Safety and Efficacy of Simplified Antibiotic Regimens for Outpatient Treatment of Suspected Sepsis in Neonates and Young Infants in Bangladesh (SAT)

Funded by USAID  |  Feb 2008 to Sep 2013

What?

This was a three-cell, randomized, open-label, non-inferiority trial to establish that simplified, home-based antibiotic regimens, for families that refuse hospitalization, were not inferior compared to the standard course of parenteral antibiotics that are used for the empiric treatment of suspected sepsis in young infants.  Two alternative regimens were compared with a standard (reference) regimen of injectable procaine-benzyl penicillin and gentamicin once daily each for seven days.  Alternative regimens are (1) injectable gentamicin once daily and oral amoxicillin twice daily for seven days; and, (2) injectable penicillin and gentamicin once daily for two days followed by oral amoxicillin twice daily for five days. The primary hypothesis is that the proportion of infants who fails treatment will be 10 percent in the reference group and each of the alternative treatment groups

Why?

Although many developing countries have witnessed declines in both post-neonatal child deaths, neonatal death rates have remained relatively constant, with an estimated 2.9 million annual neonatal deaths globally, almost a quarter of which are attributed to infections mostly occurring in developing countries, which usually have high rates of home deliveries. Thus, Strategies for timely identification and management of infections in young infants (0-59 days) including neonates are urgently needed.  The WHO recommends that all cases of suspected severe infection in young infants (0-59 days old) are treated in hospitals with a 7-10 day course of injectable antibiotics – penicillin (or ampicillin) and gentamicin. However, in many developing countries, this care is often not available or accessible, or not acceptable to families, and has multiple disadvantages – many babies may not be able to get to the hospital; routine hospitalization and the use of injectable antibiotics substantially increases cost; and hospitalization increases risk of acquiring nosocomial infections.

Strategies for community-based management of infections in young infants have been developed and evaluated in several research settings. “Projahnmo”, has completed a trial of a package of maternal and neonatal interventions in Sylhet district, Bangladesh, and demonstrated significant reduction of neonatal mortality. Outcome of this study suggests that treatment of neonates by CHWs was generally acceptable to the community. Home treatment of suspected sepsis in neonates by CHWs is effective in low-resource settings. There are, however, major challenges associated with current community-based strategies for injectable therapy: it is difficult to ensure availability of trained health workers, and to ensure supplies and quality assurance; a regimen of parenteral antibiotic therapy presents specific challenges to community acceptance and compliance;  unsupervised use of injection at the community level may be unsafe. Therefore, it is important to reduce the number of injections to be used in the community. Furthermore, the rationale for 7-10 days of parenteral antibiotic therapy is not fully established. There is evidence that oral antibiotic therapy also reduces mortality in neonates with infections. To overcome the disadvantages of hospitalization and challenges of community-based injectable therapy, recent research has looked at the potential use of oral treatment for severe pneumonia in older infants. In the fall of 2007, Saving Newborn Lives (SNL) of Save the Children-US, USAID and WHO convened a global consultation to review the new study findings on infection management in young infants in community-based settings and to guide future research priorities.  Based on the existing research findings at that time, the consultation participants concluded that there was still insufficient evidence to make policy recommendations for global programs.  The consultation charged future research to test optimal combination of oral and intramuscular (IM) antibiotic regimens that would be feasible to implement in first-level facilities and community and will be acceptable to families for settings characterized by weak health systems. We designed this study with these recommendations in mind.

How?

Young infants were recruited from the outpatient departments of Dhaka Shishu Hospital, Shishu Sasthya Hospital in Dhaka, Institute of Child and Mother Health Hospital in Dhaka, Chittagong Ma O Shishu Hospital in Chittagong, and a rural surveillanc sites in Sylhet, Bangladesh. All 4 hospitals are located in the urban areas of two major cities of Bangladesh where they receive young infants with similar complaints and clinical management is also similar. In the rural site, all pregnant women in the study area are identified by female community health workers (CHW) through established pregnancy surveillance. Prompt birth notification was set in place and based on that, CHWs tried to visit all newborns in the home within 6 and no later than 24 hours after birth to capture early-onset infections. Infants were initially assessed, and the CHW returned on days 2, 6, 13, 20, 27, 34, 41, 48 and 59 after birth to inquire about any illness, and to reassess the status of the infant. CHWs referred infants meeting the criteria for “suspected severe infection” to two designated hospitals for further evaluation and care.

In the urban hospitals, young infants presenting to the outpatient departments were screened by research assistants to determine initial eligibility criteria with regard to age and place of residence.  Potentially eligible infants were screened by the study physician for signs of suspected severe infections. In case of hospitalization, families were offered to participate in an observational cohort sub-study consisting to document treatments administered, duration of hospitalization, and treatment outcome. As per standard procedure, babies were referred to another hospital when bed is not available, but families rarely pursued this alternative because pediatric bed availability at other public hospitals is very limited. After informed consent, infants were randomized to one of three home-treatment regimens using site and age-specific computer-generated randomization sequences with varying random block sizes. Dosages were selected to optimize efficacy, safety, and feasibility. All enrolled infants were given the first doses of the assigned antibiotics and discharged to home after counseling on home management. Study physicians provided intramuscular injections at home and assessed infants daily for the next 7 days to assess for treatment failure and on days 11 and day 15 to determine relapse. Caregivers were taught to give the oral antibiotics. Treatment failure within 7, compliance of the doses, relapse on treatment, death and adverse event rates were observed as a outcome of the study. Blood were collected from each infant at enrollment, and in the case of confirmed treatment failure based on clinical criteria, and blood cultures performed. Urine samples were obtained from infants whenever feasible upon entrance into the study to assess recent antibiotic usage.

What we found

The trial builds upon previous research conducted by this research team in Bangladesh; the results of which demonstrated a significant morality reduction through community management.  Despite these results, the approach was not widely accepted in part because of issues of feasibility and concern about the large number of injections. A new proposed research will address these issues by demonstrating whether simplified antibiotic treatment regimens that include fewer doses of parenteral antibiotics are as efficacious as standard parenteral antibiotics for the treatment of suspected severe infection in young infants. In the context of the study, steps have been taken to ensure that the trial does not provide an incentive to accept home-based care in lieu of hospital care when hospital care is available and medically recommended.

Resources:

  • Protocol (Coming soon!)
  • SOPs (Coming soon!)
  • Data Forms (Coming soon!)
  • Flow charts/Diagram (Coming soon!)
  • Publications:
    • Esamai F. et al. Ongoing Trials of Simplified Antibiotic Regimens for the Treatment of Serious Infections in Young Infants in South Asia and Sub-Saharan Africa: Implications for Policy. Pediatr. Infect. Dis. J. Sep 2013, 32(S1): S46-49. doi: 10.1097/INF.0b013e31829ff941
    • Zaidi AK et al. Scientific rationale for study design of community-based simplified antibiotic therapy trials in newborns and young infants with clinically diagnosed severe infections or fast breathing in South Asia and sub-Saharan Africa. Pediatr. Infect. Dis. J. Sep 2013, 32(S1): S7-11.  doi: 10.1097/INF.0b013e31829ff5fc
    • Baqui AH et alSafety 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. Pediatr. Infect. Dis. J. Sep 2013, 32(S1): S12-18.  doi: 10.1097/INF.0b013e31829ff790.

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