Intracellular Killing of Mycobacterium avium Complex by Rifapentine and Liposome-Encapsulated Amikacin

Bacteremia caused by organisms belonging to the Mycobacterium avium complex (MAC) is commonly a cause of death in patients with AIDS [1, 2]. Therapeutic failure could be related to delayed diagnosis, the resistance of MAC to common antituberculous drugs [3], and the failure of drugs to reach intracellular sites of infection [4]. Aminoglycosides, such as amikacin, are active in vitro against MAC [5], but they may not attain high intraphagocytic concentrations [6]. Nevertheless, Crowle et al. [7] have demonstrated that streptomycin inhibits growth of Mycobacterium tuberculosis within macrophages, and we reasoned that methods that increase intracellular concentrations of aminoglycosides could augment their chemotherapeutic effect. Liposomal drug-delivery systems have been successfully used to deliver antineoplastic drugs, antibiotics [8], and immunomodulators [9] to intracellular sites. Liposomeencapsulated streptomycin is superior to free streptomycin in the intracellular killing of Staphylococcus aureus [10], and liposome-encapsulated compounds were also more efficacious than free drugs for treating candidal, cryptococcal, and leishmanial infections in vivo [11-13]. Rifapentine [14], a piperazinyl hydrazone derivative of 3-formyl rifamycin, has greater therapeutic efficacy than rifampin in experimental M. tuberculosis and Mycobacterium leprae infections. Because rifapentine has good activity in vitro against MAC [5] and is likely to penetrate cytoplasmic membranes well, we evaluated this agent in a macrophage model of MAC infection [7]. We tested the ability of rifapentine and liposome-encapsulated amikacin (LE-AK), alone and in combination, to kill MAC within cultured human macrophages, and we compared our results with those obtained from experiments with free amikacin.