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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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