Shortening Tuberculosis Treatment With Fluoroquinolones: Lost in Translation?

Abstract

The disappointing recent failure of fluoroquinolone-containing regimens to shorten the duration of tuberculosis treatment in costly phase 3 trials has raised serious questions about the reliability of preclinical tuberculosis models, especially mice, and the current paradigm of regimen development. Therefore we re-examined data from murine models and early-stage clinical trials on which the pivotal trials were based, concluding that phase 3 trial results were in line with preceding studies. Finally, we offer suggestions for a more efficient and integrated preclinical and clinical regimen development program where quantitative pharmacokinetic and pharmacodynamic models more predictive of curative treatment durations are set forth.

Keywords: OFLOTUB; REMox-TB; fluoroquinolones; shortening regimen; tuberculosis.

Figure 1.

Estimating treatment-shortening effects. Solid red triangles represent the proportion of mice relapsing after receiving the control regimen for various durations (error bars represent the 95% confidence interval) (see panel A). Yellow line indicates the hypothetical proportion of mice expected to relapse if a test regimen was capable of shortening the duration of treatment by 1 month without affecting the relapse rate. Likewise, the green line indicates the hypothetical proportion of mice expected to relapse if a test regimen was capable of shortening the duration of treatment by 2 months. Blue circle indicates the proportion of mice relapsing after treatment with the test regimen. If the test regimen is capable of shortening the treatment duration by 2 months or more, then the proportion of mice relapsing should fall within the green filled area under this curve.

Figure 2.

Shortening effects of moxifloxacin-containing regimens. See Figure 1 for explanation of the schematic. A, high-dose aerosol infection model in BALB/c mice, where substitution of M for H conferred a treatment-shortening effect that falls between 1 and 2 months (4 experiments) [, –33]; (B) high-dose intravenous infection model in Swiss and BALB/c mice, where substitution of M for H conferred a treatment-shortening effect of <2 months (2 experiments) [31, 34]; (C) low-dose aerosol infection model in BALB/c mice, where substitution of M for H conferred a treatment-shortening effect of 1 month (3 experiments) [31, 35]; (D) low-dose aerosol infection model in C3HeB/FeJ mice, where substitution of M for H conferred a treatment-shortening effect of <1 month (2 experiments) [35]; (E) low-dose aerosol infection model in BALB/c mice, where substitution of M for E conferred a treatment-shortening effect of <1 month (2 experiments) [31, 35]; (F) low-dose aerosol infection model in C3HeB/FeJ mice, where substitution of M for E conferred a treatment-shortening effect of <1 month (2 experiments) [31, 35].