Incidence and etiology of clinically-attended, antibiotic-treated diarrhea among children under five years of age in low-and middle-income countries: Evidence from the global enteric multicenter study

Diarrhea is a leading cause of antibiotic consumption among children in low-and middle-income countries. While vaccines may prevent diarrhea infections for which children often receive antibiotics, the contribution of individual enteropathogens to antibiotic use is mini-mally understood. We used data from the Global Enteric Multicenter Study (GEMS) to estimate pathogen-specific incidence of antibiotic-treated diarrhea among children under five years old residing in six countries of sub-Saharan Africa and South Asia before rotavirus vaccine implementation. GEMS was an age-stratified, individually-matched case-control study. Stool specimens were obtained from children presenting to sentinel health clinics with newly-onset, acute diarrhea (including moderate-to-severe and less-severe diarrhea) as well as matched community controls without diarrhea. We used data from conventional and quantitative molecular diagnostic assays applied to stool specimens to estimate the proportion of antibiotic-treated diarrhea cases attributable to each pathogen. Antibiotics were administered or prescribed to 9,606 of 12,109 moderate-to-severe cases and 1,844 of 3,174 less-severe cases. Across all sites, incidence rates of clinically-attended, antibiotic-treated diarrhea were 12.2 (95% confidence interval: 9.0–17.8), 10.2 (7.4–13.9) and 1.9 (1.3–3.0) episodes per 100 child-years at risk at ages 6 weeks to 11 months, 12–23 months, and 24– 59 months, respectively. Based on the recommendation for antibiotic treatment to be reserved for cases with dysentery, we estimated a ratio of 12.6 (8.6–20.8) inappropriately-treated diarrhea cases for each appropriately-treated case. Rotavirus, adenovirus serotypes 40/41, Shigella, sapovirus, Shiga toxin-producing Escherichia coli, and Cryptosporidium were the leading antibiotic-treated diarrhea etiologies. Rotavirus caused 29.2% (24.5– 35.2%) of antibiotic-treated cases, including the largest share in both the first and second years of life. Shigella caused 14.9% (11.4–18.9%) of antibiotic-treated cases, and was the leading etiology at ages 24–59 months. Our findings should inform the prioritization of vaccines with the greatest potential to reduce antibiotic exposure among children.