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With the rise in fluoroquinolone-resistant Salmonella Typhi and the recent emergence of ceftriaxone resistance, azithromycin is one of the last oral drugs available against typhoid for which resistance is uncommon. Its increasing use, specifically in light of the ongoing outbreak of extensively drug-resistant (XDR) Salmonella Typhi (resistant to chloramphenicol, ampicillin, cotrimoxazole, streptomycin, fluoroquinolones and third-generation cephalosporins) in Pakistan, places selective pressure for the emergence and spread of azithromycin-resistant isolates. However, little is known about azithromycin resistance in Salmonella, and no molecular data are available on its mechanism. We conducted typhoid surveillance in the two largest pediatric hospitals of Bangladesh from 2009-2016. All typhoidal Salmonella strains were screened for azithromycin resistance using disc diffusion and resistance was confirmed using E-tests. In total, we identified 1,082 Salmonella Typhi and Paratyphi A strains; among these, 13 strains (12 Typhi, 1 Paratyphi A) were azithromycin-resistant (MIC range: 32-64 μg/ml) with the first case observed in 2013. We sequenced the resistant strains, but no molecular basis of macrolide resistance was identified by the currently available antimicrobial resistance prediction tools. A whole genome SNP tree, made using RAxML, showed that the 12 Typhi resistant strains clustered together within the 4.3.1.1 sub-clade (H58 lineage 1). We found a non-synonymous single-point mutation exclusively in these 12 strains in the gene encoding AcrB, an efflux pump that removes small molecules from bacterial cells. The mutation changed the conserved amino acid arginine (R) at position 717 to a glutamine (Q). To test the role of R717Q present in azithromycin-resistant strains, we cloned acrB from azithromycin-resistant and sensitive strains, expressed them in E. coli, Typhi and Paratyphi A strains and tested their azithromycin susceptibility. Expression of AcrB-R717Q in E. coli and Typhi strains increased the minimum inhibitory concentration (MIC) for azithromycin by 11- and 3-fold respectively. The azithromycin-resistant Paratyphi A strain also contained a mutation at R717 (R717L), whose introduction in E. coli and Paratyphi A strains increased MIC by 7- and 3-fold respectively, confirming the role of R717 mutations in conferring azithromycin resistance. This report confirms 12 azithromycin-resistant Salmonella Typhi strains and one Paratyphi A strain. The molecular basis of this resistance is one mutation in the AcrB protein at position 717. This is the first report demonstrating the impact of this non-synonymous mutation in conferring macrolide resistance in a clinical setting. With increasing azithromycin use, strains with R717 mutations may spread and be acquired by XDR strains. An azithromycin-resistant XDR strain would shift enteric fever treatment from outpatient departments, where patients are currently treated with oral azithromycin, to inpatient departments to be treated with injectable antibiotics like carbapenems, thereby further burdening already struggling health systems in endemic regions. Moreover, with the dearth of novel antimicrobials in the horizon, we risk losing our primary defense against widespread mortality from typhoid. In addition to rolling out the WHO prequalified typhoid conjugate vaccine in endemic areas to decrease the risk of pan-resistant Salmonella Typhi strains, it is also imperative to implement antimicrobial stewardship and water sanitation and hygiene intervention to decrease the overall burden of enteric fever.

Background Three large new trials of unprecedented scale and cost, which included novel factorial designs, have found no effect of basic water, sanitation and hygiene (WASH) interventions on childhood stunting, and only mixed effects on childhood diarrhea. Arriving at the inception of the United Nations’ Sustainable Development Goals, and the bold new target of safely managed water, sanitation and hygiene for all by 2030, these results warrant the attention of researchers, policy-makers and practitioners. Main body Here we report the conclusions of an expert meeting convened by the World Health Organization and the Bill and Melinda Gates Foundation to discuss these findings, and present five key consensus messages as a basis for wider discussion and debate in the WASH and nutrition sectors. We judge these trials to have high internal validity, constituting good evidence that these specific interventions had no effect on childhood linear growth, and mixed effects on childhood diarrhea. These results suggest that, in settings such as these, more comprehensive or ambitious WASH interventions may be needed to achieve a major impact on child health. Conclusion These results are important because such basic interventions are often deployed in low-income rural settings with the expectation of improving child health, although this is rarely the sole justification. Our view is that these three new trials do not show that WASH in general cannot influence child linear growth, but they do demonstrate that these specific interventions had no influence in settings where stunting remains an important public health challenge. We support a call for transformative WASH, in so much as it encapsulates the guiding principle that – in any context – a comprehensive package of WASH interventions is needed that is tailored to address the local exposure landscape and enteric disease burden.

