Safety and effi cacy 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 eff ective 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 fi eld site in Bangladesh to determine whether two alternative antibiotic regimens with reduced numbers of injectable antibiotics combined with oral antibiotics had similar effi cacy 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 stratifi ed 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 prespecifi ed 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 fulfi lled 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 diff erence –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 effi cacious as the standard regimen. This fi nding could increase treatment options in resource-poor settings when referral care is not available or acceptable

Rates and determinants of neonatal mortality in two rural sub-districts of Sylhet, Bangladesh.

INTRODUCTION:Reducing neonatal mortality rate (NMR) is a challenge in many low- and middle-income countries including Bangladesh. In 2014, the estimated NMR in this country was 28 per 1,000 live births. This rate is higher in rural regions compared to the national average. Currently, Sylhet Division has the highest NMR in Bangladesh. Investigating rates and determinants of neonatal mortality in rural regions of this high-risk division is particularly important to implement evidence-based programs. This study examined rates and determinants of neonatal deaths in a large rural cohort in Sylhet Division. METHODS:We analyzed data from a multi-country cohort study, Aetiology of Neonatal Infections in South Asia. From November 2011 to December 2013, this study was conducted in two rural sub-districts in Sylhet Division. Community health workers followed 28,960 pregnant women and their newborns up to two months postpartum and collected data on pregnancy outcomes and newborns' survival status. The NMR was obtained by dividing total number of neonatal deaths with all studied newborns. Logistic regression was employed to calculate adjusted odds ratios (AORs) and 95% confidence intervals (CIs) for factors associated with neonatal mortality. Stata 14.0 was used for data analysis. RESULTS:This study analyzed data of 21,227 newborns. The NMR was 43.4 (95% CI: 39.3-48.0) per 1,000 live births (N = 922). Multivariable analysis showed that the odds of neonatal mortality were significantly higher among male newborns (AOR: 1.5, 95% CI: 1.2-1.8), babies born before 34 weeks of gestation (AOR: 5.0, 95% CI: 4.1-6.1), those who were twins or triplets (AOR: 6.2, 95% CI: 3.6-10.9), and first-born child (AOR: 2.9, 95% CI: 1.6-5.3). Additionally, maternal age 30-35 years (AOR: 1.4, 95% CI: 1.-1.8), history of child death (AOR: 1.6, 95% CI: 1.2-2.2), and delivery complications (AOR: 2.1, 95% CI: 1.6-2.6) had positive associations with neonatal deaths. CONCLUSION:Public health programs in Bangladesh need to adopt a comprehensive strategy to address the individual, maternal, and intrapartum factors associated with neonatal mortality in rural regions. Interventions should aim to prioritize managing pre-term deliveries, first-born child, and delivery complications among pregnant women

Incidence and risk factors of neonatal infections in a rural Bangladeshi population: a community-based prospective study

