Linezolid Effective in Suppression of XDR Pulmonary TB
Use of once daily linezolid in patients with XDR pulmonary tuberculosis results in confirmed culture conversion in 87% of patients within six months, but side effects are frequent. Dave Halterman, PharmD February 17, 2013 – A recent study suggests that linezolid is effective in the treatment of extensively drug-resistant (XDR) tuberculosis. When the drug was added to their standard regimen, 87% of patients treated with linezolid had a negative sputum culture within six months. However, 82% of patients suffered clinically significant adverse events and acquired resistance to linezolid was noted. Dr. Myungsun Lee, MD, of the International Tuberculosis Research Center along with colleagues in South Korea, Singapore and the United States, presented the findings in the October 18, 2012, issue of the New England Journal of Medicine. Linezolid exhibits bacteriostatic activity against Mycobacterium tuberculosis in vitro, but according to the researchers, previous preclinical studies concluded that the drug had a limited role in treatment of MDR tuberculosis. However, case reports and retrospective studies have suggested linezolid may be effective in the treatment of chronic XDR tuberculosis. The phase 2a, randomized, two-group study was initiated in South Korea. In addition to their regular treatment regimen, patients in the two groups were randomly assigned to receive 600 mg linezolid once daily. One group received the dose immediately, the other after a 2-month delay. Patients continued this regimen until sputum culture conversion (the primary end point of the study) or until they had received linezolid therapy for four months. At that point, a second randomization occurred and the patients either continued to receive the 600 mg daily dose or were reduced to 300 mg once daily. In the immediate start group, 79% of patients (15 of 19) achieved sputum-culture conversion by four months along with 35% of patients (7 of 20) in the delayed start group (p=0.001). Additionally, 34 of 39 patients in the combined groups achieved culture conversion by 6 months (median: 75 days after initiation of linezolid). Adverse events were common among the 38 patients exposed to linezolid with 31 (82%) suffering events thought to be related to treatment with the drug. Myelosuppression and neuropathies—both known side effects of linezolid—were most common; however only 3 patients (2 with optic neuropathy, 1 with anemia) permanently discontinued linezolid treatment due to drug toxicity. The researchers also noted that the isolates of the four patients who did not have a response to treatment showed increased MICs, indicating acquired linezolid resistance. The four patients were split evenly between the 300 mg and 600 mg groups. Despite the adverse events and drug resistance, the researchers were encouraged by the results, noting that an 87% culture conversion rate at 3 months compared favorably to studies of streptomycin (19% culture conversion) and isoniazid (less than 32% culture conversion). In addition, they note a recent five- drug study showed less than a 10% culture conversion after two months, leading them to determine “Linezolid alone would therefore appear to be similar to the five-drug chemotherapy regimen currently
used as second-line treatment, and the incorporation of linezolid into second-line regimens may substantially improve culture-conversion rates.” The authors reported no conflicts of interest. Lee M, Lee J, Carroll MW. Linezolid for treatment of chronic extensively drug-resistant tuberculosis. N Engl J Med. 2012;367:1508-18.
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