The Sterilizing Effect of Intermittent Tedizolid for Pulmonary Tuberculosis.
Tawanda Gumbo M.D.
Srivastava, S., D. Deshpande, E. Nuermberger, P. S. Lee, K. Cirrincione, K. Dheda and T. Gumbo (2018). “The Sterilizing Effect of Intermittent Tedizolid for Pulmonary Tuberculosis.” Clin Infect Dis 67(suppl_3): S336-s341.
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.