The Sterilizing Effect of Intermittent Tedizolid for Pulmonary Tuberculosis

Abstract

Background

Linezolid exhibits remarkable sterilizing effect in tuberculosis; however, a large proportion of patients develop serious adverse events. The congener tedizolid could have a better side-effect profile, but its sterilizing effect potential is unknown.

Methods

We performed a 42-day tedizolid exposure-effect and dose-fractionation study in the hollow fiber system model of tuberculosis for sterilizing effect, using human-like intrapulmonary pharmacokinetics. Bacterial burden was examined using time to positivity (TTP) and colony-forming units (CFUs). Exposure-effect was examined using the inhibitory sigmoid maximal kill model. The exposure mediating 80% of maximal kill (EC₈₀) was defined as the target exposure, and the lowest dose to achieve EC₈₀ was identified in 10000-patient Monte Carlo experiments. The dose was also examined for probability of attaining concentrations associated with mitochondrial enzyme inhibition.

Results

At maximal effect, tedizolid monotherapy totally eliminated 7.1 log₁₀ CFU/mL Mycobacterium tuberculosis over 42 days; however, TTP still demonstrated some growth. Once-weekly tedizolid regimens killed as effectively as daily regimens, with an EC₈₀ free drug 0- to 24-hour area under the concentration–time curve-to-minimum inhibitory concentration (MIC) ratio of 200. An oral tedizolid of 200 mg/day achieved the EC₈₀ in 92% of 10000 patients. The susceptibility breakpoint was an MIC of 0.5 mg/L. The 200 mg/day dose did not achieve concentrations associated with mitochondrial enzyme inhibition.

Conclusions

Tedizolid exhibits dramatic sterilizing effect and should be examined for pulmonary tuberculosis. A tedizolid dose of 200 mg/day or 700 mg twice a week is recommended for testing in patients; the intermittent tedizolid dosing schedule could be much safer than daily linezolid.

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