Adjunct linezolid in patients with tuberculous meningitis for mortality or neurological disability prevention: a meta-analysis of randomized controlled trials

doi:10.21203/rs.3.rs-4966196/v1

Background

This systematic review aimed to evaluate the effectiveness of linezolid as an adjunct to the current tuberculous meningitis standard of care in preventing death and neurological disability.

Methods

The MEDLINE, Embase, and CENTRAL databases were searched until 5 January 2024. We included randomized controlled trials in individuals with clinically diagnosed tuberculous meningitis comparing adjunct linezolid to standard treatment alone. We synthesized results using an inverse-variance random-effects meta-analysis, reporting the probability of treatment benefit with a Bayesian hierarchical normal-normal model.

Results

Three trials were included. There was a risk reduction in mortality (RR 0.45, 95% CI 0.21 to 0.97; 3 RCTs, n = 87 patients; moderate certainty evidence). The probability of a clinically relevant benefit (RR < 0.9) was 93.95%, and 74.86% for a large prevention in mortality (RR < 0.5). The probability of harm is less than 2.5% (RR > 1.1). However, the effect on neurological disability was uncertain (RR 0.76, 95% CI 0.45 to 1.28; 2 RCTs, n = 64 patients; very low certainty evidence).

Conclusions

Linezolid shows considerable promise in reducing mortality in patients with tuberculous meningitis, one of the most severe and challenging central nervous system infections. Larger-scale trials should elucidate its effect on neurological disability and optimize dosing strategies.

Tuberculosis

Meningitis

Linezolid

Central nervous system

Description of the condition

Mycobacterium tuberculosis infection of the central nervous system can result in the inflammation of the meninges around the brain and spinal cord, accounting for nearly 14% of all cases of meningitis[1]. Historically, it has been one of the most devastating forms of tuberculosis[2]. Even with adequate treatment, the case fatality rate is estimated to be 27%[3]. Permanent disability is also common among survivors, affecting an estimated 32% of all adult survivors[3].

Description of the intervention

Currently, the standard antituberculous treatment for patients with central nervous system infection has limitations[4, 5]. It consists of an intensive phase of isoniazid, rifampin, pyrazinamide, and ethambutol or streptomycin for two months, followed by isoniazid and rifampin in a continuation phase that can last between 7 and 10 months, assuming the strain is not resistant[6].

Linezolid is an oxazolidinone antimicrobial that inhibits bacterial protein synthesis by preventing the formation of a functional 70S initiation complex[7]. Adding linezolid to pulmonary drug-resistant antituberculous treatment has demonstrated an efficacy of 90% in clinical trials[8, 9]. It is currently recommended in the World Health Organization guidelines for managing most forms of drug-resistant tuberculosis, but its role in central nervous system tuberculosis needs clarification[6]. Exploratory findings from observational studies indicate that patients with tuberculous meningitis, including both the pediatric and adult populations[10, 11] and people living with HIV[12], benefit from adjunct linezolid. Additionally, pharmacokinetic studies have shown that linezolid has excellent central nervous system penetration at therapeutic doses of 600 mg[13].

Why is it important to do this review

Despite promising findings, research on the use of linezolid for TBM remains exploratory and no clear conclusions have been reached. Therefore, we aimed to systematically assess the current trial data to determine the direction of the effect, the probability of treatment benefit, and whether significant adverse events that could potentially limit therapy in this population have been identified.

Criteria for considering studies for this review

We considered randomized controlled trials with individuals of any age and clinically diagnosed tuberculous meningitis, comparing linezolid to standard treatment.

We grouped outcomes as follows:

1. Death: number of deaths at the study’s endpoint, at one month, and at three months after the beginning of therapy;

2. Neurological disability: score measured in the modified Rankin Scale (mRS) at the study’s endpoint, at one month, and at three months after the beginning of therapy;

3. Adverse effects: adverse events reported by authors and according to the Common Toxicity Criteria for Adverse Events (CTCAE).

