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

Abstract

We compared the activities of two different biological-response modifiers with that of clarithromycin against Mycobacterium avium complex infection in C57BL/6 mice. Mice were pretreated daily with clarithromycin (50 mg/kg of body weight subcutaneously [s.c.]), RU-40555 (100 mg/kg s.c.), or granulocyte colony-stimulating factor (G-CSF) at low dose (15 micrograms/kg intraperitoneally [i.p.]) or high dose (300 micrograms/kg i.p.) 3 days before intravenous challenge with 2.5 x 10(7) CFU of the MO-1 strain of M. avium complex. Mice were treated daily until sacrifice at day 1, 8, 15, or 21 after challenge, and the numbers of CFU were measured per gram of tissue in lung and spleen. Compared at day 21 with control treatment, clarithromycin significantly decreased the level of infection in spleen (P < 0.0001) and lungs (P < 0.0001). Compared with control treatment, G-CSF at low dose had no activity, but G-CSF in combination with clarithromycin was more effective than clarithromycin alone in spleen (P < 0.05) and lungs (P < 0.015). The high dose of G-CSF was as effective as the low dose. RU-40555 alone had no beneficial activity. The RU-40555-clarithromycin combination was more effective than control treatment in spleen (P = 0.0001) and lungs (P < 0.0005) and more effective than clarithromycin alone in spleen (P < 0.009) but not in lungs. Thus, our experiments suggest that clarithromycin alone or in combination with G-CSF should be further evaluated for the prophylaxis of M. avium complex infection.

Effects of recombinant granulocyte-colony stimulating factor administration duringMycobacterium aviuminfection in mice

“…Thus, our data do not support previous observations by other groups. Lazard et al [20] invoked a beneficial effect of G-CSF as adjunct therapy in their chemotherapy studies in BALB/c mice infected with a non-virulent strain of M. avium. We should note, however, that we find that such effects in their work were extremely minor.…”

“…Newman et al [19] have shown that neutrophils from AIDS patients significantly inhibited M. avium growth after administration of rHuG-CSF ex vivo. Using a mouse model, Lazard et al [20] have shown that G-CSF in combination with clarithromycin was more effective than clarithromycin alone against M. avium infections. Also, Bermudez and colleagues [21] showed recently an equally beneficial effect of G-CSF on its own on M. avium infections in mice.…”

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

“…The MO-1 strain of MAC, used in our previous studies (2,(8)(9)(10)(11)(12), was isolated from a patient with AIDS and used after a single subculture on mycobacterial Middlebrook 7H11 agar (Difco Laboratories, Detroit, Mich.) supplemented with Middlebrook OADC enrichment (Difco). One flat transparent colony was picked and cultivated at 37ЊC in Middlebrook 7H9 broth (Difco) supplemented with ADC enrichment (Difco) in Falcon tissue culture flasks (Becton Dickinson, Oxnard, Calif.).…”

“…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.…”

Pharmacokinetics, toxicity, and efficacy of liposomal capreomycin in disseminated Mycobacterium avium beige mouse model

“…Numerous studies have been performed either in vitro (25,28,36,49) or on macrophages (46) and in animal models (6,21,34,38,39) with classic or more recent antituberculous agents (ciprofloxacin, sparfloxacin, azithromycin, and clarithromycin) alone or in combi-…”