Innovative Treatment Regimens for Severe Infections in Young Infants

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A special series published in this month’s Pediatric Infectious Disease Journal sets the stage for important new evidence that will bolster our fight against one of the top three causes of newborn deaths around the world. Each year more than 710,000 newborns lose their lives to largely preventable severe infections, accounting for nearly one third of the total burden of newborn deaths.  Most of these lives can be saved by improving hygiene and reducing exposure to life-threatening bacterial infections particularly in the first week of life, and by making antibiotics available to newborns who become sick.

Visits made by health workers in the community and at home have allowed health interventions to reach sick newborns in an unprecedented manner and at times of greatest vulnerability. Until recently, newborn deaths caused by severe infections were considered difficult to address, but several advances are paving the way for a concrete strategy and action plan to prevent these deaths. In pursuit of innovative approaches to provide the right care at the right time and in the right place, the series presents research in South Asia and Africa testing several simplified antibiotic regimens for the treatment of severe newborn infections in community-based settings, when referral is not possible. The 9-paper supplement details the studies’ methods, the development and rationale of their approach, the standardization and quality control processes across studies, and the global policy implications.

This multi-partner research initiative was undertaken to evaluate the possibility of providing simplified antibiotic regimens for newborns with infections outside the hospital setting. Managing newborn sepsis in community settings has been part of interventions packages proven to reduce neonatal mortality, yet there was no conclusive evidence that newborn infections could be treated successfully with simplified antibiotics, namely fewer injections working just as well as the standard 14 injection regimen.  Three trials were designed specifically to address this question, paving the way for possible change in global recommendations for newborn sepsis treatment. The studies, known as the SATT and AFRINEST trials,  are being conducted in Bangladesh, Pakistan, the DRC, Kenya and Nigeria. 

Designed to follow the same research protocol testing the same antibiotic regimens, the combined results of these trials are expected to inform World Health Organization guidelines on simple, safe and effective regimens for the treatment of newborns with severe infection and pneumonia, when referral is not possible. The current recommendation for treatment is hospitalization, yet hospital care is not generally available outside of large cities, and even when available, is suboptimal or unaffordable for many families. 

The supplement is freely available through the links below:

New Research on Community Management of Severe Neonatal Infections: An OverviewStoll, Barbara J.; Bhan, Maharaj K.

An Innovative Multipartner Research Program to Address Detection, Assessment and Treatment of Neonatal Infections in Low-resource SettingsQazi, Shamim Ahmad; Wall, Steve; Brandes, Neal; et al. 

Background: In pursuit of innovative approaches for the management of severe infections in young infants, which is a major cause of mortality, a multipartner research program was conceptualized to provide right care in the right place. The primary objective was to generate evidence and identify a simple, safe and effective treatment regimen for young infants with severe infections that can be provided closer to home by trained health workers where referral is not possible. Research: Published and nonpublished data on community-based approaches for the management of neonatal sepsis were critically reviewed by an independent expert panel convened in 2007 by the World Health Organization in collaboration with the United States Agency for International Development and Save the Children/Saving Newborn Lives. These stakeholders agreed to 1) undertake research to improve the specificity of a diagnostic algorithm and revise World Health Organization/United Nations International Children’s Emergency Fund Integrated Management of Childhood Illness guidelines to identify sick young infants for referral, 2) develop research studies with common research designs (1 site in each Bangladesh and Pakistan and a multicentre site in Democratic Republic of Congo, Kenya and Nigeria) and oversight mechanisms to evaluate antibiotic regimens (when referral is not accepted by the family) that are safe and efficacious, appropriate to the severity of infection, and deployable on a large scale and 3) utilize existing program delivery structures incorporating community health workers, skilled health workers to deliver simple antibiotic treatment when referral is not possible. Conclusions: This research program facilitated innovative research in different geographical, cultural and administrative milieus to generate recommendations for policy.

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 AfricaZaidi, Anita K. M.; Baqui, Abdullah H.; Qazi, Shamim Ahmad; et al.

