Cotrimoxazole prophylaxis was associated with enteric commensal bacterial resistance among HIV-exposed infants in a randomized controlled trial, Botswana

Abstract

Introduction: Despite declining risk of vertical HIV transmission, prophylactic cotrimoxazole (CTX) remains widely used to reduce morbidity and mortality in the event of HIV infection among exposed infants, with an inherent risk of conferring commensal antimicrobial resistance. Using data from a randomized, placebo-controlled trial of infant CTX prophylaxis, we sought to quantify emergence of antibiotic resistance.

Methods: HIV-exposed uninfected infants enrolled in the Botswana Mpepu study were randomized to prophylactic CTX or placebo between 14 and 34 days of life and continued through 15 months. Stool samples were collected from a subset of participating infants at randomization, three, and six months, and stored at -70°C prior to culture. Specimens that grew Escherichia coli (E. coli) or Klebsiella species (Klebsiella spp.) underwent antibiotic susceptibility testing by Kirby Bauer method using CTX (CTX 1.25/23.75 μg) and Amoxicillin (10 μg) in Mueller Hinton agar. Fisher's exact testing was used to compare prevalence of resistance by randomization arm (CTX/placebo).

Results and discussion: A total of 381 stool samples from 220 infants were cultured: 118 at randomization, 151 at three months, and 112 at six-months. E. coli was isolated from 206 specimens and Klebsiella spp. from 138 specimens. Resistance to CTX was common in both E. coli and Klebsiella spp. at the randomization visit (52.2% and 37.7% respectively) and did not differ by study arm. E. Coli isolates from CTX recipients at three and six months had 94.9% and 84.2% CTX resistance, as compared with 51.4% and 57.5% CTX resistance in isolates from placebo recipients (p=0.01). Klebsiella spp. isolates from CTX recipients had 79.0% and 68.8% CTX resistance at three and six months, as compared with 19.1% and 14.3% in isolates from placebo recipients (p<0.01).

Conclusions: HIV-exposed infants randomized to CTX prophylaxis had increased CTX-resistant commensal gastrointestinal bacteria compared with placebo recipients. Additional research is needed to determine the longer-term clinical, microbiologic, and public health consequences of antimicrobial resistance selected by infant CTX prophylaxis.

Trial registration: ClinicalTrials.gov NCT01229761.

Keywords: HIV-exposed infants; commensal organism resistance; cotrimoxazole prophylaxis.