Tuberculosis: Advances in Diagnosis and Therapy

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Things to be learnt from TB treatment?

Nelly

http://www.medscape.com/viewarticle/522380?src=mp

Treatment of TB

The Challenges

At the 2005 ICAAC there was also considerable focus on new therapeutic agents for TB. Since rifampin was introduced in 1967, no novel compounds have been approved for first-line therapy of TB. It is obvious that therapy would be simplified if we had more potent regimens that could be given for shorter periods of time. It is also clear that in some areas of the world, drug resistance rates are astonishingly high. For instance, at ICAAC 2005, Finnish investigators reported that in Murmansk, Russia, 114 (26%) of 439 isolates were resistant to at least INH and rifampin.[7] In fact, 93 (82%) of the multidrug-resistant strains were resistant to all 4 first-line drugs.

********New Agents

There are now 4 promising agents in 4 new classes entering clinical trials according to Nuermberger[8] from s Hopkins, who reviewed these drugs and potential strategies for using them. The 4 new classes are the *****methoxyfluoroquinolones (eg, moxifloxacin), ******nitroimidazopyrans (eg, PA-824), *****the diarylquinolines (eg, R207910), and the ******pyrrole derivatives (eg, LL-3858). All are bactericidal and are potent against organisms that are not actively multiplying. Having new agents provides opportunities to intensify regimens and potentially shorten their duration as well as providing more options for multiresistant mycobacteria.**********

In a late-breaker poster, Bill Burman and colleagues[9] reported on a 287-patient multicenter trial conducted in Africa (62% of patients) and North America (38% of patients) that compared moxifloxacin with ethambutol in a randomized and blinded trial. For this trial all patients received a "backbone" regimen of INH, rifampin, and pyrazinamide plus the blinded agent. Drugs were given daily for 2 weeks and then either 3 or 5 days per week. In this study, 22% of patients were HIV-infected and 75% had lung cavitation on x-ray. Sputum culture conversions at 2 months were similar in both arms (69% and 70%, respectively, were negative), but patients in the moxifloxacin arm converted their cultures to negative faster (median, 43 days) than the ethambutol arm (median, 56 days). There were no substantial differences in culture conversion rate between the 3-day-a-week and the 5-day-a-week groups. The regimens in both arms were well tolerated, with 88% and 89% of the patients randomized to the 2 drug regimens completing therapy. There was more nausea associated with the moxifloxacin group (20%) than the ethambutol group (10%). These results indicate that at 2 months, moxifloxacin is safe and effective compared with ethambutol when used as part of multidrug therapy for drug-naive patients. This provides more evidence that moxifloxacin could be used effectively as part of our anti-TB armamentarium.

In another late-breaker poster, Lienhardt and colleagues[10] reported parallel results to the Burman study in a phase 2 investigation conducted in South Africa. Patients received the standard backbone (INH-rifampin-pyrazinamide) of TB therapy. Lienhardt's group evaluated the efficacy of ethambutol, moxifloxacin, gatifloxacin, or ofloxacin as the fourth drug. This investigation was a randomized study of 216 patients. Patients were evaluated at 10 timepoints over the initial 2 months of therapy. Evaluation of colony-forming units and time to sputum conversion demonstrated that gatifloxacin and moxifloxacin (but not ofloxacin) were associated with more rapid elimination of bacilli than was ethambutol. This study further supports the use of certain quinolones for anti-TB therapy, and raises the potential for finding shorter courses of therapy.

Summary

Over the past decade, international organizations, the US government, foundations, pharmaceutical companies, and other funding sources have reinvigorated their TB portfolios. The presentations at ICAAC 2005 demonstrated that these investments are paying off in terms of new diagnostic and therapeutic approaches that may be able to improve our current approach to the management of TB patients.