title: Optimal Clinical Doses of Faropenem, Linezolid, and Moxifloxacin in Children With Disseminated Tuberculosis: Goldilocks.
abstract: BACKGROUND
  When treated with the same antibiotic dose, children achieve different 0- to 24-hour area under the concentration-time curves (AUC0-24) because of maturation and between-child physiological variability on drug clearance. Children are also infected by Mycobacterium tuberculosis isolates with different antibiotic minimum inhibitory concentrations (MICs). Thus, each child will achieve different AUC0-24/MIC ratios when treated with the same dose.
  
  
  METHODS
  We used 10 000-subject Monte Carlo experiments to identify the oral doses of linezolid, moxifloxacin, and faropenem that would achieve optimal target exposures associated with optimal efficacy in children with disseminated tuberculosis. The linezolid and moxifloxacin exposure targets were AUC0-24/MIC ratios of 62 and 122, and a faropenem percentage of time above MIC >60%, in combination therapy. A linezolid AUC0-24of 93.4 mg × hour/L was target for toxicity. Population pharmacokinetic parameters of each drug and between-child variability, as well as MIC distribution, were used, and the cumulative fraction of response (CFR) was calculated. We also considered drug penetration indices into meninges, bone, and peritoneum.
  
  
  RESULTS
  The linezolid dose of 15 mg/kg in full-term neonates and infants aged up to 3 months and 10 mg/kg in toddlers, administered once daily, achieved CFR ≥ 90%, with <10% achieving linezolid AUC0-24associated with toxicity. The moxifloxacin dose of 25 mg/kg/day achieved a CFR > 90% in infants, but the optimal dose was 20 mg/kg/day in older children. The faropenem medoxomil optimal dosage was 30 mg/kg 3-4 times daily.
  
  
  CONCLUSIONS
  The regimen and doses of linezolid, moxifloxacin, and faropenem identified are proposed to be adequate for all disseminated tuberculosis syndromes, whether drug-resistant or -susceptible.
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: 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: Jotam
authors.initials: J
authors.lastname: Pasipanodya
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: D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D024841:Fluoroquinolones / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D000069349:Linezolid / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008826:Microbial Sensitivity Tests; D015233:Models, Statistical; D009010:Monte Carlo Method; D000077266:Moxifloxacin; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D014376:Tuberculosis / Q000188:drug therapy* / Q000382:microbiology*; D047090:beta-Lactams / Q000008:administration & dosage* / Q000493:pharmacokinetics
chemical_list: D000995:Antitubercular Agents; D024841:Fluoroquinolones; D047090:beta-Lactams; C528565:faropenem medoxomil; D000069349:Linezolid; D000077266:Moxifloxacin
keywords: Monte Carlo experiments; combination regimen; dosage design; pharmacokinetic variability; target setting