In 2000, the WHO and Joint United Nations Programme on HIV/AIDS (UNAIDS) secretariats recommended that infants in resource-poor settings, with perinatal HIV exposure from an infected mother should receive co-trimoxazole (trimethoprim-sulfamethoxazole) prophylaxis presumptively. (1,2) Co-trimoxazole prophylaxis would continue until two conditions are satisfied: (i) the child has been fully weaned and is no longer being exposed to maternal HIV; and (ii) the child can be proven uninfected with HIV. In resource-poor settings, presumptive prophylaxis would be necessary for at least a year in most cases. While WHO's policy is intended to protect the subset of HIV-exposed infants who are (or become) HIV-infected in their first year, the majority of infants so targeted will escape HIV infection. (3)
In an earlier commentary on this policy, (4) we drew attention to multiple potential adverse consequences of presumptive co-trimoxazole prophylaxis, with a particular focus on antimicrobial resistance. To better understand how co-trimoxazole prophylaxis affects microbial colonization and resistance rates, we implemented the co-Trimoxazole in Zambian Infants (TZI) project, a longitudinal cohort study designed to measure selected microbiological consequences of WHO's policy. We selected Streptococcuspneumoniae as our sentinel pathogen for several reasons. First, the pneumococcus is a leading cause of morbidity/mortality among infants worldwide. Second, drug-resistant pneumococci are increasingly common and of particular public health concern. Third, multiple aspects of pneumococcal epidemiology can be assessed conveniently via nasopharyngeal colonization surveys. Lastly, the effectiveness of antibiotics and vaccines, our two main tools for combating pneumococcal disease, could both be degraded by widespread presumptive co-trimoxazole prophylaxis. Exposure to sulfonamides is presumably the dominant force behind the emergence of co-trimoxazole-resistant pneumococci and might induce cross-resistance to other antibiotics. (5-8) Moreover, because antibiotic resistance is often linked with specific serotypes, (9-12) exposure to co-trimoxazole might shift the prevailing pneumococcal serotypes away from those represented by the 7-valent conjugate pneumococcal vaccine.
Hence, this analysis addressed the following questions:
* Does co-trimoxazole prophylaxis alter nasopharyngeal pneumococcal colonization rates?
* Does co-trimoxazole prophylaxis induce co-trimoxazole-resistant pneumococci and, if so, how quickly?
* Does co-trimoxazole prophylaxis induce cross-resistance to other antibiotic classes?
* Does co-trimoxazole exposure alter the distribution of pneumococcal serotypes away from 7-valent vaccine strains?
The TZI project was a two-arm longitudinal cohort study whose principal objective was to measure the microbiological consequences of implementing WHO guidelines (2) for presumptive co-trimoxazole prophylaxis on pneumococcal colonization, drug resistance and seroepidemiology. The project was conducted at three antenatal clinics in Ndola, Zambia. Ndola is Zambia's third-largest city, with most of its inhabitants living below the poverty level in periurban compounds. All mother/infant pairs were enrolled at the study clinics. Eligibility criteria were: (i) residence within the catchment zone of our study clinics; (ii) signed maternal informed consent; and (iii) maternal willingness to undergo HIV testing. "Case" infants were those born to HIV-positive women and thus requiring prophylaxis per WHO guidelines. "Comparison" infants were infants born to HIV-negative women, unexposed to HIV and hence not requiring prophylaxis per WHO guidelines. Comparison infants were recruited contemporaneously 1:1 with case infants, and were age- and clinic-matched. Our sample size of 260 mother/infant pairs was powered to detect a 30% reduction in colonization and a twofold increase in co-trimoxazole resistance as a function of co-trimoxazole exposure, while accommodating up to 30% attrition. …