on July 24, 2018 by guest

Transcription

1 AAC Accepts, published online ahead of print on 17 June 2013 Antimicrob. Agents Chemother. doi: /aac Copyright 2013, American Society for Microbiology. All Rights Reserved. 1 2 WHO Group 5 drugs and difficult multidrug-resistant tuberculosis: a systematic review with cohort analysis and meta-analysis 3 4 Running title: Efficacy of WHO Group 5 drugs and difficult MDR-TB Kwok-Chiu Chang 1*, Wing-Wai Yew 2, Cheuk-Ming Tam 1, Chi-Chiu Leung 1 1 Tuberculosis and Chest Service, Department of Heath, Hong Kong SAR, China; 2 Department of Microbiology, the Chinese University of Hong Kong, Hong Kong SAR, China * Telephone: ; Fax: ; kc_chang@dh.gov.hk Downloaded from on July 24, 2018 by guest 1

2 Abstract It is often necessary to include WHO Group 5 drugs in the treatment of extensively drugresistant TB (XDR-TB) and fluoroquinolone-resistant multidrug-resistant tuberculosis (MDR- TB). As clinical evidence about 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 162 (84%), 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%, 124%) and 55% (10%, 121%), respectively. Defining significant associations by risk ratios 1.2 or 0.9, neither cohort analysis nor meta-analysis demonstrated any significant addon benefit from the use of other Group 5 drugs on outcome of patients treated with linezolid, although selection bias might have underestimated their effects. Our findings substantiated use of linezolid in the treatment of XDR-TB or fluoroquinolone-resistant MDR-TB, and calls for further studies to evaluate the roles of other Group 5 drugs. Word count: 250 Keywords: linezolid, multidrug-resistant, treatment, tuberculosis, WHO Group 5 drugs 2

3 34 INTRODUCTION Multidrug-resistant tuberculosis (MDR-TB), defined as tuberculosis (TB) with bacillary resistance to at least isoniazid and rifampin, has become a global epidemic. Concern about drugresistant TB intensified with the emergence of extensively drug-resistant TB (XDR-TB), which is MDR-TB with additional resistance to any fluoroquinolone and at least one of the second-line injectable drugs. MDR-TB (notably those with bacillary resistance to fluoroquinolones) and XDR-TB are more difficult to treat than drug-susceptible TB, with substantially worse outcome with mounting drug resistance (1 8). It is often necessary to include World Health Organization (WHO) Group 5 drugs in the treatment of XDR-TB and fluoroquinolone-resistant MDR-TB. WHO Group 5 drugs refer to anti-tb drugs with unclear efficacy or role in MDR-TB treatment (9). These include thiacetazone, linezolid, high-dose isoniazid, clofazimine, amoxicillin with clavulanate, macrolides, carbapenem, and thioridazine. Linezolid and clofazimine have been evaluated by three systematic reviews (10, 11, 12), but they provided only pooled estimates of treatment outcome without any controlled comparison. One systematic review with random effects multivariable logistic meta-regression has evaluated the role of second-line anti-tb drugs among general MDR-TB patients using individual patient data (13). Despite a large sample size of 9153 patients, it was not sufficiently powered to evaluate the role of linezolid and high-dose isoniazid. As clinical evidence about WHO Group 5 drugs and outcome in the treatment of the most complicated form of XDR-TB is scarce, we conducted a systematic review using published individual patient data. 3

4 57 METHODS USED FOR META-ANALYSIS AND COHORT ANALYSIS We searched the published literature through 7 April 2013 for publications in English to assemble a cohort with XDR-TB or fluoroquinolone-resistant MDR-TB treated with WHO Group 5 drugs. PubMed and OvidSP were used to search for biomedical articles from MEDLINE, life science journals, and EMBASE using the following key phrases with keywords in titles or abstracts with the help of Boolean operators ( and, or ): (i) tuberculosis or TB, and (ii) linezolid, or clofazimine, or clavulanate, or amoxicillin, or meropenem, or imipenem, or thioridazine, or phenothiazine, or clarithromycin, or high-dose isoniazid or thiacetazone, and (iii) drug-resistant, or multidrug-resistant, or extensively, or XDR*, or MDR*. The asterisk denotes a wild card. To increase the thoroughness of the literature search, the second key phrase with keywords in titles is combined with tuberculosis as a Medical Subject Heading (MeSH) and a third key phrase with the following keywords in titles joined by the Boolean operator or : efficacy, resistant, drug-resistant, multidrug-resistant. The search algorithm used in PubMed is shown in an appendix in the online supplement. Inclusion and exclusion criteria Patients included in the review must have pulmonary XDR-TB or fluoroquinolone-resistant MDR-TB treated with WHO Group 5 drugs alongside other anti-tb drugs. In the preliminary screening, we included all original articles with focus on treatment efficacy of MDR-TB, the availability of fluoroquinolone susceptibility testing results, and individual patient data. Thus review articles and commentaries, articles with focus on aspects other than treatment efficacy, 4

