Efficacy and safety profile of linezolid in the treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis: a systematic review and meta-analysis

Abstract

Background: Treatment options for drug-resistant tuberculosis are still limited. Linezolid has been recommended for treatment of patients with multidrug-resistant (MDR) or extensively-drug-resistant (XDR) tuberculosis, although uncertainties remain regarding its safety and tolerability in these circumstances.

Objective: To systematically evaluate the existing evidence regarding the efficacy and tolerability of linezolid in the treatment of MDR or XDR tuberculosis.

Methods: We conducted a systematic review and meta-analysis in accordance with the PRISMA guidelines. Searches were conducted in PubMed, Web of Science and EMBASE followed by direct search of abstracts in the International Journal of Tuberculosis and Lung Disease to retrieve primary studies published between January 2000 and January 2016 assessing linezolid efficacy and safety in the treatment of drug-resistant TB. We evaluated the occurrence of outcomes including culture conversion, treatment success and incidence of adverse events such as myelosuppression and neuropathy.

Results: Twenty-three (23) studies conducted in fourteen (14) countries and involving 507 patients were retrieved. Only 1 randomized controlled trial was identified and none of the identified studies involved participants from Africa. The pooled proportion for treatment success was 77.36 % (95 % CI = 71.38-82.83 %, I(2) = 37.6 %) with culture conversion rate determined as 88.45 % (95 % CI = 83.82-92.38 %, I(2) = 45.4 %). There was no strong evidence for both culture conversion (p = 0.0948) and treatment success (p = 0.0695) between linezolid daily doses ≤ 600 and > 600 mg. Only myelosuppression showed a strong statistical significance (p < 0.0001) between dose comparisons. The incidence of neuropathy and other adverse events leading to permanent discontinuation of linezolid also showed no significance upon dose comparisons (p = 0.3213, p = 0.9050 respectively).

Conclusion: Available evidence presents Linezolid as a viable option in the treatment of MDR/XDR TB although patients ought to be monitored closely for the incidence of major adverse events such as myelosuppression and neuropathy. Additionally, highly powered randomized controlled trials including participants from endemic regions are urgently needed to better inform the magnitude and significance of Linezolid treatment effect in MDR and XDR TB patients.

Keywords: Drug therapy; Extensively drug resistant; Infectious diseases; Linezolid; Meta-analysis; Multi-drug resistance; Tuberculosis.

Fig. 1

A schematic flow diagram of studies’ search and retrieval process

Fig. 2

Forest plot of culture conversion, individual and pooled (random effects)

Fig. 3

Forest plot of treatment success, individual and pooled (random effects)

Fig. 4

Forest plot of discontinuation due to linezolid adverse effects, individual and pooled (random effects)

Fig. 5

Forest plot of reported myelosuppression, individual and pooled (random effects)

Fig. 6

Forest plot of reported neuropathy, individual and pooled (random effects)

Fig. 7

Forest plot of reported other adverse events, individual and pooled (random effects)

Fig. 8

Bias assessment (funnel) plots of publication bias for the outcomes evaluated (a culture conversion; b treatment success; c myelosuppression; d neuropathy; e discontinuation due to linezolid adverse effects; f presence of any other adverse events)