ArticlesTreatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis
Introduction
WHO estimated that in 2016, there were almost 600 000 new cases of multidrug-resistant tuberculosis, defined as disease due to Mycobacterium tuberculosis that is resistant to isoniazid and rifampin; of the 99 165 people with multidrug-resistant tuberculosis that started treatment in 2014, only 53 549 (54%) were cured.1 These poor cure rates reflect the lengthy treatment with second-line tuberculosis drugs, which are less effective and more toxic than those used for drug-susceptible tuberculosis.2, 3 To date, there have been very few phase 3 randomised controlled trials investigating the treatment of multidrug-resistant tuberculosis, so most evidence for regimen selection is still from observational studies,3 or individual patient data (meta-analyses of these studies).4
In the past decade, several experimental and observational studies have documented the use of new and repurposed drugs, such as bedaquiline,5, 6 linezolid,7, 8 delamanid, clofazimine,9 and the carbapenems.10, 11 We assembled a database of individual records of patients treated for multidrug-resistant tuberculosis to estimate the association of treatment outcomes with use of specific anti-tuberculosis drugs, as well the optimal number and duration of treatment with those drugs.
Section snippets
Search strategy and selection criteria
The protocol for this study followed PRISMA guidelines and is available from the authors.
In September 2015, we did a systematic review to identify studies published between Jan 1, 2009, and Sept 15, 2015, of treatment of multidrug-resistant tuberculosis, including extensively drug-resistant tuberculosis.12 We updated the search in April, 2016, using the same search terms in MEDLINE, Embase, and the Cochrane library (appendix p 2). We also searched reference lists from all systematic reviews of
Results
We identified 87 individual studies, of which 50 (57%) provided adequate data for patients with confirmed pulmonary rifampin resistance (n=12 030; figure).5, 7, 8, 10, 11, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77 Of these patients, 11 918 (99·1%) had documented isoniazid resistance, 31 (0·3%) had
Discussion
We assessed 50 datasets from 25 countries, with 12 030 patients treated for multidrug-resistant tuberculosis. Of the drugs analysed, levofloxacin, moxifloxacin, linezolid, and bedaquiline were associated with greater treatment success and reduced death. Clofazimine and the carbapenems were associated with significantly improved treatment success but not reduced death. Pyrazinamide, streptomycin, amikacin, and cycloserine and terizidone were associated with modest benefits, but only in patients
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