Azithromycin, rifabutin, and rifapentine were used to treat or prevent disseminated Mycobacterium avium complex (MAC) infections produced in rats immunosuppressed with cyclosporine. Animals with bacteremic infections were treated 1 week after intravenous inoculation with 107 CFU of MAC with azithromycin, 100 mg/kg of body weight administered subcutaneously for 5 days and then 75 mg/kg on Monday, Wednesday, and Friday, or with rifabutin or rifapentine, 20 mg/kg administered intraperitoneally on Monday through Friday. All three drugs showed efficacy after 1 and 2 months. Rifabutin cleared the organisms from tissues more rapidly than azithromycin or rifapentine. To approximate prophylaxis, treatment was started 2 weeks before intravenous inoculation with 104 organisms. MAC infections were undetectable in treated animals after 4 months, while control animals had disseminated infections. These findings support the rationale for clinical trials of treatment and prophylaxis with these agents. The cyclosporine-treated rat appears to be a useful model in which to evaluate compounds for the treatment and prophylaxis of disseminated MAC infections.Disseminated infection with the Mycobacterium avium complex (MAC) is the most common cause of bacteremia in patients with AIDS, occurring in up to 50% of these patients (14). Survival of MAC-and human immunodeficiency virusinfected patients is half that of those with similar stages of human immunodeficiency virus infection but who do not have disseminated MAC infections (13). Treatment regimens with significant activity against MAC have been described, but relapses have occurred and none of the regimens have reliably eradicated the infection (9,10,11,20,25). Thus, there is an urgent need for more effective agents and approaches to the treatment and prevention of MAC infections.Successful treatment of established infections probably requires combination therapy with two or more effective drugs having different mechanisms of action (17). Rifabutin and rifapentine are new rifamycin analogs which demonstrate significant in vitro activity against MAC isolates.Studies of treatment with these agents in animal models have produced contradictory results (4,5,15,16). Azithromycin is a new azilide antibiotic which, despite its low in vitro activity against MAC, has shown promise as a treatment in animal studies (12) and early human trials (26). This efficacy may stem from its unusual pharmacokinetic profile, which can result in high concentrations in tissues (6).A new model of disseminated MAC infection has recently been described in Sprague-Dawley rats immunosuppressed with cyclosporine (CsA) (2). We evaluated the response to treatment with azithromycin, rifabutin, or rifapentine in CsA-treated rats with bacteremic MAC infections. As a model of prophylaxis, we also tested whether these drugs prevent the progression of low-grade infection.(Results of the studies described here were presented in
MATERIALS AND METHODSDrugs. Azithromycin was provided by Pfizer Central Research, Groton, Conn. ...