Preserved Efficacy and Reduced Toxicity with Intermittent Linezolid Dosing in Combination with Bedaquiline and Pretomanid in a Murine Tuberculosis Model

Abstract

The novel regimen of bedaquiline, pretomanid, and linezolid (BPaL) is highly effective against drug-resistant tuberculosis, but linezolid toxicities are frequent. We hypothesized that, for a similar total weekly cumulative dose, thrice-weekly administration of linezolid would preserve efficacy while reducing toxicity compared with daily dosing, in the context of the BPaL regimen. Using C3HeB/FeJ and BALB/c mouse models of tuberculosis disease, thrice-weekly linezolid dosing was compared with daily dosing, with intermittent dosing introduced (i) from treatment initiation or (ii) after an initial period of daily dosing. In all animals, BPa was dosed daily throughout treatment. Blood counts were used to assess hematologic toxicity. After unexpected findings of apparent antagonism, we conducted additional experiments to investigate strain-to-strain differences in the contribution of linezolid to regimen efficacy by comparing each 1- and 2-drug component to the BPaL regimen in BALB/c mice infected with Mycobacterium tuberculosis H37Rv or HN878. Giving linezolid daily for 1 to 2 months achieved the greatest efficacy but, after that, results were similar if the drug was stopped, dosed thrice-weekly, or continued daily. Erythrocyte counts were lower with daily than thrice-weekly dosing. Linezolid had additive effects with BPa against M. tuberculosis H37Rv but antagonistic effects with BPa against M. tuberculosis HN878. However, the overall efficacy of BPaL was high and similar against both strains. Dosing linezolid daily for the first 2 months and then less frequently thereafter may optimize its therapeutic margin. Linezolid's contribution to BPaL regimens may depend on the M. tuberculosis strain.

Keywords: animal model; bedaquiline; linezolid; pharmacokinetic; pretomanid; toxicity.

FIG 1

Lung CFU counts in C3HeB/FeJ mice after treatment with BPa with or without L at differing doses and dosing frequencies. (A) Comparison of BPa with or without at L at 45 mg/kg once a day (q.d.), 90 mg/kg q.o.d., or 90 mg/kg q.d. after 2 months of treatment in HN878-infected mice in experiment 1. (B) Comparison of BPa with or without at L at 25 mg/kg q.d., 50 mg/kg q.d., or 100 mg/kg q.d. after 1 month of treatment in H37Rv-infected mice in experiment 2. Abbreviations: B, bedaquiline; Pa, pretomanid; L, linezolid; m, month; q.d., once a day (5/7). Doses used were as follows: 25 mg/kg B q.d., 50 mg/kg Pa (A) or 100 mg/kg Pa q.d. (B). *, P < 0.05. Dark horizontal bars indicate the median value for each group.

FIG 2

Results of complete blood counts performed in BALB/c mice after 2 months of treatment with BPa with or without L at differing dosing frequencies and doses in experiment 3. (A) RBC counts. (B) Hemoglobin concentrations. (C) Hematocrits. (D) Platelet counts. Abbreviations: B, bedaquiline; Pa, pretomanid; L, linezolid; Ut, untreated; m, month; q.d., once a day (5/7); q.o.d., every other day dosing (3/7). Doses used were as follows: 25 mg/kg B q.d., 50 mg/kg Pa, with L as indicated. *, P < 0.05; **, P < 0.01.

FIG 3

Lung CFU counts after 2 months of treatment with one-, two-, and three-drug combinations of B, Pa, and L in BALB/c mice infected with M. tuberculosis strains H37Rv or HN878 in experiment 4. (A) Results for combinations using 50 mg/kg Pa q.d. in mice infected with M. tuberculosis H37Rv. (B) Results for combinations using 100 mg/kg Pa q.d. in mice infected with M. tuberculosis H37Rv. (C) Results for combinations using 50 mg/kg Pa q.d. in mice infected with M. tuberculosis HN878. (D) Results for combinations using 100 mg/kg Pa q.d. in mice infected with M. tuberculosis HN878. Abbreviations: B, bedaquiline; Pa, pretomanid; L, linezolid; q.d., once a day (5/7); NA, not available due to contamination of samples. Doses used were as follows: 25 mg/kg B q.d. and 45 or 90 mg/kg L q.d., as indicated.