Extensively Drug-Resistant Tuberculosis Responds to Linezolid, at High Cost

Martha Kerr

October 07, 2008

October 7, 2008 (Berlin, Germany) — Extensively drug-resistant strains of tuberculosis (XDR-TB) are emerging across Europe and North America, and are particularly linked to immigration from the former Soviet Republic. Investigators are finding that linezolid appears to have high but brief bactericidal activity, which comes at a very high cost, both in adverse effects and price.

Alternative treatments for XDR-TB are the subject of a number of presentations here at the European Respiratory Society 2008 Annual Congress.

Principal investigators Christoph Lange, MD, from the division of clinical infectious diseases at the Research Center Borstel, in Germany, and Giovanni Battista Migliori, from the World Health Organization's Collaborating Centre for TB and Lung Disease at Fondazione S. Maugeri, Care and Research Institute, in Tradate, Italy, led an international study evaluating the prevalence of XDR-TB, primarily in Europe, and the efficacy and tolerability of linezolid in the treatment of the prevalent strains.

"The oxazolidone antibiotic linezolid is frequently used in the treatment against [multidrug resistant] and [extensively drug-resistant] tuberculosis, based on in vitro drug susceptibility data and anecdotal case reports," Drs. Lange and Migliori note. "However, data on the clinical efficacy and the tolerability of linezolid in the treatment against Mycobacterium tuberculosis are lacking."

The researchers found that, of 7026 culture-confirmed TB cases, 265 cases (3.8%) were multidrug resistant (MDR)-TB and 17 cases (0.2%) were XDR-TB. Linezolid-based treatment was used in 82 MDR-TB cases and in 7 XDR-TB cases.

The median treatment duration was 116 days. Linezolid-related adverse effects were observed in 32 of 89 cases, of which 38% were MDR-TB and 14% were XDR-TB cases.

Linezolid was clinically successful in 31 of 38 cases (81.6%), and in 67 of 89 cases (75%) there was sputum smear and culture conversion.

Linezolid was interrupted in 25 of 32 cases (78%) and could not be reinstituted in 17 of 25 cases (68%). Adverse effects appeared after a median of 61.5 days. Severe anemia appeared in 20 of 32 cases (62.5%). Polyneuropathy also developed in a significant number of patients.

"The efficacy of linezolid-containing regimes in the treatment of MDR-TB and XDR-TB seems to be high, but severe adverse events very commonly cause discontinuation of linezolid treatment after 2 months," Dr. Lange told the Congress. However, "all of these effects were reversible and there were no linezolid-related deaths," he added.

Studies using half doses of the oxazolidinon-type antibiotic are ongoing, not only to minimize adverse effects, but also because this drug is extremely expensive.

Korean investigators presented data showing that, of 11 patients with XDR-TB, 9 showed susceptibility. However, Hae Seong Nam, MD, and colleagues from Samsung Medical Center at Sungkyunkwan University School of Medicine, in Seoul, Korea, reported that 9 patients had to discontinue treatment after a median of 5 months because of adverse events.

Robert Loddenkemper, MD, professor of medicine at Charité Hospital and Secretary General of German Central Committee Against Tuberculosis, in Berlin, will be chairing a symposium on MDR-TB at the Congress. In an interview with Medscape Pulmonary Medicine, he noted that "really severe neutropenia and neuropathy develop in at least 10% of patients on linezolid."

"While linezolid is certainly 1 of the sideline drugs, I would consider it really more of a third-line drug, used in combination with other drugs and perhaps surgery. . . . Linezolid has only modest bactericidal activity," Dr. Loddenkemper commented.

"The fluoroquinolones are better second-line treatment, as are cycloviran and some of the other antibiotics."

Not only is linezolid very toxic, "it isvery expensive and is not an option for developing countries," Dr. Loddenkemper said. "Estimates are that it costs €93 for 600 mg, and that is a half dose. . . . It can really only be used in the wealthiest countries."

XDR-TB is a significant problem, especially in areas with immigrants from the former Soviet Republic. "Patients who fail first-line treatment have a very poor prognosis. They are going to die, and they are very infectious," Dr. Loddenkemper remarked. "This is becoming a big problem."

None of the investigators presenting data on XDR-TB disclosed any relevant financial relationships.

European Respiratory Society (ERS) 2008 Annual Congress: Abstracts 1355, 1356, and 1357. Presented October 5, 2008.


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