Nipah virus is a highly virulent zoonotic pathogen. In this report from Bangladesh, which included 40% of the world’s known cases, the risk factors for human-to-human transmission were evaluated. No asymptomatic cases were identified. Increased respiratory symptoms in the patient and prolonged close contact from caregivers were associated with secondary transmission.

Nipah virus (NiV) is a paramyxovirus whose reservoir host is fruit bats of the genus Pteropus . Occasionally the virus is introduced into human populations and causes severe illness characterized by encephalitis or respiratory disease. The first outbreak of NiV was recognized in Malaysia, but 8 outbreaks have been reported from Bangladesh since 2001. The primary pathways of transmission from bats to people in Bangladesh are through contamination of raw date palm sap by bats with subsequent consumption by humans and through infection of domestic animals (cattle, pigs, and goats), presumably from consumption of food contaminated with bat saliva or urine with subsequent transmission to people. Approximately one-half of recognized Nipah case patients in Bangladesh developed their disease following person-to-person transmission of the virus. Efforts to prevent transmission should focus on decreasing bat access to date palm sap and reducing family members' and friends' exposure to infected patients' saliva.

Nipah virus spillovers via consumption of date palm sap in Bangladesh vary substantially between years and have been associated with lower winter temperatures and precipitation. However, the mechanisms driving the interannual variation and the influence of weather remain unexplained. Here we investigated the hypothesis that weather patterns change human sap consumption and explain interannual variation in observed spillovers. We analyzed responses from a nationally representative survey conducted in Bangladesh in 2013–2016 on household date palm sap consumption and weather data for each division of Bangladesh, using logistic regression to examine whether sap consumption is associated with weather variability. We found significant associations of lower minimum temperatures and precipitation with increased household sap consumption during the sap harvesting season. This relationship was largely similar within all months and divisions, and strong associations of temperature (χ 2 (1, n = 5,027) = 7.74, p < 0.01) and, independently, precipitation (χ 2 = 8.00, p < 0.01) remained strong after accounting for month, location, and annual sap season. Interannual variation in date palm sap consumption in Bangladesh is likely best explained by temperature and precipitation patterns, where colder, drier winter days pose a higher risk for Nipah virus spillover. The knowledge gained in this study may be valuable for targeting timing of future behavioral interventions against consumption of date palm sap in Bangladesh.

BackgroundMany adolescent girls in low-income and middle-income countries lack appropriate facilities and support in school to manage menstruation. Little research has been conducted on how menstruation affects school absence. This study examines the association of menstrual hygiene management knowledge, facilities and practice with absence from school during menstruation among Bangladeshi schoolgirls.MethodsWe conducted a nationally representative, cross-sectional study in Bangladeshi schools from March to June 2013 among girls 11 to 17 years old who reached menarche. We sampled 700 schools from 50 urban and 50 rural clusters using a probability proportional to size technique. We interviewed 2332 schoolgirls and conducted spot checks in each school for menstrual hygiene facilities. To assess factors associated with reported school absence, we estimated adjusted prevalence difference (APD) for controlling confounders’ effect using generalised estimating equations to account for school-level clustering.ResultsAmong schoolgirls who reached menarche, 41% (931) reported missing school, an average of 2.8 missed days per menstrual cycle. Students who felt uncomfortable at school during menstruation (99% vs 32%; APD=58%; CI 54 to 63) and who believed menstrual problems interfere with school performance (64% vs 30%; APD=27; CI 20 to 33) were more likely to miss school during menstruation than those who did not. School absence during menstruation was less common among girls attending schools with unlocked toilet for girls (35% vs 43%; APD=−5.4; CI −10 to –1.6). School absence was more common among girls who were forbidden from any activities during menstruation (41% vs 33%; APD=9.1; CI 3.3 to 14).ConclusionRisk factors for school absence included girl’s attitude, misconceptions about menstruation, insufficient and inadequate facilities at school, and family restriction. Enabling girls to manage menstruation at school by providing knowledge and management methods prior to menarche, privacy and a positive social environment around menstrual issues has the potential to benefit students by reducing school absence.

