Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the efficacy of linezolid when used as part of a second‐line regimen for treating people with multidrug‐resistant (MDR‐) and extensively drug‐resistant (XDR‐) pulmonary tuberculosis (TB), and to assess the prevalence and severity of adverse events associated with linezolid use in this patient group.
Background
Description of the condition
Tuberculosis (TB) is caused by infection with bacteria of the Mycobacterium tuberculosis complex. It remains one of the leading infectious causes of death worldwide despite significant reductions in incidence; there were 1.4 million deaths from TB worldwide in 2015, with an additional 0.4 million deaths from TB amongst people living with human immunodeficiency virus (HIV) (WHO TB Report 2016). Pulmonary TB is the most common form of TB, and the most important from a public health point of view because TB is transmitted by aerosolized droplets from people with active pulmonary TB when they cough (Vashishtha 2013). It is estimated that around one third of the world's population is infected with TB, although of these only one in ten will develop active TB disease (WHO 2009).
Most people with TB are infected with strains of M. tuberculosis that are treatable with the standard first‐line drugs recommended by the World Health Organization (WHO) guidelines: rifampicin, isoniazid, pyrazinamide, and ethambutol (WHO 2010). Early diagnosis and treatment with effective drugs is one of the mainstays of TB disease control, as well as being a life‐saving intervention for people with TB.
Multidrug‐resistant TB (MDR‐TB) is TB disease that is caused by M. tuberculosis strains that have acquired resistance to two important drugs in the first‐line regimen: rifampicin and isoniazid (Sharma 2006). Extensively drug‐resistant TB (XDR‐TB) occurs when M. tuberculosis strains are resistant to rifampicin, isoniazid, and any of the antibiotics in the fluoroquinolone class, as well as any of the three injectable drugs used in the second‐line treatment of TB: amikacin, kanamycin, and capreomycin (WHO 2016).
The WHO estimates that 480,000 cases of MDR‐TB occurred in 2015, with 190,000 people dying of MDR‐TB worldwide, and an estimated 9.5% of people with MDR‐TB actually have XDR‐TB (WHO TB Report 2016). Detection of drug‐resistant TB is challenging and currently requires costly laboratory services, and access to effective treatment is far from universal. Though there has been rapid progress, only 12% of new TB cases were tested for drug resistance in 2014, with case detection at only 41% (WHO 2015). Over the last decade treatment success rates have remained static at around 50% (WHO 2015), and the international TB community has recognized that new drugs and drug regimens with improved efficacy are urgently needed to improve cure rates. The WHO End TB Strategy outlines measures for post‐2015 TB control, including aims to detect and treat everyone with drug‐resistant TB, which will require significant scaling up of resources and efforts (WHO 2014).
Constructing MDR‐TB therapy regimens is recognized as a difficult balancing act, with several of the agents available being expensive and toxic, and of uncertain antituberculous efficacy due to limited evidence from clinical trials (Chang 2013a). This is especially true for XDR‐TB. This has led to efforts being channeled towards investigation of new and existing drugs and regimens, with a drive to standardize trial design and reporting (Mitnick 2015), and focus on low‐resource settings which are disproportionately affected by TB and MDR‐TB globally (Sloan 2016).
Description of the intervention
The recently updated WHO guidelines for treatment of drug‐resistant TB suggest linezolid as a "group C: other core second‐line agent", and recommend that two such drugs are required within a core drug‐resistant TB regimen (WHO 2016). However, concerns about serious adverse effects prompt the guidelines to state that, where close monitoring for adverse events is not available, "linezolid would best be reserved for MDR‐TB patients who have additional drug resistance...or who are intolerant to other components of the core regimen" (WHO 2016).
This upgrades the status of linezolid, which in the previous iteration of the WHO drug‐resistant TB guidelines was a "group 5" drug (WHO 2011). Evidence of efficacy and safety of group 5 drugs was deemed insufficient to recommend their use as core drugs within a regimen. In fact, the number of cases treated was so small that the evidence for linezolid was not analysed separately for the WHO 2011 guidelines.
