Powerful bactericidal activity of sparfloxacin (AT-4140) against Mycobacterium tuberculosis in mice.
The bactericidal activities of various monotherapies and combined regimens were compared in mice at different stages after infection with Mycobacterium tuberculosis. These therapies mimicked the initial and continuation phases of chemotherapy for human tuberculosis. As monotherapy, the bactericidal activity of sparfloxacin (SPFX) was dose related; the activity of SPFX at 100 mg/kg of body weight was comparable to that of rifampin (RMP) and was significantly greater than those of isoniazid (INH), pyrazinamide (PZA), or ofloxacin (OFLO) during both the initial and continuation phases of chemotherapy. During the initial phase, the addition of SPFX did not enhance or diminish the activities of the combinations INH-RMP-PZA or RMP-PZA; the combinations SPFX-PZA-streptomycin (SM) and SPFX-PZA-kanamycin (KANA) displayed powerful bactericidal activity. Because the area under the plasma concentration-time curve of SPFX (100 mg/kg) in mice is similar to that of SPFX (400 mg) in humans, the promising bactericidal activity displayed by SPFX in mice might be achieved in humans by administration of the drug in a clinically tolerated dosage. In addition, the combinations SPFX-PZA-SM and SPFX-PZA-KANA may be useful for the treatment of multidrug-resistant tuberculosis.
Faculté de Médecine Pitié-Salpétrire, Paris, France.
V
V
Lalande
C
C
Truffot-Pernot
A
A
Paccaly-Moulin
J
J
Grosset
B
B
Ji
D000818:Animals; D000995:Antitubercular Agents / Q000627:therapeutic use*; D015169:Colony Count, Microbial; D004359:Drug Therapy, Combination; D005260:Female; D024841:Fluoroquinolones; D008168:Lung / Q000382:microbiology; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D015363:Quinolones / Q000627:therapeutic use*; D013154:Spleen / Q000382:microbiology; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality
D000995:Antitubercular Agents; D024841:Fluoroquinolones; D015363:Quinolones; C061363:sparfloxacin