Cotrimoxazole Effect on Microbiome of Infants Exposed to HIV But Uninfected

Treatment with cotrimoxazole in infants exposed to HIV but uninfected (HEU) increases resistance gene prevalence and α-diversity and decreases microbial taxonomic, functional pathway, and resistance gene β-diversity, according to results of a study published in Clinical Infectious Diseases.

Guidelines from the World Health Organization recommend that HEU infants receive cotrimoxazole prophylactically from age 4 to 6 weeks until breastfeeding ceases. Antibiotic treatment at this pivotal developmental period may cause gut microbiome perturbations.

Therefore, researchers analyzed the whole-metagenome sequencing data from 163 longitudinally collected stool samples of HEU infants (N=63) who were randomly assigned to receive prophylactic cotrimoxazole treatment (n=34) or no treatment with cotrimoxazole (n=29). Cotrimoxazole was administered once daily during the study period; infants under 5 kg received 20 mg trimethoprim/100 mg sulfamethoxazole orally, and infants 5 kg to 15 kg received 40 mg trimethoprim and 200 mg sulfamethoxazole orally. Stool samples were collected from infants at 3 intervals (6 weeks, 4 months, and 6 months). The taxonomic, functional pathway, and resistance gene profiles for each sample were used to compare microbiome signatures between the 2 groups of infants.

Metagenomic comparison of infants who received cotrimoxazole treatment and those who did not did resulted in no significant differences in taxonomic or functional pathway α-diversity. However, resistance gene prevalence and α-diversity increased in infants who received cotrimoxazole (P =.00719 and P =.0045, respectively). Inter-individual gut microbiome taxonomic (mean, -0.11; 95% CI, -0.15 to -0.077), functional taxonomic (mean, -0.05; 95% CI, -0.084 to -0.017), and resistance gene (mean, -0.13; 95% CI, -0.17 to -0.099) β-diversity all decreased in infants who received cotrimoxazole compared those who did not.

Limitations of this study included the short duration of collection time points, because further changes may manifest between infants who received and those who did not received cotrimoxazole after sampling. Researchers can only establish relative and not absolute abundance differences, and cannot determine whether there existed a difference in total gut bacterial load between infants who received cotrimoxazole and those who did not. Due to daily dosing regimens, researchers also cannot verify adherence beyond verbal confirmation from mothers that infants received cotrimoxazole and not any other antibiotics.

The researchers shed light on the effects of cotrimoxazole prophylaxis on HEU infant microbiomes and provide information for future treatment recommendations. In contrast to previous studies on antibiotic use in infants, researchers did not observe significant microbiome dysbiosis. Increases in resistance gene prevalence and diversity are important for public health and antibiotic stewardship discussions. “Unnecessary antibiotic prescriptions may contribute to resistance disparities, and there is mounting evidence that cotrimoxazole treatment of HEU infants in countries with low malaria prevalence is ineffective,” the researchers concluded. “Since South Africa has low malaria prevalence and high infant HIV-exposure, WHO recommendations on prophylactic cotrimoxazole may unnecessarily contribute to increasing resistance; however, more research on treatment consequences of high background antibiotic resistance for HIV-exposed infants is needed to refine guidelines.”

Reference

D’Souza AW, Moodley-Govender E, Berla B, et al. Cotrimoxazole prophylaxis increases resistance gene prevalence and α-diversity but decreases β-diversity in the gut microbiome of HIV-exposed, uninfected infants [published online December 13, 2019]. Clin Infect Dis. doi: 10.1093/cid/ciz1186