Subsequent publications have suggested linezolid may have a more significant role in regimens, especially in the context of XDR‐TB. The International Union Against TB and Lung Disease guidelines recommend it should be the third drug to consider within group 5 (Caminero 2013).
Three meta‐analyses have examined the evidence for linezolid in drug‐resistant TB (Cox 2012; Sotgiu 2012; Zhang 2015). They include mostly observational data, much of it retrospective, and few randomized trials have been undertaken. There is much debate surrounding linezolid, without consensus, due to the lack of high quality evidence. Many suggest it should be more widely used, hence its upgrade in the recent WHO guidelines (Caminero 2015; WHO 2016).
Inclusion of retrospective data for treatment outcome may well have exacerbated the effect of confounders in the meta‐analyses of treatment efficacy (Cox 2012; Sotgiu 2012; Zhang 2015). These reviews focus on efficacy more than safety, with selection of studies based on the former. Safety is a major area of concern with linezolid (Ramachandran 2015).
How the intervention might work
Linezolid is an oxazolidinone antibiotic that disrupts protein synthesis by binding to the 70S initiation complex of bacterial ribosomes (Sloan 2016). It also binds to human mitochondria and inhibits protein synthesis, which is the mechanism of toxicity in clinical use (De Vriese 2006). It is active against most Gram‐positive bacteria, with extensive evidence of in vitro activity against isolates of M. tuberculosis, including those resistant to first‐line drugs (Erturan 2005; Huang 2008).
Linezolid can be taken orally or intravenously, with excellent oral bioavailability, and therefore does not require ongoing injections throughout a regimen (Dryden 2011). Though an adult dose of 600 mg twice daily is most commonly used to treat infections due to Gram‐positive bacteria, a variety of dosing strategies have been used for linezolid in the context of drug‐resistant TB. These have ranged from 300 mg to 1200 mg, as once‐ or twice‐daily regimens, and lower doses have been tried in an attempt to increase tolerability and reduce toxicity (Park 2006; Migliori 2009; Yew 2009; Koh 2012). A thrice‐weekly intermittent dosing regimen has also been tried in limited cohorts to prolong linezolid duration for as long as possible, with the suggestion of promising outcomes (Chang 2013b). The optimal dosing and duration of linezolid remains unclear from the perspective of preventing emergence of resistance, as well as efficacy, tolerability, and toxicity.
Adverse effects of linezolid include suppression of the bone marrow causing anaemia and thrombocytopenia, peripheral neuropathy and optic neuropathy leading to disability and blindness which is usually irreversible, and most commonly gastrointestinal upset which may lead to difficulties with adherence to treatment (Ramachandran 2015). Adverse events with courses of linezolid longer than one month appear to be common, affecting over 80% of participants in some studies (Lee 2012, Tang 2015).
Why it is important to do this review
Uncertainties about the balance between benefits and risks of linezolid use in drug‐resistant TB mean a systematic review that assesses the efficacy and adverse events related to linezolid is highly desirable. Its recent inclusion as a core agent in second‐line regimens in WHO guidance, with a warning regarding availability of monitoring for adverse events and lack of firm guidance on dosing, means that clinicians and policy makers will need an up‐to‐date appraisal of the evidence (WHO 2016). It should assist policy makers who are deciding on the place of linezolid in their national and regional drug‐resistant TB programmes, as well as individual clinicians trying to interpret the wide variety of published data on how effective, safe, and tolerable linezolid is in people being treated for MDR‐TB and XDR‐TB.
Objectives
To assess the efficacy of linezolid when used as part of a second‐line regimen for treating people with multidrug‐resistant (MDR‐) and extensively drug‐resistant (XDR‐) pulmonary tuberculosis (TB), and to assess the prevalence and severity of adverse events associated with linezolid use in this patient group.
Methods
Criteria for considering studies for this review
Types of studies
To assess the efficacy of linezolid we will include randomized controlled trials (RCTs) and quasi‐RCTs.
