On April 2, the Lancet and the Lancet Global Health released results of randomized, open-label equivalence trials conducted in Bangladesh, the Democratic Republic of Congo, Kenya, and Nigeria evaluating the effectiveness of simplified antibiotic regimens administered in the outpatient setting, when hospital referral is not possible, for treatment of possible serious bacterial infection (PSBI) in neonates.1,2 The simplified regimens, which consist of combinations of intramuscular injections of gentamicin and penicillin and oral amoxicillin, give treatment access to families that might not otherwise have access to the WHO standard of care for PSBI in neonates (7–10 days of inpatient admission and parenteral antibiotics). Following publication of these studies, the World Health Organization has released a guideline, Managing possible serious bacterial infection in young infants when referral is not possible.
The intention of the simplified regimens was not to challenge the appropriateness of hospitalization for PSBI, but to provide safe, alternative outpatient regimens for managing PSBI when hospitalization is not possible. In the Bangladesh and African study sites, the simplified regimens of 2, 4, or 7 injections were found to be as efficacious as the reference regimen of 14 injections of daily penicillin and gentamicin, delivered on an outpatient basis.
As a global health professional, I found these studies exciting, intriguing, and robust. Accessing hospital care for PSBI can be overwhelmingly difficult for poor families—transport, cost, access to quality services, and sociocultural barriers are just some obstacles to seeking advanced care for PSBI, to the point that families stay home as their ill neonate deteriorates, and in some cases, dies a preventable death.
On the other hand, as a general pediatrician, I felt uneasy with the idea of managing PSBI in an outpatient or community setting. From my experience, neonates with sepsis can present nonspecifically and deteriorate rapidly. They should be treated with inpatient admission, laboratory and clinical monitoring, parenteral antibiotics, and supportive care. The thought of detecting PSBI, administering intramuscular injections, and completing treatment and monitoring for clinical deterioration on an outpatient basis or in the home sounded like delivery of substandard care.
Although the evidence from the Bangladesh and African trials is clear – that the simplified regimens are as efficacious as the reference regimen – the studies are complex, and need to be applied carefully. But it is also important to appreciate what they do tell us, so we do not miss the opportunity to reach newborns that are dying needlessly from preventable causes. Understanding some key features of the trials can help clinical professionals interpret and apply this important evidence appropriately:
- The purpose of the trials was not to show that outpatient treatment with simplified antibiotic regimens is equivalent to hospital care, but a safe alternative when hospitalization is not possible. Simplified regimens were not compared to the WHO standard of care, (7–10 days inpatient admission and parenteral antibiotics), but to a reference arm of 14 total injections of daily penicillin and gentamicin delivered on an outpatient basis. Neonates were only enrolled for the simplified regimens and outpatient treatment when families refused hospital referral or could not go to hospital. This is the reality for hundreds of thousands of newborns across Africa and Asia.
- Newborns were enrolled and treated appropriate to the severity of infection. Babies appearing to be critically ill were excluded. Patients with convulsions, unconsciousness, inability to feed or cry, apnea, cyanosis, dehydration, bulging fontanelle, major congenital malformation, active bleeding, surgical comorbidities, persistent vomiting, or <1500 grams were felt to be too sick for the simplified regimens and were immediately referred to hospital care.
- The trials tested not only the simplified regimens, but also the complete package of case detection and follow-up that occurred at each study site. In some studies, study physicians were evaluating cases and offering treatment. This needs to be considered in implementation of the simplified regimens in a programmatic setting, where physician services may not be so widely available.
- The potential for ototoxicity secondary to gentamicin therapy is of great concern to those providing care to newborns. Toxicity is a function of drug trough levels, and therefore dosing interval. Data suggests that gentamicin therapy has less toxicity when given over extended intervals (>24 hrs).3 The simplified regimens provide an effective option with two doses of gentamicin at the extended interval dosing.
- The authors of these papers emphasize the importance of concurrently strengthening inpatient neonatal care in hospitals. The simplified regimens should not detract from these very important efforts.
- The simplified regimens address equity. Simplified, outpatient regimens can provide hundreds of thousands of the most marginalized, vulnerable newborns in low-resource settings live-saving care to which they otherwise would not have access. We should not let these babies die preventable deaths at home while we wait for stronger NICU and facility care – these efforts can be pursued simultaneously.
The trials are not without weaknesses and limitations, and significant implementation challenges exist, including ensuring the training and quality of health workers, ensuring simplified regimens are used only when hospital referral is not possible, maintaining skills and adherence to protocols, establishing adequate monitoring and evaluation, setting up surveillance systems for antibiotic resistance, and ensuring antibiotic supply. But outpatient regimens are now an evidence-based option when hospitalization is not possible.
Engagement from professional associations of pediatric and neonatal professionals around the world is needed to ensure proper use of this evidence in the programmatic setting, ask the tough questions, and help us deliver much-needed care to the world’s most vulnerable newborns.