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

Abstract

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 minimally 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.

Fig 1. Antibiotics administered and prescribed.

We illustrate the proportion of clinically-attended, antibiotic-treated diarrhea cases (stratified as moderate-to-severe diarrhea [MSD] and less-severe diarrhea [LSD] cases) receiving various classes of antibiotics. Proportions are calculated among all cases administered or prescribed an antibiotic who were not diagnosed with pneumonia/lower respiratory tract infection, meningitis or other invasive infection, or typhoid. Totals may not sum to 100%, as each case could receive multiple antibiotics. Estimates are not presented for LSD in Pakistan due to low counts (47 antibiotic-treated cases, total). Data on LSD cases were not collected in Kenya. Lines denote 95% confidence intervals around point estimates.

Fig 2. Adjusted association of pathogen with antibiotic prescribing, dysentery, and hospitalization.

We illustrate adjusted odds ratios for the association of each pathogen with antibiotic treatment among (A) MSD cases, and (B), LSD cases. We next stratify estimates for the association of pathogen with antibiotic receipt, among MSD cases, by (C) sub-Saharan African sites and (D) South Asian sites, and among LSD cases, by (E) sub-Saharan African sites and (D) South Asian sites. Last, we illustrate the association of each pathogen with (G) dysentery and (H) hospitalization, among MSD cases. Analyses of pathogen presence in MSD define presence as Cq<35 and absence as Cq≥35. Adjusted odds ratios are computed with conditional logistic regression models defining matching strata by country, age (in months), and period (in fortnights); all models further adjust for presence of other pathogens and occurrence of any non-diarrhea diagnosis. Children diagnosed with other conditions justifying antibiotic treatment (lower respiratory tract infection, meningitis or other invasive infection, and typhoid) are excluded from analyses. Lines indicate 95% confidence intervals around (median) point estimates.

Fig 3. Pathogen-attributable incidence of clinically-attended, antibiotic-treated diarrhea, by site and age stratum.

We illustrate age-specific incidence of clinically-attended, antibiotic-treated diarrhea estimates per 100 children annually, according to etiology: (A) all causes; (B) rotavirus; (C) adenovirus serotypes 40/41; (D) Shigella; (E) sapovirus (F) ST-ETC; (G) Cryptosporidium; (H) norovirus GII; (I) C. jejuni; and (J) V. cholerae O1. Incidence rates are estimated as the summed rates of incidence of all-cause clinically-attended, antibiotic treated MSD and LSD (S3 Table) multiplied by site-specific adjusted attributable fraction estimates for each pathogen in each of these syndromes (Table 2; S5 Table; S6 Table). Lines denote 95% confidence intervals around median rate estimates (bars). Arrows indicate where upper confidence bounds exceeded the plotted range. Estimated incidence rates exclude diarrhea cases receiving antibiotics who were also diagnosed with pneumonia/lower respiratory tract infection, meningitis or other invasive disease, or typhoid, as these conditions warrant antibiotic treatment irrespective of diarrhea symptoms.

Fig 4. Incidence of clinically-attended, antibiotic-treated diarrhea attributable to enteric pathogens, by age stratum and severity.

We illustrate age-specific incidence of diarrhea episodes resulting in antibiotic treatment per 100 children annually, for the twelve leading etiologies in each age group, aggregated across all sites (excluding Kenya). Incidence rates in the left column are estimated as the summed rates of incidence of all-cause clinically-attended, antibiotic-treated MSD and LSD (S3 Table) multiplied by site-specific adjusted attributable fraction estimates for each pathogen (Table 2; S5 Table; S6 Table). The two right columns present estimates for MSD and LSD. Lines denote 95% confidence intervals around median rate estimates (bars). Arrows indicate where upper confidence bounds exceeded the plotted range. Estimated incidence rates exclude diarrhea cases receiving antibiotics who were also diagnosed with pneumonia/lower respiratory tract infection, meningitis or other invasive disease, or typhoid, as these conditions warrant antibiotic treatment irrespective of diarrhea symptoms. Abbreviations: ST-ETEC (ST-only or LT/ST): Toxigenic E. coli encoding Shiga toxin (stable toxin or heat-labile toxin); tEPEC: Typical enteropathogenic E. coli.