Search methods for identification of studies

We searched both published and unpublished data from trials. Up to 5 January 2024, we searched Pubmed, EMBASE, and the Cochrane Library using the terms (tuberculosis OR 'Koch`s disease' OR 'M. tuberculosis infection' OR 'Mycobacterium tuberculosis infection' OR 'TB (tuberculosis)' OR 'TB case' OR 'TB cases' OR 'TB disease' OR 'TB infection' OR 'active TB' OR 'active tuberculosis' OR 'case of TB' OR 'cases of TB' OR 'chronic tuberculosis' OR 'infection by M. tuberculosis' OR 'infection by Mycobacterium tuberculosis' OR 'infection due to M. tuberculosis' OR 'infection due to Mycobacterium tuberculosis' OR 'infection of M. tuberculosis' OR 'infection of Mycobacterium tuberculosis' OR 'minimal tuberculosis' OR 'minimum tuberculosis' OR 'tuberculosis' OR 'tuberculous infection' OR 'tuberculous lesion') AND linezolid AND (randomized controlled trial OR 'controlled trial, randomized' OR 'randomised controlled study' OR 'randomised controlled trial' OR 'randomized controlled study' OR 'randomized controlled trial' OR 'trial, randomized controlled'). There were no publication date or language restrictions.

Authors of ongoing trials were contacted by email asking whether they could provide preliminary findings or information about the study’s stage.

Data collection and analysis

Two authors (GL and GC) independently screened the title and abstract of the identified records. If one of the authors considered the record eligible, both assessed the full text. Disagreements were solved by discussion and consulting a third reviewer (CB).

We tried to contact the authors of ongoing trials. An email was sent asking for further details about the stage of the trial and whether there was any additional relevant data they would like to share. If there was no answer, we sent a second email within two weeks of the first one.

The same authors were responsible for selecting studies extracted information about study characteristics to a prestructured file. Data was extracted from five domains: study characteristics, methods, participants, interventions, and outcomes. They included authorship, funding, conflicts, study design, country, methodological qualities, unit of allocation, number of study arms, period of the study, methods used for diagnosis, population description, HIV status, tuberculous meningitis severity, inclusion, and exclusion criteria, number of participants, interventions, dosage and duration of intervention, duration of follow up, concomitant therapies, primary and secondary outcomes as reported by the authors, potential confounders and sources of bias and the results of interest to this review (number of deaths, measurement of neurological disability, occurrence of adverse events and grading of the severity of the adverse event according to CTCAE).

The number of randomized patients in the studied arms and the number that experienced the event of interest was recorded for dichotomous outcomes.

Risk of bias assessment in included studies

Two independent reviewers (GL and GC) used the Cochrane risk-of-bias tool for randomized trials (RoB 2)[14], version of August 2019, to assess the risk of bias/quality of the included studies.

Synthesis methods

We included all trials that analyzed the addition of linezolid to standard antituberculous treatment (rifampicin, isoniazid, pyrazinamide, and ethambutol or streptomycin) compared with antituberculous treatment alone for the management of patients with tuberculous meningitis.

We used an inverse-variance random effects model, reporting dichotomous data as Relative Risk (RR) with 95% Confidence or Credible intervals (CI). Statistical heterogeneity was assessed by calculating tau (between study variance), I² (percentage of total variation across studies that is due to heterogeneity), and Cochran's Q (test assessing the null hypothesis that all studies in the analysis share a common effect size) statistics; I² higher than 50% was considered as a significant indicator of heterogeneity or a p-value lower than 0.10.

Analyses of the trials’ results with a Bayesian approach were designed under a weakly informative neutral prior (μ = 0, σ = 4). Prior selection and strength of belief are presented in the supplementary material. We used funnel plots to assess publication bias. A sensitivity analysis was performed, accounting for the follow-up losses with worst-case scenario analysis.

Analyses were conducted in RevMan Web, version 7.2.0, and R software, version 4.3.3, with the meta, metafor, and bayesmeta packages[15, 16].

Investigation of heterogeneity and subgroup analysis

Clinical diversity and methodological diversity were described in the study’s PICO table, accounting for variability in patients (tuberculous meningitis severity and HIV status), interventions (duration of therapy and drug dosing), and risk of bias (for which we conducted a sensitivity analysis comparing studies at a high vs low/some concerns risk of bias). A subgroup analysis including trials exclusively with HIV-positive patients was conducted. There was insufficient data to allow statistical analysis of outcomes according to age group (< or > 18 years), linezolid dose, and duration of therapy, as planned per protocol.

Sensitivity analysis

Losses to follow-up were investigated with a worst-case scenario analysis. We considered the worst outcome for every follow-up loss in the intervention arm (death or bad mRS score) and the best outcome for losses in the control arm.

