The therapeutic efficacy of the
benzoxazinorifamycin KRM-1648 was studied in an experimental rabbit
infection system with avian Mycobacterium avium. The infected rabbits died from Yersin type
infections, a peculiar type of experimental
bovine tuberculosis characterized by a very rapid course, enlargement of the spleen and liver, and septic
infection, 14 to 20 days after bacterial challenge, as evidenced by
bacteremia and severe bacterial loads in the visceral organs. Histopathologic studies of the visceral organs of the infected rabbits revealed the development of numerous typical granulomatous lesions. This experimental rabbit
infection system, features of which resemble certain features of disseminated M. avium complex
infections in
AIDS patients, was used to evaluate the therapeutic efficacy of
KRM-1648, a newly synthesized
benzoxazinorifamycin.
KRM-1648 given orally at 25 and 50 mg/kg of
body weight reduced the incidence and degree of
bacteremia in infected rabbits and protected against subsequent death. Moreover, the
drug allowed almost complete recovery of infected rabbits by week 7.
KRM-1648 cleared
infections in the lungs, liver, spleen, and kidneys and restored histopathologic features of healthy tissue in the visceral organs.
KRM-1648 exhibited a more potent
therapeutic effect against M. avium
infection than
rifampin and
clarithromycin.