Linezolid for infants and toddlers with disseminated tuberculosis: First steps.
Deshpande, D.; Srivastava, S .; Pasipanodya, J.G .; Bush, S.J.; Nuermberger, E .; Swaminathan, S.; Gumbo, T.
Clinical Infectious Diseases; 2016; 63; S80-S87.
Background: Infants and toddlers often present with disseminated and lymph node tuberculosis, in which Mycobacterium tuberculosis ( Mtb ) is predominantly intracellular. Linezolid, used to treat tuberculosis in adults, has not been formally studied in infants. Infants clear linezolid 5 times faster than adults and achieve lower 0- to 24-hour area under the concentration-time curves (AUC 0–24).
Methods: To mimic intracellular disease, we infected human-derived THP-1 macrophages with Mtb and inoculated hollow fiber systems. We performed dose-effect and dose-scheduling studies in which we recapitulated the linezolid half-life of 3 hours encountered in infants. Repetitive sampling for linezolid pharmacokinetics, Mtb intracellular burden, viable monocyte count, and RNA sequencing reads were performed up to 28 days.
Results: The linezolid extracellular half-life was 2.64 ± 0.38 hours, whereas intracellular half-life was 8.93±1.30 hours ( r2 = 0.89). Linezolid efficacy was linked to the AUC 0–24to minimum inhibitory concentration (MIC) ratio ( r2 = 0.98). The exposure associated with maximal Mtb kill was an AUC 0–24 /MIC of 23.37 ± 1.16. We identified a 414-gene transcript on exposure to toxic linezolid doses. The largest number of genes mapped to ribosomal proteins, a signature hitherto not associated with linezolid toxicity. The second-largest number of differentially expressed genes mapped to mitochondrial enzyme inhibition. Linezolid AUC 0–24 best explained the mitochondrial gene inhibition, with 50% inhibition at 94 mg × hour/L (highest r2 = 0.98).
Conclusions: We identified the linezolid AUC 0–24 /MIC target for optimal efficacy against pediatric intracellular tuberculosis, and an AUC 0–24 threshold associated with mitochondrial inhibition. These constitute a therapeutic window to be targeted for optimal linezolid doses in children with tuberculosis.
Keywords: Disseminated tuberculosis; pharmacokinetics/pharmacodynamics; toxicity; hollow fiber model; RNA sequencing.
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