Sparfloxacin, ethambutol, and cortisol receptor inhibitor RU-40 555 treatment for disseminated Mycobacterium avium complex infection of normal C57BL/6 mice

Abstract

Sparfloxacin (50 mg/kg of body weight given subcutaneously each day), alone or in combination with ethambutol (50 mgtkg given subcutaneously each day), was examined for its therapeutic efficacy against experimental infection induced with the Mycobacterium avium complex in normal C57BL/6 mice. In addition, the potential anti-infective role of RU-40 555 (100 mg/kg given intraperitoneally each day), a drug that inhibits the cortisol receptors, was examined in the same model. Treatments were started 24 h after intravenous bacterial challenge and were continued for 21 days. Compared with controls, sparfloxacin or ethambutol decreased the CFU counts in spleens and lungs (P < 0.001). The sparfioxacin plus ethambutol combination was more effective than sparfloxacin alone in spleens (P < 0.001) but not in lungs. The sparfloxacin plus ethambutol plus RU-40 555 combination was more effective than the sparfloxacin plus ethambutol combination in spleens and lungs (P < 0.001). Thus, in this model, RU-40 555 enhanced the antibacterial activities of the antibiotics tested. Results of the study showed that normal C57BV6 mice infected with the M. avium complex can be used for the evaluation of antimicrobial agents. fluoroquinolones (4, 6, 11, 20, 21, 30, 31). Sparfloxacin is a fluoroquinolone that exhibits a good efficacy against the M. avium complex in vitro and in a model of intracellular infection within human macrophages (26,31,36). Ethambutol, which inhibits bacterial cell envelope synthesis, has been shown to be synergistic with fluoroquinolones against the M. avium complex (32). Mifepristone (RU-38 486; Roussel-UCLAF, Romainville, Seine-Saint Denis, France), an inhibitor of the progesterone receptors, is used in humans as a short course of treatment for early pregnancy interruption and for prolonged periods, with good tolerance, for the treatment of some cases of breast cancer, meningioma, and Cushing's syndrome (2,27,33,34). It has been shown in animals that mifepristone is also an inhibitor of the cortisol receptors and could enhance the inflammatory reaction (5, 7, 8, 10, 12, 17, 18, 23-25, 28, 35 In a preliminary study, mice were kept untreated after the

Efficacy of granulocyte colony-stimulating factor and RU-40555 in combination with clarithromycin against Mycobacterium avium complex infection in C57BL/6 mice

“…The administered dose of clarithromycin was chosen to provide a concentration in the sera of mice that was close to the peak concentration obtained in the sera of AIDS patients given the drug orally at a dose of 2 g/day (4.3 ,ug of clarithromycin per ml) (13 We found the same efficacy for RU-40555 in with antibiotics as was found in a previous studs curative treatment (25), but the benefit of RU-405 in the spleen. RU-40555 alone, which showed n the spleen, increased the CFU count in lungs cor control counts.…”

“…The MO-1 strain of M. avium, which was used in our previous studies (25,27) and was isolated from a patient with AIDS, was used after a single subculture on mycobacterial 7H11 agar (Difco Laboratories, Detroit, Mich.) supplemented with Middlebrook OADC enrichment (Difco). One flat transparent colony of the strain was picked and cultivated at 37°C in Middlebrook 7H9 broth (Difco) supplemented with Middlebrook OADC enrichment (Difco) in Falcon tissue culture flasks (Becton Dickinson Labware, Oxnard, Calif.).…”

“…Clarithromycin is one of the most active antibiotics against in vitro and in vivo M. avium infections (7,26,27,29) and is already used for the treatment of M. avium infection in AIDS patients (4, 5). We have previously shown the potential in vivo efficacy of a cortisol receptor inhibitor RU-40555 against M. avium infection (25). Moreover, recombinant human granulocyte colony-stimulating factor (G-CSF) is efficient in preventing experimental infections (10,33).…”

“…G-CSF is already used in patients with AIDS to reverse the myelotoxic effects of drugs such as ganciclovir and zidovudine (14,20). The aim of the present study was to compare the activity of clarithromycin with that of RU-40555 or G-CSF in the normal C57BL/6 mouse model (25). Drugs were started before bacterial challenge and were subsequently administered after the challenge to mimic prophylactic treatment given to patients with AIDS.…”

Use of normal C57BL/6 mice with established Mycobacterium avium infections as an alternative model for evaluation of antibiotic activity

“…The bacterial load reaches concentrations higher than 10 8 CFU/g of spleen and higher than 10 7 CFU/g of lung after 6 months of infection, without the spontaneous clearance of bacteria observed with Swiss Webster mice (4-6). The model of early infection of normal C57BL/6 mice may be used for a rapid screening of drugs (8,9,10). In patients with AIDS, MAC infection has a subacute or a chronic clinical course.…”