Cotrimoxazole (CTX) prophylaxis reduces morbidity and mortality in HIV-infected children, even in settings with high background rates of CTX-resistant pathogens. However, with declining mother-to-child HIV transmission globally, the risks and benefits of infant empiric CTX prophylaxis need to be re-evaluated, including the potential for higher rates of resistance to CTX and other antibiotics following CTX prophylaxis.
The Mpepu Study randomized HIV-exposed infants to either CTX or placebo starting between 14-34 days of life and continued through 15 months of age. In 2014-2015, stool was collected from a subset of participating infants at randomization and at 3 and 6 months of age, and stored at -70°C prior to culture. In specimens that grew E coli or Klebsiella spp, antibiotic susceptibility testing by Kirby Bauer method was done for CTX (CTX 25µg) in Mueller Hinton agar. Amoxicillin (Amox 10µg) testing was also performed for E. coli isolates. Clinical & Laboratory Standards Institute guidelines for disc diffusion were used to classify resistant isolates. Fisher’s exact testing was used to compare resistance by randomization arm (CTX/placebo) and to evaluate clinical outcomes.
A total of 380 stool samples from 221 infants were cultured: 116 at randomization, 152 at 3 months, and 112 at 6 months. Two hundred and six samples grew E. coli, 139 samples grew Klebsiella spp, and 101 samples grew other species. Resistance to both E. coli and Klebsiella spp was common at the randomization visit and did not differ by study arm (Figure 1). At 3 and 6 months, infants randomized to CTX were significantly more likely to have E. coli and Klebsiella. spp resistant to CTX (all comparisons p<0.01), and E. coli isolates were also more likely to be resistant to Amox (all comparisons p < 0.05). Of 78 infants with CTX resistant E. coli and/or Klebsiella spp at 3 and/or 6 months, 1% died, 4% had grade 3/4 diarrheal illness, and 1% had grade 3/4 pneumonia in the first 12 months. Clinical comparison to CTX-sensitive infants was precluded, as there were only 8 such infants.
In the setting of high baseline CTX- and Amox-bacterial resistance, infant CTX prophylaxis further increased both CTX- and Amox-resistant isolates of commensal gastrointestinal bacterial. There were few adverse clinical events among infants with resistance. Additional research is needed to determine the longer-term clinical, microbiologic, and public health impact of resistance selected by CTX prophylaxis.