5 those containing only in vitro data, pharmacokinetic data, animal data, or genomic data, and those with no fluoroquinolone susceptibility testing results or individual patient data were excluded. Articles or individual patients were subsequently excluded for one or more of the following reasons: (i) no data on in vitro activity of fluoroquinolone, (ii) bacillary susceptibility to fluoroquinolone in vitro, (iii) disease involving only extrapulmonary sites, (iv) non-use of WHO Group 5 drugs, and (v) lack of evaluable outcome regarding treatment efficacy. Data of included articles were extracted from the published paper and any online repositories by the first author, and randomly checked by the other co-authors. Cohort analysis The assembled patients constituted a retrospective cohort that can be evaluated by cohort analysis with control for confounding at the individual patient level. Treatment efficacy of Group 5 drugs was evaluated by examining the strength of association between drug use and favorable outcome, which was defined as sputum culture conversion, cure, or treatment completion in the absence of death, default, treatment failure, or relapse. As the majority of patients in the assembled cohort received linezolid, we first evaluated the relationship between favorable outcome and linezolid use, with consideration of the following potential confounding factors: gender, age group, HIV co-infection, other comorbidities that may predispose to TB disease, treatment supervision, adjunct surgery in the latest episode of anti-tb treatment involving the use of Group 5 drugs, previous second-line TB treatment, additional resistance to any second-line injectable drug (SLID), use of adjunct immunotherapy, and 5

6 concurrent use of other anti-tb drugs including other Group 5 drugs. If treatment duration was available, use of an anti-tb drug for less than one month was considered as non-use. When missing data exceeded 5%, a categorical subgroup for missing data was created to include missing data in the analysis. To optimize inclusion of major factors that may confound the relationship between favorable outcome and linezolid use, we followed basic principles in epidemiological studies with emphasis on the strength of association rather than statistical significance (14). We screened potential confounders by examining risk ratios in univariate analysis rather than p-values. A potential confounder must meet at least two criteria (14). First, it must be at least weakly associated with both outcome and the exposure variable. Risk ratios 1.2 or 0.9 were used to denote at least weak association (15). In the presence of a categorical subgroup for missing data, the potential confounder was included when the risk ratio involving the predominant comparison subgroup relative to the reference subgroup met the criteria for at least weak association. Second, a potential confounder must cause at least 10% change in the coefficient of the exposure term when it is added in the regression model. Using the approach described above, we ascertained the adjusted risk ratio of favorable outcome from linezolid use in Model A with robust Poisson regression analysis, which is probably the best available method (16). To evaluate possible add-on effects of each non-linezolid Group 5 drug, we further constructed Model B by force-entering use of each non-linezolid Group 5 drug into Model A. Multicollinearity was considered before multivariable analysis, and assessed by the variance inflation factor, which was regarded as unacceptable when its value exceeds 5 (17). 6

7 Univariate and robust Poisson regression analyses were conducted in R with the packages gmodels and sandwich (18), respectively Meta-analysis To estimate the pooled risk ratio of favorable outcome from use of Group 5 drugs, randomeffects meta-analyses were conducted in R with the package metafor (19). To control for the confounding effect of linezolid, the pooled estimate of each non-linezolid Group 5 drug was ascertained after restricting analysis to subjects treated with linezolid-containing regimens. Publication bias was examined using the random-effects version of the Egger s regression test for funnel plot asymmetry (20). Heterogeneity between studies was tested by the chi-square test of heterogeneity (Q-test). FINDINGS AND CONCLUSIONS A total of 196 articles were initially identified in the literature search. These included prospective and retrospective observational studies. Figure 1 shows how a cohort of fluoroquinoloneresistant MDR-TB patients treated with WHO Group 5 drugs was assembled from 20 articles (6, 21 39). The cohort consisted of 194 patients from 12 countries: 117 from four Asian regions (South Korea, China, Hong Kong, India), 40 from five European countries (Portugal, Italy, Germany, Belgium, and Spain), 36 from two American countries (US, Argentina), and 1 from South Africa. 7

8 Cohort analysis Data were missing in > 5% in seven variables (proportion of missing data): gender (32%), age (32%), status about previous second-line treatment (SLT) (18%), HIV status (12%), comorbidities other than HIV (36%), use of adjunctive surgery (11%), and mode of treatment supervision (29%). Among 131 patients with known gender and age, 77 (59%) were males and 54 (41%) were females. The median age (interquartile range) was 39 (28-46) years. A total of 156 (98%) out of 160 patients with available information had previous SLT. Among 170 patients with data on HIV status, 3 (2%) were HIV-positive. Of 124 patients with known status about comorbidities other than HIV, 23 (19%) had diseases that could predispose to TB disease. A total of 8 (5%) out of 172 patients with available data had adjunctive surgery. Of 138 patients with data about the mode of treatment supervision, 80 (58%) had directly observed treatment (DOT). Data were complete in the other variables including use of anti-tb drugs. A total of seven WHO Group 5 drugs were included in the treatment of this cohort: linezolid, high-dose isoniazid (at least 10 mg/kg/dose), clofazimine, amoxicillin with clavulanate, macrolides (clarithromycin or azithromycin), carbapenem with or without clavulanate, and thioridazine. In descending order of frequency, linezolid was used in 162 (84%), macrolides in 84 (43%), clofazimine in 65 (34%), amoxicillin with clavulanate in 56 (29%), thioridazine in 18 (9%), carbapenem with or without clavulanate in 16 (8%), and high-dose isoniazid in 16 (8%). None received thiacetazone. 8