To assess the prevalence and severity of adverse events associated with the use of linezolid, we will include RCTs and quasi‐RCTs, and both prospective and retrospective cohort studies, as defined by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011b), where some participants receive linezolid and others do not.
Types of participants
Adults and children with a diagnosis of multidrug‐resistant (MDR‐) or extensively drug‐resistant (XDR‐) pulmonary tuberculosis (TB).
Types of interventions
Intervention
Antituberculous treatment (ATT) regimens that contained linezolid at any dose and for any duration.
Control
ATT regimens that did not contain linezolid.
Types of outcome measures
These outcome measures are based on those specified by the WHO for TB programme outcome reporting in MDR‐ and XDR‐TB (WHO 2013).
Primary outcomes
All‐cause death: all deaths that occurred during each included study and until the end of follow‐up.
TB‐associated death: all deaths attributed to TB by the study investigators that occurred during each study and until the end of follow‐up.
Treatment failure: participants who did not show sputum culture conversion by the end of the intensive phase of ATT, or who had reverted from culture negative to culture positive, or who had failed to respond clinically to treatment as defined by the study investigators.
Cure: participants who completed ATT as planned without evidence of failure and had at least three consecutive negative sputum cultures in specimens taken at least 30 days apart after the intensive phase of treatment.
Secondary outcomes
Treatment interrupted (default): participants who stopped taking ATT for one month or more at any point in the course of treatment.
Treatment completed: participants who completed ATT as planned but did not have at least three consecutive negative sputum cultures in specimens taken at least 30 days apart after the intensive phase of treatment..
Time to sputum culture conversion: the length of time between starting treatment and conversion from sputum culture positive to sputum culture negative.
Adverse events
All adverse events.
All serious adverse events.
Adverse events that led to discontinuation of antituberculous drugs or dose reduction.
Adverse events attributed to linezolid, particularly peripheral and optic neuropathy, anaemia, thrombocytopenia, lactic acidosis, and serotonin syndrome.
Search methods for identification of studies
We will attempt to identify all relevant trials regardless of language or publication status (published, unpublished, in press, and in progress).
Electronic searches
We will search the following databases for relevant studies: the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL) published in the Cochrane Library; MEDLINE (PubMed); Embase (OVID); and LILACS, using the search terms detailed in Appendix 1. We will also check the WHO International Clinical Trials Registry Platform (WHO ICTRP; www.who.int/ictrp/en/) and ClinicalTrials.gov (https://clinicaltrials.gov/ct2/home) for ongoing trials using the terms: "linezolid" and "tuberculosis".
Searching other resources
We will also contact researchers in the field to identify unpublished or ongoing trials.
Data collection and analysis
Selection of studies
Two review authors (BS and DC) will screen the titles and abstracts of the search results independently and code them as either 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'. We will retrieve the full‐text study reports of all potentially eligible studies and two review authors (BS and DC) will independently screen them for inclusion and will record the reasons for exclusion of ineligible studies. We will resolve any disagreement through discussion or, if required, we will consult a third review author. We will identify and exclude duplicates and collate multiple reports of the same study so that each study, rather than each report, is the unit of interest in the review. We will contact study authors for clarification if a study's eligibility is unclear. We will resolve any disagreements through discussion and list the excluded studies and the reasons for their exclusion in the 'Characteristics of excluded studies' table. We will record the selection process in sufficient detail to complete a PRISMA flow diagram.
Data extraction and management
We will design and pilot a data extraction form, and modify the form based on the results of the pilot. Two review authors (BS and DC) will independently extract data from each included study using the finalized data extraction form. BS and DC will compare the extracted data to identify any possible errors, and will resolve any discrepancies through discussion and by referring to the original study articles. We will extract the following data from each included study.
Country and clinical setting, start and end dates of the study, study design, inclusion and exclusion criteria applied, number of participants eligible for inclusion and number of participants allocated to each group.
