WHO Group 5 Drugs and Difficult Multidrug-Resistant Tuberculosis: a Systematic Review with Cohort Analysis and Meta-Analysis

Abstract

It is often necessary to include WHO group 5 drugs in the treatment of extensively drug-resistant tuberculosis (XDR-TB) and fluoroquinolone-resistant multidrug-resistant tuberculosis (MDR-TB). As clinical evidence about the use of group 5 drugs is scarce, we conducted a systematic review using published individual patient data. We searched PubMed and OvidSP through 7 April 2013 for publications in English to assemble a cohort with fluoroquinolone-resistant MDR-TB treated with group 5 drugs. Favorable outcome was defined as sputum culture conversion, cure, or treatment completion in the absence of death, default, treatment failure, or relapse. A cohort of 194 patients was assembled from 20 articles involving 12 geographical regions. In descending order of frequency, linezolid was used in treatment of 162 (84%) patients, macrolides in 84 (43%), clofazimine in 65 (34%), amoxicillin with clavulanate in 56 (29%), thioridazine in 18 (9%), carbapenem in 16 (8%), and high-dose isoniazid in 16 (8%). Cohort analysis with robust Poisson regression models and random-effects meta-analysis similarly suggested that linezolid use significantly increased the probability (95% confidence interval) of favorable outcome by 57% (10% to 124%) and 55% (10% to 121%), respectively. Defining significant associations by risk ratios > 1.2 or < 0.9, neither cohort analysis nor meta-analysis demonstrated any significant add-on benefit from the use of other group 5 drugs with respect to outcome for patients treated with linezolid, although selection bias might have led to underestimation of their effects. Our findings substantiated the use of linezolid in the treatment of XDR-TB or fluoroquinolone-resistant MDR-TB and call for further studies to evaluate the roles of other group 5 drugs.

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

“…• Ideally use at least four drugs, in addition to pyrazinamide, to which the strain has proven or probable susceptibility (drugs previously taken for ≥1 month are generally avoided) 238 • Use a backbone of a later-generation fluoroquinolone (eg, moxifloxacin or levofloxacin; group A drug), plus a second-line injectable drug (amikacin or kanamycin, or capreomycin; group B drugs; used for ≥4 months after culture conversion and for a minimum of 6 months) 238 • Add any first-line drug and additional group C drugs (eg, cycloserine or terizidone, ethionamide or prothionamide, clofazimine, or linezolid if appropriate) to which the isolate is susceptible • The WHO recommended treatment duration is 20 months; however, this recommendation is based on very low-quality evidence) 238 • Bedaquiline or delamanid (group D2) can be added to the regimen if toxicity or resistance precludes formulation of a regimen containing ≥4 drugs that are likely to be effective, particularly if a group A or B drug cannot be used (both prolong QT interval, and thus require monitoring) 270,271 • Oxazolidinones (linezolid) can be used (group C drug), particularly in fluoroquinolone-resistant MDR or XDR tuberculosis, but monitoring for toxicity (neuropathy and bone marrow suppression) is required 272,273,274 • Given the specific and conditional nature of the recommendation (poor-quality evidence), the decision to use the newer WHO-recommended 9-12-month short course versus the ~20-month regimen in selected patients will be dependent on several factors, including previous treatment, local resistance profiles, patient acceptance, and the requirement for proven or highly likely fluoroquinolone and aminoglycoside isolate susceptibility, and absence of probable or proven resistance to any of the components of the regimen (except isoniazid) 68 • Whatever the duration of the regimen used, psychosocial and financial support are crucial elements to maintain adherence • Patients should be monitored for adverse drug reactions, which are common 275 • A single drug should not be added to a failing regimen • The patient's HIV status should be established and antiretroviral therapy initiated in all HIV-infected patients…”

Classification of antituberculosis drugs: a new proposal based on the most recent evidence

“…Evidence on good efficacy is accumulating, including meta-analyses [28,29] and two RCTs [30,31], in addition to observational studies [28,[32][33][34][35][36][37]. Unfortunately, the current cost and the documented toxicity [28][29][30][31][32][33][34][35][36][37] can be a barrier to its wider use. Nonetheless, the price of generic, quality-assured linezolid has reduced significantly in the last year and further cost reduction globally is expected soon [38].…”

Barriers to new drug development in respiratory disease

“…Bedaquiline and delamanid have not been studied together and are being added to the existing weak regimen with companion drugs that have limited efficacy data in TB [6]. The danger of this is already being seen with the first cases of bedaquiline resistance being reported [7].…”