Pharmacokinetics and pharmacodynamics of linezolid in children with cystic fibrosis.
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.


OBJECTIVE
(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.


OBJECTIVE
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 DeltaF508 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 (>or=10 years). The PK indices of children with homozygous DeltaF508 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.
Santos
Roberto P
RP
Division of Infectious Diseases, Department of Pediatrics, University of Texas Southwestern Medical Center Dallas, Dallas, Texas, USA. santosr@mail.amc.edu
Prestidge
Claude B
CB
Brown
Michael E
ME
Urbancyzk
Brenda
B
Murphey
Donald K
DK
Salvatore
Christine M
CM
Jafri
Hasan S
HS
McCracken
George H
GH
Ahmad
Naveed
N
Sanchez
Pablo J
PJ
Siegel
Jane D
JD
D000081:Acetamides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000293:Adolescent; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000188:drug therapy*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005260:Female; D006801:Humans; D000069349:Linezolid; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects*; D023303:Oxazolidinones / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D012189:Retrospective Studies
D000081:Acetamides; D000890:Anti-Infective Agents; D023303:Oxazolidinones; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000069349:Linezolid