Optimising linezolid use for drug-resistant tuberculosis: pharmacokinetics, toxicity, and resistance

Doctoral Thesis

2022

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Background: Rifampicin-resistant tuberculosis (RR-TB) accounts for an expanding proportion of incident global TB cases and is a major barrier to global tuberculosis control. There is a need for more effective, safe, and well-tolerated drugs. Linezolid is a repurposed oxazolidinone antimicrobial with bactericidal activity against M. tuberculosis. Guidelines recommend linezolid as a preferred antituberculosis agent for RR-TB, and it is widely used in national programmes. The major drawback of linezolid is dose-related mitochondrial toxicity that may be treatment limiting. The incidence and risk factors for linezolid adverse events have not been systematically studied in TB programmes, particularly in populations from sub-Saharan Africa with high rates of HIV co-infection, which could increase the risk of toxicity. Exposure-response relationships for linezolid toxicity are also not well characterised. In addition, limited data exist on clinical associations and genotypic correlates of linezolid resistance in M. tuberculosis, needed to inform strategies for resistance testing. My thesis aimed to address these knowledge gaps to optimise use of this important agent in RR-TB. Methods: We conducted a prospective observational cohort study among patients with RR-TB across three sites in South Africa to characterise the pharmacokinetics (PK) and clinical toxicity of linezolid in programmatic settings with high HIV prevalence. Participants were followed for up to 24 months after linezolid initiation. We did monthly screening for peripheral and optic neuropathy, and collected clinical samples for toxicity outcomes, drug concentrations, and mitochondrial DNA analysis. Intensive PK sampling was performed on a subgroup of participants. Drug exposure was described using non-compartmental analysis and mixed effects modelling was used to analyse toxicity outcomes. For the resistance aims, we did a separate retrospective cohort study of patients with RR-TB and linezolid-based treatment failure at two TB referral hospitals in South Africa. Clinical information was extracted and recovered isolates underwent linezolid minimum inhibitory concentration (MIC) testing and targeted sequencing of rrl and rplC. Results: Among 30 participants enrolled in the intensive PK study, linezolid exposure was related to body weight and age, but not HIV positivity. The standard 600 mg dose achieved the PK efficacy target at wild type MIC values, but trough concentrations 5 were above the putative toxicity threshold in almost 60%. 151 participants, 63% HIVpositive, were enrolled in the prospective cohort. Premature discontinuation of linezolid for toxicity was common but grade 3 or 4 adverse events occurred in 22 (15%). Linezolid trough concentration, male sex, and age (but not HIV-positivity) were independently associated with a decrease in haemoglobin > 2 g/dL. Trough linezolid concentration of 2.5 mg/L or higher resulted in optimal model performance to describe changing haemoglobin and was strongly associated with treatment-emergent anaemia. Single nucleotide polymorphisms 2706A>G and 3010G>A in mitochondrial DNA were not associated with linezolid toxicity. Thirty-nine patients with linezolidbased treatment failure were identified in the retrospective cohort, 13 (33%) of whom had phenotypic or genotypic linezolid resistance after a median duration of 22 months linezolid therapy. All isolates with phenotypic resistance were associated with known resistance mutations, most frequently due to the T460C substitution in rplC. Conclusions: Our PK analysis confirmed the narrow therapeutic index of linezolid and there was no effect of HIV on linezolid exposure. Severe adverse events were uncommon at the standard dose of 600 mg daily and HIV co-infection was not independently associated with linezolid toxicity. Linezolid trough concentration of 2.5 mg/L should be evaluated as a target for therapeutic drug monitoring as a strategy to reduce toxicity. Resistance occurred late and was predicted by a limited number of mutations. Screening for genotypic resistance should be considered for patients with a positive culture after 4 months of linezolid therapy. These findings support current linezolid dosing in TB programmes.
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