Background: Newborns and young infants suffer high rates of infections in South Asia and sub-Saharan Africa. Timely access to appropriate antibiotic therapy is essential for reducing mortality. In an effort to develop community case management guidelines for young infants, 0–59 days old, with clinically diagnosed severe infections, or with fast breathing, 4 trials of simplified antibiotic therapy delivered in primary care clinics (Pakistan, Democratic Republic of Congo, Kenya and Nigeria) or at home (Bangladesh and Nigeria) are being conducted. Methods: This article describes the scientific rationale for these trials, which share major elements of trial design. All the trials are in settings of high neonatal mortality, where hospitalization is not feasible or frequently refused. All use procaine penicillin and gentamicin intramuscular injections for 7 days as reference therapy and compare this to various experimental arms utilizing comparatively simpler combination regimens with fewer injections and oral amoxicillin. Conclusion: The results of these trials will inform World Health Organization policy regarding community case management of young infants with clinical severe infections or with fast breathing.

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 TrialBaqui, Abdullah H.; Saha, Samir Kumar; Ahmed, A. S. M. Nawshad Uddin; et al.

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.

Simplified Antibiotic Regimens for the Management of Clinically Diagnosed Severe Infections in Newborns and Young Infants in First-level Facilities in Karachi, Pakistan: Study Design for an Outpatient Randomized Controlled Equivalence TrialZaidi, Anita K. M.; Tikmani, Shiyam Sundar; Sultana, Shazia; et al.

Background: Infection in young infants is a major cause of morbidity and mortality in low-middle income countries, with high neonatal mortality rates. Timely case management is lifesaving, but the current standard of hospitalization for parenteral antibiotic therapy is not always feasible. Alternative, simpler antibiotic regimens that could be used in outpatient settings have the potential to save thousands of lives. Methods: This trial aims to determine whether 2 simplified antibiotic regimens are equivalent to the reference therapy with 7 days of once-daily (OD) intramuscular (IM) procaine penicillin and gentamicin for outpatient management of young infants with clinically presumed systemic bacterial infection treated in primary health-care clinics in 5 communities in Karachi, Pakistan. The reference regimen is close to the current recommendation of the hospital-based intravenous ampicillin and gentamicin therapy for neonatal sepsis. The 2 comparison arms are (1) IM gentamicin OD and oral amoxicillin twice daily for 7 days; and (2) IM penicillin and gentamicin OD for 2 days, followed by oral amoxicillin twice daily for 5 days; 2250 “evaluable” infants will be enrolled. The primary outcome of this trial is treatment failure (death, deterioration or lack of improvement) within 7 days of enrollment. Results are expected by early 2014. Discussion: This trial will determine whether simplified antibiotic regimens with fewer injections in combination with high-dose amoxicillin are equivalent to 7 days of IM procaine penicillin and gentamicin in young infants with clinical severe infection. Results will have program and policy implications in countries with limited access to hospital care and high burden of neonatal deaths.

Simplified Regimens for Management of Neonates and Young Infants With Severe Infection When Hospital Admission Is Not Possible: Study Protocol for a Randomized, Open-label Equivalence TrialAFRINEST (AFRIcan NEonatal Sepsis Trial) Group

Background: In resource-limited settings, most young infants with signs of severe infection do not receive the recommended inpatient treatment with intravenous broad spectrum antibiotics for 10 days or more because such treatment is not accessible, acceptable or affordable to families. This trial was initiated in the Democratic Republic of Congo, Kenya and Nigeria to assess the safety and efficacy of simplified treatment regimens for the young infants with signs of severe infection who cannot receive hospital care. Methods: This is a randomized, open-label equivalence trial in which 3600 young infants with signs of clinical severe infection will be enrolled. The primary outcome is treatment failure in 7 days after enrollment, which includes death or worsening of the clinical condition on any day, or no improvement in the clinical condition by day 4 of treatment. Secondary outcomes include compliance with study therapy, adverse effects due to the study drugs and relapse or death during the week after completion of treatment. Discussion: The results of this study, along with ongoing studies in Pakistan and Bangladesh, will inform the development of global policy for treatment of severe neonatal infections in resource-limited settings.