Certainty of the evidence assessment

The overall quality of the body of evidence was assessed by one reviewer (GL) using the GRADE approach, formulating a summary of findings and certainty of evidence tables containing the critical outcomes investigated. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) handbook was followed to determine the evidence profile of the analyses conducted[17]. In this evaluation, evidence can be divided into four grades based on how certain the outcomes are: high (we are very confident that the true effect lies close to that of the estimate of the effect), moderate (the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different), low (the true effect may be substantially different from the estimate of the effect) and very low (the true effect is likely to be substantially different from the estimate of effect). The tables were generated in the GRADEpro GDT software[18].

Results of the search

We identified 106 records across three different databases; 88 underwent screening of their titles and abstracts, and 15 were fully assessed for eligibility criteria (Fig. 1). Among these, we encountered five relevant RCTs. Only two RCTs have been completed, and the final results have been published. Two are ongoing, with no results published, and one has been completed, but only preliminary results have been published (Supplementary material).

Included studies

Three RCTs (ESCALATE[19], LASER-TBM[20], and preliminary ALTER findings[21]) were included in this review, with 87 participants. A summary of the characteristics of the included studies is provided in Table 1. The detailed description of the PICO of each study is presented in the supplementary material.

Table 1 - Characteristics of included studies

Excluded studies

All excluded studies were nonrandomized or ongoing trials without preliminary findings.

Risk of bias

No trial was at a high risk of bias. The risk of bias assessment for each study is presented in the forest plots. The detailed assessment is provided in the supplementary material.

Death

All three trials reported death outcomes, favoring the linezolid arm (Fig. 2). Only one trial reported death at six months (RR 0.50, 95% CI 0.16 to 1.57; 1 trial, n = 35). In the overall analysis, the mean death rate was 37.8% in the control group. The Bayesian random-effects model included no effect (RR 0.45, 95% CI 0.18 to 1.11; I² = 12.29%), however, the posterior probability of meaningful benefit (RR < 0.9) was 93.92% and 74.86% for a large benefit (RR < 0.5)(Fig. 3). The GRADE summary of evidence indicated moderate certainty evidence for this outcome.

Neurological disability

Two trials evaluated the neurological disability of patients, measured as scores indicating good and bad outcomes on the mRS scale. The LASER-TBM considered 4–6 scores a bad outcome; meanwhile, the ESCALATE considered 3–6 a bad outcome. We calculated the RR of a bad outcome as reported by the authors (Fig. 4). Both trials assessed neurological disability at 1 month (Fig. 4), and the ESCALATE also assessed the mRS score at 3 months (RR 0.75, 95% CI 0.42 to 1.33; n = 29). The mean number of patients with bad scores was 44.1% in the control group. The GRADE summary of evidence indicated very low certainty evidence for this outcome.

Adverse events

All three trials provided information on adverse events. A detailed description of these events is presented in the Table of adverse events (Table S3). Grade 3 events were reported in two trials (Fig. 5). Grade 4 adverse events only occurred in one trial (Fig. 5). The GRADE summary of evidence indicated very low certainty evidence for the adverse events analysis.

Subgroup analysis

Two trials only included HIV-positive patients (Fig. 6).

Sensitivity analysis

Only two trials report follow-up losses; the reasons provided were similar in both arms and did not indicate an association with adverse effects from therapy. Under the most unfavorable assumptions, the observed effect of linezolid is uncertain in mortality (RR 0.79, 95% CI 0.38 to 1.65; 2 trials, n = 87) and disability (RR 0.92, 95% CI 0.58 to 1.48; 2 trials, n = 87).

Publication bias

Visual inspection of publication bias was provided for the death outcome from included studies (Fig. 7).

Summary of main results

Three RCTs investigating adjunct linezolid for the treatment of tuberculous meningitis patients were included in this review. Follow-up ranged from 1 to 6 months. The outcomes of death, neurological disability, and adverse events were summarized in the Summary of Findings table (Table 2). Considering the study population included in this review, linezolid likely prevents 208 deaths per 1000 patients (RR 0.45), which means a reduction from 37.8% mortality, on average, to 17.0%. The probability of benefit (RR < 0.9) was 93.95%. A more conservative estimate would be an RR of 0.64, as the supplementary material details. However, the evidence is very uncertain about the effect of linezolid on neurological disability or the occurrence of serious (grade 3) and life-threatening (grade 4) adverse events.