9 Univariate analysis showed eight variables that might possibly associate with favorable outcome by consideration of risk ratios (see Table 1): directly observed treatment, previous second-line treatment, use of interferon-gamma, use of rifabutin, use of linezolid, use of high-dose isoniazid, use of clofazimine, and use of thioridazine. Table 2 shows the results of univariate analysis of linezolid use and each of the other seven variables. Although each risk ratio denotes at least weak association, each variable caused < 10% change in the coefficient for linezolid use upon inclusion in the robust Poisson regression model (findings not shown). Table 3 shows two robust Poisson regression models regarding favorable outcome and use of Group 5 drugs. Model A shows that linezolid use substantially increased the probability (95% confidence interval, CI) of favorable outcome by 57% (10%, 124%). Model B shows that adding all non-linezolid Group 5 drugs into Model A hardly changes the risk ratio of favorable outcome from linezolid use. Furthermore, using risk ratios 1.2 or 0.9 to denote at least weak association, none of the nonlinezolid Group 5 drugs confers any significant add-on benefit. Meta-analysis Table 4 summarizes the results of random-effect meta-analysis regarding favorable outcome and use of Group 5 drugs. The Q-test showed no evidence of heterogeneity. The pooled estimate of risk ratio (95% CI) of favorable outcome from linezolid use relative to non-use was 1.55 (1.10, 2.21). Among patients given linezolid, corresponding pooled estimates were 0.95 (0.67, 1.33) for high-dose isoniazid, 0.99 (0.76, 1.31) for clofazimine, 1.01 (0.78, 1.30) for amoxicillin plus clavulanate, 0.96 (0.76, 1.22) for macrolides, 0.76 (0.48, 1.22) for carbapenem with or without clavulanate, and 0.78 (0.54, 1.13) for thioridazine. Forest plots of risk ratios are shown in the 9

10 online supplement. The random-effects version of the Egger s regression test for funnel plot asymmetry showed non-significant findings for each Group 5 drug Discussion To our knowledge, this is the first systematic review with cohort analysis and meta-analysis that has evaluated the role of WHO Group 5 drugs in the treatment of fluoroquinolone-resistant MDR-TB and XDR-TB, and with emphasis on the strength of association rather than statistical significance. We have systematically collected individual patient data from 20 articles in English to assemble a cohort of 194 fluoroquinolone-resistant MDR-TB patients treated with WHO Group 5 drugs. Statistical analyses showed neither between-study heterogeneity nor publication bias. Both cohort analysis using robust Poisson regression models and meta-analysis using random-effects models showed that use of linezolid substantially and significantly increased the probability of favorable outcome by 50-60%. Defining clinically significant improvement by risk ratios 1.2 or 0.9, neither cohort analysis nor meta-analysis demonstrated any add-on benefit from the use of the other Group 5 drugs (high-dose isoniazid, clofazimine, amoxicillin with clavulanate, macrolides, carbapenem, and thioridazine) on outcome of XDR-TB or fluoroquinolone-resistant MDR-TB patients treated with linezolid. Our findings further corroborated the important role of linezolid in the treatment of the most complicated forms of MDR-TB (9, 40), and calls for further studies to evaluate the clinical roles of other Group 5 drugs. 10

11 Although it may be unusual to conduct cohort analysis alongside meta-analysis, this is probably appropriate as we have indeed assembled a cohort by well-defined criteria, and perhaps also necessary for the following reasons. Unlike meta-analysis based on quality randomized controlled trials, meta-analysis based on observational studies and case reports is inevitably prone to errors from selection bias and confounding. While meta-regression may help identify causes of heterogeneity between studies, it does not control for confounding at individual patient level. Although cohort analysis by the standard methods of univariate and multivariable analyses cannot mitigate selection bias, it addresses major confounding factors and allows better estimation of the actual strength of association between drug use and outcome. To evaluate the impact of drug use on outcome, we have used robust Poisson regression analysis instead of logistic regression analysis because adjusted risk ratios (from the former) may be more direct and comprehensible than adjusted odds ratios (from the latter). A number of uncontrolled clinical studies have demonstrated a beneficial role of linezolid in the treatment of complicated MDR-TB (10, 11). The need of giving linezolid for a prolonged period with associated side effects has generally restricted its use to the most complicated MDR-TB (40). The prominent role of linezolid may be partly related to its high penetrability into sputum (39, 41, 42), and partly related to a very low minimum inhibitory concentration (MIC) relative to achievable serum drug levels (21, 43). Despite a low mutant prevention concentration (44), acquired resistance to linezolid in Mycobacterium tuberculosis has emerged (21, 45). To ensure treatment success and prevent amplification of drug resistance, it is necessary to optimize the dosing schedule of linezolid and give as many likely effective companion drugs as possible. Although non-linezolid Group 5 drugs may not add much to linezolid activity, it is possible that 11

