No Clinical Benefit of Empirical Antimicrobial Therapy for Pediatric Diarrhea in a High-Usage, High-Resistance Setting

Duong, Vu Thuy; Tuyen, Ha Thanh; Minh, Pham Van; Campbell, James I.; Phuc, Hoang Le; Nhu, Tran Do Hoang; Tu, Le Thi Phuong; Chau, Tran Thi Hong; Nhi, Le Thi Quynh; Hưng, Nguyễn Thành; Ngọc, Nguyễn Minh; Hương, Nguyễn Thị; Lan, Lu; Thompson, Corinne N.; Thwaites, Guy; Alwis, Ruklanthi de; Baker, Stephen

doi:10.1093/cid/cix844

Cited by 37 publications

(55 citation statements)

References 28 publications

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“…In the clinical study in which the S. sonnei described here were isolated, the majority of S. sonnei infected children (85%, 67/79) were treated empirically with ciprofloxacin. We found that the clinical outcomes (duration of hospitalization) between children infected with cipR (51 cases) versus cipS S. sonnei (16 cases) were comparable (median 4 days (IQR: 3-6.5 days) versus 3 days (IQR: 2-4)) 79 . Additionally, four cases (three infected with cipR S. sonnei ) did not receive antimicrobial treatment but still recovered in a similar time period.…”

Section: Discussionmentioning

confidence: 84%

“…The S. sonnei used in this study were isolated during a 2-year observational study conducted at three tertiary hospitals (Children’s Hospital 1, Children’s Hospital 2, and the Hospital for Tropical Diseases) in HCMC, Vietnam, between May 2014 and April 2016, as previously described (Supplementary Table 1) 23 . In brief, children aged <16 years admitted to one of the three study hospitals with diarrhea (defined as ≥3 passages of loose stools within 24 hours) and >1 loose stool containing blood and/or mucus were recruited.…”

Section: Methodsmentioning

confidence: 99%

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Ciprofloxacin facilitates the transfer of XDR plasmids from commensalE. coliinto epidemic fluoroquinolone-resistantShigella sonnei

Pham

Nguyen

Duong

et al. 2019

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The global dissemination of a ciprofloxacin-resistant (cipR) S. sonnei clone outlines the mobility of this important agent of diarrheal disease, and threatens the utility of ciprofloxacin as a first-line antimicrobial for shigellosis. Here, we aimed to track the emergence of cipR S. sonnei in Vietnam to understand how novel antimicrobial resistant (AMR) Shigella clones become established in new locations. From 2014 to 2016, we isolated and genome sequenced 79 S. sonnei from children hospitalized with dysenteric diarrhea in southern Vietnam. The novel cipR S. sonnei clone displaced the resident ciprofloxacin-susceptible lineage while acquiring resistance against third-generation cephalosporins, macrolides, and aminoglycosides. This process was not the result of a single clonal expansion, as we identified at least thirteen independent acquisitions of ESBL-encoding plasmids. The frequency and diversity of the variable AMR repertoire in an expanding clonal background of S. sonnei is unprecedented and we speculated that it was facilitated by horizontal gene transfer from commensal organisms in the human gut. Consequently, we characterized non-Shigella Enterobacteriaceae from Shigella-infected and healthy children by shotgun metagenomics. We identified a wide array of AMR genes and plasmids in the commensal Enterobacteriaceae, including an E. coli isolated from a Shigella-infected child with an identical ESBL plasmid to that characterized in the infecting S. sonnei. We confirmed that these AMR plasmids could be exchanged between commensal E. coli and S. sonnei and found that supplementation of ciprofloxacin into the conjugation media significantly increased the conjugation frequency of IncI/blaCTX-M-15, IncB/O/blaCTX-M-27 and IncF/blaCTX-M-27 plasmids. 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. Our work highlights the role of the gut microbiota in transferring resistance plasmids into enteric pathogens and provides essential data to restrict the use of ciprofloxacin globally.

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Section: Discussionmentioning

confidence: 84%

Section: Methodsmentioning

confidence: 99%

Ciprofloxacin facilitates the transfer of XDR plasmids from commensalE. coliinto epidemic fluoroquinolone-resistantShigella sonnei

Pham

Nguyen

Duong

et al. 2019

Preprint

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“…Those with diarrhoeal illness (cases) were de ned as ≥ 3 passages of loose stools within 24-hour period along with at least one loose stool containing blood and/or mucus [42]. We excluded children if they had suspected or con rmed intussusception at the time of enrolment [43]. Controls were healthy children between the age of 12-60 months enrolled in diarrhoeal disease cohort in District 8 in HCMC from 2014 to 2016 [17].…”

Section: Methodsmentioning

confidence: 99%

“…Diarrhoeal faecal specimens were collected in sterile containers and transported to the laboratory within 24 hours [43]. Anal swabs from non-diarrhoeal children were also transported to the laboratory within 24 hours for processing.…”

Section: Specimen Culture and Storagementioning

confidence: 99%

Novel multiplex real-time PCR assays reveal a high prevalence of diarrhoeagenic Escherichia coli pathotypes in healthy and diarrhoeal children in the South of Vietnam