Participant characteristics: age, sex, history of previous TB treatment, known contact with MDR‐TB patient, duration of symptoms at presentation, comorbidity (human immunodeficiency virus (HIV) infection, other immunosuppression and other diseases), diagnostic methods used (for example, culture‐based drug susceptibility testing, Xpert MTB/RIF, line probe assay for drug susceptibility), drug susceptibility profile of participants at entry to the study.
Intervention data: description of drugs, dose, route of administration in both the intensive and continuation phase, and duration of all drugs for both phases. Administration of other drugs or therapeutic procedures, including surgery.
Primary outcomes
For the primary outcomes we will extract the following data.
All‐cause death
Number of deaths, stratified by drug susceptibility profile, age and HIV status, if available.
Timing of death after start of treatment.
TB‐associated death
Number of deaths attributed to TB by the investigators, stratified by drug susceptibility profile, age and HIV status, if available.
Treatment failure
Number of participants who have not shown sputum culture conversion by the end of the intensive phase of ATT, stratified by drug susceptibility profile, age and HIV status, if available.
Number of participants who have reverted from culture negative to culture positive, stratified by drug susceptibility profile, age and HIV status, if available.
Number of participants who have failed to respond clinically to treatment as defined by the investigators, stratified by drug susceptibility profile, age and HIV status, if available.
Method of monitoring treatment and defining treatment failure.
Time between start of treatment and treatment failure.
Outcome following classification as treatment failure.
Cure
Number of participants who have completed ATT as planned and have had at least three negative sputum cultures in specimens taken at least 30 days apart during the last months of treatment, stratified by drug susceptibility profile, age, and HIV status, if available.
Secondary outcomes
For the secondary outcomes we will extract the following data.
Treatment interrupted
Number of participants who stopped taking ATT for one month or more at any point in the course of treatment, stratified by drug susceptibility profile, age and HIV status, if available.
Method of monitoring treatment adherence.
Reasons for treatment interruption, if available.
Treatment completed
Number of participants who completed ATT as planned but did not have at least three negative sputum cultures in specimens taken at least 30 days apart during the last months of treatment.
Method of monitoring treatment.
Time to sputum culture conversion
Time between starting treatment and conversion from sputum culture positive to sputum culture negative.
Method of monitoring treatment, including frequency of sputum sampling.
Follow‐up
Length of follow‐up, follow‐up methods, number and characteristics of losses to follow‐up.
Adverse events
We will extract information on the total number of the following.
Adverse events.
Serious adverse events.
Participants experiencing adverse events.
Adverse events that led to discontinuation of antituberculous drugs or dose reduction.
Adverse events that attributed to linezolid, particularly peripheral and optic neuropathy, anaemia, thrombocytopenia, lactic acidosis, and serotonin syndrome.
For each outcome, we will extract the number of participants assigned and the number of participants analysed in each treatment group. For dichotomous outcomes, we will extract the number of participants who experienced the event. For count data outcomes, we will extract the number of events in the intervention and control group.
Assessment of risk of bias in included studies
For randomized controlled trials (RCTs) and quasi‐RCTs, two review authors will independently assess the methodological quality of each included trial using the Cochrane 'Risk of bias' tool and report the results in a 'Risk of bias' table (Higgins 2011a). We will resolve any disagreements through discussion. Regarding generation of allocation sequence and allocation concealment, we will classify each as either adequate, inadequate, or unclear in each included trial according to Jüni 2001. We will report who was blinded in each included trial, and we will assess the risk of bias associated with blinding separately for each primary outcome. If at least 90% of participants were followed up to the trial's completion we will classify inclusion of all randomized participants as adequate; otherwise we will classify inclusion as inadequate. We will attempt to contact the trial authors if information is unspecified or unclear.
For non‐randomized studies, we will use the ROBINS‐I risk of bias tool (Sterne 2016), and will adapt and pilot it before we use it to assess all included non‐randomized studies. The following are areas of confounding that we expect to be relevant to all or most included studies.
Extent of drug resistance: number of effective drugs available.
Severity of TB disease at start of treatment.
HIV co‐infection.
Timing of addition of linezolid to the regimen.
Duration of linezolid treatment.
Background antituberculous therapy regimen.
