Viridans streptococci group: Antibiotic susceptibility profiles, cotrimoxazole prophylaxis and the molecular basis of cotrimoxazole resistance in Uganda

Abstract

This thesis is about studies on the viridians streptococci group (VSG). It focused on two main bacterial species groups, the mutans and the mitis groups of commensal bacteria, which are commonly neglected. These bacteria are not only important in causing dentaln and extra-oral infections like sub acute bacterial endocarditis, but in addition can act as reservoirs for resistance to antibiotics and can transfer resistance determinants to related pathogenic bacteria. We have written 3 reports (Paper I-III) on the antibiotic susceptibility profiles of the most frequently used antibiotics in dental practice in Uganda and the mechanism of resistance to one of the most commonly used antibiotics, cotrimoxazole. In Paper I, the mechanisms of resistance to Cotrimoxazole (SXT) in commensal mitis streptococci group from Uganda were determined and compared to S. pneumoniae. The mechanism was found to be point mutations in the target genes folA and folP. We noted a high diversity of mutations, which suggests that chromosomal changes have been acquired through dynamic interchange of DNA among related species. We also observed a high rate of resistance to SXT, which is a warning that SXT may not be useful for treatment of pneumococcal infections. We recommend that during the treatment of pneumococcal infections, SXT should be used with caution. In Paper II, we evaluated the selection of bacterial resistance by cotrimoxazole prophylaxis and characterized the mechanism of Streptococcus mutans and Streptococcus sobrinus resistance to SXT. It was found that cotrimoxazole prophylaxis selects for cognate resistance in oral bacteria by 6.5 times and that genetic transfer in the folate pathway genes does not seem to be the mechanism of resistance acquisition. There was a high rate of resistance of Streptococcus mutans and Streptococcus sobrinus to tetracycline and ceftriaxone in the studied Ugandan patients independent of SXT prophylaxis. Hence tetracycline and ceftriaxone should be used with caution in treatment of oral bacterial Infections. Other antibiotics like amoxicillin should be used and antibiotic susceptibility tests for other VGS which were not part of this thesis should also be carried out. Paper III reports on the findings of mutagenesis experiments that addressed the question of the influence of individual amino acid differences in resistance to sulfonamide and the influence of gene expression in the folA gene of resistant strains of Streptococcus mutans as compared to susceptible ones. Point mutations (A37V, N172D and R193Q) in the folP gene were found to partly explain resistance to sulfonamide while over expression (by six folds) of the folA gene causes resistance of Streptococcus mutans to trimethoprim. We could not rule out other mechanisms of resistance in these isolates. Thus other mechanisms of SXT resistance in Streptococcus mutans should be sought for. Regular surveillance for antimicrobial resistance in the VGS should periodically be carried out.