Impact of azithromycin and nitazoxanide on the enteric infections and child growth: Findings from the Early Life Interventions for Childhood Growth and Development in Tanzania (ELICIT) trial

Abstract

Background: Early childhood enteric infection with Shigella/EIEC, enteroaggregative E. coli (EAEC), Campylobacter, and Giardia has been associated with reduced child growth, yet a recent randomized trial of antimicrobial therapy to reduce these infections did not improve growth outcomes. To interrogate this discrepancy, we measured the enteric infections from this study.

Methods: We leveraged the Early Life Interventions for Childhood Growth and Development in Tanzania (ELICIT) trial, a randomized double-blind placebo-controlled trial of antimicrobial therapy with azithromycin and nitazoxanide provided quarterly to infants from 6 to 15 months of age. We tested 5,479 stool samples at time points across the study for 34 enteropathogens using quantitative PCR.

Results: There was substantial carriage of enteropathogens in stool. Azithromycin administration led to reductions in Campylobacter jejuni/coli, enteroaggregative E. coli, and Shigella/EIEC (absolute risk difference ranged from -0.06 to 0.24) 2 weeks after treatment however there was no effect after 3 months. There was no difference in Giardia after nitazoxanide administration (ARR 0.03 at the 12 month administration). When examining the effect of azithromycin versus placebo on the subset of children infected with specific pathogens at the time of treatment, a small increase in weight-for-age Z score was seen only in those infected with Campylobacter jejuni/coli (0.10 Z score, 95% CI -0.01-0.20; length-for-age Z score 0.07, 95% CI -0.06-0.20).

Conclusion: The antimicrobial intervention of quarterly azithromycin plus or minus nitazoxanide led to only transient decreases in enteric infections with Shigella/EIEC, enteroaggregative E. coli (EAEC), Campylobacter, and Giardia. There was a trend towards improved growth in children infected with Campylobacter that received quarterly azithromycin.

Fig 1. Overall pathogen prevalence in the stool of ELICIT children at 6, 12, and 18 months by qPCR.

Y axis shows prevalence or proportion positive. EAEC = enteroaggregative E. coli; EIEC = enteroinvasive E. coli; LT-ETEC = heat labile toxin producing E. coli; ST-ETEC = heat stabile toxin producing E. coli; tEPEC = typical enteropathogenic E. coli.

Fig 2. Difference in enteropathogen detection in the antibiotic versus placebo arms at 6, 6.5, 12, 12.5, and 18 months.

X axis is the absolute difference in pathogen prevalence between the antibiotic and placebo arms. Negative values to the left of 0.0 represent lower carriage in the active arm.

Fig 3. Difference in pathogen detection in children that recently received non-study antibiotics.

X axis is the absolute difference in those that received non-study antibiotics during the month prior to 6, 12, and 18 months versus those that did not receive non-study antibiotics. Negative values to the left of 0.0 represent lower carriage with receipt of non-study antibiotics.

Fig 4. Difference in 3 month growth outcomes by treatment arm stratified by pathogen detection at 6 and 12 months of age.

Shown are the subset of children at 6 and 12 months with Shigella/EIEC, enteroaggregative E. coli (EAEC), Campylobacter, Giardia, or Cryptosporidium detected compared with those without the pathogen detected. The X axis is the difference in the length (left) or weight (right) for age Z score in the antimicrobial arm–the Z score in the placebo arm, such that a difference in Z score above 0.0 represents an increase in child length or weight with antimicrobials.