Young children frequently defecate in the living environment in low-income countries. Unsafe child feces disposal has been associated with risk of diarrhea. Additionally, reported practices can underestimate socially undesirable unhygienic behaviors. This analysis aimed to assess (1) the sensitivity of reported child feces disposal practices as an indicator for observed presence of human feces in the domestic environment, (2) household characteristics associated with reported unsafe feces disposal and (3) whether unsafe feces disposal is associated with fly presence and diarrhea among children <3 years. We recorded caregiver-reported feces disposal practices for children <3 years; unsafe disposal was defined as feces put/rinsed into a drain, ditch, bush or garbage heap or left on the ground and safe disposal as feces put/rinsed into latrine or specific pit or buried. We conducted spot checks for human feces, counted flies in the compound and recorded caregiver-reported child diarrhea prevalence among 803 rural Bangladeshi households. We assessed associations using generalized estimating equations (GEE) and generalized linear models (GLM) with robust standard errors. Unsafe disposal of child feces was reported by 80% of households. Reported disposal practices had high sensitivity (91%) but low positive predictive value (15%) as an indicator of observed feces in the compound. Unsafe disposal was more common among households that reported daily adult open defecation (PR: 1.13, 1.02-1.24) and had children defecating in a nappy or on the ground versus in a potty (PR: 2.92, 1.98-4.32), and less common in households where adults reported always defecating in latrines (PR: 0.91, 0.84-0.98). The presence of observed human feces was similarly associated with these household characteristics. Reported unsafe feces disposal or observed human feces were not associated with fly detection or child diarrhea. Despite access to on-site sanitation, unsafe child feces disposal was reported by the majority of households. However, this practices was not associated with diarrhea; suggesting that child feces may not be the most important fecal exposure. Before resources are invested to improve child feces management practices, studies should explore whether these contribute meaningfully to risk of enteric disease.

Diarrhea and acute respiratory infection (ARI) are leading causes of death in children. The WASH Benefits Bangladesh trial implemented a multicomponent sanitation intervention that led to a 39% reduction in the prevalence of diarrhea among children and a 25% reduction for ARI, measured 1 to 2 years after intervention implementation. We measured longer-term intervention effects on these outcomes between 1 to 3.5 years after intervention implementation, including periods with differing intensity of behavioral promotion. WASH Benefits Bangladesh was a cluster-randomized controlled trial of water, sanitation, hygiene, and nutrition interventions (NCT01590095). The sanitation intervention included provision of or upgrades to improved latrines, sani-scoops for feces removal, children's potties, and in-person behavioral promotion. Promotion was intensive up to 2 years after intervention initiation, decreased in intensity between years 2 to 3, and stopped after 3 years. Access to and reported use of latrines was high in both arms, and latrine quality was significantly improved by the intervention, while use of child feces management tools was low. We enrolled a random subset of households from the sanitation and control arms into a longitudinal substudy, which measured child health with quarterly visits between 1 to 3.5 years after intervention implementation. The study period therefore included approximately 1 year of high-intensity promotion, 1 year of low-intensity promotion, and 6 months with no promotion. We assessed intervention effects on diarrhea and ARI prevalence among children <5 years through intention-to-treat analysis using generalized linear models with robust standard errors. Masking was not possible during data collection, but data analysis was masked. We enrolled 720 households (360 per arm) from the parent trial and made 9,800 child observations between June 2014 and December 2016. Over the entire study period, diarrheal prevalence was lower among children in the sanitation arm (11.9%) compared to the control arm (14.5%) (prevalence ratio [PR] = 0.81, 95% CI 0.66, 1.00, p = 0.05; prevalence difference [PD] = -0.027, 95% CI -0.053, 0, p = 0.05). ARI prevalence did not differ between sanitation (21.3%) and control (22.7%) arms (PR = 0.93, 95% CI 0.82, 1.05, p = 0.23; PD = -0.016, 95% CI -0.043, 0.010, p = 0.23). There were no significant differences in intervention effects between periods with high-intensity versus low-intensity/no promotion. Study limitations include use of caregiver-reported symptoms to define health outcomes and limited data collected after promotion ceased. The observed effect of the WASH Benefits Bangladesh sanitation intervention on diarrhea in children appeared to be sustained for at least 3.5 years after implementation, including 1.5 years after heavy promotion ceased. Existing latrine access was high in the study setting, suggesting that improving on-site latrine quality can deliver health benefits when latrine use practices are in place. Further work is needed to understand how latrine adoption can be achieved and sustained in settings with low existing access and how sanitation programs can adopt transformative approaches of excreta management, including safe disposal of child and animal feces, to generate a hygienic home environment. ClinicalTrials.gov; NCT01590095; https://clinicaltrials.gov/ct2/show/NCT01590095.