12 one or more of them used alongside newer-generation fluoroquinolone and other second-line drugs may help protect linezolid from acquiring bacillary resistance, and vice versa Selection bias might have underestimated the therapeutic effects of non-linezolid Group 5 drugs, especially high-dose isoniazid, carbapenem, and thioridazine that were used in < 10% of patients in the assembled cohort. With excellent drug concentration in lung and high achievable serum drug levels, high-dose isoniazid may be beneficial when isoniazid MIC is below 1 mg/ and possibly below 5 mg/l. In contrast to our findings, a recent case-control study has suggested that meropenem with clavulanate may non-significantly improve sputum culture conversion in linezolid-based treatment of MDR-TB (46). The add-on effect became statistically significant after excluding XDR-TB patients. Further studies may be required to better delineate the role of high-dose isoniazid and meropenem with clavulanate in the treatment of the most complicated form of MDR-TB. It has been suggested for over a decade that amoxicillin with clavulanate (47 49), macrolides (50, 51), and thioridazine (52, 53) may have a role in the treatment of MDR-TB. More data are required to address this controversy. Clofazimine has been used as part of a nine-month gatifloxacin-containing regimen in the treatment of MDR-TB patients (54), but the targeted patients were largely SLT-naïve. Any observed benefit from the use of clofazimine could have been partly or entirely attributed to the co-administration of high-dose gatifloxacin. In a retrospective study involving predominantly MDR-TB patients with previous SLT (55), the role of clofazimine also appeared less impressive. With inclusion of this study through another article (34), our systematic review suggested that clofazimine might have only a limited role in the treatment of XDR-TB or fluoroquinolone- 12

13 261 resistant MDR-TB treated with linezolid-containing regimens There are several limitations in this review. First and foremost is the relatively small sample size and possible selection bias. We have only included articles published in English in our systematic review. Owing to substantial difficulty in obtaining unpublished data from different investigators within a reasonably short timeframe, we have excluded studies that have not released individual patient data in press or via online repositories. This approach could have introduced selection bias, but it is impossible to tell whether data from excluded studies may ameliorate the bias. Although the Egger s regression test for funnel plot asymmetry showed nonsignificant findings for each Group 5 drug, concerns about publication bias and other causes of selection bias cannot be totally excluded. Second, a substantial proportion of data were missing in seven variables. In the absence of an obvious systematic factor that may cause selection bias, these missing data were assumed to cause non-differential rather than differential information bias (14). The drawback has probably been partly addressed by including missing data as a subcategory in the analysis. Third, we did not control for drug susceptibility testing results, but they would probably be closely related to drug use. Finally, most of the included studies provided either no definition regarding sputum culture conversion and cure or used different definitions (see online supplement). This is unfortunately a reality in the majority of the published literature on this subject. In conclusion, our systematic review with meta-analysis and cohort analysis of individual patient data substantiates the use of linezolid in the treatment of XDR-TB or fluoroquinolone-resistant MDR-TB, and calls for further studies to evaluate the roles of other Group 5 drugs. 13

14 ACKNOWLEDGMENTS This study was conducted without any funding. We have no conflicts of interest to declare. 14

15 REFERENCES 1. Orenstein EW, Basu S, Shah NS, Andrews JR, Friedland GH, Moll AP, Gandhi NR, Galvani AP Treatment outcomes among patients with multidrug-resistant tuberculosis: systematic review and meta-analysis. Lancet Infect Dis 9: Migliori GB, Besozzi G, Girardi E, Kliiman K, Lange C, Toungoussova OS, Ferrara G, Cirillo DM, Gori A, Matteelli A, Spanevello A, Codecasa LR, Raviglione MC Clinical and operational value of the extensively drug-resistant tuberculosis definition. Eur Respir J 30: Shah NS, Pratt R, Armstrong L, Robison V, Castro KG, Cegielski JP Extensively drug-resistant tuberculosis in the United States, JAMA 300: Mitnick CD, Shin SS, Seung KJ, Rich ML, Atwood SS, Furin JJ, Fitzmaurice GM, Alcantara Viru FA, Appleton SC, Bayona JN, Bonilla CA, Chalco K, Choi S, Franke MF, Fraser HSF, Guerra D, Hurtado RM, Jazayeri D, Joseph K, Llaro K, Mestanza L, Mukherjee JS, Muñoz M, Palacios E, Sanchez E, Sloutsky A, Becerra MC Comprehensive treatment of extensively drug-resistant tuberculosis. N. Engl. J. Med. 359: Kim H-R, Hwang SS, Kim HJ, Lee SM, Yoo C-G, Kim YW, Han SK, Shim Y-S, Yim J- J Impact of extensive drug resistance on treatment outcomes in non-hiv-infected patients with multidrug-resistant tuberculosis. Clin. Infect. Dis. 45: Eker B, Ortmann J, Migliori GB, Sotgiu G, Muetterlein R, Centis R, Hoffmann H, Kirsten D, Schaberg T, Ruesch-Gerdes S, Lange C Multidrug- and extensively drug-resistant tuberculosis, Germany. Emerging Infect. Dis. 14:

