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Non-typhoidal Salmonella (NTS) is a major cause of bacterial enterocolitis globally but also causes invasive bloodstream infections. Antimicrobial resistance (AMR) hampers the treatment of these infections and understanding how AMR spreads between NTS may help in developing effective strategies. We investigated NTS isolates associated with invasive disease, diarrhoeal disease and asymptomatic carriage in animals and humans from Vietnam. Isolates included multiple serovars and both common and rare phenotypic AMR profiles; long- and short-read sequencing was used to investigate the genetic mechanisms and genomic backgrounds associated with phenotypic AMR profiles. We demonstrate concordance between most AMR genotypes and phenotypes but identified large genotypic diversity in clinically relevant phenotypes and the high mobility potential of AMR genes (ARGs) in this setting. We found that 84 % of ARGs identified were located on plasmids, most commonly those containing IncHI1A_1 and IncHI1B(R27)_1_R27 replicons (33%), and those containing IncHI2_1 and IncHI2A_1 replicons (31%). The vast majority (95%) of ARGS were found within 10 kbp of IS6/IS26 elements, which provide plasmids with a mechanism to exchange ARGs between plasmids and other parts of the genome. Whole genome sequencing with targeted long-read sequencing applied in a One Health context identified a comparatively limited number of insertion sequences and plasmid replicons associated with AMR. Therefore, in the context of NTS from Vietnam and likely for other settings as well, the mechanisms by which ARGs move contribute to a more successful AMR profile than the specific ARGs, facilitating the adaptation of bacteria to different environments or selection pressures.

Despite the sporadic detection of fluoroquinolone-resistant Shigella in Asia in the early 2000s and the subsequent global spread of ciprofloxacin-resistant (cipR) Shigella sonnei from 2010, fluoroquinolones remain the recommended therapy for shigellosis1-7. The potential for cipR S. sonnei to develop resistance to alternative second-line drugs may further limit future treatment options8. Here, we aim to understand the evolution of novel antimicrobial resistant (AMR) S. sonnei variants after introduction into Vietnam. We found that cipR S. sonnei displaced the resident ciprofloxacin-susceptible (cipS) lineage while rapidly acquiring additional resistance to multiple alternative antimicrobial classes. We identified several independent acquisitions of extensively drug-resistant/multidrug-resistant-inducing plasmids, probably facilitated by horizontal transfer from commensals in the human gut. By characterizing commensal Escherichia coli from Shigella-infected and healthy children, we identified an extensive array of AMR genes and plasmids, including an identical multidrug-resistant plasmid isolated from both S. sonnei and E. coli in the gut of a single child. We additionally found that antimicrobial usage may impact plasmid transfer between commensal E. coli and S. sonnei. These results suggest that, in a setting with high antimicrobial use and a high prevalence of AMR commensals, cipR S. sonnei may be propelled towards pan-resistance by adherence to outdated international treatment guidelines.

Nontyphoidal Salmonella (NTS) are among the most common etiological agents of diarrheal diseases worldwide and have become the most commonly detected bacterial pathogen in children hospitalized with diarrhea in Vietnam. Aiming to better understand the epidemiology, serovar distribution, antimicrobial resistance (AMR), and clinical manifestation of NTS gastroenteritis in Vietnam, we conducted a clinical genomics investigation of NTS isolated from diarrheal children admitted to one of three tertiary hospitals in Ho Chi Minh City., Nontyphoidal Salmonella (NTS) are among the most common etiological agents of diarrheal diseases worldwide and have become the most commonly detected bacterial pathogen in children hospitalized with diarrhea in Vietnam. Aiming to better understand the epidemiology, serovar distribution, antimicrobial resistance (AMR), and clinical manifestation of NTS gastroenteritis in Vietnam, we conducted a clinical genomics investigation of NTS isolated from diarrheal children admitted to one of three tertiary hospitals in Ho Chi Minh City. Between May 2014 and April 2016, 3,166 children hospitalized with dysentery were recruited into the study; 478 (∼15%) children were found to be infected with NTS by stool culture. Molecular serotyping of the 450 generated genomes identified a diverse collection of serogroups (B, C1, C2 to C3, D1, E1, G, I, K, N, O, and Q); however, Salmonella enterica serovar Typhimurium was the most predominant serovar, accounting for 41.8% (188/450) of NTS isolates. We observed a high prevalence of AMR to first-line treatments recommended by WHO, and more than half (53.8%; 242/450) of NTS isolates were multidrug resistant (MDR; resistant to ≥3 antimicrobial classes). AMR gene detection positively correlated with phenotypic AMR testing, and resistance to empirical antimicrobials was associated with a significantly longer hospitalization (0.91 days; P = 0.04). Our work shows that genome sequencing is a powerful epidemiological tool to characterize the serovar diversity and AMR profiles in NTS. We propose a revaluation of empirical antimicrobials for dysenteric diarrhea and endorse the use of whole-genome sequencing for sustained surveillance of NTS internationally.

