[Studies on therapeutic efficacy of a new anti-tuberculous drug, benzoxazinorifamycin, against murine experimental mycobacterial infections: attempt at various regimens and protocols].
Because of the recent AIDS endemic, there is a worldwide increase in intractable mycobacterial infections including extrapulmonary tuberculosis due to multidrug-resistant M. tuberculosis and disseminated M. avium complex (MAC) infections. Therefore, development of new anti-tuberculous drugs having an excellent antimycobacterial activity and protocols for clinical use of presently available antimicrobials are urgently desired. In this study, we performed in vitro and in vivo experiments to assess the chemotherapeutic efficacy of a newly synthesized benzoxazinorifamycin derivative, KRM-1648 (KRM), against experimental infections due to MAC and M. tuberculosis. In addition, we attempted to improve the therapeutic efficacy of the KRM against MAC infections by changing its administration protocols and timing or by combined use with other antimicrobials, including clarithromycin (CAM), clofazimine (CFZ), sparfloxacin (SPFX), streptomycin (SM), and ethambutol (EB). Furthermore, we examined therapeutic efficacy of KRM against rifampicin (RFP)-resistant M. tuberculosis in details. KRM showing much more potent in vitro activity against the MAC organisms compared to rifabutin (RBT) and RFP, also exerted markedly greater therapeutic efficacy against the MAC infections induced in mice or rabbits in terms of reducing the incidence and the extent of gross pulmonary lesions and the bacterial loads in the lungs and spleens. However, in the case of mouse experimental infections, regrowth of the organisms was initiated after week 4 to 6 even in the animals given KRM. Since KRM-resistant organisms could not be isolated from infected mice given continuous KRM administrations, some unknown mechanisms other than the acquisition of drug resistance by infected organisms may be important for the establishment of the regrowth of MAC organisms.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Microbiology and Immunology, Shimane Medical University, Izumo, Japan.
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Tomioka
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Saito
D000818:Animals; D000904:Antibiotics, Antitubercular / Q000494:pharmacology / Q000627:therapeutic use*; D000995:Antitubercular Agents / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D051379:Mice; D008826:Microbial Sensitivity Tests; D009162:Mycobacterium avium / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D012294:Rifamycins / Q000494:pharmacology / Q000627:therapeutic use*; D014376:Tuberculosis / Q000188:drug therapy*
D000904:Antibiotics, Antitubercular; D000995:Antitubercular Agents; D012294:Rifamycins; C068980:KRM 1648