Arif Mahmud

Safety and efficacy of alternative antibiotic regimens compared with 7 day injectable procaine benzylpenicillin and gentamicin for outpatient treatment of neonates and young infants with clinical signs of severe infection when referral is not possible: a randomised, open-label, equivalence trial

BACKGROUND Severe infections remain one of the main causes of neonatal deaths worldwide. Possible severe infection is diagnosed in young infants (aged 0-59 days) according to the presence of one or more clinical signs. The recommended treatment is hospital admission with 7-10 days of injectable antibiotic therapy. In low-income and middle-income countries, barriers to hospital care lead to delayed, inadequate, or no treatment for many young infants. We aimed to identify effective alternative antibiotic regimens to expand treatment options for situations where hospital admission is not possible. METHODS We did this randomised, open-label, equivalence trial in four urban hospitals and one rural field site in Bangladesh to determine whether two alternative antibiotic regimens with reduced numbers of injectable antibiotics combined with oral antibiotics had similar efficacy and safety to the standard regimen, which was also used as outpatient treatment. We randomly assigned infants who showed at least one clinical sign of severe, but not critical, infection (except fast breathing alone), whose parents refused hospital admission, to one of the three treatment regimens. We stratified randomisation by study site and age (<7 days or 7-59 days) using computer-generated randomisation sequences. The standard treatment was intramuscular procaine benzylpenicillin and gentamicin once per day for 7 days (group A). The alternative regimens were intramuscular gentamicin once per day and oral amoxicillin twice per day for 7 days (group B) or intramuscular procaine benzylpenicillin and gentamicin once per day for 2 days, then oral amoxicillin twice per day for 5 days (group C). The primary outcome was treatment failure within 7 days after enrolment. Assessors of treatment failure were masked to treatment allocation. Primary analysis was per protocol. We used a prespecified similarity margin of 5% to assess equivalence between regimens. This study is registered with ClinicalTrials.gov, number NCT00844337. FINDINGS Between July 1, 2009, and June 30, 2013, we recruited 2490 young infants into the trial. We assigned 830 infants to group A, 831 infants to group B, and 829 infants to group C. 2367 (95%) infants fulfilled per-protocol criteria. 78 (10%) of 795 per-protocol infants had treatment failure in group A compared with 65 (8%) of 782 infants in group B (risk difference -1.5%, 95% CI -4.3 to 1.3) and 64 (8%) of 790 infants in group C (-1.7%, -4.5 to 1.1). In group A, 14 (2%) infants died before day 15, compared with 12 (2%) infants in group B and 12 (2%) infants in group C. Non-fatal relapse rates were similar in all three groups (12 [2%] infants in group A vs 13 [2%] infants in group B and 10 [1%] infants in group C). INTERPRETATION Our results suggest that the two alternative antibiotic regimens for outpatient treatment of clinical signs of severe infection in young infants whose parents refused hospital admission are as efficacious as the standard regimen. This finding could increase treatment options in resource-poor settings when referral care is not available or acceptable.

Causes and incidence of community-acquired serious infections among young children in south Asia (ANISA): an observational cohort study

Summary Background More than 500 000 neonatal deaths per year result from possible serious bacterial infections (pSBIs), but the causes are largely unknown. We investigated the incidence of community-acquired infections caused by specific organisms among neonates in south Asia. Methods From 2011 to 2014, we identified babies through population-based pregnancy surveillance at five sites in Bangladesh, India, and Pakistan. Babies were visited at home by community health workers up to ten times from age 0 to 59 days. Illness meeting the WHO definition of pSBI and randomly selected healthy babies were referred to study physicians. The primary objective was to estimate proportions of specific infectious causes by blood culture and Custom TaqMan Array Cards molecular assay (Thermo Fisher, Bartlesville, OK, USA) of blood and respiratory samples. Findings 6022 pSBI episodes were identified among 63 114 babies (95·4 per 1000 livebirths). Causes were attributed in 28% of episodes (16% bacterial and 12% viral). Mean incidence of bacterial infections was 13·2 (95% credible interval [CrI] 11·2–15·6) per 1000 livebirths and of viral infections was 10·1 (9·4–11·6) per 1000 livebirths. The leading pathogen was respiratory syncytial virus (5·4, 95% CrI 4·8–6·3 episodes per 1000 livebirths), followed by Ureaplasma spp (2·4, 1·6–3·2 episodes per 1000 livebirths). Among babies who died, causes were attributed to 46% of pSBI episodes, among which 92% were bacterial. 85 (83%) of 102 blood culture isolates were susceptible to penicillin, ampicillin, gentamicin, or a combination of these drugs. Interpretation Non-attribution of a cause in a high proportion of patients suggests that a substantial proportion of pSBI episodes might not have been due to infection. The predominance of bacterial causes among babies who died, however, indicates that appropriate prevention measures and management could substantially affect neonatal mortality. Susceptibility of bacterial isolates to first-line antibiotics emphasises the need for prudent and limited use of newer-generation antibiotics. Furthermore, the predominance of atypical bacteria we found and high incidence of respiratory syncytial virus indicated that changes in management strategies for treatment and prevention are needed. Given the burden of disease, prevention of respiratory syncytial virus would have a notable effect on the overall health system and achievement of Sustainable Development Goal. Funding Bill & Melinda Gates Foundation