BACKGROUND: Infections cause about one fifth of the estimated 2.7 million annual neonatal deaths worldwide. Population-based data on burden and risk factors of neonatal infections are lacking in developing countries, which are required for the appropriate design of effective preventive and therapeutic interventions in resource-poor settings. METHODS: We used data from a community-based cluster-randomized trial conducted to evaluate the impact of two umbilical cord cleansing regimens with chlorhexidine solution on neonatal mortality and morbidity in a rural area of Sylhet District in Bangladesh. Newborns were assessed four times in the first 9 days of life by trained community health workers (CHWs) using a WHO IMCI-like clinical algorithm. Cumulative incidence of the first episode of infections in the first 9 days of life was estimated using survival analysis technique accounting for survival bias and competing risk of death before the occurrence of infection. A multivariable generalized estimating equation log-binomial regression model was used to identify factors independently associated with infections. RESULTS: Between 2007 and 2009, 30,267 newborns who received at least one postnatal assessment visit by a CHW within the first 9 days of life were included in this study. Cumulative incidence of infections in the first 9 days of life was 14.5% (95% CI 14.1–14.9%). Significant risk factors included previous child death in the family [RR 1.10 (95% CI 1.02–1.19)]; overcrowding [RR 1.14 (95% CI 1.04–1.25)]; home delivery [RR 1.86 (95% CI 1.58–2.19)]; unclean cord care [RR 1.15 (95% CI 1.03–1.28)]; multiple births [RR 1.34 (95% CI 1.15–1.56)]; low birth weight [reference: ≥ 2500 g, RR (95% CI) for &lt; 1500, 1500–1999, and 2000–2499 g were 4.69 (4.01–5.48), 2.15 (1.92–2.42), and 1.15 (1.07–1.25) respectively]; and birth asphyxia [RR 1.65 (1.51–1.81)]. Higher pregnancy order lowered the risk of infections in the study population [compared to first pregnancy, RR (95% CI) for second, third, and ≥ fourth pregnancy babies were 0.93 (0.85–1.02), 0.88 (0.79–0.97), and 0.79 (0.71–0.87), respectively]. CONCLUSION: Neonatal infections and associated deaths can be reduced by identifying and following up high-risk mothers and newborns and promoting facility delivery and clean cord care in resource-poor countries like Bangladesh where the burden of clinically ascertained neonatal infections is high. Further research is needed to measure the burden of infections in the entire neonatal period, particularly in the second fortnight and its association with essential newborn care. TRIAL REGISTRATION: NCT00434408. Registered February 9, 2007

Effect of a package of integrated demand- and supply-side interventions on facility delivery rates in rural Bangladesh: Implications for large-scale programs

<div><p>Background</p><p>According to the Bangladesh Demographic and Health Survey 2014, only approximately 37 percent of women deliver in a health facility. Among the eight administrative divisions of Bangladesh, the facility delivery rate is lowest in the Sylhet division (22.6 percent) where we assessed the effect of integrated supply- and demand-side interventions on the facility-based delivery rate.</p><p>Methods</p><p>Population-based cohort data of pregnant women from an ongoing maternal and newborn health improvement study being conducted in a population of ~120,000 in Sylhet district were used. The study required collection and processing of biological samples immediately after delivery. Therefore, the project assembled various strategies to increase institutional delivery rates. The supply-side intervention included capacity expansion of the health facilities through service provider refresher training, 24/7 service coverage, additions of drugs and supplies, and incentives to the providers. The demand-side component involved financial incentives to cover expenses, a provision of emergency transport, and referral support to a tertiary-level hospital. We conducted a before-and-after observational study to assess the impact of the intervention in a total of 1,861 deliveries between December 2014 and November 2016.</p><p>Results</p><p>Overall, implementation of the intervention package was associated with 52.6 percentage point increase in the proportions of facility-based deliveries from a baseline rate of 25.0 percent to 77.6 percent in 24 months. We observed lower rates of institutional deliveries when only supply-side interventions were implemented. The proportion rose to 47.1 percent and continued increasing when the project emphasized addressing the financial barriers to accessing obstetric care in a health facility.</p><p>Conclusions</p><p>An integrated supply- and demand-side intervention was associated with a substantial increase in institutional delivery. The package can be tailored to identify which combination of interventions may produce the optimum result and be scaled. Rigorous implementation research studies are needed to draw confident conclusions and to provide information about the costs, feasibility for scale-up and sustainability.</p></div

Incidence and risk factors of neonatal infections in a rural Bangladeshi population: a community-based prospective study