Supportive care available in study setting.
Measures of treatment effect
We will use relative risk as the measure of treatment effect for analysis.
Unit of analysis issues
We do not anticipate that any cluster‐RCTs will meet the inclusion criteria of the review.
For multi‐armed studies, where we wish to include more than one intervention study arm, we will split the control group to avoid including the same participants more than once.
Dealing with missing data
The primary analysis is an intention‐to‐treat analysis where all participants randomized to treatment are included in the denominator. This analysis assumes that all losses to follow‐up have good outcomes. We will carry out a sensitivity analysis to explore the impact of the missing data on the summary effect estimate for all‐cause death and cure.
Assessment of heterogeneity
We will assess heterogeneity by visually inspecting the forest plots to determine closeness of point estimates with each other and overlap of confidence intervals (CIs). We will use the Chi² test with a P value of 0.10 to indicate statistical significance, and the I² statistic to assess heterogeneity with a value of 50% taken to indicate significant statistical heterogeneity.
Assessment of reporting biases
We will conduct visual inspection of the funnel plot of the trials for any obvious asymmetry that could be evidence of publication bias.
Data synthesis
Using Review Manager 5 (RevMan 5) (RevMan 2014), we will perform a meta‐analysis on the data in included trials. We will not combine data from RCTs and non‐RCTs. As we anticipate significant variability in the samples of participants across the different studies, we will use a random‐effects model for meta‐analysis, unless there is a very small number of included studies with low heterogeneity, in which case we will use a fixed‐effect model.
For non‐randomized data, we will not perform a meta‐analysis. We will report these data descriptively in a table that includes how the data is collected, and the reported outcomes (unadjusted). If the study authors have adjusted data, we will provide this estimate with a short description of the adjustments the study authors made.
We will assess the certainty of the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. We will use GRADEpro GDT software to construct 'Summary of findings' tables (GRADEpro GDT 2014).
Subgroup analysis and investigation of heterogeneity
We plan to investigate heterogeneity through the following subgroup analyses.
Drug resistance profile, determined by: (a) % XDR, (b) % fluoroquinolone‐resistant (resistant to any fluoroquinolone, but susceptible to injectables), (c) % injectable‐resistant (resistant to any injectable, but susceptible to fluoroquinolones).
HIV status (seropositive and seronegative).
Age (adults and children).
Daily dose of linezolid (600 mg or less and over 600 mg adult equivalent).
Duration of linezolid (six months or less and longer than six months).
Total cumulative dose of linezolid.
Other drugs within the background antituberculous drug regimen.
Sensitivity analysis
We will perform a worst‐case scenario analysis by imputing the missing data as poor outcomes in the linezolid group and good outcomes in the control group, and by comparing this to an available‐case analysis to explore the effect of missing data on the primary outcomes all‐cause death and cure.
Acknowledgements
We thank Vittoria Lutje, the Cochrane Infectious Diseases Group (CIDG) Information Specialist, for designing the search strategy. We also thank Paul Garner (CIDG Co‐ordinating Editor), David Sinclair, Geraint Davies, and Bertie Squire for their contributions to the conception of this review, and particularly Geraint Davies for his advice on protocol design.
During the writing of the protocol, HR was supported by the Effective Health Care Research Consortium. This Consortium and the editorial base of the Cochrane Infectious Diseases Group are funded by UK aid from the UK Government for the benefit of developing countries (Grant: 5242). The views expressed in this review do not necessarily reflect UK government policy.