Antepartum complications and perinatal mortality in rural Bangladesh

BackgroundDespite impressive improvements in maternal survival throughout the world, rates of antepartum complications remain high. These conditions also contribute to high rates of perinatal deaths, which include stillbirths and early neonatal deaths, but the extent is not well studied. This study examines patterns of antepartum complications and the risk of perinatal deaths associated with such complications in rural Bangladesh.MethodsWe used data on self-reported antepartum complications during the last pregnancy and corresponding pregnancy outcomes from a household survey (N = 6,285 women) conducted in Sylhet district, Bangladesh in 2006. We created three binary outcome variables (stillbirths, early neonatal deaths, and perinatal deaths) and three binary exposure variables indicating antepartum complications, which were antepartum hemorrhage (APH), probable infection (PI), and probable pregnancy-induced hypertension (PIH). We then examined patterns of antepartum complications and calculated incidence rate ratios (IRR) to estimate the associated risks of perinatal mortality using Poisson regression analyses. We calculated population attributable fraction (PAF) for the three antepartum complications to estimate potential risk reductions of perinatal mortality associated them.ResultsWe identified 356 perinatal deaths (195 stillbirths and 161 early neonatal deaths). The highest risk of perinatal death was associated with APH (IRR = 3.5, 95% CI: 2.4–4.9 for perinatal deaths; IRR = 3.7, 95% CI 2.3–5.9 for stillbirths; IRR = 3.5, 95% CI 2.0–6.1 for early neonatal deaths). Pregnancy-induced hypertension was a significant risk factor for stillbirths (IRR = 1.8, 95% CI 1.3–2.5), while PI was a significant risk factor for early neonatal deaths (IRR = 1.5, 95% CI 1.1–2.2). Population attributable fraction of APH and PIH were 6.8% and 10.4% for perinatal mortality and 7.5% and 14.7% for stillbirths respectively. Population attributable fraction of early neonatal mortality due to APH was 6.2% and for PI was 7.8%.ConclusionsIdentifying antepartum complications and ensuring access to adequate care for those complications are one of the key strategies in reducing perinatal mortality in settings where most deliveries occur at home.

Implementation of the ANISA Protocol in Sylhet, Bangladesh: Challenges and Solutions

Background: Despite the high rate of deaths in young infants (0-59 days) attributable to infections in resource-poor countries, data on bacterial and viral etiologies of community-acquired infections in this age group are limited. These data are needed to develop appropriate preventive strategies and suitable antibiotic treatment regimens for reducing the number of young infant deaths from infections. The Aetiology of Neonatal Infection in South Asia (ANISA) study is designed to generate these critical data and is being implemented in Bangladesh, India and Pakistan. The Sylhet site in Bangladesh was selected because neonatal mortality is high in this country and particularly in Sylhet District. In this article, we describe the contextual challenges in implementing the ANISA study in Sylhet, as well as the strategies developed by our team to address these challenges. Contextual Challenges: The major challenge in implementing the ANISA protocol in Sylhet is conducting the first postnatal visit within 24 hours of birth. This problem stems from several social, cultural and geographical characteristics of the study population and its demographic profile. In this area, most births take place at home, referral compliance for newborn illness to health facilities is low and the blood culture contamination rate is high. Community mobilization, cellphone-based birth notification by families, delivery of quality services at study hospitals and referral support to families in need were some of the strategies adopted by the Sylhet site team for overcoming these challenges during study implementation. Quality control in specimen collection, transportation and processing also plays a role in ensuring satisfactory performance. Conclusion: Our research team, with support from the ANISA coordination center, has successfully addressed these challenges and is implementing the study protocol while maintaining the high quality benchmark set by the coordination center.

