Dipak K. Mitra

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.

Reasons for Preference of Home Delivery with Traditional Birth Attendants (TBAs) in Rural Bangladesh: A Qualitative Exploration.

Background and Objectives Although Bangladesh has made significant progress in reducing maternal and child mortality in the last decade, childbirth assisted by skilled attendants has not increased as much as expected. An objective of the Bangladesh National Strategy for Maternal Health 2014–2024 is to reduce maternal mortality to 50/100,000 live births. It also aims to increase deliveries with skilled birth attendants to more than 80% which remains a great challenge, especially in rural areas. This study explores the underlying factors for the major reliance on home delivery with Traditional Birth Attendants (TBA) in rural areas of Bangladesh. Methods This was a qualitative cross-sectional study. Data were collected between December 2012 and February 2013 in Sunamganj district of Sylhet division and data collection methods included key informant interviews (KII) with stakeholders; formal and informal health service providers and health managers; and in-depth interviews (IDI) with community women to capture a range of information. Key questions were asked of all the study participants to explore the question of why women and their families prefer home delivery by TBA and to identify the factors associated with this practice in the local community. Results The study shows that home delivery by TBAs remain the first preference for pregnant women. Poverty is the most frequently cited reason for preferring home delivery with a TBA. Other major reasons include; traditional views, religious fallacy, poor road conditions, limited access of women to decision making in the family, lack of transportation to reach the nearest health facility. Apart from these, community people also prefer home delivery due to lack of knowledge and awareness about service delivery points, fear of increased chance of having a caesarean delivery at hospital, and lack of female doctors in the health care facilities. Conclusions The study findings provide us a better understanding of the reasons for preference for home delivery with TBA among this population. These identified factors can inform policy makers and program implementers to adopt socially and culturally appropriate interventions that can improve deliveries with skilled attendants and thus contribute to the reduction of maternal and neonatal mortality and morbidity in rural Bangladesh.

Risk Factors Associated with Clinical Malaria Episodes in Bangladesh: A Longitudinal Study

Malaria is endemic to Bangladesh. In this longitudinal study, we used hydrologic, topographic, and socioeconomic risk factors to explain single and multiple malaria infections at individual and household levels. Malaria incidence was determined for 1,634 households in 54 villages in 2009 and 2010. During the entire study period 21.8% of households accounted for all (n = 497) malaria cases detected; 15.4% of households had 1 case and 6.4% had ≥ 2 cases. The greatest risk factors for malaria infection were low bed net ratio per household, house construction materials (wall), and high density of houses. Hydrologic and topographic factors were not significantly associated with malaria risk. This study identifies stable malaria hotspots and risk factors that should be considered for cost-effective targeting of malaria interventions that may contribute to potential elimination of malaria in Bangladesh.

Safety and Efficacy of Simplified Antibiotic Regimens for Outpatient Treatment of Serious Infection in Neonates and Young Infants 0-59 Days of Age in Bangladesh Design of a Randomized Controlled Trial

Background: Because access to care is limited in settings with high mortality, exclusive reliance on the current recommendation of 7–10 days of parenteral antibiotic treatment is a barrier to provision of adequate treatment of newborn infections. Methods: We are conducting a trial to determine if simplified antibiotic regimens with fewer injections are as efficacious as the standard course of parenteral antibiotics for empiric treatment of young infants with clinical signs suggestive of severe infection in 4 urban hospitals and in a rural surveillance site in Bangladesh. The reference regimen of intramuscular procaine-benzyl penicillin and gentamicin given once daily for 7 days is being compared with (1) intramuscular gentamicin once daily and oral amoxicillin twice daily for 7 days and (2) intramuscular penicillin and gentamicin once daily for 2 days followed by oral amoxicillin twice daily for additional 5 days. All regimens are provided in the infant’s home. The primary outcome is treatment failure (death or lack of clinical improvement) within 7 days of enrolment. The sample size is 750 evaluable infants enrolled per treatment group, and results will be reported at the end of 2013. Discussion: The trial builds upon previous studies of community case management of clinical severe infections in young infants conducted by our research team in Bangladesh. The approach although effective was not widely accepted in part because of feasibility concerns about the large number of injections. The proposed research that includes fewer doses of parenteral antibiotics if shown efficacious will address this concern.

