Pharmacodynamic Correlates of Linezolid Activity and Toxicity in Murine Models of Tuberculosis. (29th January 2020)

• Record Type: Journal Article
• Authors: Bigelow, Kristina M; Deitchman, Amelia N; Li, Si-Yang; Barnes-Boyle, Kala; Tyagi, Sandeep; Soni, Heena; Dooley, Kelly E; Savic, Rada M; Nuermberger, Eric L
• Is Part Of: Journal of infectious diseases. Volume 223:Number 11(2021)
• Page Start: 1855
• Page End: 1864
• Publication Date: 2020-01-29
• Subjects: linezolid -- mouse -- pharmacodynamics -- pharmacokinetics -- tuberculosis; Communicable diseases -- Periodicals; Diseases -- Causes and theories of causation -- Periodicals; Medicine -- Periodicals; Communicable Diseases -- Periodicals; Electronic journals; 616.9
• DOI: 10.1093/infdis/jiaa016
• Languages: English
• ISSNs: 0022-1899

Abstract

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. Abstract : Linezolid is an efficacious TB drug that exhibits dose- and duration-dependent toxicity. Using animal models, we show that decreasing dosing frequency while maintaining the same total weekly dose may be a viable strategy to maintain efficacy while decreasing toxicity.