Activity of KRM-1648, a new benzoxazinorifamycin, against Mycobacterium tuberculosis in a murine model.
The activity of KRM-1648 was evaluated in a murine model of tuberculosis. Approximately 10(7) viable Mycobacterium tuberculosis ATCC 35801 organisms were given intravenously to 4-week-old female outbred mice. Treatment was started 1 week postinfection and given by gavage for 4 weeks. Viable-cell counts were determined from homogenates of spleen and lung tissues. The activity of KRM-1648 was compared with those of rifampin and rifabutin at 20 mg/kg of body weight. KRM-1648 was more active than either rifampin or rifabutin against organisms in spleens and lungs. KRM-1648 alone and in combination with either isoniazid, ethambutol, pyrazinamide, or levofloxacin was evaluated. Other treatment groups received isoniazid, ethambutol, pyrazinamide, or levofloxacin as single agents. KRM-1648 was the most active single agent evaluated. KRM-1648-pyrazinamide and KRM-1648-isoniazid were the most active combinations. These combinations were more active than KRM-1648 alone. The promising activity of KRM-1648 in M. tuberculosis-infected mice suggests that it is a good candidate for clinical development as a new antituberculosis agent.
Klemens
S P
SP
SUNY Health Science Center, Syracuse 13210.
Grossi
M A
MA
Cynamon
M H
MH
D000818:Animals; D000904:Antibiotics, Antitubercular / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D007538:Isoniazid / Q000627:therapeutic use; D051379:Mice; D011718:Pyrazinamide / Q000627:therapeutic use; D017828:Rifabutin / Q000627:therapeutic use; D012293:Rifampin / Q000627:therapeutic use; D012294:Rifamycins / Q000008:administration & dosage / Q000627:therapeutic use*; D014376:Tuberculosis / Q000188:drug therapy*
D000904:Antibiotics, Antitubercular; D012294:Rifamycins; C068980:KRM 1648; D017828:Rifabutin; D011718:Pyrazinamide; D007538:Isoniazid; D012293:Rifampin