Sulfamethoxazole enhances the antimycobacterial activity of rifampicin

DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, MRC Centre for Molecular and Cellular Biology, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 19063/Francie van Zijl Drive, Tygerberg 7505, South Africa

1. Lubabalo Macingwana1,
2. Bienyameen Baker1,
3. Andile H. Ngwane1,
4. Catriona Harper1,
5. Mark F. Cotton2,
6. Anneke Hesseling2,
7. Andreas H. Diacon1,
8. Paul van Helden1 and
9. Ian Wiid1,*

+ Author Affiliations

1. 1DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, MRC Centre for Molecular and Cellular Biology, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 19063/Francie van Zijl Drive, Tygerberg 7505, South Africa

2. 2Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, PO Box 19063/Francie van Zijl Drive, Tygerberg 7505, South Africa

1. ?*Corresponding author. Tel: +(27)-21-9389475 begin_of_the_skype_highlighting +(27)-21-9389475 end_of_the_skype_highlighting; Fax: +(27)-21-9389476;

Abstract

Objectives To investigate the effect of trimethoprim/sulfamethoxazole on the survival of Mycobacterium tuberculosis and trimethoprim and sulfamethoxazole individually and combined with the first-line tuberculosis drugs (isoniazid, rifampicin and ethambutol).

Methods M. tuberculosis strains were exposed to either trimethoprim/sulfamethoxazole combination or sulfamethoxazole and trimethoprim alone at various concentrations. The strains were also exposed to sulfamethoxazole in combination with existing antibiotics to assess the combined effect on the growth of M. tuberculosis in the BACTEC 460TB system. The effect of the drugs was compared with vehicle-treated controls. Drug interactions were interpreted using quotient values obtained from the growth index of cultures treated with a single drug or the combination.

Results Trimethoprim showed a negligible effect on the growth of M. tuberculosis while sulfamethoxazole inhibited 80% of the growth of M. tuberculosis at 4.75 mg/L. There was no synergistic activity between sulfamethoxazole and trimethoprim, although an additive effect was observed. A statistically significant synergistic effect was observed between sulfamethoxazole and rifampicin. Sulfamethoxazole also had an additive effect with ethambutol, but there was no interaction with isoniazid.

Conclusions Sulfamethoxazole is the main active compound against M. tuberculosis in the combination trimethoprim/sulfamethoxazole and has a synergistic effect with rifampicin. These findings suggest that sulfamethoxazole has potential in the multidrug regimen against M. tuberculosis.