Rapid selection of antimicrobial resistance by cotrimoxazole in HIV-infected Tanzanians

Cotrimoxazole (CTX) prophylaxis rapidly selected CTX-resistant fecal Escherichia coli in HIV-infected Tanzanians, according to the findings of a longitudinal study published in the April 15th edition of the Journal of Acquired Immune Deficiency Syndromes.

CTX prophylaxis also led to resistance to other important antibiotics. The study highlights the conundrum associated with CTX prophylaxis in Africa: it reduces morbidity and mortality and yet might compromise the efficacy of CTX and other antimicrobials used to treat opportunistic infections.

Cotrimoxazole is a cheap, widely available and safe combination antibiotic which prevents serious infections in people with HIV thereby improving their quality of life. These infections include bacterial and Pneumocystis pneumonia, some forms of diarrhea, and malaria.

Randomised studies in Africa have shown that CTX significantly decreases mortality and hospitalisations with no serious adverse effects. A Ugandan study demonstrated that CTX prophylaxis in HIV-infected patients also benefited family members.

Following World Health Organization (WHO) recommendations, CTX prophylaxis in HIV-infected patients is now widely practiced in Africa. However, the litany of the benefits of CTX prophylaxis in Africa is tempered with concern about CTX selection of antimicrobial resistance.

In order to obtain a greater understanding about the role of CTX prophylaxis in the emergence of antimicrobial resistance, a team of Tanzanian and US investigators used fecal E. coli, an indicator organism for gut pathogens as a model to study the emergence of bacteria resistant to CTX and other antibiotics in patients on CTX prophylaxis.

The study took place at HIV voluntary counselling and testing centres (VCTs) in Moshi, Tanzania between August 2004 and December 2005. The VCTs referred study participants to the Infectious Diseases Clinic (IDC) at Kilimanjaro Christian Medical Centre where management of HIV infection and study enrolment took place. The study participants were HIV-uninfected (group A), HIV-infected but not requiring CTX (group B), and HIV-infected and eligible for CTX (group C) adults.

All patients in group B were in WHO stage I while the majority of patients in group C were in WHO stages 3 or 4. The median CD4 count at baseline was 297 (56 to 1200 cells/mm³) and 187 (2 to 1322 cells/mm³) in groups B and C, respectively. Of 181 subjects, 118 (65.1%) were female and the median (range) age was 36 (20 to 72) years.

After providing informed consent, a standardised clinical history was taken and a physical examination carried out for each participant. Only pregnant women in the second to third trimesters were included. WHO staging of HIV infection was carried out and stool samples taken at baseline and after 1, 2, 4, and 24 weeks of CTX prophylaxis.

At baseline, E. coli nonsusceptible to CTX was isolated from 23 (53.5%) of 43 patients in group A, 25 (67.6%) of 37 patients in group B, and 37 (64.9%) of 57 patients in group C. These differences between the groups were not significant. However, there was a rapid selection of nonsusceptible E. coli upon the initiation of CTX prophylaxis.

Within one week, CTX nonsusceptibility was present in 43.6 % of group A subjects, 72.5 % of group B subjects, and 86.2 % of group C subjects. This represented more than a 5-fold increase in resistance due to CTX prophylaxis in HIV-infected patients.

An increasing proportion of nonsusceptible E.coli was recovered from group C by comparison with group A at weeks 1, 2, and 4 and in group B relative to group A at weeks 1 and 2. A statistical model showed that the odds ratios for resistance in group C by comparison with the baseline were 3.4 (P = 0.013), 3.0 (P = 0.019), 2.9 (P = 0.019), and 1.5 (P = 0.515) at weeks 1, 2, 3, and 24. As expected, the model did not reveal any differences between groups A or B when compared to baseline.

In order to obtain insights into the impact of CTX prophylaxis on co-selection of antimicrobial resistance to other antibiotics, fecal E. coli isolates from patients on prophylaxis were assessed for susceptibility to other common antibiotics. CTX nonsusceptibility was significantly associated with nonsusceptibility to ampicillin, chloramphenicol, ciprofloxacin, and nalidixic acid.

The rapid selection for resistance to CTX and other important antibiotics by CTX prophylaxis should be a wake up call. The authors recommend some critical studies that urgently need to be carried out including the identification and evaluation of alternative and cheaper antimicrobials to replace CTX.