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

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.

Keywords: linezolid; mouse; pharmacodynamics; pharmacokinetics; tuberculosis.

Figure 1.

(A) Observed versus model-predicted linezolid (LZD) concentration-time curves. (B) Observed versus model-predicted LZD concentrations and regression line (y = 0.86x + 5.6).

Figure 2.

Mean lung colony-forming unit (CFU) counts (±standard deviation) in BALB/c mice after 28 days of treatment with linezolid (LZD) alone or in combination with pretomanid (Pa) in dose-fractionation studies. (A) Linezolid alone in acute infection model. (B) Linezolid in combination with Pa 12.5 mg/kg in acute infection model. (C) Linezolid alone in chronic infection model. (D) Linezolid in combination with Pa 50 mg/kg in acute infection model. Four total weekly LZD doses (0, 100, 300, and 1000 mg/kg per week) were fractionated into 4 dosing schedules: 3 doses/week, 5 doses/week, either 7 or 10 doses/week, and 14 doses/week. The isoniazid (INH), rifampin (RIF), and LZD controls received commonly used doses of 10, 10, and 100 mg/kg per day, respectively, 5 doses/week. Thick horizontal lines indicate the mean CFU count at treatment initiation. Statistical significance determined using one-way analysis of variance with Tukey’s posttest to adjust for multiple comparisons within each dose level: *, P < .05; **, P < .01; ***, P < .001.

Figure 3.

Relationships between linezolid (LZD) pharmacokinetic/pharmacodynamics parameters and change in lung colony-forming unit (CFU) counts in each infection model. (A) Linezolid monotherapy in acute infection model. (B) Linezolid in combination with pretomanid at 12.5 mg/kg in acute infection model. (C) Linezolid monotherapy in chronic infection model. (D) Linezolid in combination with pretomanid at 50 mg/kg in acute infection model. Dotted horizontal line indicates no change from CFU count in untreated controls (A and C) or no change from CFU count after treatment with pretomanid alone (B and D). AUC/MIC, area under the concentration-time curve above the minimum inhibitory concentration; C_max, LZD maximum concentration; Time_>MIC, time above minimum inhibitory concentration.

Figure 4.

Exposure-response relationship for linezolid (LZD)-induced anemia, as measured by hemoglobin in infected BALB/c mice. (A) Mean hemoglobin by total weekly dose and dosing frequency. (B) Relationships between pharmacokinetic/toxicodynamic parameters and hemoglobin. Three total weekly LZD doses (0, 100, 300, and 1000 mg/kg per week) were fractionated into 3 dosing schedules: 3 doses/week, 5 doses/week, and 10 doses/week. Statistical significance determined using one-way analysis of variance with Tukey’s posttest to adjust for multiple comparisons within each dose level: *, P < .05; **, P < .01; ***, P < .001. AUC, area under the concentration-time curve; C_max, LZD maximum concentration; C_min, LZD minimum concentration.