Patterns and Determinants of Care-Seeking for Antepartum and Intrapartum Complications in Rural Bangladesh: Results from a Cohort Study.

Background The burden of maternal complications during antepartum and intrapartum periods is high and care seeking from a trained provider is low, particularly in low middle income countries of sub-Saharan Africa and South Asia. Identification of barriers to access to trained care and development of strategies to address them will contribute to improvements in maternal health. Using data from a community-based cohort of pregnant women, this study identified the prevalence of antepartum and intrapartum complications and determinants of care-seeking for these complications in rural Bangladesh. Methods The study was conducted in 24,274 pregnant women between June 2011 and December 2013 in rural Sylhet district of Bangladesh. Women were interviewed during pregnancy to collect data on demographic and socioeconomic characteristics; prior miscarriages, stillbirths, live births, and neonatal deaths; as well as data on their ability to make decision to go to health center alone. They were interviewed within the first 7 days of child birth to collect data on self-reported antepartum and intrapartum complications and care seeking for those complications. Bivariate analysis was conducted to explore association between predisposing (socio-demographic), enabling (economic), perceived need, and service related factors with care-seeking for self-reported antepartum and intrapartum complications. Multivariable multinomial logistic regression was performed to examine the association of selected factors with care-seeking for self-reported antepartum and intrapartum complications adjusting for co-variates. Results Self-reported antepartum and intrapartum complications among women were 14.8% and 20.9% respectively. Among women with any antepartum complication, 58.9% sought care and of these 46.5% received care from a trained provider. Of the women with intrapartum complications, 61.4% sought care and of them 46.5% did so from a trained provider. Care-seeking for both antepartum and intrapartum complications from a trained provider was significantly higher for women with higher household wealth status, higher literacy level of both women and their husbands, and for those living close to a health facility (<10 km). Women’s decision making ability to go to health centre alone was associated with untrained care only for antepartum complications, but was associated with both trained and untrained care for intrapartum complications. Conclusions Nearly 40.0% of the women who experienced either an antepartum or intrapartum complications did not seek care from any provider and 11.5% -14.9% received care from untrained providers, primarily because of economic and geographic barriers to access. Development and evaluation of context specific, cost-effective, and sustainable strategies that will address these barriers to access to care for the maternal complications will enhance care seeking from trained health care providers and improve maternal health.

Pneumococcal Conjugate Vaccine impact assessment in Bangladesh

The study examines the impact of the introduction of 10-valent Pneumococcal Conjugate Vaccine (PCV10) into Bangladesh’s national vaccine program. PCV10 is administered to children under 1 year-old; the scheduled ages of administration are at 6, 10, and 18 weeks. The study is conducted in ~770,000 population containing ~90,000 <5 children in Sylhet, Bangladesh and has five objectives: 1) To collect data on community-based pre-PCV incidence rates of invasive pneumococcal diseases (IPD) in 0-59 month-old children in Sylhet, Bangladesh; 2) To evaluate the effectiveness of PCV10 introduction on Vaccine Type (VT) IPD in 3-59 month-old children using an incident case-control study design. Secondary aims include measuring the effects of PCV10 introduction on all IPD in 3-59 month-old children using case-control study design, and quantifying the emergence of Non Vaccine Type IPD; 3) To evaluate the effectiveness of PCV10 introduction on chest radiograph-confirmed pneumonia in children 3-35 months old using incident case-control study design. We will estimate the incidence trend of clinical and radiologically-confirmed pneumonia in 3-35 month-old children in the study area before and after introduction of PCV10; 4) To determine the feasibility and utility of lung ultrasound for the diagnosis of pediatric pneumonia in a large sample of children in a resource-limited setting. We will also evaluate the effectiveness of PCV10 introduction on ultrasound-confirmed pneumonia in 3-35 month-old children using an incident case-control design and to examine the incidence trend of ultrasound-confirmed pneumonia in 3-35 month-old children in the study area before and after PCV10 introduction; and 5) To determine the direct and indirect effects of vaccination status on nasopharyngeal colonization on VT pneumococci among children with pneumonia . This paper presents the methodology. The study will allow us to conduct a comprehensive and robust assessment of the impact of national introduction of PCV10 on pneumococcal disease in Bangladesh.