Cotrimoxazole prophylaxis increases resistance gene prevalence and α-diversity but decreases β-diversity in the gut microbiome of HIV-exposed, uninfected infants.

BACKGROUND: Prophylactic cotrimoxazole treatment is recommended in HIV exposed, uninfected (HEU) infants, but the effects of this treatment on developing HEU infant gut microbiotas and resistomes are largely undefined. METHODS: We analyzed whole-metagenome sequencing data from 163 longitudinally collected stool samples from 63 HEU infants randomized to receive (n=34) or to not receive (n=29) prophylactic cotrimoxazole treatment. We generated taxonomic, functional pathway, and resistance gene profiles for each sample and compared microbiome signatures between cotrimoxazole treated HEU infants (CTX-T infants) and HEU infants not treated with cotrimoxazole (CTX-N infants). RESULTS: Metagenomic analysis did not reveal significant differences in taxonomic or functional pathway α-diversity between CTX-T infants and CTX-N infants. In contrast, resistance gene prevalence (p=0.00719) and α-diversity (p=0.0045) increased in CTX-T. These differences increased over time for both resistance gene prevalence measured by log normalized abundance (4 months mean 0.71, 95% CI [0.2, 1.2] and 6 months mean 0.85; 95% CI [0.1, 1.7]) and α-diversity (p=0.0045). Unlike α-diversity, interindividual gut microbiome taxonomic (mean -0.11; 95% CI [-0.15, -0.077]), functional taxonomic (mean -0.050; 95% CI [-0.084, -0.017]), and resistance gene (mean -0.13; 95% CI [-0.17, -0.099]) β-diversity decreased in CTX-T infants compared to CTX-N infants. These results are consistent with persistent antibiotic selection pressure. CONCLUSIONS: Cotrimoxazole prophylaxis in HEU infants decreased gut microbiome β-diversity and increased antibiotic resistance gene α-diversity and prevalence. Antibiotic resistance is a growing threat, especially in low- and middle-income countries where the higher perinatal HIV-exposure rates result in cotrimoxazole prophylaxis. Understanding effects from current HEU infant antibiotic prophylaxis guidelines will inform guideline revisions and efforts to reduce increasing antibiotic resistance.