Pharmacokinetics and pharmacodynamics of linezolid in children with cystic fibrosis

Roberto P. Santos, Claude B. Prestidge, Michael E. Brown, Brenda Urbancyzk, Donald K. Murphey, Christine M. Salvatore, Hasan S. Jafri, George H. McCracken, Naveed Ahmad, Pablo J. Sanchez, Jane D. Siegel

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

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 AF508 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 AF508 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 cysticfibrosis; it is likely that higher doses will be needed.

Original languageEnglish (US)
Pages (from-to)148-154
Number of pages7
JournalPediatric Pulmonology
Volume44
Issue number2
DOIs
StatePublished - Feb 2009

Fingerprint

Linezolid
Cystic Fibrosis
Pharmacokinetics
Methicillin-Resistant Staphylococcus aureus
Regulator Genes
Mutation
Lung

Keywords

  • Genotype
  • Pharmacodynamics
  • Pharmacokinetics
  • Phenotype
  • Staphylococcus aureus

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Pulmonary and Respiratory Medicine

Cite this

Santos, R. P., Prestidge, C. B., Brown, M. E., Urbancyzk, B., Murphey, D. K., Salvatore, C. M., ... Siegel, J. D. (2009). Pharmacokinetics and pharmacodynamics of linezolid in children with cystic fibrosis. Pediatric Pulmonology, 44(2), 148-154. https://doi.org/10.1002/ppul.20966

Pharmacokinetics and pharmacodynamics of linezolid in children with cystic fibrosis. / Santos, Roberto P.; Prestidge, Claude B.; Brown, Michael E.; Urbancyzk, Brenda; Murphey, Donald K.; Salvatore, Christine M.; Jafri, Hasan S.; McCracken, George H.; Ahmad, Naveed; Sanchez, Pablo J.; Siegel, Jane D.

In: Pediatric Pulmonology, Vol. 44, No. 2, 02.2009, p. 148-154.

Research output: Contribution to journalArticle

Santos, RP, Prestidge, CB, Brown, ME, Urbancyzk, B, Murphey, DK, Salvatore, CM, Jafri, HS, McCracken, GH, Ahmad, N, Sanchez, PJ & Siegel, JD 2009, 'Pharmacokinetics and pharmacodynamics of linezolid in children with cystic fibrosis', Pediatric Pulmonology, vol. 44, no. 2, pp. 148-154. https://doi.org/10.1002/ppul.20966
Santos RP, Prestidge CB, Brown ME, Urbancyzk B, Murphey DK, Salvatore CM et al. Pharmacokinetics and pharmacodynamics of linezolid in children with cystic fibrosis. Pediatric Pulmonology. 2009 Feb;44(2):148-154. https://doi.org/10.1002/ppul.20966
Santos, Roberto P. ; Prestidge, Claude B. ; Brown, Michael E. ; Urbancyzk, Brenda ; Murphey, Donald K. ; Salvatore, Christine M. ; Jafri, Hasan S. ; McCracken, George H. ; Ahmad, Naveed ; Sanchez, Pablo J. ; Siegel, Jane D. / Pharmacokinetics and pharmacodynamics of linezolid in children with cystic fibrosis. In: Pediatric Pulmonology. 2009 ; Vol. 44, No. 2. pp. 148-154.
@article{f194f5382f3443ce802ab8b31fd85013,
title = "Pharmacokinetics and pharmacodynamics of linezolid in children with cystic fibrosis",
abstract = "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 AF508 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 AF508 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 cysticfibrosis; it is likely that higher doses will be needed.",
keywords = "Genotype, Pharmacodynamics, Pharmacokinetics, Phenotype, Staphylococcus aureus",
author = "Santos, {Roberto P.} and Prestidge, {Claude B.} and Brown, {Michael E.} and Brenda Urbancyzk and Murphey, {Donald K.} and Salvatore, {Christine M.} and Jafri, {Hasan S.} and McCracken, {George H.} and Naveed Ahmad and Sanchez, {Pablo J.} and Siegel, {Jane D.}",
year = "2009",
month = "2",
doi = "10.1002/ppul.20966",
language = "English (US)",
volume = "44",
pages = "148--154",
journal = "Pediatric Pulmonology",
issn = "8755-6863",
publisher = "Wiley-Liss Inc.",
number = "2",

}

TY - JOUR

T1 - Pharmacokinetics and pharmacodynamics of linezolid in children with cystic fibrosis

AU - Santos, Roberto P.

AU - Prestidge, Claude B.

AU - Brown, Michael E.

AU - Urbancyzk, Brenda

AU - Murphey, Donald K.

AU - Salvatore, Christine M.

AU - Jafri, Hasan S.

AU - McCracken, George H.

AU - Ahmad, Naveed

AU - Sanchez, Pablo J.

AU - Siegel, Jane D.

PY - 2009/2

Y1 - 2009/2

N2 - 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 AF508 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 AF508 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 cysticfibrosis; it is likely that higher doses will be needed.

AB - 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 AF508 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 AF508 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 cysticfibrosis; it is likely that higher doses will be needed.

KW - Genotype

KW - Pharmacodynamics

KW - Pharmacokinetics

KW - Phenotype

KW - Staphylococcus aureus

UR - http://www.scopus.com/inward/record.url?scp=59949083248&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=59949083248&partnerID=8YFLogxK

U2 - 10.1002/ppul.20966

DO - 10.1002/ppul.20966

M3 - Article

C2 - 19137597

AN - SCOPUS:59949083248

VL - 44

SP - 148

EP - 154

JO - Pediatric Pulmonology

JF - Pediatric Pulmonology

SN - 8755-6863

IS - 2

ER -