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ABSTRACT & COMMENTARY

Antibiotics for Severe Acute Malnutrition

March 1, 2013
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By Hal B. Jenson, MD, FAAP, Dean, Western Michigan University School of Medicine, Kalamazoo, Michigan, is Editor for Infectious Disease Alert.

Dr. Jenson reports no financial relationships in this field of study.

Synopsis: In a large study of children with uncomplicated severe acute malnutrition in Malawi, the addition of amoxicillin or cefdinir to therapeutic food regimens was associated with significant improvement in recovery and mortality rates.

Source: Trehan I, et al: Antibiotics as part of the management of severe acute malnutrition. N Engl J Med 2013;368:425-435.

A randomized, double-blind, placebo-controlled clinical trial was conducted from December 2009 through January 2011 at 18 feeding sites in Malawi. This region of oral sub-Saharan Africa has a subsistence farming population with an estimated 11% of adults infected with the human immunodeficiency virus (HIV).

Children 6 to 59 months of age with severe acute malnutrition were randomized to receive amoxicillin (80-90 mg/kg/day in two divided doses), cefdinir (14 mg/kg/day in two divided doses), or placebo (twice daily) for seven days. Providers reported excellent adherence. All children received standardized counseling and ready-to-use therapeutic food.

A total of 2,767 children with severe acute malnutrition were enrolled. The overall study recovery rate was 88.3%. Children with treatment failure were significantly younger and less likely to have their father alive and still in the home. Symptoms of acute infections and poor appetite at enrollment and at the first follow-up visit were also associated with increased risk of treatment failure.

The recovery rates were 88.7% for treatment with amoxicillin, 90.9% for cefdinir, and 85.1% for placebo. The relative risk of treatment failure with placebo versus amoxicillin was 1.32 (95% CI, 1.04 to 1.68), and with placebo versus cefdinir was 1.64 (95% CI, 1.27 to 2.11). The mortality rates were 4.8% (amoxicillin), 4.1% (cefdinir), and 7.4% (placebo). The relative risk of death with placebo versus amoxicillin was 1.55 (95% CI, 1.07 to 2.24), and with placebo versus cefdinir was 1.80 (95% CI, 1.22 to 2.64). The rate of weight gain was increased among children receiving antibiotics compared to children receiving placebo. No interaction was observed between interventions and the type of severe acute malnutrition. The rates of common adverse effects, such as diarrhea, were lower among children receiving antibiotics than among children receiving placebo. No cases of severe allergy or anaphylaxis were identified.

The cost of amoxicillin was $2.67 per child, and the cost of cefdinir was $7.85 per child. The cost of ready-to-use therapeutic food was approximately $50 per child.

Commentary

It is estimated that more than 20 million children worldwide have severe wasting and that more than 1 million children annually still die from malnutrition. Even with international consensus guidelines and availability of ready-to-use therapeutic food regimens for children with severe acute malnutrition, approximately 10-15% of children do not recover. Many studies have shown a high prevalence of clinically significant infections among children with severe acute malnutrition, leading to treatment guidelines recommending the use of antibiotics routinely for these children. This is the first prospective study of the routine administration of oral antibiotics as part of the management of severe acute malnutrition to improve nutritional and mortality outcomes.

In this prospective study, amoxicillin was associated with a 24.4% reduction in the treatment-failure rate, and cefdinir was associated with a 38.9% reduction. Secondary outcomes were also consistent with these findings.

The mechanism of the benefits of antibiotics for malnutrition remains speculative. The lower rates of diarrhea among children receiving antibiotics may suggest that this is via reduction of dehydrating diarrhea. Alternatively, antibiotics may decreasing the rate of concomitant infections, including even subclinical infections, such as bacterial pneumonia.

There is always concern about the adverse impact of widespread use of broad-spectrum antibiotics among a large population of children. Changes in the balance and resistance patterns of intestinal flora do occur with only a few days of antibiotic treatment. The resulting changes in the individual child’s microbiome, and also in the community, in this setting have not been clarified, let alone defining the clinical significance of the changes. These concerns should always be weighed against the proven benefits of antibiotics. Based on the benefits observed in this study of nutritional recovery and reduced risk of death, the authors advocate for the serious consideration of routine use of antibiotics for specific populations of high-risk children with severe acute malnutrition.