Clarithromycin, dapsone, and a combination of both used to treat or prevent disseminated Mycobacterium avium infection in beige mice

Abstract

Bacteremic infection caused by organisms of the Mycobacterium avium complex (MAC) is common in patients with AIDS. We evaluated both clarithromycin and dapsone alone and in combination for the treatment and prevention of disseminated MAC disease in beige mice. In the therapeutic model, C57BL/6 beige mice were infected intravenously with strain 101 of MAC (serovar 1). After 1 week postinfection, mice were given clarithromycin (200 mg/kg of body weight per day) and dapsone (15 mg/kg of body weight per day) alone or in combination by gavage. Treatment with clarithromycin resulted in a significant reduction in bacteremia and the numbers of CFU of MAC in the liver and spleen. Treatment with dapsone had no effect on the mycobacterial counts in blood, liver, or spleen, and the combination of dapsone with clarithromycin was no better than clarithromycin as a single agent. Clarithromycin and dapsone were used to prevent systemic disease in beige mice infected orally with MAC 101. Clarithromycin prophylaxis was associated with a significant reduction in the numbers of bacteria in the liver, spleen, and appendix compared with those in controls. Prophylaxis with dapsone resulted in a mild reduction in the numbers of MAC in the spleen but not in the other tissues. Clarithromycin both treats and prevents MAC disease in beige mice. Dapsone has no therapeutic effect, but it does have a slight prophylactic eflect, and in combination with clarithromycin it does not abrogate the effect of clarithromycin.Organisms of the Mycobacterium avium complex (MAC) are the most common cause of bacterial infection in patients with AIDS. Autopsy studies in AIDS patients have shown a large number of acid-fast bacilli in the liver, spleen, bone marrow, and intestines (17,20,28). Current observations suggest that most of the cases of MAC infection in AIDS patients are acquired by the gastrointestinal tract, and colonization of the gut appears to precede the onset of bacteremia (5,8).MAC is resistant to many of the standard antituberculosis antimicrobial agents, but some strains may be susceptible in vitro and in vivo to agents such as ethambutol, amikacin, rifabutin, macrolides, and azalides (clarithromycin, roxithromycin, and azithromycin), clofazimine, and certain fluoroquinolones (9, 10, 12-14, 22, 23). Clarithromycin, a new macrolide that is structurally related to erythromycin, is active in vitro (19,(25)(26)(27), inhibiting 90% of MAC strains (MICs, 1 to 8 ,ug/ml). Clarithromycin concentrates within macrophages and tissues (2), and it has also been shown to be active in experimental animals (12, 24) and AIDS patients with MAC infection, as shown in clinical trials (7, 9-11). The development of MAC resistance to clarithromycin has been observed in patients taking the antibiotic (18). For instance, in a recent compassionate-use study, resistance following clarithromycin therapy developed in 33% of patients (9).Dapsone is a synthetic antifolate that has activity against Mycobacterium leprae (15) vitro activity against MAC (16). We now report o...

Activity of Moxifloxacin by Itself and in Combination with Ethambutol, Rifabutin, and Azithromycin In Vitro and In Vivo against Mycobacterium avium

“…MAC strains 510 to 513, JJL, and JWL are clarithromycin-resistant strains isolated from patients. MAC 101 is a virulent strain in the mouse test system that causes reproducible levels of infection and mortality in beige mice (1). MAC organisms were cultured in Middlebrook 7H10 medium (Difco Laboratories, Detroit, Mich.) supplemented with oleic acid, albumin, dextrose, and catalase (OADC; Difco) for 10 days at 37°C.…”

Beige mouse model for Mycobacterium avium complex disease

“…It is of interest that rifabutin has now been approved for use as prophylaxis against MAC disease in humans. More recent studies were done with azithromycin, dapsone, and clarithromycin for similar purposes (2,4).…”

In Vitro and In Vivo Activities of Novel Fluoroquinolones Alone and in Combination with Clarithromycin against Clinically Isolated Mycobacterium avium Complex Strains in Japan

“…Mice were infected with MAC strains N016, N018, and N084, as well as the two reference strains, by injection of 100 l bacterial suspension containing 1.0 ϫ 10 7 to 3.0 ϫ 10 7 CFU of each MAC through the tail vein (4,18). After 21 days, treatment with antimicrobial agents was initiated.…”

“…The mice were treated with one of the three FQs alone (MXF, 100 mg/kg of body weight/day; GAT, 100 mg/kg/day; or LVX, 200 mg/ kg/day), CLR alone (200 mg/kg/day), or an FQ-CLR combination, with both agents at the same doses described above. The dose of each antibiotic was based on that in previous studies (1,(3)(4)(5). Each therapeutic study group included five mice ( Fig.…”

“…Female C57BL/6J mice (8 weeks old) were purchased from Charles River Laboratories Japan (Kanagawa, Japan). The mice were intravenously infected with 1.0 ϫ 10 7 to 3.0 ϫ 10 7 CFU of M. avium JATA51-01 in 100 l saline suspension (4,18), and mortality was observed for 130 days after infection. In total, 10 mice per study were used for the determination of mortality, and each study was performed twice.…”