Pharmacodynamic Correlates of Linezolid Activity and Toxicity in Murine Models of Tuberculosis

Kristina M. Bigelow, Amelia N. Deitchman, Si Yang Li, Kala Barnes-Boyle, Sandeep Tyagi, Heena Soni, Kelly E. Dooley, Rada M. Savic, Eric L. Nuermberger

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Linezolid (LZD) is bactericidal against Mycobacterium tuberculosis, but it has treatment-limiting toxicities. A better understanding of exposure-response relationships governing LZD efficacy and toxicity will inform dosing strategies. Because in vitro monotherapy studies yielded conflicting results, we explored LZD pharmacokinetic/pharmacodynamic (PK/PD) relationships in vivo against actively and nonactively multiplying bacteria, including in combination with pretomanid. Methods: Linezolid multidose pharmacokinetics were modeled in mice. Dose-fractionation studies were performed in acute (net bacterial growth) and chronic (no net growth) infection models. In acute models, LZD was administered alone or with bacteriostatic or bactericidal pretomanid doses. Correlations between PK/PD parameters and lung colony-forming units (CFUs) and complete blood counts were assessed. Results: Overall, time above minimum inhibitory concentration (T>MIC) correlated best with CFU decline. However, in growth-constrained models (ie, chronic infection, coadministration with pretomanid 50 mg/kg per day), area under the concentration-Time curve over MIC (AUC/MIC) had similar explanatory power. Red blood cell counts correlated strongly with LZD minimum concentration (Cmin). Conclusions: Although T>MIC was the most consistent correlate of efficacy, AUC/MIC was equally predictive when bacterial multiplication was constrained by host immunity or pretomanid. In effective combination regimens, administering the same total LZD dose less frequently may be equally effective and cause less Cmin-dependent toxicity.

Original languageEnglish (US)
Pages (from-to)1855-1864
Number of pages10
JournalJournal of Infectious Diseases
Volume223
Issue number11
DOIs
StatePublished - Jun 1 2021

Keywords

  • linezolid
  • mouse
  • pharmacodynamics
  • pharmacokinetics
  • tuberculosis

ASJC Scopus subject areas

  • General Medicine

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