Balancing Individual Benefit Against Public Health Risk: The Impact of Cotrimoxazole Prophylaxis in HIV-infected Patients on Antimicrobial Resistance

Abstract

Cotrimoxazole (trimethoprim-sulfamethoxazole) is routinely provided to individuals with AIDS in the United States and Europe for prevention of opportunistic infections, especially Pneumocystis jerovici pneumonia. In Africa, it has been shown to reduce human immunodeficiency virus (HIV)associated mortality and morbidity, 1,2 including reductions in the incidence of malaria, pneumonia, diarrhea, and hospital admissions. 2,3 The addition of insecticide-treated bednets (ITN) and antiretroviral therapy to cotrimoxazole prophylaxis has been demonstrated to have an even more profound impact on malaria rates than cotrimoxazole alone. 3 Despite the favorable outcomes associated with cotrimoxazole use in HIV-seropositive people, concerns have been raised that the widespread use of this drug for prophylaxis will contribute to antimicrobial resistance. 4 Because cotrimoxazole targets the same antifolate pathway enzymes, dihydrofolate reductase (DHFR) and dihydropteroate synthase (DHPS), as the antimalarial sulfadoxine-pyrimethamine (SP), its widespread use could theoretically contribute to increased rates of SP resistance. In this month’s issue of The American Journal of Tropical Medicine & Hygiene, Hamel and colleagues describe the effect of cotrimoxazole prophylaxis on antimicrobial resistance rates among HIV-positive and negative Kenyan adults using a prospective cohort methodology. 5 They selected Streptococcus pneumoniae and Escherichia coli as their sentinel bacterial pathogens. In addition, they assessed the effect of cotrimoxazole prophylaxis on Plasmodium falciparum malaria by screening isolates from parasitemic patients for mutations in the DHFR and DHPS genes. The study included three arms: HIV-negative individuals not receiving cotrimoxazole, HIVpositives with high CD4 counts ( 350 cells/L) who were not receiving cotrimoxazole, and HIV-positives with low CD4 counts who were taking cotrimoxazole. All patients were screened through nasopharyngeal and rectal swabs (for the pneumococcus and E. coli respectively) and by blood smears, at baseline, and then repeatedly out to six months of observation. Their analyses focused on within group changes in the rates of resistance to the sentinel pathogens, as opposed to looking at differences between the three groups in the cohort. This is an important point to emphasize, and is chiefly wherein some of our questions reside in interpreting their findings. Increased resistance to cotrimoxazole occurred within two weeks in the case of the pneumococcus and E. coli, a finding highly concordant with our own investigations of the effect of cotrimoxazole prophylaxis on pneumococcal resistance in infants exposed to HIV at birth. 6 However, the within group analysis found no effect of cotrimoxazole on the prevalence of P. falciparum isolates with resistance mutations. More specifically, among HIV-positive patients receiving cotrimoxazole, the proportion of those parasitemic who had triple or quintuple mutations present (these being the most important combinations in terms of resistance to DHFR or both DHFR and DHPS simultaneously, and hence of primary clinical relevance) was about the same when comparing those patients at baseline with six months later. The authors concluded that while cotrimoxazole use clearly accelerated antibiotic resistance, there was no evidence to suggest that the same problem was developing in P. falciparum. Moreover, parasitemia rates were reduced by almost 90% among those taking prophylaxis. Thus, this suggests a highly beneficial effect of prophylaxis, without evidence of a cost at the population level in terms of SP resistance. But was that really the case? Our reluctance to fully em