        • et al.
        Antimicrobial resistance in Africa: a systematic review.
        BMC Infect Dis. 2017; 17: 616
        • Trongjit S.
        • Angkititrakul S.
        • Tuttle R.E.
        • Poungseree J.
        • Padungtod P.
        • Chuanchuen R.
        Prevalence and antimicrobial resistance in Salmonella enterica isolated from broiler chickens, pigs and meat products in Thailand-Cambodia border provinces.
        Microbiol Immunol. 2017; 61: 23-33
        • Trongjit S.
        • Angkittitrakul S.
        • Chuanchuen R.
        Occurrence and molecular characteristics of antimicrobial resistance of Escherichia coli from broilers, pigs and meat products in Thailand and Cambodia provinces.
        Microbiol Immunol. 2016; 60: 575-585
        • Turner P.
        • Fox-Lewis A.
        • Shrestha P.
        • Dance D.A.B.
        • Wangrangsimakul T.
        • Cusack T.P.
        • et al.
        Microbiology Investigation Criteria for Reporting Objectively (MICRO): a framework for the reporting and interpretation of clinical microbiology data.
        BMC Med. 2019; 17: 70
        • Turner P.
        • Turner C.
        • Suy K.
        • Soeng S.
        • Ly S.
        • Miliya T.
        • et al.
        Pneumococcal infection among children before introduction of 13-valent pneumococcal conjugate vaccine, Cambodia.
        Emerg Infect Dis. 2015; 21: 2080-2083
        • Unemo M.
        • Del Rio C.
        • Shafer W.M.
        Antimicrobial resistance expressed by Neisseria gonorrhoeae: a major global public health problem in the 21st century.
        Microbiol Spectr. 2016; 4
        • Vernel-Pauillac F.
        • Ratsima E.H.
        • Guillard B.
        • Goursaud R.
        • Lethezer C.
        • Hem S.
        • et al.
        Correlation between antibiotic susceptibilities and genotypes in Neisseria gonorrhoeae from different geographical origins: determinants monitoring by real-time PCR as a complementary tool for surveillance.
        Sex Transm Infect. 2010; 86: 106-111
        • Vlieghe E.R.
        • Huang T.D.
        • Phe T.
        • Bogaerts P.
        • Berhin C.
        • De Smet B.
        • et al.
        Prevalence and distribution of beta-lactamase coding genes in third-generation cephalosporin-resistant Enterobacteriaceae from bloodstream infections in Cambodia.
        Eur J Clin Microbiol Infect Dis. 2015; 34: 1223-1229
        • Vlieghe E.R.
        • Phe T.
        • De Smet B.
        • Veng C.H.
        • Kham C.
        • Bertrand S.
        • et al.
        Azithromycin and ciprofloxacin resistance in Salmonella bloodstream infections in Cambodian adults.
        PLoS neglected tropical diseases. 2012; 6: e1933
        • Vlieghe E.R.
        • Phe T.
        • De Smet B.
        • Veng C.H.
        • Kham C.
        • Sar D.
        • et al.
        Increase in Salmonella enterica serovar paratyphi A infections in Phnom Penh, Cambodia, January 2011 to August 2013.
        Euro Surveill. 2013; 18
        • Vlieghe E.R.
        • Phe T.
        • De Smet B.
        • Veng H.C.
        • Kham C.
        • Lim K.
        • et al.
        Bloodstream infection among adults in Phnom Penh, Cambodia: key pathogens and resistance patterns.
        PLoS One. 2013; 8e59775
        • Vlieghe E.R.
        • Sary S.
        • Lim K.
        • Sivuthy C.
        • Phe T.
        • Parry C.
        • et al.
        First national workshop on antibiotic resistance in Cambodia: Phnom Penh, Cambodia, 16-18 November 2011.
        J Glob Antimicrob Resist. 2013; 1: 31-34
        • WHO
        Global report on surveillance: antimicrobial resistance.
        2014
        • WHO
        Manual for early implementation: global antimicrobial resistance surveillance system.
        2015
        • WHO
        Worldwide country situation analysis: response to antimicrobial resistance.
        2015
        • Wijedoru L.P.
        • Kumar V.
        • Chanpheaktra N.
        • Chheng K.
        • Smits H.L.
        • Pastoor R.
        • et al.
        Typhoid fever among hospitalized febrile children in Siem Reap, Cambodia.
        J Trop Pediatr. 2012; 58: 68-70
        • Wong V.K.
        • Baker S.
        • Pickard D.J.
        • Parkhill J.
        • Page A.J.
        • Feasey N.A.
        • et al.
        Phylogeographical analysis of the dominant multidrug-resistant H58 clade of Salmonella Typhi identifies inter- and intracontinental transmission events.
        Nat Genet. 2015; 47: 632-639
        • Zellweger R.M.
        • Carrique-Mas J.
        • Limmathurotsakul D.
        • Day N.P.J.
        • Thwaites G.E.
        • Baker S.
        • et al.
        A current perspective on antimicrobial resistance in Southeast Asia.
        J Antimicrob Chemother. 2017; 72: 2963-2972