Linezolid for treatment of chronic extensively drug-resistant tuberculosis

Abstract

Background: Linezolid has antimycobacterial activity in vitro and is increasingly used for patients with highly drug-resistant tuberculosis.

Methods: We enrolled 41 patients who had sputum-culture-positive extensively drug-resistant (XDR) tuberculosis and who had not had a response to any available chemotherapeutic option during the previous 6 months. Patients were randomly assigned to linezolid therapy that started immediately or after 2 months, at a dose of 600 mg per day, without a change in their background regimen. The primary end point was the time to sputum-culture conversion on solid medium, with data censored 4 months after study entry. After confirmed sputum-smear conversion or 4 months (whichever came first), patients underwent a second randomization to continued linezolid therapy at a dose of 600 mg per day or 300 mg per day for at least an additional 18 months, with careful toxicity monitoring.

Results: By 4 months, 15 of the 19 patients (79%) in the immediate-start group and 7 of the 20 (35%) in the delayed-start group had culture conversion (P=0.001). Most patients (34 of 39 [87%]) had a negative sputum culture within 6 months after linezolid had been added to their drug regimen. Of the 38 patients with exposure to linezolid, 31 (82%) had clinically significant adverse events that were possibly or probably related to linezolid, including 3 patients who discontinued therapy. Patients who received 300 mg per day after the second randomization had fewer adverse events than those who continued taking 600 mg per day. Thirteen patients completed therapy and have not had a relapse. Four cases of acquired resistance to linezolid have been observed.

Conclusions: Linezolid is effective at achieving culture conversion among patients with treatment-refractory XDR pulmonary tuberculosis, but patients must be monitored carefully for adverse events. (Funded by the National Institute of Allergy and Infectious Diseases and the Ministry of Health and Welfare, South Korea; ClinicalTrials.gov number, NCT00727844.).

Figure 1. Enrollment, Randomization, and Follow-Up of the Study Patients

Between December 2008 and May 2011, a total of 50 patients were screened for eligibility and 41 underwent randomization. Two patients were subsequently withdrawn owing to preexisting peripheral neuropathy that was discovered during the baseline examination; the remaining 39 patients were included in the modified intention-to-treat analysis. Two other patients who withdrew before culture conversion were considered to have treatment failure: 1 patient, who had an adverse event requiring a drug holiday, was withdrawn 79 days after starting treatment with linezolid because the drug holiday exceeded the protocol-specified window (28 days before sputum-culture conversion and 42 days after sputum-culture conversion); the other patient was withdrawn 32 days after study entry because of a diagnosis of advanced colon cancer (this patient was in the delayed-start group and had not received any linezolid). Thirty-three patients underwent the second randomization; 17 patients were randomly assigned to continue receiving linezolid at a dose of 600 mg per day, and 16 to receive the reduced dose of 300 mg per day. The 6 patients who did not undergo the second randomization included 4 who had dose reductions due to adverse events before culture conversion and the 2 withdrawn patients mentioned above who were included in the modified intention-to-treat analysis as having treatment failure.

Figure 2. Kaplan–Meier Curves for Culture Conversion According to Time since Randomization

Panel A shows the results for solid culture medium, and Panel B the results for liquid culture medium. In both panels, the dashed vertical lines indicate the start of treatment (at 2 months) in the delayed-treatment group and the time of data censoring (at 4 months). Panel C shows the time to culture conversion on solid medium (solid line) along with the 95% confidence interval (dashed lines) for the 38 participants who received linezolid, according to the duration of linezolid therapy. Tick marks indicate the censored observations at the time of the last follow-up visit with culture results.

Figure 3. Probability of Event-free Survival over Time

The Kaplan–Meier curves in Panel A show the time to the onset of clinically significant adverse events that resulted in a drug holiday or dose adjustment during the study. Symbols indicate data-censoring points for patients remaining in the study (see Table 3 in the Supplementary Appendix for detailed risk estimates corrected for person-years of exposure). The curves in Panel B show the time to the first adverse event in patients after the second randomization to either a continuation of the 600-mg daily dose or a reduced dose of 300 mg per day. Tick marks indicate data-censoring points for individual patients who continued to receive the study drug.

Figure 4. Resistance to and Pharmacokinetics of Linezolid

Acquired resistance to linezolid was observed in the isolates from four patients; mutations in the linezolid-binding site of the 23S ribosomal RNA (rRNA) developed in two patients, and mutations in the mycobacterial ribosomal protein L3 gene (rplC) in the other two (Panel A). Numbers for 23S rRNA indicate the location of mutations according to Escherichia coli numbering. The pharmacokinetics of exposure to linezolid were measured for all patients while they were receiving 600 mg per day and for all patients who subsequently received 300 mg per day (Panel B). Plasma concentrations for the four patients in whom resistant organisms developed are shown in red, and the dose the patient was taking at the time of resistance detection is indicated by triangles (600 mg) or circles (300 mg). The minimum inhibitory concentration (MIC) for linezolid in the initial isolates from the patients and the mean MIC (horizontal line) are shown at the right.