Table 2

Summary of findings
Adjunct linezolid compared to standard antituberculous treatment for tuberculous meningitis
Patient or population: tuberculous meningitis Setting: hospital or clinics Intervention: adjunct linezolid Comparison: standard antituberculous treatment
Outcomes	Anticipated absolute effects^* (95% CI)		Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Outcomes	Risk with standard antituberculous treatment	Risk with adjunct linezolid	Relative effect (95% CI)	№ of participants (studies)	Certainty of the evidence (GRADE)	Comments
Mortality follow-up: range 1 months to 6 months	378 per 1 000	170 per 1 000 (79 to 366)	RR 0.45 (0.21 to 0.97)	87 (3 RCTs)	⨁⨁⨁◯ Moderate^a,b
Neurologic disability assessed with: mRS score follow-up: range 1 months to 6 months	441 per 1 000	335 per 1 000 (199 to 565)	RR 0.76 (0.45 to 1.28)	64 (2 RCTs)	⨁◯◯◯ Very low^c,d
Grade 3 adverse events assessed with: CTCAE score follow-up: range 1 months to 6 months	235 per 1 000	304 per 1 000 (141 to 659)	RR 1.29 (0.60 to 2.80)	64 (2 RCTs)	⨁◯◯◯ Very low^c,d
Grade 4 adverse events assessed with: CTCAE score follow-up: range 1 months to 6 months	100 per 1 000	267 per 1 000 (56 to 1 000)	RR 2.67 (0.56 to 12.69)	35 (1 RCT)	⨁◯◯◯ Very low^c,e
*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence High certainty: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate certainty: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low certainty: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low certainty: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

Explanations

a. Outcome assessment is not affected by blinding

b. Small sample size

c. Open label design

d. Small sample size and 95% CI includes serious harm or benefit

e. Small sample size, 95%CI includes serious harm or benefit and upper boundary is three times higher the RR

Limitations of the evidence included in the review

The number of included patients was low, which is a significant limitation to the statistical power of this review. The length of therapy and starting dose also varied between studies. All trials included adult patients. Hence, the effects of treatment on the pediatric population could not be determined. Ongoing trials are set to include patients from this age group. Most trials included HIV-positive patients, with a similar RR of death to the overall analysis, so findings may be extended to the HIV-positive population.

The trials included in the analysis had an open-label design. Only the ALTER trial had a blinded outcome assessment. We downgraded all outcomes by one level due to imprecision caused by the small sample size. Additionally, we made further downgrades in the domain of imprecision. For the outcomes of neurological disability and grade 3 adverse events, we downgraded by one level because the wide confidence intervals couldn't rule out significant benefit or harm. For the outcome of grade 4 adverse events, we downgraded by two levels because the upper boundary of the confidence interval was more than three times the relative risk.

Agreements and disagreements with other studies or reviews

To achieve the World Health Organization's goal of reducing tuberculosis mortality by 95%, significant therapeutic efforts must address the many challenges in managing tuberculous meningitis[22]. This meta-analysis presents important findings supporting linezolid for this condition. Crucially, we provide moderate evidence of a high probability of meaningful benefit (93.95%), when using 600–1200 mg of linezolid for 28–56 days, combined with standard treatment, over follow-ups of 3–6 months. There is substantial evidence of benefit from previous clinical trials, reporting favorable outcomes in almost 90% of patients with drug-resistant tuberculosis[8, 9, 23]. The effect of linezolid on resistant strains may have influenced our results, as the prevalence of drug-resistant tuberculous meningitis is considerable (> 11%) and may be increasing[24, 25]. Of great concern, resistance is not necessarily associated with a growth-fitness tradeoff[26], highlighting the relevancy of linezolid in treating tuberculous meningitis patients.

One of the main challenges with linezolid regimens has been adverse drug reactions interrupting treatment. However, a randomized controlled trial demonstrated the minimization of adverse effects with doses of 600 mg[9]. In the included studies, serious adverse reactions may have been more common in linezolid-treated participants, although the data were very uncertain. Despite this, a high number of patients managed to complete the treatment regimen.

The mortality benefit observed in our study considered a baseline mortality of 37.8% for patients receiving standard treatment. Our study population included hospitalized patients, clinic attendees, and HIV-positive individuals from India, Uganda, and South Africa. Other estimates, from both randomized and nonrandomized studies, range from a 27.5% case fatality rate in the general population to 42.12% in hospitalized patients and over 50% in patients with HIV[3, 27, 28]. The population of the studies included in our review was from low-income countries and may not directly apply to other regions. Indeed, low-income countries face the highest burden of tuberculous meningitis[29], nonetheless, high-income countries are increasingly affected due to migration[30], which makes this distinction less clear.

