How Should We Treat “Difficult” Multidrug-Resistant Tuberculosis?

Abstract

To the Editor: We read with great interest the case series elegantly reported by Condos and associates1Condos R Hadgiangelis N Leibert E et al.Case series report of a linezolid-containing regimen for extensively drug-resistant tuberculosis.Chest. 2008; 134: 187-192Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar in the July issue of CHEST, regarding the good efficacy and reasonable tolerability of linezolid in the treatment of extensively drug-resistant tuberculosis. However, it appears that four of the six adult patients cited in the article were switched from a linezolid regimen of 600 mg twice daily to one of 600 mg once daily after the onset of drug-induced toxic effects, mainly hematologic ones. The relatively short half-life of linezolid, alongside its limited postantibiotic effect against Mycobacterium tuberculosis, would theoretically favor the use of a “standard” dosage of 600 mg twice daily to achieve the optimal therapeutic effect.2Hui M Au-Yeang C Wong KT et al.Post-antibiotic effects of linezolid and other agents against Mycobacterium tuberculosis.Int J Antimicrob Agents. 2008; 31: 395-396Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar Moreover, neurotoxicity might not be readily minimized even with once-daily dosing.3Park IN Hong SB Oh YM et al.Efficacy and tolerability of daily-half dose linezolid in patients with intractable multidrug-resistant tuberculosis.J Antimicrob Chemother. 2006; 58: 701-704Crossref PubMed Scopus (144) Google Scholar In the last few years, we acquired preliminary experience regarding the efficacy of a limited duration (generally 2 to 3 months) for the initial administration of linezolid at this conventional dosing, on top of therapy with fluoroquinolones and other second-line antituberculosis drugs, in the long-term treatment of fluoroquinolone-resistant, multidrug-resistant tuberculosis.4Yew WW Chau CH Wen KH Linezolid in the treatment of “difficult” multidrug-resistant tuberculosis.Int J Tuberc Lung Dis. 2008; 12: 345-346PubMed Google Scholar Linezolid, alongside other new agents such as TMC-207, PA-824, and OPC-67683, showed sterilizing activity against the bacillary persisters of bacillus Calmette-Guerin and/or M tuberculosis in the Wayne model (Kevin Pethe, PhD; personal communication, March 17, 2008). Similar activity was also demonstrated in the murine model of tuberculosis. These observations might help to explain the possible efficacy of our current chemotherapy approach of adding linezolid to therapy only in the intensive phase. Such a strategy would potentially reduce toxicity and curtail the development of drug resistance during chemotherapy with the new agent in formidable drug resistance scenarios. It seems that further evaluation of this approach is warranted. Clearly, the judicious use of adjunctive surgery may also be indicated for select candidates,5Chan ED Laurel V Strand MJ et al.Treatment and outcome analysis of 205 patients with multidrug-resistant tuberculosis.Am J Respir Crit Care Med. 2004; 169: 1103-1109Crossref PubMed Google Scholar preferably during the window of opportunity, 3 to 6 months after the start of chemotherapy.