16 Keshavjee S, Gelmanova IY, Farmer PE, Mishustin SP, Strelis AK, Andreev YG, Pasechnikov AD, Atwood S, Mukherjee JS, Rich ML, Furin JJ, Nardell EA, Kim JY, Shin SS Treatment of extensively drug-resistant tuberculosis in Tomsk, Russia: a retrospective cohort study. Lancet 372: Gandhi NR, Shah NS, Andrews JR, Vella V, Moll AP, Scott M, Weissman D, Marra C, Lalloo UG, Friedland GH HIV coinfection in multidrug- and extensively drugresistant tuberculosis results in high early mortality. Am. J. Respir. Crit. Care Med. 181: World Health Organization Guidelines for the Programmatic Management of Drug- Resistant Tuberculosis: Emergency Update WHO/HTM/TB/ Geneva, WHO. 10. Cox H, Ford N Linezolid for the treatment of complicated drug-resistant tuberculosis: a systematic review and meta-analysis. Int. J. Tuberc. Lung Dis. 16: Sotgiu G, Centis R, D Ambrosio L, Alffenaar J-WC, Anger HA, Caminero JA, Castiglia P, Lorenzo SD, Ferrara G, Koh W-J, Schecter GF, Shim TS, Singla R, Skrahina A, Spanevello A, Udwadia ZF, Villar M, Zampogna E, Zellweger J-P, Zumla A, Migliori GB Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB: systematic review and meta-analysis. Eur Respir J 40: Dey T, Brigden G, Cox H, Shubber Z, Cooke G, Ford N Outcomes of clofazimine for the treatment of drug-resistant tuberculosis: a systematic review and meta-analysis. J. Antimicrob. Chemother. 13. Ahuja SD, Ashkin D, Avendano M, Banerjee R, Bauer M, Bayona JN, Becerra MC, Benedetti A, Burgos M, Centis R, Chan ED, Chiang C-Y, Cox H, D Ambrosio L, 16

17 DeRiemer K, Dung NH, Enarson D, Falzon D, Flanagan K, Flood J, Garcia-Garcia ML, Gandhi N, Granich RM, Hollm-Delgado MG, Holtz TH, Iseman MD, Jarlsberg LG, Keshavjee S, Kim H-R, Koh W-J, Lancaster J, Lange C, de Lange WCM, Leimane V, Leung CC, Li J, Menzies D, Migliori GB, Mishustin SP, Mitnick CD, Narita M, O Riordan P, Pai M, Palmero D, Park S, Pasvol G, Peña J, Pérez-Guzmán C, Quelapio MID, Ponce-de-Leon A, Riekstina V, Robert J, Royce S, Schaaf HS, Seung KJ, Shah L, Shim TS, Shin SS, Shiraishi Y, Sifuentes-Osornio J, Sotgiu G, Strand MJ, Tabarsi P, Tupasi TE, van Altena R, Van der Walt M, Van der Werf TS, Vargas MH, Viiklepp P, Westenhouse J, Yew WW, Yim J-J Multidrug resistant pulmonary tuberculosis treatment regimens and patient outcomes: an individual patient data meta-analysis of 9,153 patients. PLoS Med. 9:e Rothman KJ Using regression models in epidemiological analysis. Epidemiology: an introduction. Oxford University Press. 15. Monson R Occupational Epidemiology, 2nd edition. Boca Raton, Florida: CRC Press Inc. 16. Zou G A modified poisson regression approach to prospective studies with binary data. Am. J. Epidemiol. 159: Menard S Applied logistic regression analysis. Sage University Paper Series on Quantitative Applications in the Social Sciences, Thousand Oaks, CA: Sage. 18. Zeileis A Object-oriented Computation of Sandwich Estimators. J Stat Softw 16: Viechtbauer W Conducting Meta-Analyses in R with the metafor Package. J Stat Softw 36:

