The activities of clarithromycin, sulfisoxazole, and rifabutin against three virulent strains of Mycobacterium avium complex isolated from patients with acquired immunodeficiency syndrome were evaluated in a model of intracellular infection. Human monocyte-derived macrophages were infected at day 6 of culture with M. avium complex. Intracellular bacteria were counted 60 min after inoculation. Extra-and intracellular bacteria were counted at days 4 and 7 after inoculation. The concentrations used were 4 ,ug of clarithromycin per ml (MICs for the three strains, 4, 4, and 4 ,ug/ml), 50 pg of sulfisoxazole per ml (MICs, 50, 25, and 25 ,ug/ml), and 0.5 pg of rifabutin per ml (MICs, 2, 0.5, and 0.5 pg/ml). Compared with controls, clarithromycin and rifabutin slowed the intracellular replication of the three strains (at day 7 after inoculation, P was <0.01 for the first strain and <0.001 for the two others). Sulfisoxazole was ineffective against the three strains. Clarithromycin was as effective as rifabutin. Clarithromycin plus rifabutin was as effective as each single agent. Clarithromycin plus sulfisoxazole was as effective as clarithromycin alone.
The activities of sparfloxacin, azithromycin, temafloxacin, and rifapentine against two virulent strains of the Mycobacterium avium complex isolated from patients with AIDS were evaluated in a model of intracellular infection and were compared with that of clarithromycin. Human monocyte-derived macrophages were infected with the M. avium complex at day 6 of culture. The intracellular CFU was counted 60 min after inoculation. The intracellular and supernatant CFU was counted on days 4 and 7 after inoculation. The concentrations used, which were equal to peak levels in serum, were 10 ,ug of rifapentine per ml (MICs for the two strains, 4 and 16 ,ug/ml), 4 ,ug of clarithromycin per ml (MICs, 8 and 4 ,ug/ml), 1 ,ug of azithromycin per ml (MICs, 32 and 16 ,ug/ml), 4 ,ug of temafloxacin per ml (MICs, 2 and 16 ,ug/ml), and 1 ,ug of sparfloxacin per ml (MICs, 0.5 and 2 ,ug/ml). Compared with controls on day 7 after inoculation, clarithromycin (P < 0.001), sparfloxacin (P < 0.001), and azithromycin (P < 0.001 for the first strain, P < 0.02 for the second) slowed intracellular replication. Rifapentine (P < 0.001) and temafloxacin (P < 0.001) slowed intracellular replication of the first strain but not of the second strain. Azithromycin plus sparfloxacin was as effective as sparfloxacin alone. In this macrophage model, sparfloxacin or clarithromycin (difference not significant) exhibited a better efficacy than rifapentine, azithromycin, or temafloxacin against intracellular M. avium complex infection.Mycobacterium avium complex infection remains a frequent opportunistic infection in patients with AIDS (25, 26). New drugs with potent intracellular activity against the M. avium complex inside phagocytes are needed to improve the treatment of this persistent infection. Cell models permit assessment of the activity of antimicrobial agents against the M. avium complex when it is multiplying within human macrophages (1,2,3,20). We have previously shown in a human macrophage model that clarithromycin could be a promising drug in the treatment of M. avium complex infections (20). In a pilot randomized trial, clarithromycin decreased the bacterial counts in the blood of patients with AIDS who presented with a disseminated M. avium complex infection (7). The aim of the present study was to evaluate, in the same model, the activities of new drugs active in vitro against the M. avium complex. The new drugs tested were a macrolide, azithromycin, two fluoroquinolones, temafloxacin and sparfloxacin, and a rifamycin, rifapentine (1, 2, 14-17). Their activities were compared with that of clarithromycin, which was studied in the same model (20 (Becton Dickinson Labware, Oxnard, Calif.). After 21 days of culturing, the bacterial suspension was adjusted to a density of 1 mg/ml with a turbidimeter (Institut Pasteur Production, Paris, France). For each strain, counts of CFU on 7H11 agar correlated this density to a bacterial concentration of 1.5 x 108 and 5 x 108 CFU/ml, respectively. Aliquots of the bacterial suspensions were frozen at -80掳...
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