Non-typhoidal Salmonella (NTS) serovars, sequences types and antimicrobial susceptibility profiles have specific associations with animal and human infections in Vietnam. Antimicrobial resistance may have an effect on the manifestation of human NTS infections, with isolates from asymptomatic individuals being more susceptible to antimicrobials than those associated with animals and human diarrhoea.

Background Nontyphoidal Salmonella (NTS) are associated with both diarrhea and bacteremia. Antimicrobial resistance (AMR) is common in NTS in low-middle income countries, but the major source(s) of AMR NTS in humans are not known. Here, we aimed to assess the role of animals as a source of AMR in human NTS infections in Vietnam. We retrospectively combined and analyzed 672 NTS human and animal isolates from four studies in southern Vietnam and compared serovars, sequence types (ST), and AMR profiles. We generated a population structure of circulating organisms and aimed to attribute sources of AMR in NTS causing invasive and noninvasive disease in humans using Bayesian multinomial mixture models. Results Among 672 NTS isolates, 148 (22%) originated from human blood, 211 (31%) from human stool, and 313 (47%) from animal stool. The distribution of serovars, STs, and AMR profiles differed among sources; serovars Enteritidis, Typhimurium, and Weltevreden were the most common in human blood, human stool, and animals, respectively. We identified an association between the source of NTS and AMR profile; the majority of AMR isolates were isolated from human blood (p, Highlights • The major source(s) of antimicrobial resistance (AMR) in nontyphoidal Salmonella (NTS) are unknown. • We analyzed 672 NTS isolates, 148 (41%) from human blood, 211 (59%) from human stool, and 136 (43%) from animal stool. • Enteritidis, Typhimurium, and Weltevreden were the common serovars in human blood, human stool, and animals, respectively. • The majority of AMR isolates were associated with human blood. • NTS from animals does explain the full extent of AMR in human NTS infections.

Purpose. Antimicrobial-resistant bacterial infections in low- and middle-income countries (LMICs) are a well-established global health issue. We aimed to assess the prevalence of and epidemiological factors associated with the carriage of ciprofloxacin- and ceftriaxone-resistant Escherichia coli and associated resistance genes in a cohort of 498 healthy children residing in urban Vietnam. Methodology. We cultured rectal swabs onto MacConkey agar supplemented with resistant concentrations of ciprofloxacin and ceftriaxone. Additionally, we screened meta-E. coli populations by conventional PCR to detect plasmid-mediated quinolone resistance (PMQR)- and extended-spectrum β-lactamase (ESBL)-encoding genes. We measured the associations between phenotypic/genotypic resistance and demographic characteristics using logistic regression. Results/key findings. Ciprofloxacin- and ceftriaxone-resistant E. coli were cultured from the faecal samples of 67.7 % (337/498) and 80.3 % (400/498) of children, respectively. The prevalence of any associated resistance marker in the individual samples was 86.7 % (432/498) for PMQR genes and 90.6 % (451/498) for β-lactamase genes. Overweight children were significantly more likely to carry qnr genes than children with lower weight-for-height z-scores [odds ratios (OR): 1.24; 95 % confidence interval (CI): 10.5–1.48 for each unit increase in weight for height; P=0.01]. Additionally, younger children were significantly more likely to carry ESBL CTX-M genes than older children (OR: 0.97, 95 % CI: 0.94–0.99 for each additional year, P=0.01). Conclusion. The carriage of genotypic and phenotypic antimicrobial resistance is highly prevalent among E. coli in healthy children in the community in Vietnam. Future investigations on the carriage of antimicrobial resistant organisms in LMICs should focus on the progression of carriage from birth and structure of the microbiome in obesity.

