A new macrolide, clarithromycin (CAM), with increased acid-stability and thus having a markedly improved absorption efficiency from gastrointestinal tract, was evaluated for its
in vitro antimicrobial activity against various mycobacterial species. CAM had nearly the same level of anti-mycobacterial activity as that of sparfloxacin (SPFX) and slightly higher activity than rifampicin (RFP), except that its anti-
M. tuberculosis activity was much lower than those of SPFX and RFP. Anti-
M. avium complex activity of CAM (MIC90 values against
M. avium and
M. intracellulare were 12.5 and 6.25ug/
ml, respectively) was in similar level as SPFX and RFP. However, MIC distribution pattern revealed that anti-
M. avium activity was in the order of SPFX>CAM>RFP, while anti-
M. intracellulare activities of them were almost the same with each other. Moreover, CAM showed bactericidal action against
M. intracellulare growing in 7H9 medium.
Furthermore, we investigated the therapeutic efficacy of CAM against
M. intracellulare infection induced in mice and also determined its combined effect with other antimicrobials including KRM-1648, SPFX and ethambutol (EB). When CAM suspended in 5% gum arabic saline was given s.c. to mice infected i.v. with
M. intracellulare (8×10
6 CFU) at 0.2 to 2 mg/mouse/day, once daily six times per week from day 1 for 8 weeks, CAM exhibited a potent therapeutic efficacy, in terms of reduction in the incidence of gross lung lesions and reduction of bacterial loads in the visceral organs (reduction of bacterial CFU by 0.9-3.4 log units in the lung and by 0.4-4.6 log units in the spleen during week 4 to 8, depending on its administration dose).
When mice infected i.v. with
M. intracellulare (2×10
7 CFU) were given either CAM (1.0mg/mouse/day) alone, KRM-1648 (0.2 mg/mouse/day) alone, or a combination of both (1.0mg/0.2 mg), by gavage, in the same protocol as above from day 1 to the end of experiment (weeks 12), both of CAM and KRM-1648 showed a significant therapeutic efficacy, and reduced the incidence of gross lung lesions and decreased bacterial loads in the lungs and spleen. SPFX (0.5mg) and EB (0.4mg) failed to show such an action. CAM and KRM-1648 reduced the bacterial CFU in the lungs by 2.1 and 0.9-1.3 log units, respectively, at weeks 4, 8, and 12. The combined use of the two drugs caused an additive potentiation and decreased the bacterial CFU in the lungs by 2.7-3.3 log units. A similar combined effect was also noted for the bacterial loads in the spleen. However, multidrug therapy such as CAM with KRM-1648 in additional combinations with SPFX or EB or both of them failed to achieve more improved therapeutic efficacy as compared to the two drug combination of CAM with KRM-1648.
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