Pharmacokinetics and Pharmacodynamics of Linezolid in Children With Cystic Fibrosis

• Published in: Pediatric pulmonology Vol. 44; no. 2; pp. 148 - 154
• Main Authors: Santos, Roberto P., Prestidge, Claude B., Brown, Michael E., Urbancyzk, Brenda, Murphey, Donald K., Salvatore, Christine M., Jafri, Hasan S., McCracken Jr, George H., Ahmad, Naveed, Sanchez, Pablo J., Siegel, Jane D.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.02.2009; Wiley-Liss
• Subjects: Acetamides - administration & dosage; Acetamides - pharmacokinetics; Acetamides - therapeutic use; Adolescent; Anti-Infective Agents - administration & dosage; Anti-Infective Agents - pharmacokinetics; Anti-Infective Agents - therapeutic use; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Child; Child, Preschool; Cystic Fibrosis - drug therapy; Cystic Fibrosis Transmembrane Conductance Regulator; Errors of metabolism; Female; General aspects; genotype; Humans; Linezolid; Male; Medical sciences; Metabolic diseases; Methicillin-Resistant Staphylococcus aureus - drug effects; Miscellaneous hereditary metabolic disorders; Oxazolidinones - administration & dosage; Oxazolidinones - pharmacokinetics; Oxazolidinones - therapeutic use; pharmacodynamics; pharmacokinetics; Pharmacology. Drug treatments; phenotype; Pneumology; Retrospective Studies; Staphylococcus aureus; Human; Linezolid; Pediatrics; Typing; Respiratory disease; pharmacodynamics; Metabolic diseases; Genotype; Cystic fibrosis; Biological activity; Genetic disease; Phenotype; Microbiological investigation; Bacteria; Micrococcales; Digestive diseases; Micrococcaceae; Antibacterial agent; Pharmacokinetics; Child; Staphylococcus aureus; Pancreatic disease; Pneumology
• DOI: 10.1002/ppul.20966
• ISSN: 8755-6863

Alternative antimicrobial regimens are needed for treatment of methicillin‐resistant Staphylococcus aureus (MRSA)‐associated pulmonary exacerbations in children with cystic fibrosis (CF). There are no published pharmacokinetic (PK) and pharmacodynamic (PD) data for linezolid in children with CF. Objectives (1) To determine the PK and PD profile of linezolid among children with CF; (2) to characterize the effect of linezolid on MRSA infection; (3) to determine the effect of age and CF transmembrane regulator (CFTR) gene mutations on drug clearance. Hypotheses Linezolid clearance is enhanced in children with CF requiring a higher dosage regimen. Age and CFTR gene mutations affect drug clearance. Methods This was a retrospective cohort study; medical records of children with MRSA‐associated pulmonary exacerbations treated with linezolid (10 mg/kg/dose IV every 8h) were reviewed. Linezolid peak and trough concentrations in serum were determined by high performance liquid chromatography, PK profiles determined using standard noncompartmental method, and PD indices were evaluated. Results 10 children (mean ± SD, 10.2 ± 5.5 years) received 14 courses of linezolid at 10 ± 0.4 mg/kg/dose every 8h for 15.4 ± 3.2 days. Seven had homozygous ΔF508 CFTR mutation. Peak and trough linezolid concentrations varied widely (range, 8.4–20.5 and 0.1–11.5 mcg/mL respectively). The PK profile of children <10 years differed significantly from older patients (≥10 years). The PK indices of children with homozygous ΔF508 differed marginally from those with heterozygous CFTR mutations, but there were too few subjects to allow separation of age and CFTR mutations effect. No patient achieved the target PD ratio of AUC/MIC >80. MRSA persisted in sputum or throat culture after treatment with linezolid. Conclusions Additional PK and PD data are needed to optimize linezolid therapy in children with cystic fibrosis; it is likely that higher doses will be needed. Pediatr Pulmonol. 2009; 44:148–154. © 2009 Wiley‐Liss, Inc.