18 Sterne J, Egger M Regression methods to detect publication and other bias in metaanalysis, p In Publication Bias in Meta-Analysis: Prevention, Assessment and Adjustments (eds H. R. Rothstein, A. J. Sutton and M. Borenstein). John Wiley & Sons, Ltd, Chichester, UK. 21. Lee M, Lee J, Carroll MW, Choi H, Min S, Song T, Via LE, Goldfeder LC, Kang E, Jin B, Park H, Kwak H, Kim H, Jeon H-S, Jeong I, Joh JS, Chen RY, Olivier KN, Shaw PA, Follmann D, Song SD, Lee J-K, Lee D, Kim CT, Dartois V, Park S-K, Cho S-N, Barry CE 3rd Linezolid for treatment of chronic extensively drug-resistant tuberculosis. N. Engl. J. Med. 367: Fortún J, Martín-Dávila P, Navas E, Pérez-Elías MJ, Cobo J, Tato M, De la Pedrosa EG-G, Gómez-Mampaso E, Moreno S Linezolid for the treatment of multidrugresistant tuberculosis. J. Antimicrob. Chemother. 56: Chambers HF, Turner J, Schecter GF, Kawamura M, Hopewell PC Imipenem for treatment of tuberculosis in mice and humans. Antimicrob. Agents Chemother. 49: Park I-N, Hong S-B, Oh Y-M, Kim M-N, Lim C-M, Lee SD, Koh Y, Kim WS, Kim DS, Kim WD, Shim TS Efficacy and tolerability of daily-half dose linezolid in patients with intractable multidrug-resistant tuberculosis. J. Antimicrob. Chemother. 58: Nam H-S, Koh W-J, Kwon OJ, Cho S-N, Shim TS Daily half-dose linezolid for the treatment of intractable multidrug-resistant tuberculosis. Int. J. Antimicrob. Agents 33: Schecter GF, Scott C, True L, Raftery A, Flood J, Mase S Linezolid in the treatment of multidrug-resistant tuberculosis. Clin. Infect. Dis. 50:

19 Anger HA, Dworkin F, Sharma S, Munsiff SS, Nilsen DM, Ahuja SD Linezolid use for treatment of multidrug-resistant and extensively drug-resistant tuberculosis, New York City, J. Antimicrob. Chemother. 65: Manfredi R, Nanetti A, Dal Monte P, Calza L Increasing pathomorphism of pulmonary tuberculosis: an observational study of slow clinical, microbiological and imaging response of lung tuberculosis to specific treatment. Which role for linezolid? Braz J Infect Dis 13: Sasse J, Teichmann D Disseminated multiorgan MDR-TB resistant to virtually all first-line drugs. Eur Respir Rev 18: Kjöllerström P, Brito MJ, Gouveia C, Ferreira G, Varandas L Linezolid in the treatment of multidrug-resistant/extensively drug-resistant tuberculosis in paediatric patients: experience of a paediatric infectious diseases unit. Scand. J. Infect. Dis. 43: Udwadia ZF, Sen T, Pinto LM Safety and efficacy of thioridazine as salvage therapy in Indian patients with XDR-TB. Recent Pat Antiinfect Drug Discov 6: Villar M, Sotgiu G, D Ambrosio L, Raymundo E, Fernandes L, Barbedo J, Diogo N, Lange C, Centis R, Migliori GB Linezolid safety, tolerability and efficacy to treat multidrug- and extensively drug-resistant tuberculosis. Eur. Respir. J. 38: Abbate E, Vescovo M, Natiello M, Cufré M, García A, Gonzalez Montaner P, Ambroggi M, Ritacco V, van Soolingen D Successful alternative treatment of extensively drug-resistant tuberculosis in Argentina with a combination of linezolid, moxifloxacin and thioridazine. J. Antimicrob. Chemother. 67: Xu H-B, Jiang R-H, Xiao H-P Clofazimine in the treatment of multidrug-resistant tuberculosis. Clin. Microbiol. Infect. 18:

20 Payen MC, De Wit S, Martin C, Sergysels R, Muylle I, Van Laethem Y, Clumeck N Clinical use of the meropenem-clavulanate combination for extensively drug-resistant tuberculosis. Int. J. Tuberc. Lung Dis. 16: De Lorenzo S, Centis R, D Ambrosio L, Sotgiu G, Migliori GB On linezolid efficacy and tolerability. Eur. Respir. J. 39: Xu H-B, Jiang R-H, Li L, Xiao H-P Linezolid in the treatment of MDR-TB: a retrospective clinical study. Int. J. Tuberc. Lung Dis. 16: Rose PC, Hallbauer UM, Seddon JA, Hesseling AC, Schaaf HS Linezolidcontaining regimens for the treatment of drug-resistant tuberculosis in South African children. Int. J. Tuberc. Lung Dis. 16: Chang K-C, Yew W-W, Cheung S-W, Leung C-C, Tam C-M, Chau C-H, Wen PK-H, Chan RC-Y Can intermittent dosing optimize prolonged linezolid treatment of difficult multidrug-resistant tuberculosis? Antimicrob. Agents Chemother. 40. Migliori GB, Eker B, Richardson MD, Sotgiu G, Zellweger J-P, Skrahina A, Ortmann J, Girardi E, Hoffmann H, Besozzi G, Bevilacqua N, Kirsten D, Centis R, Lange C A retrospective TBNET assessment of linezolid safety, tolerability and efficacy in multidrug-resistant tuberculosis. Eur. Respir. J. 34: Conte JE Jr, Golden JA, Kipps J, Zurlinden E Intrapulmonary pharmacokinetics of linezolid. Antimicrob. Agents Chemother. 46: Saralaya D, Peckham DG, Hulme B, Tobin CM, Denton M, Conway S, Etherington C Serum and sputum concentrations following the oral administration of linezolid in adult patients with cystic fibrosis. J. Antimicrob. Chemother. 53:

