Activity of HMR3004 against Mycobacterium avium complex in vitro, in human macrophages and in beige mice

Abstract

Objective To evaluate in vitro, in a cultured macrophage system and in beige mice, the potential therapeutic activity of HMR3004, a new ketolide, against organisms of the Mycobacterium avium complex (MAC). Methods The activity of HMR 3004 against MAC was evaluated in vitro (BACTEC) method) in the human macrophage system and in the beige mouse model. Results HMR3004 was inhibitory for 50% of 24 MAC strains at 8 mg/L and for 90% of the MAC strains at 16 mg/L by the radiometric macrobroth dilution method. The activity in vitro was improved if the MIC determination was carried out at pH 7.2 instead of pH 6.8. When tested in the macrophage system against three strains of MAC, HMR3004 showed inhibitory activity when used at 0.25 mg/L compared with untreated controls. Administration of HMR3004 to beige mice infected with MAC 101 strain caused significant reduction in the number of bacteria in the blood, liver and spleen. The reductions were dose-related, with 200 mg/kg per day for 4 weeks being more effective than 100 mg/kg per day or 50 mg/kg per day (although a dose-dependent relationship was not observed in mortality). Conclusion The ketolide HMR3004 has been shown to be active against MAC, and further assessment of both the therapeutic and prophylactic activity are warranted.