Terizidone 250mg tablets

BackgroundRising prevalence of bedaquiline resistance undermines benefits from this life-saving drug for rifampicin-resistant tuberculosis (RR tuberculosis). Despite increasing awareness, patient-level outcomes for bedaquiline-resistant tuberculosis have not been well characterised and case management has been poorly defined.MethodsWe did a retrospective cohort study of bedaquiline-resistant tuberculosis with matched RR tuberculosis controls at a tuberculosis referral hospital in East London, South Africa. Cases included patients aged 13 years or older with a phenotypic bedaquiline-resistant Mycobacterium tuberculosis isolate identified between Jan 1, 2018 and June 30, 2023. Controls with confirmed bedaquiline-susceptible tuberculosis, matched 1:1 by baseline culture status, age, and HIV status, were selected from a prospective observational study conducted during an overlapping period at the same facility. Primary outcomes included time to sputum culture conversion (SCC), a modified WHO-defined unfavourable outcome, and tuberculosis-free survival (alive, with SCC, and in care or treatment completed) up until 18 months. Adjusted analyses used Cox proportional hazards and logistic regression models.Findings82 patients with bedaquiline-resistant tuberculosis were included, 57 (70%) of whom were HIV positive. Bedaquiline was prescribed for 72 (88%) of 82 patients and meropenem (plus amoxicillin-clavulanate) for 32 (39%) of 82. Together with bedaquiline, the most frequently prescribed drugs included clofazimine, linezolid, and terizidone. Median time to SCC after treatment initiation was 175 days (IQR 100-254) in the bedaquiline-resistant cohort and 32 days (30-42) in matched controls. In the analysis of the combined cohorts, bedaquiline resistance (adjusted hazard ratio 0·03, 95% CI 0·0023-0·29, p=0·003) was associated with longer time to SCC when adjusted for baseline microscopy grade and baseline fluoroquinolone resistance. WHO treatment outcomes in those with bedaquiline-resistant tuberculosis were unfavourable in 54 (67%) of 81 patients, driven by treatment failure in 35 (43%) of 81. At 18 months, 43 (52%) of 82 patients had reached tuberculosis-free survival, 19 (23%) of 82 had died, and 50 (79%) of 63 survivors were still on treatment.InterpretationCurrent treatment options for bedaquiline-resistant tuberculosis result in prolonged therapy, delayed microbiological responses, and poor clinical outcomes. Implementation of more rapid resistance testing, including targeted next-generation sequencing, and access to novel treatment options within randomised controlled trials for bedaquiline-resistant tuberculosis, are priorities for tuberculosis programmes.FundingThe South African Medical Research Council.

Abstract licence: CC BY

Tuberculous meningitis (TBM) treatment outcomes are poor, partly due to suboptimal drug penetration into the cerebrospinal fluid (CSF). Little is known about the CSF pharmacokinetics of many TB drugs, both established and new. This study investigated the CSF penetration of cycloserine (administered as terizidone) and clofazimine, two core second-line drugs for drug-resistant tuberculosis (TB). We recruited participants with pulmonary drug-resistant TB, but without TBM, receiving terizidone and/or clofazimine for at least 2 weeks and collected serial plasma samples and a single CSF sample. Drug concentrations were quantified with validated liquid chromatography-tandem mass spectrometry methods. Pharmacokinetic parameters were determined using noncompartmental analysis, and population pharmacokinetic modeling was used to estimate the partition coefficient and equilibration half-life. Data were available from 27 participants, with a median age of 36 (range 20-60) and a weight of 52 kg (30-73 kg), who contributed 216 plasma and 27 CSF samples. The plasma pharmacokinetics of both drugs was in line with previous reports. Terizidone, measured as cycloserine, achieved CSF exposure of 69% relative to plasma, with plasma and CSF concentrations equilibrating with a half-life of 4.7 hours. Clofazimine CSF penetration was 0.13% of plasma exposure, with an equilibration half-life of 55.4 hours. Cycloserine and clofazimine concentrations in CSF approximated their estimated unbound (active) concentration in plasma, thus suggesting good penetration of the unbound drug into the CSF, supporting their potential use in TBM regimens. This study demonstrates a feasible and reproducible method for effective assessment of CSF drug penetration for CNS infections.

Abstract licence: CC BY 4.0