Nontyphoidal Salmonella (NTS), particularly Salmonella enterica serovar Typhimurium, is among the leading etiologic agents of bacterial enterocolitis globally and a well-characterized cause of invasive disease (iNTS) in sub-Saharan Africa. In contrast, S. Typhimurium is poorly defined in Southeast Asia, a known hot spot for zoonotic disease with a recently described burden of iNTS disease. Here, we aimed to add insight into the epidemiology and potential impact of zoonotic transfer and antimicrobial resistance (AMR) in S. Typhimurium associated with iNTS and enterocolitis in Vietnam. We performed whole-genome sequencing and phylogenetic reconstruction on 85 human (enterocolitis, carriage, and iNTS) and 113 animal S. Typhimurium isolates isolated in Vietnam. We found limited evidence for the zoonotic transmission of S. Typhimurium. However, we describe a chain of events where a pandemic monophasic variant of S. Typhimurium (serovar I:4,[5],12:i:− sequence type 34 [ST34]) has been introduced into Vietnam, reacquired a phase 2 flagellum, and acquired an IncHI2 multidrug-resistant plasmid. Notably, these novel biphasic ST34 S. Typhimurium variants were significantly associated with iNTS in Vietnamese HIV-infected patients. Our study represents the first characterization of novel iNTS organisms isolated outside sub-Saharan Africa and outlines a new pathway for the emergence of alternative Salmonella variants into susceptible human populations. IMPORTANCE Salmonella Typhimurium is a major diarrheal pathogen and associated with invasive nontyphoid Salmonella (iNTS) disease in vulnerable populations. We present the first characterization of iNTS organisms in Southeast Asia and describe a different evolutionary trajectory from that of organisms causing iNTS in sub-Saharan Africa. In Vietnam, the globally distributed monophasic variant of Salmonella Typhimurium, the serovar I:4,[5],12:i:− ST34 clone, has reacquired a phase 2 flagellum and gained a multidrug-resistant plasmid to become associated with iNTS disease in HIV-infected patients. We document distinct communities of S. Typhimurium and I:4,[5],12:i:− in animals and humans in Vietnam, despite the greater mixing of these host populations here. These data highlight the importance of whole-genome sequencing surveillance in a One Health context in understanding the evolution and spread of resistant bacterial infections.

Background Broad-spectrum antimicrobials are commonly used as empirical therapy for infections of presumed bacterial origin. Increasing resistance to these antimicrobial agents has prompted the need for alternative therapies and more effective surveillance. Better surveillance leads to more informed and improved delivery of therapeutic interventions, potentially leading to better treatment outcomes. Methods We screened 1017 Gram negative bacteria (excluding Pseudomonas spp. and Acinetobacter spp.) isolated between 2011 and 2013 from positive blood cultures for susceptibility against third generation cephalosporins, ESBL and/or AmpC production, and associated ESBL/AmpC genes, at the Hospital for Tropical Diseases in Ho Chi Minh City. Results Phenotypic screening found that 304/1017 (30%) organisms were resistance to third generation cephalosporins; 172/1017 (16.9%) of isolates exhibited ESBL activity, 6.2% (63/1017) had AmpC activity, and 0.5% (5/1017) had both ESBL and AmpC activity. E. coli and Aeromonas spp. were the most common organisms associated with ESBL and AmpC phenotypes, respectively. Nearly half of the AmpC producers harboured an ESBL gene. There was no significant difference (p > 0.05) between the antimicrobial resistance phenotypes of the organisms associated with community and hospital-acquired infections. Conclusion AmpC and ESBL producing organisms were commonly associated with bloodstream infections in this setting, with antimicrobial resistant organisms being equally distributed between infections originating from the community and healthcare settings. Aeromonas spp., which was associated with bloodstream infections in cirrhotic/hepatitis patients, were the most abundant AmpC producing organism. We conclude that empirical monotherapy with third generation cephalosporins may not be optimum in this setting. Electronic supplementary material The online version of this article (10.1186/s13756-017-0265-1) contains supplementary material, which is available to authorized users.

We identified high antimicrobial usage and high antimicrobial resistance in children hospitalized with bloody and/or mucoid bacteria-associated diarrhea. There was no clinical benefit of antimicrobial therapy in children with diarrhea; adequately powered randomized controlled trials are required., Background Pediatric diarrheal disease presents a major public health burden in low- to middle-income countries. The clinical benefits of empirical antimicrobial treatment for diarrhea are unclear in settings that lack reliable diagnostics and have high antimicrobial resistance (AMR). Methods We conducted a prospective multicenter cross-sectional study of pediatric patients hospitalized with diarrhea containing blood and/or mucus in Ho Chi Minh City, Vietnam. Clinical parameters, including disease outcome and treatment, were measured. Shigella, nontyphoidal Salmonella (NTS), and Campylobacter were isolated from fecal samples, and their antimicrobial susceptibility profiles were determined. Statistical analyses, comprising log-rank tests and accelerated failure time models, were performed to assess the effect of antimicrobials on disease outcome. Results Among 3166 recruited participants (median age 10 months; interquartile range, 6.5–16.7 months), one-third (1096 of 3166) had bloody diarrhea, and 25% (793 of 3166) were culture positive for Shigella, NTS, or Campylobacter. More than 85% of patients (2697 of 3166) were treated with antimicrobials; fluoroquinolones were the most commonly administered antimicrobials. AMR was highly prevalent among the isolated bacteria, including resistance against fluoroquinolones and third-generation cephalosporins. Antimicrobial treatment and multidrug resistance status of the infecting pathogens were found to have no significant effect on outcome. Antimicrobial treatment was significantly associated with an increase in the duration of hospitalization with particular groups of diarrheal diseases. Conclusions In a setting with high antimicrobial usage and high AMR, our results imply a lack of clinical benefit for treating diarrhea with antimicrobials; adequately powered randomized controlled trials are required to assess the role of antimicrobials for diarrhea.