21 Koh W-J, Kang YR, Jeon K, Kwon OJ, Lyu J, Kim WS, Shim TS Daily 300 mg dose of linezolid for multidrug-resistant and extensively drug-resistant tuberculosis: updated analysis of 51 patients. J. Antimicrob. Chemother. 67: Rodríguez JC, Cebrián L, López M, Ruiz M, Jiménez I, Royo G Mutant prevention concentration: comparison of fluoroquinolones and linezolid with Mycobacterium tuberculosis. J. Antimicrob. Chemother. 53: Huang T-S, Liu Y-C, Sy C-L, Chen Y-S, Tu H-Z, Chen B-C In vitro activities of linezolid against clinical isolates of Mycobacterium tuberculosis complex isolated in Taiwan over 10 years. Antimicrob. Agents Chemother. 52: De Lorenzo S, Alffenaar JW, Sotgiu G, Centis R, D Ambrosio L, Tiberi S, Bolhuis MS, van Altena R, Viggiani P, Piana A, Spanevello A, Migliori GB Efficacy and safety of meropenem/clavunate added to linezolid containing regimens in the treatment of M/XDR- TB. Eur. Respir. J. 47. Chambers HF, Kocagöz T, Sipit T, Turner J, Hopewell PC Activity of amoxicillin/clavulanate in patients with tuberculosis. Clin. Infect. Dis. 26: Cynamon MH, Palmer GS In vitro activity of amoxicillin in combination with clavulanic acid against Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 24: Nadler JP, Berger J, Nord JA, Cofsky R, Saxena M Amoxicillin-clavulanic acid for treating drug-resistant Mycobacterium tuberculosis. Chest 99: Cavalieri SJ, Biehle JR, Sanders WE Jr Synergistic activities of clarithromycin and antituberculous drugs against multidrug-resistant Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 39:

22 Luna-Herrera J, Reddy VM, Daneluzzi D, Gangadharam PR Antituberculosis activity of clarithromycin. Antimicrob. Agents Chemother. 39: Amaral L, Kristiansen JE, Abebe LS, Millett W Inhibition of the respiration of multi-drug resistant clinical isolates of Mycobacterium tuberculosis by thioridazine: potential use for initial therapy of freshly diagnosed tuberculosis. J. Antimicrob. Chemother. 38: Amaral L, Viveiros M Why thioridazine in combination with antibiotics cures extensively drug-resistant Mycobacterium tuberculosis infections. Int. J. Antimicrob. Agents 39: Van Deun A, Maug AKJ, Salim MAH, Das PK, Sarker MR, Daru P, Rieder HL Short, highly effective, and inexpensive standardized treatment of multidrug-resistant tuberculosis. Am J Respir Crit Care Med 182: Xu H-B, Jiang R-H, Tang S-J, Li L, Xiao H-P Role of clofazimine in the treatment of multidrug-resistant tuberculosis: a retrospective observational cohort assessment. The Journal of Antimicrobial Chemotherapy. 22

23 Search in MEDLINE and EMBASE via PubMed and OVIDSP identified 195 articles in English One original article from investigators of the current review 196 articles in English 172 articles were excluded for the following reasons: Age of study subjects < 12 years (n=2) In vitro, ex vivo, pharmacokinetic, or animal studies (n=69) Substantial duplication of data (n=6) Unrelated to MDR-TB (n=14) Focus on aspects other than treatment efficacy (n=11) Other publication types with no original data (n=53) Individual data not accessible (n=8) All fluoroquinolone-susceptible MDR-TB (n=3) No data on in vitro bacillary resistance to fluoroquinolone (n = 6) 24 articles with individual data from 268 MDR-TB patients 74 patients from 4 articles were excluded for the following reasons: No data on in vitro bacillary resistance to fluoroquinolone (n=1) Fluoroquinolone-susceptible MDR-TB (n=64) Extrapulmonary TB without pulmonary TB (n=1) No evaluable data on treatment outcome (n=4) Group 5 drugs not given (n=4) patients with individual data from 20 articles were included in the final analysis FIG 1 Flow chart from literature search to selection of articles and patients for the final analysis 23