Duong¹,

Tuyen

et al. 2020

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Abstract Background: Diarrhoeagenic Escherichia coli (DEC) infections are common in children in low-middle income countries (LMICs). However, detecting the various DEC pathotypes is complex as they cannot be differentiated by classical microbiology. We developed four multiplex real-time PCR assays were to detect virulence markers of six DEC pathotypes; specificity was tested using DEC controls and other enteric pathogens. PCR amplicons from the six E. coli pathotypes were purified and amplified to be used to optimize PCR reactions and to calculate reproducibility. After validation, these assays were applied to clinical samples from healthy and diarrhoeal Vietnamese children and associated with clinical data. Results: The multiplex real-time PCRs were found to be reproducible, and specific. At least one DEC variant was detected in 34.7% (978/2,815) of the faecal samples from diarrhoeal children; EAEC, EIEC and atypical EPEC were most frequent Notably, 41.2% (205/498) of samples from non-diarrhoeal children was positive with a DEC pathotype. In this population, only EIEC, which was detected in 34.3% (99/289) of diarrhoeal samples vs. 0.8% (4/498) non-diarrhoeal samples (p<0.001), was significantly associated with diarrhoea. Multiplex real-time PCR when applied to clinical samples is an efficient and high-throughput approach to DEC pathotypes. Conclusions: This approach revealed high carriage rates of DEC pathotypes among Vietnamese children. We describe a novel diagnostic approach for DEC, which provides baseline data for future surveillance studies assessing DEC burden in LMICs.

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“…12 This lack of a confirmative diagnosis results in the empirical use of antimicrobials 78 in the community or a healthcare facility. However, many of those receiving antimicrobials for 79 diarrhoea may not require them 13 , as the disease is generally self-limiting, is most likely to be of viral 80 aetiology, 14 and in LMICs in Asia many diarrheagenic bacteria are resistant to empirical 81 antimicrobials. 82 83 Vietnam is a rapidly developing LMIC in Southeast Asia with a current population of >90 million 84 people, which is estimated to be >100 million by 2020 15 .…”

Section: Introduction 58mentioning

confidence: 99%

Quantifying antimicrobial access and practices for paediatric diarrheal disease in an urban community setting in Southeast Asia

Ltq

Lam

et al. 2017

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30Antimicrobial-resistant infections are increasing across Asia. Aiming to evaluate antimicrobial access 31 and practices in Ho Chi Minh City (HCMC) of Vietnam, we mapped pharmacy locations and used a 32 simulated client method to calculate antimicrobial sales for paediatric diarrheal disease. We 33 additionally evaluated healthcare choices for parents and caregivers when their children experienced 34 diarrhoea. District 8 (population 396,175) of HCMC had 301 pharmacies (one for every 1,316 people), 35 with a density of 15.8 pharmacies/km 2 . A wide range of different treatments (n=57) were sold for 36 paediatric diarrheal disease, with 8% (3/37) and 22% (8/37) of the sampled pharmacies selling 37 antimicrobials for watery and mucoid diarrhoea, respectively. Despite the apparent abundance of 38 pharmacies, the majority of caregivers chose to take their child to a specialized hospital, with 81% 39 (319/396) and 88% (347/396) of responders selecting this as their first, second, or third choice for 40 watery and mucoid diarrhoea, respectively. Lastly, by combining denominators derived from 41 caregiver interviews and diarrheal incidence figures, we calculated that 16% (2,359/14,427) of watery 42 or mucoid diarrhoea episodes of the District 8 population aged 1 to <5 years would receive an 43 antimicrobial for diarrhoea annually, but antimicrobial prescribing was almost ten times greater in 44 hospitals than in the community. Our novel mixed-methods approach found that, whilst antimicrobials 45 are commonly available for paediatric diarrhoea in the community of HCMC, usage is greater in 46 hospitals. The observed non-standardized approach to diarrheal treatments is indicative of poor 47 recommendations. We advocate better guidelines, training and dissemination of information regarding 48 antimicrobials and their use in this location. 49 50 51 52 53 54 55 56 57 Committee (OxTREC approval 5110-16) and the local Institutional Review Board (IRB) of the 102 University of Medicine and Pharmacy at HCMC (No. 220/DHYD-HD). Written informed consent 103 was obtained from all participants over 18 years of age, or from parents and guardians if participant 104 was under 18 years. 105 106 Study setting and design 107With an estimated population of >8 million people, HCMC is the largest city in southern Vietnam 17 . 108

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No Clinical Benefit of Empirical Antimicrobial Therapy for Pediatric Diarrhea in a High-Usage, High-Resistance Setting

Cited by 37 publications

References 28 publications

Ciprofloxacin facilitates the transfer of XDR plasmids from commensalE. coliinto epidemic fluoroquinolone-resistantShigella sonnei

Ciprofloxacin facilitates the transfer of XDR plasmids from commensalE. coliinto epidemic fluoroquinolone-resistantShigella sonnei

Novel multiplex real-time PCR assays reveal a high prevalence of diarrhoeagenic Escherichia coli pathotypes in healthy and diarrhoeal children in the South of Vietnam

Quantifying antimicrobial access and practices for paediatric diarrheal disease in an urban community setting in Southeast Asia

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