title: Linezolid for Infants and Toddlers With Disseminated Tuberculosis: First Steps.
abstract: 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 (AUC0-24).
  
  
  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 AUC0-24to minimum inhibitory concentration (MIC) ratio (r2= 0.98). The exposure associated with maximal Mtb kill was an AUC0-24/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 AUC0-24best explained the mitochondrial gene inhibition, with 50% inhibition at 94 mg × hour/L (highest r2= 0.98).
  
  
  CONCLUSIONS
  We identified the linezolid AUC0-24/MIC target for optimal efficacy against pediatric intracellular tuberculosis, and an AUC0-24threshold associated with mitochondrial inhibition. These constitute a therapeutic window to be targeted for optimal linezolid doses in children with tuberculosis.
authors.affiliation: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas.
authors.forename: Devyani
authors.initials: D
authors.lastname: Deshpande
authors.affiliation: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas.
authors.forename: Shashikant
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas.
authors.forename: Jotam G
authors.initials: JG
authors.lastname: Pasipanodya
authors.affiliation: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Bush
authors.affiliation: Center for Tuberculosis Research, Department of Medicine Department of International Health, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Eric
authors.initials: E
authors.lastname: Nuermberger
authors.affiliation: Tuberculosis Research Center, Chennai, India.
authors.forename: Soumya
authors.initials: S
authors.lastname: Swaminathan
authors.affiliation: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, Texas Department of Medicine, University of Cape Town, Observatory, South Africa.
authors.forename: Tawanda
authors.initials: T
authors.lastname: Gumbo
mesh_terms: D000367:Age Factors; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D002460:Cell Line; D002675:Child, Preschool; D016903:Drug Monitoring; D005260:Female; D020869:Gene Expression Profiling; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D000069349:Linezolid / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D012269:Ribosomal Proteins / Q000235:genetics; D014376:Tuberculosis / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000382:microbiology*
chemical_list: D000995:Antitubercular Agents; D012269:Ribosomal Proteins; D000069349:Linezolid
keywords: RNA sequencing; disseminated tuberculosis; hollow fiber model; pharmacokinetics/pharmacodynamics; toxicity