The Sterilizing Effect of Intermittent Tedizolid for Pulmonary Tuberculosis. (28th November 2018)

• Record Type: Journal Article
• Authors: Srivastava, Shashikant; Deshpande, Devyani; Nuermberger, Eric; Lee, Pooi S; Cirrincione, Kayle; Dheda, Keertan; Gumbo, Tawanda
• Is Part Of: Clinical infectious diseases. Volume 67(2018)Supplement 3
• Page Start: S336
• Page End: S341
• Publication Date: 2018-11-28
• Subjects: optimal dose -- intermittent dosing -- pharmacokinetics/pharmacodynamics -- time to positivity -- susceptibility breakpoint; Communicable diseases -- Periodicals; 616.905
• DOI: 10.1093/cid/ciy626
• Languages: English
• ISSNs: 1058-4838

Abstract

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.