Study Population and Eligibility

We enrolled children from December 2009 through January 2011 at 18 feeding clinics in rural Malawi. Each child's weight, length, and mid-upper-arm circumference were measured. Children who were 6 to 59 months of age, with edema (indicative of kwashiorkor), a weight-for-height z score of less than −3 (indicative of marasmus),24 or both (marasmic kwashiorkor), were eligible for enrollment. Each eligible child was given a 30-g test feeding of RUTF25 under the supervision of a nurse to verify that the child was an appropriate candidate for outpatient therapy. Children who were too ill to consume the test dose in the clinic were hospitalized for inpatient management. Detailed descriptions of the study methods are provided in the Supplementary Appendix and the study protocol, both of which are available with the full text of this article at NEJM.org.

Study Oversight

The study was approved by ethics boards of the University of Malawi, Washington University in St. Louis, and the Malawi government. A data and safety monitoring board monitored adverse events and interim study outcomes. Caretakers of eligible children provided informed oral and written consent before enrollment. Antibiotics were purchased at cost from the St. Louis Children's Hospital Pharmacy. RUTF was purchased at cost from Project Peanut Butter, which is based in Blantyre, Malawi. The first and last authors vouch for the accuracy and completeness of the data and analyses reported, as well as the fidelity of the report to the study protocol.

Study Design and Interventions

This randomized, double-blind, placebo-controlled clinical trial compared nutritional and mortality outcomes among children with uncomplicated severe acute malnutrition who received treatment as outpatients with or without antibiotics. All children received standardized counseling and RUTF that provided approximately 175 kcal per kilogram of body weight per day. One group received 80 to 90 mg of amoxicillin suspension per kilogram per day, divided into two daily doses; the second group received approximately 14 mg of cefdinir suspension per kilogram per day, divided into two daily doses. A suspension of 250 mg of amoxicillin per 5 ml was used, and the dose to be given to each child was based on a rounded amount that could be given by the field research pharmacist using the markings on a plastic syringe; a similar rounding of medication dose was used for cefdinir. The control group received placebo twice daily. Caretakers were instructed to administer the study drug in addition to RUTF during the initial 7 days of therapy.

Study Procedures

Participants were assigned to their study group when caregivers drew an opaque envelope containing one of nine coded letters corresponding to one of the three intervention groups. Caregivers and study personnel involved in clinical assessments and data analysis were unaware of the intervention assignments. Medications and placebo were distributed in opaque plastic bottles, with a plastic syringe marked with the appropriate dose for the child. After distribution of the study interventions, nurses instructed each caretaker in the use of the syringe to give the study medications and supervised the administration of the first dose in the clinic.

After enrollment and caretaker instruction, each child was discharged home with the assigned study medication and a 2-week supply of RUTF.25 If the household included a healthy child who was close in age to the participant and with whom the food might be shared, an extra allotment of RUTF was provided. Children were scheduled for follow-up visits at 2-week intervals, at which time anthropometric measurements were repeated; caretakers were also asked about the child's interim history and adherence to the assigned intervention.

Children who continued to have bipedal pitting edema or a weight-for-height z score below −2 at follow-up visits24 remained in the study and received nutritional counseling and another 2-week supply of RUTF. Any child whose condition substantially deteriorated during the study or who was still malnourished after six follow-up visits was referred for inpatient care. Children who did not return for follow-up visits were visited at home by community health workers and a member of the study team. Children were considered to have recovered when they were without edema and had a weight-for-height z score of −2 or higher. Children who withdrew from the study, were still malnourished after six follow-up visits, were hospitalized for any reason during the study, or died were considered to have had treatment failure.

Statistical Analysis

The primary end points were the nutritional recovery and mortality rates in the three study groups. We calculated that a sample of 900 children in each group would provide the study with 80% power at an alpha level of 0.05 to detect a reduction of 4 percentage points in the rate of treatment failure from an estimated baseline of 11%26 and a reduction of 3.5 percentage points in the mortality rate from an estimated baseline of 8%.

In addition, one prespecified subgroup analysis was conducted to evaluate the interaction between type of severe acute malnutrition and the intervention received, again with the use of recovery and mortality rates as the primary end points. This interaction was evaluated in a multiple logistic-regression model that included baseline characteristics that were significantly correlated with the primary outcomes in a univariate analysis.

Secondary outcomes of interest included weight gain, length gain, whether the antibiotics were associated with increased rates of adverse events, and time to recovery. Intention-to-treat analyses were used, and all tests were two-sided. Dichotomous outcomes were compared with the use of the chi-square test and Fisher's exact test; continuous variables were compared by means of Student's t-test and analysis of variance. The relative-risk ratios for the outcomes in the three intervention groups were also computed, and Kaplan–Meier plots of time to recovery and time to death were prepared.