The role of age, ethnicity and environmental factors in modulating malaria risk in Rajasthali, Bangladesh

BackgroundMalaria is endemic in the Rajasthali region of the Chittagong Hill Tracts in Bangladesh and the Rajasthali region is the most endemic area of Bangladesh. Quantifying the role of environmental and socio-economic factors in the local spatial patterns of malaria endemicity can contribute to successful malaria control and elimination. This study aimed to investigate the role of environmental factors on malaria risk in Rajasthali and to quantify the geographical clustering in malaria risk unaccounted by these factors.MethodA total of 4,200 (78.9%; N = 5,322) households were targeted in Rajasthali in July, 2009, and 1,400 individuals were screened using a rapid diagnostic test (Falci-vax). These data were linked to environmental and socio-economic data in a geographical information system. To describe the association between environmental factors and malaria risk, a generalized linear mixed model approach was utilized. The study investigated the role of environmental factors on malaria risk by calculating their population-attributable fractions (PAF), and used residual semivariograms to quantify the geographical clustering in malaria risk unaccounted by these factors.ResultsOverall malaria prevalence was 11.7%. Out of 5,322 households, 44.12% households were living in areas with malaria prevalence of ≥ 10%. The results from statistical analysis showed that age, ethnicity, proximity to forest, household density, and elevation were significantly and positively correlated with the malaria risk and PAF estimation. The highest PAF of malaria prevalence was 47.7% for third tertile (n = 467) of forest cover, 17.6% for second tertile (n = 467) of forest cover and 19.9% for household density >1,000.ConclusionTargeting of malaria health interventions at small spatial scales in Bangladesh should consider the social and socio-economic risk factors identified as well as alternative methods for improving equity of access to interventions across whole communities.

Infection Surveillance Protocol for a Multicountry Population-based Study in South Asia to Determine the Incidence Etiology and Risk Factors for Infections Among Young Infants of 0 to 59 Days Old.

Background: Insufficient knowledge of the etiology and risk factors for community-acquired neonatal infection in low-income countries is a barrier to designing appropriate intervention strategies for these settings to reduce the burden and treatment of young infant infection. To address these gaps, we are conducting the Aetiology of Neonatal Infection in South Asia (ANISA) study among young infants in Bangladesh, India and Pakistan. The objectives of ANISA are to establish a comprehensive surveillance system for registering newborns in study catchment areas and collecting data on bacterial and viral etiology and associated risk factors for infections among young infants aged 0–59 days. Methods: We are conducting active surveillance in 1 peri-urban and 4 rural communities. During 2 years of surveillance, we expect to enroll an estimated 66,000 newborns within 7 days of their birth and to follow-up them until 59 days of age. Community health workers visit each young infant in the study area 3 times in the first week of life and once a week thereafter. During these visits, community health workers assess the newborns using a clinical algorithm and refer young infants with signs of suspected infection to health care facilities where study physicians reassess them and provide care if needed. On physician confirmation of suspected infection, blood and respiratory specimens are collected and tested to identify the etiologic agent. Conclusions: ANISA is one of the largest initiatives ever undertaken to understand the etiology of young infant infection in low-income countries. The data generated from this surveillance will help guide evidence-based decision making to improve health care in similar settings.

Validity of Newborn Clinical Assessment to Determine Gestational Age in Bangladesh.

