LENAERTS AJ, GRUPPO R, BROOKS J, ORME IM; Interscience Conference on Antimicrobial Agents and Chemotherapy (42nd : 2002 : San Diego, Calif.).

Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2002 Sep 27-30; 42: abstract no. B-1050.

Colorado State University, Fort Collins, CO

We have developed a rapid new in vivo method for screening experimental drugs for their activity against M.tuberculosis. This model uses the gamma interferon gene-disrupted (GKO) C57BL/6 mouse, an animal that develops a fatal, disseminated form of disease after exposure to low dose aerosol infection. Using this model we have found that statistical differences indicating positive efficacy of active compounds can be seen after only 8 days of treatment, reflecting the rapid growth of the infection in untreated controls. As an example of the use of this model several fluoroquinolones, including ciprofloxacin, levofloxacin, moxifloxacin and gatifloxacin, as well as several experimental compounds were tested in parallel. All compounds were obtained as part of the TAACF (Tuberculosis Antimicrobial Acquisition and Coordinating Facility), a program funded by the NIAID which provides no-cost screening of compounds from industrial and academic sources. Treatment started three weeks following low dose aerosol infection with M. tuberculosis and was administered by oral gavage. All quinolones were given 5 days/week for 8 days at 100, 200 and 400 mg/kg and compared to INH at 25 mg/kg. Mice were sacrificed the day after completion of therapy and bacterial counts from spleens and lungs were determined. The results obtained showed a range of activities. Gatifloxacin and Moxifloxacin at 400 mg/kg were the most active, with large reductions in the bacterial load [5.4 and 6.1 log]. A similar dose of levofloxacin reduced the bacterial load by 3.5 log, as did several experimental compounds, compared to a similar effect by isoniazid [25mg/kg]. These results indicate that the GKO model has promise as a fast and highly sensitive way to screen compounds against M.tuberculosis. This work is funded by NIH, NIAID contract NO1 AI-95385

Publication Types:

• Meeting Abstracts

Keywords:

• Animals
• Anti-Infective Agents
• Aza Compounds
• Ciprofloxacin
• Fluoroquinolones
• Interferon Type II
• Interferon-gamma, Recombinant
• Isoniazid
• Lung
• Mice
• Mice, Inbred C57BL
• Ofloxacin
• Quinolines
• Spleen
• Tuberculosis
• gatifloxacin
• moxifloxacin
• utilization

Other ID:

• GWAIDS0027899

UI: 102267523

From Meeting Abstracts