Abstract
ABSTRACTLinezolid has an excellent sterilizing effect in tuberculosis patients but high adverse event rates. The dose that would maximize efficacy and minimize toxicity is unknown. We performed linezolid dose-effect and dose-scheduling studies in the hollow fiber system model of tuberculosis (HFS-TB) for sterilizing effect. HFS-TB units were treated with several doses to mimic human-like linezolid intrapulmonary pharmacokinetics and repetitively sampled for drug concentration, total bacterial burden, linezolid-resistant subpopulations, and RNA sequencing over 2 months. Linezolid-resistant isolates underwent whole-genome sequencing. The expression of genes encoding efflux pumps in the first 1 to 2 weeks revealed the same exposure-response patterns as the linezolid-resistant subpopulation. Linezolid-resistant isolates from the 2nd month of therapy revealed mutations in several efflux pump/transporter genes and a LuxR-family transcriptional regulator. Linezolid sterilizing effect was linked to the ratio of unbound 0- to 24-h area under the concentration-time curve (AUC0–24) to MIC. Optimal microbial kill was achieved at an AUC0–24/MIC ratio of 119. The optimal sterilizing effect dose for clinical use was identified using Monte Carlo simulations. Clinical doses of 300 and 600 mg/day (or double the dose every other day) achieved this target in 87% and >99% of 10,000 patients, respectively. The susceptibility breakpoint identified was 2 mg/liter. The simulations identified that a 300-mg/day dose did not achieve AUC0–24s associated with linezolid toxicity, while 600 mg/day achieved those AUC0–24s in <20% of subjects. The linezolid dose of 300 mg/day performed well and should be compared to 600 mg/day or 1,200 mg every other day in clinical trials.
Highlights
Linezolid has an excellent sterilizing effect in tuberculosis patients but high adverse event rates
Due to the emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB), the oxazolidinone linezolid was investigated in salvage regimens starting more than 12 years ago, while the in vitro effect against Mycobacterium species has been known for 2 decades [1, 2]
Linezolid-induced neuropathy is encountered in 16%, myelosuppression is encountered in 33%, and other adverse events are encountered in 30% of tuberculosis patients [5]
Summary
Linezolid has an excellent sterilizing effect in tuberculosis patients but high adverse event rates. Studies of the efficacy of linezolid against intracellular Mycobacterium tuberculosis in childhood disease, based on pediatric pharmacokinetics and the hollow fiber system model of tuberculosis (HFS-TB), have identified optimal linezolid doses in regimens that omit all first-line drugs and do not include an injectable agent [9,10,11,12]. We used HFS-TB for studying the sterilizing effect on adult-type pulmonary cavitary disease using intrapulmonary pharmacokinetics, in order to identify the optimal sterilizing effect dose that would minimize the rate of adverse events [13,14,15,16,17,18,19]. The present study was designed to identify the linezolid exposure target for sterilizing efficacy and suppression of ADR with no toxicity, as well as to identify ADR-related mutations based on WGS and to use transcriptomics to understand how the linezolid ADR arises
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