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

BackgroundTreatment 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.ObjectiveTo systematically evaluate the existing evidence regarding the efficacy and tolerability of linezolid in the treatment of MDR or XDR tuberculosis.MethodsWe 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.ResultsTwenty-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 %, I2 = 37.6 %) with culture conversion rate determined as 88.45 % (95 % CI = 83.82–92.38 %, I2 = 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).ConclusionAvailable 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12941-016-0156-y) contains supplementary material, which is available to authorized users.

A 10‐Year Experience of Therapeutic Drug Monitoring (TDM) of Linezolid in a Hospital‐wide Population of Patients Receiving Conventional Dosing: Is there Enough Evidence for Suggesting TDM in the Majority of Patients?

“…This could be especially valuable in preventing toxicity among patients who are experiencing drug overexposure and in preventing therapeutic failure among patients who are experiencing drug underexposure . TDM might be of utmost importance for preventing drug‐related toxicity during long‐term treatment with linezolid, as, for example, for prosthetic and/or bone and joint infections and/or for MDR tuberculosis .…”

“…Linezolid is an oxazolidinone antibiotic with time‐dependent activity, which is licensed at the conventional dose of 600 mg every 12 hr for the treatment of pneumonia and of skin and soft tissue infections due to Gram positives . Nowadays, the use of linezolid in daily clinical practice has been widened to include the treatment for other difficult infections, such as prosthetic and bone and joint infections, and multi‐drug resistant (MDR) tuberculosis . This has posed some safety concerns, considering that the duration of treatment is restricted to 28 days maximum due to the risk of drug‐related adverse events .…”

Linezolid Dose That Maximizes Sterilizing Effect While Minimizing Toxicity and Resistance Emergence for Tuberculosis

“…Linezolid is now being used for treatment of X/MDR-TB in adult patients (3–5). Salvage therapy studies demonstrated a striking sterilizing effect rate of linezolid as virtual monotherapy; negative sputum cultures were encountered as early as 2 weeks in some patients and at a median of 2.5 months in all patients (3).…”

Thioridazine: A Non-Antibiotic Drug Highly Effective, in Combination with First Line Anti-Tuberculosis Drugs, against Any Form of Antibiotic Resistance of Mycobacterium tuberculosis Due to Its Multi-Mechanisms of Action

“…Although the global acquisition of tuberculosis infections has decreased by 1.5% per year [4,5], the progression of increased resistance of Mycobacterium tuberculosis (Mtb), as a consequence of prolonged and problematic therapeutic regimens, threatens the progress that has been made since 1990 in the control and prevention of TB [5]. Although the efficacy of the repurposed and newly recommended antibiotic for resistant forms of Mtb—Linezolid—has been recently evaluated from data provided by 23 studies in 14 different countries, involving more than 500 patients, suggests an overall success rate of 77% [6], the drug is notorious for producing a plethora of serious side effects such as neuropathy and hematological disorders [7]. Other newly approved drugs for MDR and XDR-TB therapeutics—bedaquiline and delamalid—are following the same path with their recognized efficacy against resistant forms of TB being threatened by their market cost and cumulative reports of side effects and lack of safety [8].…”

“…Other newly approved drugs for MDR and XDR-TB therapeutics—bedaquiline and delamalid—are following the same path with their recognized efficacy against resistant forms of TB being threatened by their market cost and cumulative reports of side effects and lack of safety [8]. Despite the occurrence of these side effects, in the absence of better forms of effective therapeutic regimens, the World Health Organization (WHO) continues to recommend the use of these extremely costly drugs for therapy of MDR and XDR-TB [4,6,8]. But is there an inexpensive drug, in comparison to the cost of these drugs, that has been extensively studied and has been safely used for the therapy of psychosis for over 50 years producing no serious side effects if the patient are monitored properly?…”