3--hydroxy-5--(4-isobutylpiperazinyl)benzoxazinorifamycin and Body-Weight

The antibacterial effects of a new benzoxazinorifamycin, KRM-1648 (3'-hydroxy-5'-(4-isobutyl-1-piperazinyl, CAS 129791-92-0), against Mycobacterium ulcerans were evaluated in vivo in mouse foot pads, and the results were compared against those obtained with rifampicin (rifampin, CAS 13292-46-1). When mice were fed with the drugs from the day of footpad inoculations, KRM-1648, at concentrations of 0.001% and higher, mixed in mouse food, was effective in inhibiting the growth of M. ulcerans in the foot pads, and the effects were bactericidal. Effects of KRM-1648 at 0.0005% were bacteriostatic. Similar results were obtained with rifampicin, but only at concentrations of 0.008% and above. In established infection, i.e., when M. ulcerans were growing actively in footpads, bactericidal effects were observed with KRM-1648 at concentrations of 0.002% and above; to obtain similar results with rifampicin, the minimum dose was 0.032%. Thus, the results suggest the superiority of KRM-1648 over rifampicin in the treatment of M. ulcerans infection. The possibility of using KRM-1648 in combination with other antimycobacterial agents is discussed.

Topics: Animals; Anti-Bacterial Agents; Antibiotics, Antitubercular; Body Weight; Eating; Foot; Mice; Microbial Sensitivity Tests; Mycobacterium ulcerans; Rifampin; Rifamycins

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.

Topics: Animals; Antibiotics, Antitubercular; Bilirubin; Body Weight; Eosine Yellowish-(YS); Hematoxylin; Liver; Lung; Male; Mycobacterium avium; Rabbits; Rifamycins; Spleen; Staining and Labeling; Tuberculosis, Avian