© 2003 American Thoracic Society
Development of Fluoroquinolones as First-line Drugs for Tuberculosis—at Long Last!Division of Tuberculosis Elimination Centers for Disease Control and Prevention Atlanta, Georgia In 1985 in the Journal, Tsukamura and colleagues (1) reported their experience treating 19 patients with chronic, drug-resistant tuberculosis with the novel fluoroquinolone antibiotic, ofloxacin. A majority of patients had some bacteriologic response to treatment, and five became sputum-culture–negative. Importantly, the drug that was given for 6 to 9 months was well tolerated. Subsequently, a number of investigators reported similar results with both ofloxacin and another fluoroquinolone, ciprofloxacin. No randomized clinical trials, however, of a fluoroquinolone for drug-resistant tuberculosis have ever been undertaken. Despite increasing use of fluoroquinolones for drug-resistant tuberculosis, the American Thoracic Society (ATS) and the Centers for Disease Control and Prevention (CDC) in their 1993 statement on the treatment of tuberculosis only noted that these drugs might be potentially effective for the treatment of drug-resistant disease (2). In the updated guidelines on tuberculosis treatment published earlier this year, fluoroquinolones were designated as preferred agents for the treatment of multidrug-resistant tuberculosis but were specifically considered not to be first-line agents (3). This is because the few randomized, controlled trials of fluoroquinolones for drug-susceptible tuberculosis that have been conducted have not demonstrated a benefit. Today, however, nearly 20 years after Tsukamura and colleagues' report (1), there is great interest in the potential of fluoroquinolones to significantly improve the treatment of drug-susceptible tuberculosis. A number of factors have contributed to this interest. A recent study conducted by the Tuberculosis Research Centre in Chennai, India, that did not have a standard control group randomized patients with newly diagnosed pulmonary tuberculosis to one of four ofloxacin-containing regimens (4). Rates of 2-month sputum culture conversion, a marker of the sterilizing activity of tuberculosis drug regimens (5), ranged from 92–98%. This compares to an expected rate of approximately 80% with standard four-drug treatment (6). Rates of relapse during the 2 years following completion of treatment were 2% and 4% in those patients randomized to 3 months of daily isoniazid, rifampin, pyrazinamide, and ofloxacin, followed by twice weekly isoniazid and rifampin for 1 and 2 months, respectively. These results suggest that fluoroquinolones might permit substantial shortening of tuberculosis treatment from the current minimum of 6 months. Several fluoroquinolones with markedly enhanced in vitro activity against Mycobacterium tuberculosis are now available. Of these, the most potent are moxifloxacin and gatifloxacin. The minimal inhibitory concentrations of these two agents are four-fold lower than that of levofloxacin, the fluoroquinolone that is currently preferred for the treatment of drug-resistant tuberculosis (7). A recent evaluation of fluoroquinolones in a model of mycobacterial persistence found that moxifloxacin had the greatest sterilizing activity (8). The pharmacokinetic profile of moxifloxacin, with a relatively long half-life and high area under the time–concentration curve, also suggests that this agent may be an ideal antituberculosis drug (9). A series of studies of moxifloxacin in a mouse model of acute tuberculosis conducted by investigators working with Jacques Grosset have also contributed to the interest in this drug. The initial study, in which infected mice were treated for 28 days with several fluoroquinolones, found that moxifloxacin had the greatest bactericidal activity comparable to that of isoniazid (10). A second study suggested that moxifloxacin also had potent sterilizing activity and might substantially improve the efficacy of once-weekly rifapentine treatment replacing isoniazid that has been shown in clinical studies to be a poor companion drug (6, 11). The most recent study found that the combination of rifampin, pyrazinamide, and moxifloxacin had substantially greater sterilizing activity compared with the standard regimen, again suggesting the possibility that the drug would permit significant shortening of treatment (12). Finally, Bayer Healthcare made moxifloxacin available for clinical studies and is actively collaborating with investigators in a number of trials. Before, most major pharmaceutical companies involved in the development of fluoroquinolones had avoided tuberculosis. The reasons were obvious: lack of a perceived financial market for antituberculosis drugs and fear that chronic use, as in tuberculosis, might unmask previously unknown toxicities and result in the withdrawal of the drug from the market. Discussions with the Global Alliance for TB Drug Development (TB Alliance) may have been encouraging to Bayer. The TB Alliance's Scientific Blueprint for TB Drug Development outlines the process of clinical development leading to drug registration that commonly begins with an early bactericidal activity (EBA) study (13). In this issue of the Journal, Gosling and colleagues, working in Tanzania, report the results of an EBA study of moxifloxacin (14). The study demonstrated that the drug does have an EBA effect, midway between isoniazid, the drug that has the most potent EBA effect of all known agents, and rifampin, the drug with the greatest sterilizing activity. This finding is good news to those interested in new tuberculosis drugs, because an EBA study with negative results may have lessened interest in the drug (15). Two other EBA studies are underway, one being conducted by investigators in Berlin with Bayer support, and the other being conducted by the Tuberculosis Research Unit with support from the National Institutes of Health. The CDC's Tuberculosis Trials Consortium has begun enrollment into a large Phase II study of moxifloxacin being conducted under a Clinical Trials Cooperative Research and Development Agreement with Bayer. In this randomized, masked study, patients with newly diagnosed tuberculosis receive either moxifloxacin or ethambutol given daily or intermittently during the initial phase of treatment. The primary endpoints are sputum culture conversion at 2 months and safety/tolerability. A similar study is being planned by investigators at Johns Hopkins University and collaborators in Brazil to be supported by the Food and Drug Administration's Office for Orphan Products Development. CDC is also working with investigators at the Russian Research Institute for Phthisiopulmonology to implement another Phase II study that intends to evaluate moxifloxacin in place of isoniazid in the initial phase of treatment. It is hoped that results of these studies will lead to a Phase III study of moxifloxacin that would be required for a labeled indication for tuberculosis. Under the best of circumstances, however, such a study would not begin for at least two more years. Following currently promulgated regulatory requirements, approximately 1,000 patients would be enrolled, treated, and followed for relapse, the primary study endpoint. Surrogate markers must be evaluated and validated to shorten what is currently a lengthy and expensive development process. Nonetheless, there is reason to be optimistic that at long last improved tuberculosis treatment is more than a distant dream. FOOTNOTES Conflict of Interest Statement: R.J.O. has no declared conflict of interest. REFERENCES
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