Appendices
Appendix 1. Search strategy
| Search set | CIDG SR | CENTRAL | MEDLINE | Embase | LILACS |
| 1 | Tuberculosis OR TB | Tuberculosis OR TB ti, ab | Tuberculosis OR TB ti, ab | Tuberculosis OR TB ti, ab | Tuberculosis OR TB |
| 2 | Multi‐drug resistant | drug resist* OR MDR OR DR OR XDR ti, ab | drug resist* OR MDR OR DR OR XDR ti, ab | drug resist* OR MDR OR DR OR XDR ti, ab | Multi‐drug resistant |
| 3 | MDR‐TB | 1 and 2 | 1 and 2 | 1 and 2 | MDR‐TB |
| 4 | Drug‐resistant | DR‐TB OR MDR‐TB OR XDR‐TB ti, ab | DR‐TB OR MDR‐TB OR XDR‐TB ti, ab | DR‐TB OR MDR‐TB OR XDR‐TB ti, ab | Drug‐resistant |
| 5 | XDR‐TB | Tuberculosis, Multidrug‐Resistant"[Mesh] OR "Extensively Drug‐Resistant Tuberculosis"[Mesh] | Tuberculosis, Multidrug‐Resistant"[Mesh] OR "Extensively Drug‐Resistant Tuberculosis"[Mesh] | Multidrug resistant tuberculosis [Emtree] OR “extensively drug resistant tuberculosis” [Emtree] OR “drug resistant tuberculosis” [Emtree] | XDR‐TB |
| 6 | 2 or 3 or 4 or 5 | 3 or 4 or 5 | 3 or 4 or 5 | 3 or 4 or 5 | 2 or 3 or 4 or 5 |
| 7 | 1 and 6 | "Oxazolidinones"[Mesh] | "Oxazolidinones"[Mesh] | Linezolid ti, ab OR “Linezolid” [Emtree] | 1 and 6 |
| 8 | linezolid | "linezolid" [Supplementary Concept] | "linezolid" [Supplementary Concept] | LZD OR Zyvox ti, ab | linezolid |
| 9 | 7 and 8 | Linezolid OR LZD OR Zyvox ti, ab | Linezolid OR LZD OR Zyvox ti, ab | “oxazolidinone derivative” [Emtree] | 7 and 8 |
| 10 | — | 7 or 8 or 9 | 7 or 8 or 9 | 7 or 8 or 9 | — |
| 11 | — | 6 and 10 | 6 and 10 | 6 and 10 | — |
| 12 | — | — | Limit 11 to Humans | Limit 11 to Human | — |
Contributions of authors
BS and HR wrote the protocol with input from DC and DS. All protocol authors read and approved the final version of the protocol.
Sources of support
Internal sources
Liverpool School of Tropical Medicine, UK.
External sources
-
Department for International Development, UK.
Grant number: 5242
Declarations of interest
BS and HR work for the Royal Liverpool University Hospital, UK, and have no known conflicts of interest.
DC is a PhD candidate supported by a Wellcome Trust Training Fellowship in Tropical Medicine based at the Liverpool School of Tropical Medicine, UK, and has no known conflicts of interest.
DS is a Senior Clinical Lecturer at the University of St. Andrews, UK, and is a principal or co‐investigator on projects funded through grants from the Cunningham Trust, the Wellcome Trust, MRC‐Newton Fund, and EDCTP, and has no known conflicts of interest.