Implications for practice

Based on moderate evidence from clinical trials, 600–1200 mg linezolid for 28–56 days is likely to decrease tuberculous meningitis mortality in the adult population, and very low evidence suggests that it may not meaningfully increase the rate of serious adverse events.

Implications for research

Research is already taking place in large phase 3 trials. The findings here favor the beneficial effect of linezolid. Henceforth, these trials should address optimal dosing and treatment duration and provide a better estimate of treatment efficacy. Future research should also address the safety profile in specific subpopulations, such as the pediatric population.

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Availability of data and materials

The data can be shared upon request

Competing interests

The authors declare that they have no competing interests

Funding

No specific funding was available for the project

Authors' contributions

GML was responsible for conceptualizing the work, data acquisition, analysis, and writing the manuscript. GAMC was responsible for conceptualizing the work and writing the manuscript. PVMG was responsible for data analysis and revising the manuscript. JJFM was responsible for revising the manuscript.

Acknowledgments

Not applicable

Navarro-Flores A, Fernandez-Chinguel JE, Pacheco-Barrios N, Soriano-Moreno DR, Pacheco-Barrios K (2022) Global morbidity and mortality of central nervous system tuberculosis: a systematic review and meta-analysis. J Neurol 269:3482–3494. https://doi.org/10.1007/s00415-022-11052-8
Leonard JM (2017) Central Nervous System Tuberculosis. Microbiol Spectr 5:10.1128/microbiolspec.tnmi7-0044–2017. https://doi.org/10.1128/microbiolspec.tnmi7-0044-2017
Stadelman AM, Ellis J, Samuels THA, Mutengesa E, Dobbin J, Ssebambulidde K, Rutakingirwa MK, Tugume L, Boulware DR, Grint D, Cresswell FV (2020) Treatment Outcomes in Adult Tuberculous Meningitis: A Systematic Review and Meta-analysis. Open Forum Infect Dis 7:ofaa257. https://doi.org/10.1093/ofid/ofaa257
van den Boogaard J, Kibiki GS, Kisanga ER, Boeree MJ, Aarnoutse RE (2009) New Drugs against Tuberculosis: Problems, Progress, and Evaluation of Agents in Clinical Development. Antimicrob Agents Chemother 53:849–862. https://doi.org/10.1128/aac.00749-08
Cao Y, Wang T, He K, Xue J, Wang X, Liang J (2022) High-dose rifampicin for the treatment of tuberculous meningitis: a meta-analysis of randomized controlled trials. J Clin Pharm Ther 47:445–454. https://doi.org/10.1111/jcpt.13555
World Health Organization (2022) WHO consolidated guidelines on tuberculosis: module 4: treatment: drug-susceptible tuberculosis treatment. https://www.who.int/publications-detail-redirect/9789240048126. Accessed 6 Jan 2024
Azzouz A, Preuss CV (2024) Linezolid. In: StatPearls. StatPearls Publishing, Treasure Island (FL)
Conradie F, Diacon AH, Ngubane N, Howell P, Everitt D, Crook AM, Mendel CM, Egizi E, Moreira J, Timm J, McHugh TD, Wills GH, Bateson A, Hunt R, Van Niekerk C, Li M, Olugbosi M, Spigelman M, Nix-TB Trial Team (2020) Treatment of Highly Drug-Resistant Pulmonary Tuberculosis. N Engl J Med 382:893–902. https://doi.org/10.1056/NEJMoa1901814
Conradie Francesca, Bagdasaryan Tatevik R., Borisov Sergey, Howell Pauline, Mikiashvili Lali, Ngubane Nosipho, Samoilova Anastasia, Skornykova Sergey, Tudor Elena, Variava Ebrahim, Yablonskiy Petr, Everitt Daniel, Wills Genevieve H., Sun Eugene, Olugbosi Morounfolu, Egizi Erica, Li Mengchun, Holsta Alda, Timm Juliano, Bateson Anna, Crook Angela M., Fabiane Stella M., Hunt Robert, McHugh Timothy D., Tweed Conor D., Foraida Salah, Mendel Carl M., Spigelman Melvin (2022) Bedaquiline–Pretomanid–Linezolid Regimens for Drug-Resistant Tuberculosis. N Engl J Med 387:810–823. https://doi.org/10.1056/NEJMoa2119430
