Mass azithromycin distributions may amplify macrolide resistance, according to a study published in The New England Journal of Medicine

Mass distribution of azithromycin to preschool children in sub-Saharan Africa twice a year for 2 years has been demonstrated to reduce childhood mortality. To investigate the potential effect on antibiotic resistance, investigators enrolled 30 villages in Niger and randomized them to receive either azithromycin or placebo (ClinicalTrials.gov, NCT02047981) every 6 months for 4 years. All children in the villages aged 1 to 59 months were included and had rectal swabs collected at baseline, 36 months, and 48 months.

Mean coverage in the participating village was 83.2±16.4% for azithromycin and 86.6±12% for placebo. In total, 3232 samples were sequenced and analyzed. The 48-month analysis included 546 placebo samples and 504 azithromycin samples. The 36-month analysis included 554 placebo samples and 513 azithromycin samples.


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At baseline, the abundance of genetic determinants for resistance were similar in both groups. However, by month 48, macrolide-resistance determinants were 7.5 times as high (95% CI, 3.8-23.1) in villages treated with azithromycin compared to villages treated with placebo. At 36 months, the resistance determinants were 7.4 times as high (95% CI, 4.0-16.7). Investigators also found an increase in resistance determinants to several non-macrolide antibiotic; an additional 2 rounds of mass azithromycin distribution caused resistance determinants for beta-lactams to rise 2.1 times as high (95% CI, 1.2-4.0).

The trial was limited in that the storage of samples precluded phenotypic assessments of the gut organisms. This prevented the direct identification of organisms that potentially contributed to non-macrolide resistance. Generalization of the results beyond rural villages in Niger should be made with caution.

According to investigators, the trial revealed that mass azithromycin distributions were associated with increased macrolide-resistance and non-macrolide resistance genes. “Resistance surveillance should be an intrinsic component of any mass drug distribution program, and it can be achieved with metagenomic approaches,” investigators concluded.

Disclosure: A study author declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of author’s disclosures.

Reference

Doan T, Worden L, Hinterwirth A, et al. Macrolide and nonmacrolide resistance with mass azithromycin distribution. N Engl J Med. 2020;383(20):1941-1950. doi: 10.1056/NEJMoa2002606.