In vitro and in vivo synergistic effect of isoniazid with streptomycin and clofazimine against Mycobacterium avium complex (MAC)

Abstract

Setting: Isoniazid (INH), the powerful antituberculosis drug, has also been used in regimens for treating disease caused by Mycobacterium avium complex (MAC), an important opportunistic pathogen encountered in AIDS patients. Its use for treatment of MAC disease has also been endorsed by the American Thoracic Society. However some controversy has emerged recently in medical literature, discounting its role and even implying that its use is contraindicated in chemotherapy of MAC disease. Objective: In view of the controversy, we investigated its in vitro and in vivo activity in combination with streptomycin (SM) and clofazimine (CFM) against MAC. Design: In the in vitro studies, the minimal inhibitory concentrations (MIC) of individual drugs or combinations of INH and SM as well as INH and CFM were determined in a checker-board type study by both conventional and radiometric (BACTEC) methods. In vivo studies assessed the efficacy of chemotherapy with INH alone or in combination with either SM or CFM against MAC infection in beige mice. Results and conclusions: While MICs of INH and SM were 12.5 μg/ml and 6.25 μg/ml respectively, complete inhibition of growth was seen at 1.56 μg/ml with the combination of both drugs. The synergistic effect was observed both in conventional and BACTEC methods. In vivo studies demonstrated elevated activity when INH was given along with SM or CFM. Based on these observations we stress that isoniazid has still a place in chemotherapy of MAC disease, at least until other potent drugs are discovered.