Abstract Background Infections cause about one fifth of the estimated 2.7 million annual neonatal deaths worldwide. Population-based data on burden and risk factors of neonatal infections are lacking in developing countries, which are required for the appropriate design of effective preventive and therapeutic interventions in resource-poor settings. Methods We used data from a community-based cluster-randomized trial conducted to evaluate the impact of two umbilical cord cleansing regimens with chlorhexidine solution on neonatal mortality and morbidity in a rural area of Sylhet District in Bangladesh. Newborns were assessed four times in the first 9 days of life by trained community health workers (CHWs) using a WHO IMCI-like clinical algorithm. Cumulative incidence of the first episode of infections in the first 9 days of life was estimated using survival analysis technique accounting for survival bias and competing risk of death before the occurrence of infection. A multivariable generalized estimating equation log-binomial regression model was used to identify factors independently associated with infections. Results Between 2007 and 2009, 30,267 newborns who received at least one postnatal assessment visit by a CHW within the first 9 days of life were included in this study. Cumulative incidence of infections in the first 9 days of life was 14.5% (95% CI 14.1–14.9%). Significant risk factors included previous child death in the family [RR 1.10 (95% CI 1.02–1.19)]; overcrowding [RR 1.14 (95% CI 1.04–1.25)]; home delivery [RR 1.86 (95% CI 1.58–2.19)]; unclean cord care [RR 1.15 (95% CI 1.03–1.28)]; multiple births [RR 1.34 (95% CI 1.15–1.56)]; low birth weight [reference: ≥ 2500 g, RR (95% CI) for < 1500, 1500–1999, and 2000–2499 g were 4.69 (4.01–5.48), 2.15 (1.92–2.42), and 1.15 (1.07–1.25) respectively]; and birth asphyxia [RR 1.65 (1.51–1.81)]. Higher pregnancy order lowered the risk of infections in the study population [compared to first pregnancy, RR (95% CI) for second, third, and ≥ fourth pregnancy babies were 0.93 (0.85–1.02), 0.88 (0.79–0.97), and 0.79 (0.71–0.87), respectively]. Conclusion Neonatal infections and associated deaths can be reduced by identifying and following up high-risk mothers and newborns and promoting facility delivery and clean cord care in resource-poor countries like Bangladesh where the burden of clinically ascertained neonatal infections is high. Further research is needed to measure the burden of infections in the entire neonatal period, particularly in the second fortnight and its association with essential newborn care. Trial registration NCT00434408. Registered February 9, 2007

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

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.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.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.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

Population-based incidence and serotype distribution of invasive pneumococcal disease prior to introduction of conjugate pneumococcal vaccine in Bangladesh.

BACKGROUND:Bangladesh introduced the 10-valent pneumococcal conjugate vaccine (PCV-10) in 2015. We measured population-based incidence of invasive pneumococcal disease (IPD) prior to introduction of PCV-10 to provide a benchmark against which the impact of PCV-10 can be assessed. METHODS:We conducted population, facility and laboratory-based surveillance in children 0-59 months of age in three rural sub-districts of Sylhet district of Bangladesh from January 2014 to June 2015. All children received two-monthly home visits with one week recall for morbidity and care seeking. Children attending the three Upazilla Health Complexes (UHC, sub-district hospitals) in the surveillance area were screened for suspected IPD. Blood samples were collected from suspected IPD cases for culture and additionally, cerebrospinal fluid (CSF) was collected from suspected meningitis cases for culture and molecular testing. Pneumococcal isolates were serotyped by Quellung. Serotyping of cases detected by molecular testing was done by sequential multiplex polymerase chain reaction. RESULTS:Children under surveillance contributed to 126,657 child years of observations. Sixty-three thousand three hundred eighty-four illness episodes were assessed in the UHCs. Blood specimens were collected from 8,668 suspected IPD cases and CSF from 177 suspected meningitis cases. Streptococcus pneumoniae was isolated from 46 cases; 32 (70%) were vaccine serotype. The population-based incidence of IPD was 36.3/100,000 child years of observations. About 80% of the cases occurred in children below two years of age. DISCUSSION:IPD was common in rural Bangladesh suggesting the potential benefit of an effective vaccine. Measurement of the burden of IPD requires multiple surveillance modalities