Fang M-T, Su Y-F, An H-R, Zhang P-Z, Deng G-F, Liu H-M, Mao Z, Zeng J-F, Li G, Yang Q-T, Wang Z-Y (2021) Decreased mortality seen in rifampicin/multidrug-resistant tuberculous meningitis treated with linezolid in Shenzhen, China. BMC Infect Dis 21:1015. https://doi.org/10.1186/s12879-021-06705-4
Sun F, Ruan Q, Wang J, Chen S, Jin J, Shao L, Zhang Y, Zhang W (2014) Linezolid Manifests a Rapid and Dramatic Therapeutic Effect for Patients with Life-Threatening Tuberculous Meningitis. Antimicrob Agents Chemother 58:6297–6301. https://doi.org/10.1128/AAC.02784-14
Kimuda S, Kasozi D, Namombwe S, Gakuru J, Mugabi T, Kagimu E, Rutakingirwa MK, Leon KE, Chow F, Wasserman S, Boulware DR, Cresswell FV, Bahr NC (2023) Advancing Diagnosis and Treatment in People Living with HIV and Tuberculosis Meningitis. Curr HIV/AIDS Rep 20:379–393. https://doi.org/10.1007/s11904-023-00678-6
Villani P, B. Regazzi M, Marubbi F, Viale P, Pagani L, Cristini F, Cadeo B, Carosi G, Bergomi R (2002) Cerebrospinal Fluid Linezolid Concentrations in Postneurosurgical Central Nervous System Infections. Antimicrob Agents Chemother 46:936–937. https://doi.org/10.1128/aac.46.3.936-937.2002
Sterne JAC, Savović J, Page MJ, Elbers RG, Blencowe NS, Boutron I, Cates CJ, Cheng H-Y, Corbett MS, Eldridge SM, Emberson JR, Hernán MA, Hopewell S, Hróbjartsson A, Junqueira DR, Jüni P, Kirkham JJ, Lasserson T, Li T, McAleenan A, Reeves BC, Shepperd S, Shrier I, Stewart LA, Tilling K, White IR, Whiting PF, Higgins JPT (2019) RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 366:l4898. https://doi.org/10.1136/bmj.l4898
Röver C (2020) Bayesian Random-Effects Meta-Analysis Using the bayesmeta R Package. J Stat Softw 93:1–51. https://doi.org/10.18637/jss.v093.i06
Viechtbauer W (2010) Conducting meta-analyses in {R} with the {metafor} package. J Stat Softw 36:
Schünemann H, Brożek J, Guyatt G, Oxman A, editor(s) (2013) Handbook for grading the quality of evidence and the strength of recommendations using the GRADE approach (updated October 2013).
McMaster University and Evidence Prime (2024) GRADEpro GDT: GRADEpro Guideline Development Tool [Software]. gradepro.org
Sahib A, Bhatia R, Srivastava MVP, Singh MB, Komakula S, Vishnu VY, Rajan R, Gupta A, Srivastava AK, Wig N, Vikram NK, Biswas A (2023) Escalate: Linezolid as an add on treatment in the intensive phase of tubercular meningitis. A randomized controlled pilot trial. Tuberc Edinb Scotl 142:102351. https://doi.org/10.1016/j.tube.2023.102351
Davis AG, Wasserman S, Stek C, Maxebengula M, Jason Liang C, Stegmann S, Koekemoer S, Jackson A, Kadernani Y, Bremer M, Daroowala R, Aziz S, Goliath R, Lai Sai L, Sihoyiya T, Denti P, Lai RPJ, Crede T, Naude J, Szymanski P, Vallie Y, Banderker IA, Moosa MS, Raubenheimer P, Candy S, Offiah C, Wahl G, Vorster I, Maartens G, Black J, Meintjes G, Wilkinson RJ (2022) A Phase 2A Trial of the Safety and Tolerability of Increased Dose Rifampicin and Adjunctive Linezolid, With or Without Aspirin, for Human Immunodeficiency Virus–Associated Tuberculous Meningitis: The LASER-TBM Trial. Clin Infect Dis Off Publ Infect Dis Soc Am 76:1412–1422. https://doi.org/10.1093/cid/ciac932
Kibengo F, Kabarambi A, Kafeero P, Muhumuza P, Nakimbugwe M, Ssemaganda A, Tayebwa C, Nahid P, Cresswell F, Chow F (2023) Safety and tolerability of adjunctive linezolid with high or standard dose rifampin for the treatment of adults with HIV-associated tuberculous meningitis in Uganda: preliminary findings from the ALTER trial (S25.003). Neurology 100:3265. https://doi.org/10.1212/WNL.0000000000203147
