Activities of roxithromycin against Mycobacterium avium infections in human macrophages and C57BL/6 mice

Abstract

The activity of roxithromycin against three clinical isolates of Mycobacterium avium was compared with that of clarithromycin both in a model of infection of human monocyte-derived macrophages and in a model of established infection of C57BL/6 mice. In the cell culture model, roxithromycin and clarithromycin were bactericidal for strains MO-1 and N-92159 and bacteriostatic for strain N-93043. For the three strains, the differences between the intracellular activities of roxithromycin and clarithromycin were not significant after 7 days of treatment. Mice were infected with the MO-1 strain. Drugs were given by gavage at a dosage of 200 mg/kg of body weight 6 days per week for 16 weeks starting 5 weeks after infection. At the end of treatment, clarithromycin was more effective than roxithromycin in lungs; roxithromycin was as effective as clarithromycin in spleens. Thus, the activity of roxithromycin was comparable to that of clarithromycin both in vitro and in vivo.New macrolides are among the most active antibiotics against the Mycobacterium avium complex. Clarithromycin, in particular, has been proven to be effective in treating disseminated M. avium infection in AIDS patients (6, 10) and is now the reference macrolide for this indication. Among other macrolides, although roxithromycin has been shown to be active in vitro against M. avium (1, 2, 11, 14, 15), its activity has been neither compared with that of clarithromycin nor evaluated in vivo. The purpose of the present study was to evaluate the anti-M. avium activity of roxithromycin compared with that of clarithromycin both in vitro in a model of infection of human monocyte-derived macrophages and in vivo in a model of established infection in C57BL/6 mice. MO-1, N-93043, and N-92159, obtained from the blood of AIDS patients were used for the in vitro studies. Strain MO-1 was used for the in vivo studies; this strain has been used in our previous studies (3,4,12,13). Cell suspensions with predominantly (Ͼ95%) transparent colony morphologies cultivated in Middlebrook 7H9 broth (Difco Laboratories, Detroit, Mich.) supplemented with ADC enrichment (Difco) were used as described previously (13). The organisms were passaged through C57BL/6 mice to maintain the virulence of the organisms. MATERIALS AND METHODS Strains of M. avium. Three clinical isolates of M. avium,Antimicrobial agents. Roxithromycin (Roussel-Uclaf, Romainville, France) and clarithromycin (Abbott France, Rungis, Val de Marne, France) were provided as standard powders by the manufacturers. In the cell model, the lactobionate salt of clarithromycin was used and was dissolved in distilled water; roxithromycin was dissolved in methanol and was subsequently diluted in distilled water. For the in vivo studies, suspensions in carboxymethyl cellulose were used for both antibiotics tested.In vitro susceptibility. The MICs were determined by the agar macrodilution method by using Mueller-Hinton agar medium supplemented with 10% Middlebrook OADC enrichment (Difco) (17).Human macrophage model. (i) Human m...

Intracellular bioactivity of macrolides

“…Further work has pointed to the intracellular bactericidal activity of roxithromycin and clarithromycin in human macrophages and J774 for MAC strains isolated from HIV‐seropositive and HIV‐seronegative patients, and almost complete eradication using the triple combination of a macrolide plus rifampicin plus ethambutol [26, 27]. The in vitro activity of roxithromycin, clarithromycin and azithromycin has been correlated with therapeutic efficacy in animal models of infection [28–30]. Clinical trials have been started to assess the therapeutic and prophylactic efficacy of these drugs.…”

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.…”

“…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.…”

ATP Synthase Inhibition of Mycobacterium avium Is Not Bactericidal

“…Very few compounds have shown bactericidal efficacy against M. avium complex infections in the beige or the C57BL/6J mouse models. Many drugs have been tested, but with the exception of macrolides (4,11,16) and aminoglycosides (5,9,11,12), none were bactericidal. AMK is the only antimicrobial tested which was able to increase the activity of CLA in the mouse model and to prevent the selection of resistant mutants of M. avium to CLA (12).…”