Treatment of Fast Breathing in Neonates and Young Infants With Oral Amoxicillin Compared With Penicillin-Gentamicin Combination: Study Protocol for a Randomized, Open-label Equivalence Trial.  AFRINEST (AFRIcan NEonatal Sepsis Trial) Group

Background: The World Health Organization recommends hospitalization and injectable antibiotic treatment for young infants (0–59 days old), who present with signs of possible serious bacterial infection. Fast breathing alone is not associated with a high mortality risk for young infants and has been treated with oral antibiotics in some settings. This trial was designed to examine the safety and efficacy of oral amoxicillin for young infants with fast breathing compared with that of an injectable penicillin–gentamicin combination. The study is currently being conducted in the Democratic Republic of Congo, Kenya and Nigeria. Methods/Design: This is a randomized, open-label equivalence trial. All births in the community are visited at home by trained community health workers to identify sick infants who are then referred to a trial study nurse for assessment. The primary outcome is treatment failure by day 8 after enrollment, defined as clinical deterioration, development of a serious adverse event including death, persistence of fast breathing by day 4 or recurrence up to day 8. Secondary outcomes include adherence to study therapy, relapse, death between days 9 and 15 and adverse effects associated with the study drugs. Study outcomes are assessed on days 4, 8, 11 and 15 after randomization by an independent outcome assessor who is blinded to the treatment being given. Discussion: The results of this study will help inform the development of policies for the treatment of fast breathing among neonates and young infants in resource-limited settings.

Ensuring Quality in AFRINEST and SATT: Clinical Standardization and MonitoringWall, Stephen N.; Mazzeo, Corinne I.; Adejuyigbe, Ebunoluwa A.; et al.

Background: Three randomized open-label clinical trials [Simplified Antibiotic Therapy Trial (SATT) Bangladesh, SATT Pakistan and African Neonatal Sepsis Trial (AFRINEST)] were developed to test the equivalence of simplified antibiotic regimens compared with the standard regimen of 7 days of parenteral antibiotics. These trials were originally conceived and designed separately; subsequently, significant efforts were made to develop and implement a common protocol and approach. Previous articles in this supplement briefly describe the specific quality control methods used in the individual trials; this article presents additional information about the systematic approaches used to minimize threats to validity and ensure quality across the trials. Methods: A critical component of quality control for AFRINEST and SATT was striving to eliminate variation in clinical assessments and decisions regarding eligibility, enrollment and treatment outcomes. Ensuring appropriate and consistent clinical judgment was accomplished through standardized approaches applied across the trials, including training, assessment of clinical skills and refresher training. Standardized monitoring procedures were also applied across the trials, including routine (day-to-day) internal monitoring of performance and adherence to protocols, systematic external monitoring by funding agencies and external monitoring by experienced, independent trial monitors. A group of independent experts (Technical Steering Committee/Technical Advisory Group) provided regular monitoring and technical oversight for the trials. Conclusions: Harmonization of AFRINEST and SATT have helped to ensure consistency and quality of implementation, both internally and across the trials as a whole, thereby minimizing potential threats to the validity of the trials’ results.

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. Esamai, Fabian; Tshefu, Antoinette Kitoto; Ayede, Adejumoke I.; et al.

Background: The current World Health Organization (WHO) recommendation for treatment of severe infection in young infants is hospitalization and parenteral antibiotic therapy. Hospital care is generally not available outside large cities in low- and middle-income countries and even when available is not acceptable or affordable for many families. Previous research in Bangladesh and India demonstrated that treatment outside hospitals may be possible. Research: A set of research studies with common protocols testing simplified antibiotic regimens that can be provided at the lowest-level health-care facility or at home are nearing completion. The studies are large individually randomized controlled trials that are set up in the context of a program, which provides home visits by community health workers to detect serious illness in young infants with assessment and treatment at an outpatient health facility near home. This article summarizes the policy implications of the research studies. Policy Implications: The studies are expected to result in information that would inform WHO guidelines on simple, safe and effective regimens for the treatment of clinical severe infection and pneumonia in newborns and young infants in settings where referral is not possible. The studies will also inform the inputs and process required to establish outpatient treatment of newborn and young infant infections at health facilities near the home. We expect that the information from research and the resulting WHO guidelines will form the basis of policy dialogue by a large number of stakeholders at the country level to implement outpatient treatment of neonatal infections and thereby reduce neonatal and infant mortality resulting from infection. 

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