New
References
Additional references
- Caminero JA, editor. Guidelines for Clinical and Operational Management of Drug‐Resistant Tuberculosis. Paris: International Union Against Tuberculosis and Lung Disease, 2013. [ISBN: 979‐10‐91287‐03‐6] [Google Scholar]
- Caminero JA, Scardigli A. Classification of antituberculosis drugs: a new proposal based on the most recent evidence. European Respiratory Journal 2015;46(4):887‐93. [DOI] [PubMed] [Google Scholar]
- Chang KC, Yew WW. Management of difficult multidrug‐resistant tuberculosis and extensively drug‐resistant tuberculosis: update 2012. Respirology 2013;18(1):8‐21. [DOI: 10.1111/j.1440-1843.2012.02257.x] [DOI] [PubMed] [Google Scholar]
- Chang KC, Yew WW, Cheung SW, Leung CC, Tam CM, Chau CH, et al. Can intermittent dosing optimize prolonged linezolid treatment of difficult multidrug‐resistant tuberculosis?. Antimicrobial Agents and Chemotherapy 2013;57(7):3445‐9. [DOI: 10.1128/AAC.00388-13] [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cox H, Ford N. Linezolid for the treatment of complicated drug‐resistant tuberculosis: a systematic review and meta‐analysis. International Journal of Tuberculosis and Lung Disease 2012;16(4):447‐54. [DOI: 10.5588/ijtld.11.0451] [DOI] [PubMed] [Google Scholar]
- Vriese AS, Coster RV, Smet J, Seneca S, Lovering A, Haute LL, et al. Linezolid‐induced inhibition of mitochondrial protein synthesis. Clinical Infectious Diseases 2006;42(8):1111‐7. [DOI] [PubMed] [Google Scholar]
- Dryden MS. Linezolid pharmacokinetics and pharmacodynamics in clinical treatment. Journal of Antimicrobial Chemotherapy 2011;66(Suppl 4):iv7‐15. [DOI: 10.1093/jac/dkr072] [DOI] [PubMed] [Google Scholar]
- Erturan Z, Uzun M. In vitro activity of linezolid against multidrug‐resistant Mycobacterium tuberculosis isolates. International Journal of Antimicrobial Agents 2005;26(1):78‐80. [DOI: 10.1016/j.ijantimicag.2005.03.006] [DOI] [PubMed] [Google Scholar]
- GRADE Working Group, McMaster University. GRADEpro GDT. Version accessed 15 May 2017. Hamilton (ON): GRADE Working Group, McMaster University, 2014.
- Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 2011;343:d5928. [DOI: 10.1136/bmj.d5928] [DOI] [PMC free article] [PubMed] [Google Scholar]
- Higgins JP, Green S, editor(s). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.
- Huang TS, Liu YC, Sy CL, Chen YS, Tu HZ, Chen BC. In vitro activities of linezolid against clinical isolates of Mycobacterium tuberculosis complex isolated in Taiwan over 10 years. Antimicrobial Agents and Chemotherapy 2008;52(6):2226‐7. [DOI: 10.1128/AAC.00414-07] [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jüni P, Altman DG, Egger M. Systematic reviews in health care: Assessing the quality of controlled clinical trials. BMJ 2001;323(7303):42‐6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Koh WJ, Kang YR, Jeon K, Kwon OJ, Lyu J, Kim WS, et al. Daily 300 mg dose of linezolid for multidrug‐resistant and extensively drug‐resistant tuberculosis: updated analysis of 51 patients. Journal of Antimicrobial Chemotherapy 2012;67(6):1503‐7. [DOI: 10.1093/jac/dks078] [DOI] [PubMed] [Google Scholar]
- Lee M, Lee J, Carroll MW, Choi H, Min S, Song T, et al. Linezolid for treatment of chronic extensively drug‐resistant tuberculosis. New England Journal of Medicine 2012;367(16):1508‐18. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Migliori GB, Eker B, Richardson MD, Sotgiu G, Zellweger JP, Skrahina A, et al. A retrospective TBNET assessment of linezolid safety, tolerability and efficacy in multidrug‐resistant tuberculosis. European Respiratory Journal 2009;34(2):387‐93. [DOI: 10.1183/09031936.00009509] [DOI] [PubMed] [Google Scholar]
- Mitnick CD, Rusen I, Bain LJ, Horsburgh CR Jr. Issues in design and interpretation of MDR‐TB clinical trials: report of the first Global MDR‐TB Clinical Trials Landscape Meeting. BMC Proceedings 2015;9(Suppl 8):S1. [DOI: 10.1186/1753-6561-9-S8-S1] [DOI] [Google Scholar]
