Ethambutol

The symptoms of tuberculosis (TB) improve on chemotherapy well before treatment is complete and cure is reasonably certain. This predisposes to early discontinuation or selective ingestion of pills, especially when treatment is costly or logistically difficult, or causes side effects. Erratic treatment often leads to treatment failure or relapse, and importantly, to drug resistance through the selection of spontaneous genetic mutations. These dangers were recognized early in the evolution of TB chemotherapy, leading to efforts to increase the spacing of doses as widely as possible (one to three times/week), so that ingestion of each dose could be assured by direct observation. In this issue of the Journal (pp. 1457-1462). Rosenthal and colleagues compare the well-established twice-weekly intermittent "Denver regimen" with various once-weekly treatments in a murine model (1). They find that once-weekly rifapentine and moxifloxacin performed far better than the mostly twice-weekly Denver regimen.

Why are fewer doses so critical? Fewer doses, even if they are larger, usually reduce drug costs and may cause fewer side effects. More importantly, outreach workers can supervise therapy of many more patients once weekly compared with two or three times per week. This is especially important in rural areas where frequent supervision is difficult because of long distances. Successful directly observed therapy is dependent on the infrastructure available to provide supervision, and any strategy that decreases those costs will likely help expand TB treatment coverage and lead to higher cure rates.

The scientific basis for intermittent therapy began with experiments published in the mid-1960s demonstrating the "postantibiolic effect"-an in vitro delay in the beginning of regrowth after a dose of antibiotic-and by showing that guinea pigs or mice with established TB could be successfully treated with intermittent regimens (2). However, in subsequent animal experiments and human clinical trials, the limitations of such strategies became apparent. Various regimens given two or three times per week in the continuation phase were effective, whereas regimens given once weekly were not. Thus, the findings presented by Rosenthal and colleagues that the combination of rifapentine and moxifloxacin appears effective once weekly in an animal model with a good track record for guiding clinical trials is exciting news both for those on the ground supervising therapy and those in offices responsible for allocating public health resources.

The Food and Drug Administration approved rifapentine in 1998, the first new anti-TB agent approved in over 30 years. The drug is similar to the other rifamycins in most respects except for its half-life, 13 hours compared with 3 hours for rifampicin. The drug received accelerated approval because of its promise to permit dosing as infrequently as once weekly in the continuation phase of treatment. However, this promise has not been fully realized. In a clinical trial by the Tuberculosis Trials Consortium (TBTC), once-weekly rifapentine and isoniazid (INH) was compared with twice-weekly rifampicin and INH in HIV-negative patients (3). Failures were higher in the once-weekly group, predominantly among those who had signs of advanced disease, reflecting, in part, a greater bacterial burden. Once-weekly therapy had already been shown to lead to higher rates of failure and monoresistance to rifamycins in HIV-infected persons (4). An additional clinical trial by the TBTC suggested that the optimal rifapentine dose might be twice the usual 600 mg, leading to higher doses in the experiment reported here.

Rifamycins are among the most effective anti-TB drugs known, but their efficacy comes at a price, especially for the long-acting molecule rifapentine. Unless accompanied by equally long-acting companion drugs, rapid selection of drug-resistant mutants through inadvertent single-drug therapy is likely (5). In fact, in this study, the authors were able to isolate a rifapentine-resistant mutant over the relatively short treatment course in mice. Because of its efficacy and long half-life, moxifloxacin has been considered the most attractive suitor for this role, and previous mouse experiments as well as the results of the study reported here suggest that the combination could be a fairy tale marriage (6, 7).

Despite these encouraging results, a better intermittent regimen is not yet defined, nor proven. The work of Rosenthal and coworkers suggests that, at least in mice, the efficacies of rifapentine and moxifloxacin are matched well enough to allow once-weekly dosing. However, it is difficult to extrapolate these data to humans. The pharmacokinetics of both drugs, particularly moxifloxacin, are quite different in mice, requiring twice-daily dosing of moxifloxacin in mice to mimic human pharmacokinetics. In addition, disease in humans is generally far more rapidly cleared by antibiotics than infection in mice. The Denver regimen, for example, which provides good cure rates in humans, failed to cure mice in this study. However, the results are encouraging enough to support the need for a clinical trial, which is perhaps all that can be asked of the best animal models.

If a rifapentine-moxifloxacin-based intermittent regimen is proven to be effective in clinical trials, how will it impact TB therapy? The impact may be important, but possibly temporary. Recently, the Global Alliance for TB Drug Development announced a revised intermediate-term goal to fully test an entirely new treatment regimen. They have concluded that to shorten treatment to a matter of weeks, all four of the drugs used in the current 6-month regimen would most likely need to be replaced. INH must be replaced because of widespread resistance, occasional severe liver toxicity, and because in combination with other drugs, this agent sometimes seems to reduce activity, as it did in the Rosenthal study. Furthermore, INH appears to contribute little, if anything, to shortening the duration of therapy. Rifampacin must be replaced because of cytochrome P450-based drug interactions, especially with antiretroviral drugs, a characteristic of rifapentine as well. Pyrazinamide can be hard to take and toxic, whereas ethambutol is generally safe but not very potent. Fortunately, there are several new anti-TB drugs in the pipeline, some with great potential to shorten therapy, including moxifloxacin. From this ambitious perspective, any rifamycin-based regimen in the continuation phase may be an important but transient innovation. In the meantime, the fabled once-weekly regimen, if it proves safe, effective, and, as importantly, affordable in resource-limited settings, will be welcome indeed.

References

1. Rosenthal IM, Williams K, Tyagi S, Vernon AA, Peloquin CA, Bishai WR, Grosset JH, Nuermberger EL. Weekly moxifloxacin and rifapentine is more active than the Denver regimen in murine tuberculosis. Am J Respir Crit Care Med 2005;172:1457-1462.

2. Fox W, Ellard GA, Mitchison DA. Studies on the treatment of tuberculosis undertaken by the British Medical Research Council tuberculosis units, 1946-1986, with relevant subsequent publications. Int J Tuberc Lung Dis 1999;3:S231-S279.

3. Benator D, Bhattacharya M, Bozeman L, Burman W, Cantazaro A, Chaisson R, Gordin F, Horshurgh CR, Horton J, Khan A, et al; Tuberculosis Trials Consortium. Rifapentine and isoniazid once a week versus rifampicin and isoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: a randomised clinical trial. Lancet 2002;360:528-534.

4. Centers for Disease Control and Prevention. Acquired rifamycin resistance in persons with advanced HIV disease being treated for active tuberculosis with intermittent rifamycin-based regimens. MMWR Morb Mortal Wkly Rep 2002;51:214-215.

5. Milchison DA. Role of isoniazid in once-weekly rifapentine treatment of pulmonary tuberculosis. Am J Respir Crit Care Med 2003;167:1298-1299.

6. Gordin FM. Rifapentine for the treatment of tuberculosis: is it all it can be? Am J Respir Crit Care Med 2004;169:1176-1177.

7. Lounis N, Bentoucha A, Truffot-Pernot C, Ji B, O'Brien RJ, Vernon A, Roscigno G, Grosset J. Effectiveness of once-weekly rifapentine and moxifloxacin regimens against Mycobacterium tuberculosis in mice. Antimicrob Agents Chemother 2001;45:3482-3486.

DOI: 10.1164/rccm.2509003

Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

EDWARD A. NARDELL, M.D.

Brigham and Women's Hospital

Boston, Massachusetts

ERIC J. RUBIN, M.D, PH.D.

Harvard School of Public Health

Boston, Massachusetts

Copyright American Thoracic Society Dec 1, 2005
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