Drug may help in hard-to-treat TB

Among patients with extensively drug-resistant (XDR) tuberculosis, adding linezolid (Zyvox) to standard therapies appears to improve treatment response, but with a high rate of adverse events, a phase IIb trial showed.

Patients who immediately started taking linezolid, rather than waiting 2 months to add the drug, had a higher rate of sputum-culture conversion on solid medium by 4 months (79% versus 35%, P=0.001), according to Clifton Barry III, PhD, of the National Institute of Allergy and Infectious Diseases in Bethesda, Md., and colleagues.

Only four of the 39 patients in the study had a treatment failure -- all associated with acquired resistance to the drug -- but the rate of clinically significant adverse events possibly or probably related to treatment was high, at 82%, the researchers reported in the Oct. 18 issue of the New England Journal of Medicine.

"Although the small numbers of treatment failure and cases of acquired resistance are encouraging, they also preclude more in-depth analyses of the associated risk factors," the authors wrote. "Balancing the long-term risk-benefit ratio of linezolid requires identifying a dose with sufficient potency but less toxicity."

Linezolid was approved in 2000 for drug-resistant, gram-positive bacterial infections. It has been shown to have activity against Mycobacterium tuberculosis, including the multidrug-resistant and extensively drug-resistant strains, in vitro, although its results in animals and humans have been less consistent.

In the current study, which was done at two centers in South Korea, Barry and colleagues enrolled 41 patients ages 20 and older (mean age 41.2) with sputum-culture-positive XDR tuberculosis. The XDR form of tuberculosis is defined as M. tuberculosis resistant to rifampin and isoniazid, as well as to a quinolone and at least one of the following: kanamycin, capreomycin, or amikacin.

The patients had not had a response to any available chemotherapeutic option for the previous 6 months. They were hospitalized from enrollment until sputum-culture conversion and monitored closely for adverse events.

Two of the patients were removed from the study before receiving any doses of the drug and were not included in the modified intention-to-treat analyses.

The researchers randomized the patients to start taking linezolid 600 mg per day immediately or 2 months after enrollment. Background regimens remained the same.

After confirmed culture conversion or 4 months of follow-up, the patients were then randomized again to continue linezolid at a dose of 600 mg per day or to take a reduced 300-mg dose each day for an additional 18 months, with careful monitoring for toxicity.

The primary endpoint, which showed an advantage for immediately starting linezolid treatment, was the time to sputum-culture conversion on solid medium, with data censored 4 months after enrollment.

Although the primary endpoint was met, the difference in culture conversion on liquid medium -- "thought to have higher sensitivity and more reproducible results than solid-culture medium," according to the researchers -- was not statistically significant (63% versus 55%, P=0.07).

Combining patients in both randomized groups, 87% had a negative sputum culture on solid medium within 6 months of adding linezolid to the treatment regimen.

That effectiveness came at a cost, however, with the majority of patients reporting clinically significant adverse events possibly or probably related to the drug. Although three patients stopped treatment -- two because of optic neuropathy and one because of anemia -- most of the adverse events resolved quickly either with a dose reduction or a temporary cessation of linezolid, according to the researchers.

There were seven cases of myelosuppression, including anemia and neutropenia, seven cases of optic neuropathy, 21 cases of peripheral neuropathy, and one case of rhabdomyolysis.

The patients who received the 300-mg dose after the second randomization had a lower rate of adverse events related to the study drug compared with those who continued with the higher dose (69% versus 88%).

As of May 1, 2012, 17 patients were still being treated according to the protocol and 13 patients had completed therapy with no relapses. Another eight patients withdrew from the study early -- in addition to the three who withdrew because of adverse events, one left for personal reasons and four left because of treatment failure.

The four patients with treatment failure were shown to have strains of the bacteria containing genetic mutations associated with linezolid resistance.

The study was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases and by the Ministry of Health and Welfare in South Korea.

The authors reported that they had no conflicts of interest.

Primary source: New England Journal of Medicine
Source reference:
Lee M, et al "Linezolid for treatment of chronic extensively drug-resistant tuberculosis" N Engl J Med 2012; 367: 1508-1518.

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By Todd Neale

Published: Oct. 17, 2012, 10:15 p.m.

Last updated: Oct. 18, 2012, 9:29 p.m.

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