- Park IN, Hong SB, Oh YM, Kim MN, Lim CM, Lee SD, et al. Efficacy and tolerability of daily‐half dose linezolid in patients with intractable multidrug‐resistant tuberculosis. Journal of Antimicrobial Chemotherapy 2006;58(3):701‐4. [DOI] [PubMed] [Google Scholar]
- Ramachandran GS, Swaminathan S. Safety and tolerability profile of second‐line anti‐tuberculosis medications. Drug Safety 2015;38(3):253‐69. [DOI] [PubMed] [Google Scholar]
- Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager 5 (RevMan 5). Version 5.3. Copenhagen: Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
- Sharma SK, Mohan A. Multidrug‐resistant tuberculosis: a menace that threatens to destabilize tuberculosis control. Chest 2006;130(1):261‐72. [DOI] [PubMed] [Google Scholar]
- Sloan DJ, Lewis JM. Management of multidrug‐resistant TB: novel treatments and their expansion to low resource settings. Transactions of the Royal Society of Tropical Medicine and Hygiene 2016;110(3):163‐72. [DOI: 10.1093/trstmh/trv107] [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sotgiu G, Centis R, D'Ambrosio L, Alffenaar JW, Anger HA, Caminero JA, et al. Efficacy, safety and tolerability of linezolid‐containing regimens in treating MDR‐TB and XDR‐TB: systematic review and meta‐analysis. European Respiratory Journal 2012;40(6):1430‐42. [DOI: 10.1183/09031936.00022912] [DOI] [PubMed] [Google Scholar]
- Sterne JAC, Higgins JPT, Reeves BC, Jelena Savović, Lucy Turner, ROBINS‐I development group. ROBINS‐I: a tool for assessing Risk Of Bias In Non‐randomized Studies of Interventions. Available from http://www.riskofbias.info (accessed 14 June 2016).
- Tang S, Yao L, Hao X, Zhang X, Liu G, Liu X, et al. Efficacy, safety and tolerability of linezolid for the treatment of XDR‐TB: a study in China. European Respiratory Journal 2015;45(1):161‐70. [DOI] [PubMed] [Google Scholar]
- Vashishtha R, Mohan K, Singh B, Devarapu SK, Sreenivas V, Ranjan S, et al. Efficacy and safety of thrice weekly DOTS in tuberculosis patients with and without HIV co‐infection: an observational study. BMC Infectious Diseases 2013;13:468. [DOI: 10.1186/1471-2334-13-468] [DOI] [PMC free article] [PubMed] [Google Scholar]
- World Health Organization. Global Tuberculosis Control Report. Geneva: World Health Organization, 2009. [Google Scholar]
- World Health Organization. Treatment of Tuberculosis Guidelines. 4th Edition. Geneva: World Health Organization, 2010. [Google Scholar]
- World Health Organization. Guidelines for the programmatic management of drug‐resistant tuberculosis: 2011 update. Geneva: World Health Organization, 2011. [ISBN 978 92 4 150158 3] [PubMed] [Google Scholar]
- World Health Organization. Definitions and reporting framework for tuberculosis – 2013 revision (updated December 2014). Geneva: World Health Organization, 2013. [Google Scholar]
- World Health Organization. The End TB Strategy. Geneva: World Health Organization, 2014. [Google Scholar]
- World Health Organization. Global Tuberculosis Report 2015. Geneva: World Health Organization, 2015. [ISBN 978 92 4 156505 9] [Google Scholar]
- World Health Organization. WHO Treatment Guidelines for Drug‐Resistant Tuberculosis – 2016 update. Geneva: World Health Organization, 2016. [PubMed] [Google Scholar]
- World Health Organization. Global Tuberculosis Report. Geneva: World Health Organization, 2016. [Google Scholar]
- Yew WW, Chang KC, Chau CH. What is the optimal dosage of linezolid in treatment of complicated multidrug‐resistant tuberculosis?. European Respiratory Journal 2009;34(6):1492‐4. [DOI: 10.1183/09031936.00111009] [DOI] [PubMed] [Google Scholar]
- Zhang X, Falagas ME, Vardakas KZ, Wang R, Qin R, Wang J, et al. Systematic review and meta‐analysis of the efficacy and safety of therapy with linezolid containing regimens in the treatment of multidrug‐resistant and extensively drug‐resistant tuberculosis. Journal of Thoracic Disease 2015;7(4):603‐15. [DOI: 10.3978/j.issn.2072-1439.2015.03.10] [DOI] [PMC free article] [PubMed] [Google Scholar]