Activity of the Fluoroquinolone DC-159a in the Initial and Continuation Phases of Treatment of Murine Tuberculosis▿

DC-159a is a new fluoroquinolone with more potent in vitro activity than available fluoroquinolones against both drug-susceptible and fluoroquinolone-resistant Mycobacterium tuberculosis. Here, we report that DC-159a displays pharmacokinetics similar to those of moxifloxacin yet is more active than moxifloxacin during both the initial and continuation phases of treatment in a murine model. These results warrant further preclinical evaluation of DC-159a in selected drug combinations against drug-susceptible and fluoroquinolone-resistant tuberculosis. Fluoroquinolones are cornerstone agents in the treatment of multidrug-resistant (MDR) tuberculosis (TB). The most potent members of the class, moxifloxacin (MXF) and gatifloxacin, may be capable of shortening the treatment of drug-susceptible as well as MDR TB (1, 2, 11). However, the emergence of fluoroquinolone resistance in Mycobacterium tuberculosis threatens to undermine any such advances (4). Moreover, selection of fluoroquinolone resistance in other bacterial pathogens as a result of prolonged TB treatment is an increasing concern (13). DC-159a is a new 8-methoxyfluoroquinolone with an MIC 90 of 0.06 g/ml against M. tuberculosis, which is 4 and 8 times lower than that of MXF and levofloxacin (LVFX), respectively (3). With an MIC 90 of 0.5 g/ml against clinical MDR TB isolates which are resistant to other fluoroquinolones (e.g., MXF and LVFX MIC90 of 4 and 16 g/ml, respectively) (3), DC-159a may retain more activity than other fluoroquinolones against such MDR and extensively drug-resistant (XDR) TB isolates. Moreover, there is evidence that DC-159a is less likely than other fluoroquinolones to select for drug resistance in common bacterial pathogens other than mycobacteria (5, 7). Based on these promising in vitro data, we sought to compare the dose-ranging activity of DC-159a with that of MXF in a murine model of TB. Because fluoroquinolones may differ in their bactericidal activity against nonmultiplying or slowly multiplying M. tuberculosis in a fashion that may not be predicted from their activity against actively multiplying bacilli (6, 9), we compared the activities of MXF and DC-159a during the continuation phase as well as the initial phase of treatment. Because it measures a drug’s activity against a population of “persister” bacilli surviving 2 months of treatment with rifampin, isoniazid, and pyrazinamide (RHZ), the continuation phase assessment may provide greater insight into a drug’s treatment-shortening potential (8, 12).