24 464 Table 1 Univariate analysis of favorable outcome a Row Number with favorable outcome (%) RR P-value total Gender Female (69) Male (71) No data (81) Age group (years) b < (72) (69) No data (81) HIV co-infection No (72) Yes 3 2 (67) No data (83) Other diseases that predispose to TB No (69) Yes (78) No data (79) DOT No (81)

25 Yes (69) No data (73) Adjunct surgery c No (72) Yes 8 7 (88) No data (82) Previous SLT No 4 4 (100) Yes (71) No data (85) Type of MDR-TB FQ-resistant (72) XDR-TB (74) Use of streptomycin No (74) Yes (73) Use of rifabutin No (75) Yes (63) Use of ethambutol No (73) Yes (79) 25

26 Use of newer FQ No (66) Yes (76) Use of SLID No (71) Yes (76) Use of thioamide No (72) Yes (76) Use of pyrazinamide No (74) Yes (73) Use of cycloserine No (67) Yes (79) Use of PAS No (72) Yes (75) Use of IFN-γ No (75) Yes 5 2 (40) Use of linezolid No (50) 1.57 < Yes (78) 26

27 Use of high-dose isoniazid No (72) Yes (88) Use of clofazimine No (78) Yes (65) Use of amoxicillin with clavulanate No (74) Yes (73) Use of macrolides No (71) Yes (77) Use of carbapenem with or without clavulanate No (74) Yes (75) Use of thioridazine No (74) Yes (67) a Frequency (%) is shown. A subgroup for missing data is created for each factor when missing data > 5%. Factors with risk ratios 1.2 or 0.9 are shown in bold. The reference subgroup of each variable refers to the first (uppermost) one. In the presence of a subgroup with missing data, the risk ratio refers to the risk of the predominant subgroup relative to that of the reference subgroup. b Excluding missing data, the median age of the cohort was 39 years. 27

28 c Referring to the latest episode of treatment. Abbreviations: DOT, directly observed treatment; FQ, fluoroquinolones; IFN-γ, interferon-gamma; MDR-TB, multidrug-resistant tuberculosis; NA, not applicable; PAS, para-aminosalicylic acid; RR, risk of the second or the predominant subgroup relative to the first (reference) subgroup; SLT, second-line treatment; SLID, second-line injectable drugs. Downloaded from on July 24, 2018 by guest 28

29 473 Table 2 Univariate analysis of linezolid use and each of the other seven factors possibly associated with favorable outcome a Row total Number with linezolid use (%) RR P-value DOT No (93) 0.70 < Yes (65) No data (100) Previous SLT No 4 4 (100) Yes (79) No data (100) Rifabutin No (85) Yes (75) IFN-γ No (83) Yes 5 5 (100) High-dose isoniazid No (82) Yes (100) Clofazimine No (100) 0.51 < Yes (51) 29

30 Thioridazine No (82) Yes (100) a Frequency (%) is shown. The mention of a Group 5 drug or IFN-γ refers to its use. Factors with risk ratios 1.2 or 0.9 are shown in bold. The reference subgroup of each variable refers to the first (uppermost) one. In the presence of a subgroup with missing data, the risk ratio refers to the risk of the predominant subgroup relative to that of the reference subgroup. None of these seven factors were included in multivariable analysis of favorable outcome and linezolid use because each caused < 10% change in the coefficient of linezolid use upon inclusion in the robust Poisson regression model. Please refer to Table 1 for abbreviations. Downloaded from on July 24, 2018 by guest 30

31 Table 3 Robust Poisson regression models of favorable outcome and use of Group 5 drugs a Model A Predictor variable Risk ratio (95% confidence interval) Linezolid 1.57 (1.10, 2.24) Model B Predictor variable Risk ratio (95% confidence interval) Linezolid 1.61 (1.10, 2.35) High-dose isoniazid 1.12 (0.90, 1.40) Clofazimine 1.01 (0.80,1.26) Amoxicillin with clavulanate 0.88 (0.71,1.09) Macrolides 1.13 (0.92, 1.37) Carbapenem with or without clavulanate 1.09 (0.82, 1.46) Thioridazine 0.86 (0.60, 1.24) a The mention of a Group 5 drug refers to its use. 31

32 Table 4 Results of random-effects meta-analysis of favorable outcome and use of Group 5 drugs a Group 5 drug P-values of the Q- P-values of the Egger s regression Pooled estimates of risk ratio test for heterogeneity test for funnel plot asymmetry (95% confidence interval) Linezolid (1.10, 2.21) High-dose isoniazid (0.67, 1.33) Clofazimine (0.76, 1.31) Amoxicillin with clavulanate (0.78, 1.30) Macrolides (0.76, 1.22) Carbapenem with or without clavulanate (0.48, 1.22) Thioridazine (0.54, 1.13) a Meta-analysis of linezolid involves the entire cohort of 194 patients, whereas that of each non-linezolid Group 5 drugs is restricted to the 162 patients given linezolid-containing regimens. 32

33