Shallow tubewells are the primary drinking water source for most rural Bangladeshis. Fecal contamination has been detected in tubewells, at low concentrations at the source and at higher levels at the point of use. We conducted a randomized controlled trial to assess whether improving the microbiological quality of tubewell drinking water by household water treatment and safe storage would reduce diarrhea in children <2 years in rural Bangladesh. We randomly assigned 1800 households with a child aged 6-18 months (index child) into one of three arms: chlorine plus safe storage, safe storage and control. We followed households with monthly visits for one year to promote the interventions, track their uptake, test participants' source and stored water for fecal contamination, and record caregiver-reported child diarrhea prevalence (primary outcome). To assess reporting bias, we also collected data on health outcomes that are not expected to be impacted by our interventions. Both interventions had high uptake. Safe storage, alone or combined with chlorination, reduced heavy contamination of stored water. Compared to controls, diarrhea in index children was reduced by 36% in the chlorine plus safe storage arm (prevalence ratio, PR = 0.64, 0.55-0.73) and 31% in the safe storage arm (PR = 0.69, 0.60-0.80), with no difference between the two intervention arms. One limitation of the study was the non-blinded design with self-reported outcomes. However, the prevalence of health outcomes not expected to be impacted by water interventions did not differ between study arms, suggesting minimal reporting bias. Safe storage significantly improved drinking water quality at the point of use and reduced child diarrhea in rural Bangladesh. There was no added benefit from combining safe storage with chlorination. Efforts should be undertaken to implement and evaluate long-term efforts for safe water storage in Bangladesh. ClinicalTrials.gov NCT01350063.

Rotavirus vaccine has proved effective for prevention of severe rotavirus gastroenteritis in infants in developed countries, but no efficacy studies have been done in developing countries in Asia. We assessed the clinical efficacy of live oral pentavalent rotavirus vaccine for prevention of severe rotavirus gastroenteritis in infants in Bangladesh and Vietnam. In this multicentre, double-blind, placebo-controlled trial, undertaken in rural Matlab, Bangladesh, and urban and periurban Nha Trang, Vietnam, infants aged 4–12 weeks without symptoms of gastrointestinal disorders were randomly assigned (1:1) to receive three oral doses of pentavalent rotavirus vaccine 2 mL or placebo at around 6 weeks, 10 weeks, and 14 weeks of age, in conjunction with routine infant vaccines including oral poliovirus vaccine. Randomisation was done by computer-generated randomisation sequence in blocks of six. Episodes of gastroenteritis in infants who presented to study medical facilities were reported by clinical staff and from parent recollection. The primary endpoint was severe rotavirus gastroenteritis (Vesikari score ≥11) arising 14 days or more after the third dose of placebo or vaccine to end of study (March 31, 2009; around 21 months of age). Analysis was per protocol; infants who received scheduled doses of vaccine or placebo without intervening laboratory-confirmed naturally occurring rotavirus disease earlier than 14 days after the third dose and had complete clinical and laboratory results were included in the analysis. This study is registered with ClinicalTrials.gov, number NCT00362648. 2036 infants were randomly assigned to receive pentavalent rotavirus vaccine (n=1018) or placebo (n=1018). 991 infants assigned to pentavalent rotavirus vaccine and 978 assigned to placebo were included in the per-protocol analysis. Median follow up from 14 days after the third dose of placebo or vaccine until final disposition was 498 days (IQR 480–575). 38 cases of severe rotavirus gastroenteritis (Vesikari score ≥11) were reported during more than 1197 person-years of follow up in the vaccine group, compared with 71 cases in more than 1156 person years in the placebo group, resulting in a vaccine efficacy of 48·3% (95% CI 22·3–66·1) against severe disease (p=0·0005 for efficacy >0%) during nearly 2 years of follow-up. 25 (2·5%) of 1017 infants assigned to receive vaccine and 20 (2·0%) of 1018 assigned to receive placebo had a serious adverse event within 14 days of any dose. The most frequent serious adverse event was pneumonia (vaccine 12 [1·2%]; placebo 15 [1·5%]). In infants in developing countries in Asia, pentavalent rotavirus vaccine is safe and efficacious against severe rotavirus gastroenteritis, and our results support expanded WHO recommendations to promote its global use. PATH (GAVI Alliance grant) and Merck.