World Health Organization (2015) Global Tuberculosis Programme (GTB), the end TB strategy. https://www.who.int/publications-detail-redirect/WHO-HTM-TB-2015.19. Accessed 25 May 2024
Paton NI, Cousins C, Suresh C, Burhan E, Chew KL, Dalay VB, Lu Q, Kusmiati T, Balanag VM, Lee SL, Ruslami R, Pokharkar Y, Djaharuddin I, Sugiri JJR, Veto RS, Sekaggya-Wiltshire C, Avihingsanon A, Sarin R, Papineni P, Nunn AJ, Crook AM, TRUNCATE-TB Trial Team (2023) Treatment Strategy for Rifampin-Susceptible Tuberculosis. N Engl J Med 388:873–887. https://doi.org/10.1056/NEJMoa2212537
Huo F, Luo J, Shi J, Zong Z, Jing W, Dong W, Dong L, Ma Y, Liang Q, Shang Y, Huang H, Pang Y (2018) A 10-Year Comparative Analysis Shows that Increasing Prevalence of Rifampin-Resistant Mycobacterium tuberculosis in China Is Associated with the Transmission of Strains Harboring Compensatory Mutations. Antimicrob Agents Chemother 62:10.1128/aac.02303-17. https://doi.org/10.1128/aac.02303-17
Salari N, Kanjoori AH, Hosseinian-Far A, Hasheminezhad R, Mansouri K, Mohammadi M (2023) Global prevalence of drug-resistant tuberculosis: a systematic review and meta-analysis. Infect Dis Poverty 12:57. https://doi.org/10.1186/s40249-023-01107-x
Brandis G, Wrande M, Liljas L, Hughes D (2012) Fitness-compensatory mutations in rifampicin-resistant RNA polymerase. Mol Microbiol 85:142–151. https://doi.org/10.1111/j.1365-2958.2012.08099.x
Dodd PJ, Osman M, Cresswell FV, Stadelman AM, Lan NH, Thuong NTT, Muzyamba M, Glaser L, Dlamini SS, Seddon JA (2021) The global burden of tuberculous meningitis in adults: A modelling study. PLOS Glob Public Health 1:e0000069. https://doi.org/10.1371/journal.pgph.0000069
Cantier M, Morisot A, Guérot E, Megarbane B, Razazi K, Contou D, Mariotte E, Canet E, De Montmollin E, Dubée V, Boulet E, Gaudry S, Voiriot G, Mayaux J, Pène F, Neuville M, Mourvillier B, Ruckly S, Bouadma L, Wolff M, Timsit J-F, Sonneville R (2018) Functional outcomes in adults with tuberculous meningitis admitted to the ICU: a multicenter cohort study. Crit Care 22:210. https://doi.org/10.1186/s13054-018-2140-8
Rahimi BA, Niazi N, Rahimi AF, Faizee MI, Khan MS, Taylor WR (2022) Treatment outcomes and risk factors of death in childhood tuberculous meningitis in Kandahar, Afghanistan: a prospective observational cohort study. Trans R Soc Trop Med Hyg 116:1181–1190. https://doi.org/10.1093/trstmh/trac066
Pareek M, Greenaway C, Noori T, Munoz J, Zenner D (2016) The impact of migration on tuberculosis epidemiology and control in high-income countries: a review. BMC Med 14:48. https://doi.org/10.1186/s12916-016-0595-5

Table 1 is available in the Supplementary Files section

No competing interests reported.

Adjunct linezolid in patients with tuberculous meningitis for mortality or neurological disability prevention: a meta-analysis of randomized controlled trials

Status:

Version 1

Abstract

Figures

INTRODUCTION

Description of the condition

Description of the intervention

Why is it important to do this review

METHODS

RESULTS

Results of the search

Included studies

Excluded studies

Risk of bias

Death

Neurological disability

Adverse events

Subgroup analysis

Sensitivity analysis

Publication bias

DISCUSSION

Summary of main results

Limitations of the evidence included in the review

Agreements and disagreements with other studies or reviews

CONCLUSION

Implications for practice

Implications for research

Declarations

References

Table

Additional Declarations

Status:

Version 1