Linezolid for XDR-TB — final study outcomes

Among 39 patients who were enrolled in this trial, 38 received linezolid. Of these patients, 27 had negative results on sputum culture 1 year after the end of treatment, 3 were lost to follow-up, and 8 withdrew before the end of the study, including the 4 patients in whom linezolid failed, as reported previously. The median duration of tuberculosis treatment was 789 days overall, with 781 days of linezolid. Final regimens included any remaining active second-line drugs (as described in the Supplementary Appendix of our original article, available with the full text of the article at NEJM.org).

Among the 27 patients who completed the study, 4 had a dose reduction from 600 mg to 300 mg of linezolid per day before the second randomization. Among the 13 patients who were assigned to continue receiving the 600-mg dose, 9 had a subsequent reduction in the dose to 300 mg. All the dose reductions were due to adverse events. Additional serious adverse events beyond our original report included 3 patients with optic neuropathies and 1 with anemia; all these conditions resolved after the discontinuation of linezolid.

Acquired linezolid resistance was observed only in the 4 patients who were originally reported (11% of the 38 patients who received linezolid). This observed rate with monotherapy may be related to the infrequent emergence of resistance to this drug that has been observed in vitro (2). Thus, 27 of 38 patients (71%) with chronic XDR-TB were cured of the infection at 1 year after the termination of the study.

In the 2 years since our original report, the results of one additional prospective clinical trial of linezolid for XDR-TB have been published, with findings reported at the end of the study (3). Our final study results provide prospective evidence of the durable efficacy of linezolid for the treatment of XDR-TB, although our findings are limited by the small number of patients. Because relapses in TB mainly occur in the first year (4), the lack of relapses in our cohort is reassuring.

This report adds to the growing evidence of the efficacy of linezolid for XDR-TB, with use that was limited by side effects (5). Notably, these side effects were dose-related, which suggests that in future trials involving a lower dose of linezolid, the drug may have an improved side-effect profile. Newer oxazolidinones, some of which have shown potent activity against Mycobacterium tuberculosis in vitro, are also in development, although the side-effect profiles with long-term use are unknown. If our results are confirmed in future clinical trials, oxazolidinones may become an important part of combination regimens for tuberculosis treatment.

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