BACKGROUND: Gestational age (GA) is frequently unknown or inaccurate in pregnancies in low-income countries. Early identification of preterm infants may help link them to potentially life-saving interventions. METHODS: We conducted a validation study in a community-based birth cohort in rural Bangladesh. GA was determined by pregnancy ultrasound (<20 weeks). Community health workers conducted home visits (<72 hours) to assess physical/neuromuscular signs and measure anthropometrics. The distribution, agreement, and diagnostic accuracy of different clinical methods of GA assessment were determined compared with early ultrasound dating. RESULTS: In the live-born cohort (n = 1066), the mean ultrasound GA was 39.1 weeks (SD 2.0) and prevalence of preterm birth (<37 weeks) was 11.4%. Among assessed newborns (n = 710), the mean ultrasound GA was 39.3 weeks (SD 1.6) (8.3% preterm) and by Ballard scoring the mean GA was 38.9 weeks (SD 1.7) (12.9% preterm). The average bias of the Ballard was –0.4 weeks; however, 95% limits of agreement were wide (–4.7 to 4.0 weeks) and the accuracy for identifying preterm infants was low (sensitivity 16%, specificity 87%). Simplified methods for GA assessment had poor diagnostic accuracy for identifying preterm births (community health worker prematurity scorecard [sensitivity/specificity: 70%/27%]; Capurro [5%/96%]; Eregie [75%/58%]; Bhagwat [18%/87%], foot length <75 mm [64%/35%]; birth weight <2500 g [54%/82%]). Neonatal anthropometrics had poor to fair performance for classifying preterm infants (areas under the receiver operating curve 0.52–0.80). CONCLUSIONS: Newborn clinical assessment of GA is challenging at the community level in low-resource settings. Anthropometrics are also inaccurate surrogate markers for GA in settings with high rates of fetal growth restriction.

Neonatal mortality within 24 hours of birth in six low-and lower-middle-income countries

Abstract Objective To estimate neonatal mortality, particularly within 24 hours of birth, in six low- and lower-middle-income countries. Methods We analysed epidemiological data on a total of 149 570 live births collected between 2007 and 2013 in six prospective randomized trials and a cohort study from predominantly rural areas of Bangladesh, Ghana, India, Pakistan, the United Republic of Tanzania and Zambia. The neonatal mortality rate and mortality within 24 hours of birth were estimated for all countries and mortality within 6 hours was estimated for four countries with available data. The findings were compared with published model-based estimates of neonatal mortality. Findings Overall, the neonatal mortality rate observed at study sites in the six countries was 30.5 per 1000 live births (range: 13.6 in Zambia to 47.4 in Pakistan). Mortality within 24 hours was 14.1 per 1000 live births overall (range: 5.1 in Zambia to 20.1 in India) and 46.3% of all neonatal deaths occurred within 24 hours (range: 36.2% in Pakistan to 65.5% in the United Republic of Tanzania). Mortality in the first 6 hours was 8.3 per 1000 live births, i.e. 31.9% of neonatal mortality. Conclusion Neonatal mortality within 24 hours of birth in predominantly rural areas of six low- and lower-middle-income countries was higher than model-based estimates for these countries. A little under half of all neonatal deaths occurred within 24 hours of birth and around one third occurred within 6 hours. Implementation of high-quality, effective obstetric and early newborn care should be a priority in these settings.

The development and evaluation of a community-based clinical diagnosis tool and treatment regimen for postpartum sepsis in Bangladesh and Pakistan.

BackgroundPostpartum sepsis accounts for most maternal deaths between three and seven days postpartum, when most mothers, even those who deliver in facilities, are at home. Case fatality rates for untreated women are very high. Newborns of ill women have substantially higher infection risk.Methods/DesignThe objectives of this study are to: (1) create, field-test and validate a tool for community health workers to improve diagnostic accuracy of suspected puerperal sepsis; (2) measure incidence and identify associated risk factors and; (3) describe etiologic agents responsible and antibacterial susceptibility patterns. This prospective cohort study builds on the Aetiology of Neonatal Infection in South Asia study in three sites: Sylhet, Bangladesh and Karachi and Matiari, Pakistan. Formative research determined local knowledge of symptoms and signs of postpartum sepsis, and a systematic literature review was conducted to design a diagnostic tool for community health workers to use during ten postpartum home visits. Suspected postpartum sepsis cases were referred to study physicians for independent assessment, which permitted validation of the tool. Clinical specimens, including urine, blood, and endometrial material, were collected for etiologic assessment and antibiotic sensitivity. All women with puerperal sepsis were given appropriate antibiotics.DiscussionThis is the first large population-based study to expand community-based surveillance for diagnoses, referral and treatment of newborn sepsis to include maternal postpartum sepsis. Study activities will lead to development and validation of a diagnostic tool for use by community health workers in resource-poor countries. Understanding the epidemiology and microbiology of postpartum sepsis will inform prevention and treatment strategies and improve understanding of linkages between maternal and neonatal infections.

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.