The use of gatifloxacin (GAT) in combination with ethionamide (ETA) with or without pyrazinamide (PZA) for a 12-week treatment period followed by an 8-week observation period was evaluated in a model of tuberculosis in mice. Mice treated with GAT at 300 mg/kg of body weight in combination with ETA (25 mg/kg) for 5 days per week had sterile lungs, whereas mice treated with GAT (100 mg/kg) and ETA (25 mg/kg) had about 10 CFU/lung; however, there was regrowth of the organisms in both groups at the end of the observation period. When PZA (450 mg/kg 5 days per week) was added to the high-dose GAT-ETA regimen, no viable mycobacteria were present after the 8-week observation period. GAT in combination with ETA and PZA has great promise for the treatment of tuberculosis.The activities of gatifloxacin (GAT) alone and in combination with ethionamide (ETA) and pyrazinamide (PZA) were recently studied in a murine tuberculosis model (1); GAT at 100 mg/kg of body weight daily was used alone and in combination with ETA at 75 mg/kg daily and performed well. The addition of PZA at 150 mg/kg daily did not enhance the activity of the GAT-ETA regimen.One of the newer 8-methoxyquinolones (GAT or moxifloxacin) with potent in vitro and in vivo (murine model) antituberculosis activities in combination with ETA might provide an effective regimen for the treatment of patients with multipledrug-resistant tuberculosis (MDRTB). It would be useful to develop a short-course regimen against MDRTB whose efficacy is comparable to that of isoniazid (INH)-rifampin (RIF)-PZA. GAT, a DNA gyrase inhibitor, has a mechanism of action different from those of established antimycobacterial agents. ETA is active against most INH-resistant tuberculosis isolates. It is reasonable to evaluate regimens for the treatment of MDRTB caused by a pansusceptible strain if there is minimal potential for cross-resistance among the agents studied.The aims of this study were to evaluate these agents in combination regimens by using a long-term treatment model (5) to evaluate their clinical potential for the treatment of MDRTB.
MATERIALS AND METHODS
Drugs.GAT was provided by Bristol-Myers Squibb Co., Princeton, N.J. INH, RIF, PZA, and ETA were purchased from Sigma Chemical Co., St. Louis, Mo. GAT was dissolved in 20% ethanol (80% distilled water), INH was dissolved in distilled water, while RIF, ETA, and PZA were dissolved in 20% dimethyl sulfoxide. INH-RIF and ETA-PZA were prepared, aliquoted, frozen at Ϫ20°C, and then thawed before use. The drug(s) was administered in a 0.2-ml volume by gavage. The mice were treated with ETA, ETA-PZA, or INH-RIF in the morning and with GAT in the afternoon. GAT was administered separately because the high-dose preparation was a fine suspension rather than a solution.Isolate. Mycobacterium tuberculosis ATCC 35801 (strain Erdman) was obtained from the American Type Culture Collection, Manassas, Va. The MICs of the antimicrobial agents other than PZA were determined in 7H10 broth (pH 6.6; 7H10 agar formulation with agar and malachite green...