Pharmacokinetics and Pharmacodynamics of Linezolid in Children With Cystic Fibrosis^†

Corresponding Author

Roberto P. Santos MD

[email protected]

Division of Infectious Diseases, Department of Pediatrics, University of Texas Southwestern Medical Center Dallas, Dallas, Texas

Department of Pediatrics, Division of Infectious Diseases, Children's Hospital at Albany Medical Center, 47 New Scotland Avenue, MC 88—MCATS, Albany, New York 12208.Search for more papers by this author

Claude B. Prestidge MD,

Claude B. Prestidge MD

Cystic Fibrosis Care and Teaching Center, Children's Medical Center Dallas, Dallas, Texas

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Michael E. Brown MD,

Michael E. Brown MD

Cystic Fibrosis Care and Teaching Center, Children's Medical Center Dallas, Dallas, Texas

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Brenda Urbancyzk RN,

Brenda Urbancyzk RN

Cystic Fibrosis Care and Teaching Center, Children's Medical Center Dallas, Dallas, Texas

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Donald K. Murphey MD,

Donald K. Murphey MD

Cook Children's Medical Center, Fort Worth, Texas

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Christine M. Salvatore MD,

Christine M. Salvatore MD

Division of Infectious Diseases, Department of Pediatrics, University of Texas Southwestern Medical Center Dallas, Dallas, Texas

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Hasan S. Jafri MD,

Hasan S. Jafri MD

Division of Infectious Diseases, Department of Pediatrics, University of Texas Southwestern Medical Center Dallas, Dallas, Texas

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George H. McCracken Jr MD,

George H. McCracken Jr MD

Division of Infectious Diseases, Department of Pediatrics, University of Texas Southwestern Medical Center Dallas, Dallas, Texas

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Naveed Ahmad MD,

Naveed Ahmad MD

Research Department, Children's Medical Center Dallas, Dallas, Texas

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Pablo J. Sanchez MD,

Pablo J. Sanchez MD

Division of Infectious Diseases, Department of Pediatrics, University of Texas Southwestern Medical Center Dallas, Dallas, Texas

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Jane D. Siegel MD,

Jane D. Siegel MD

Division of Infectious Diseases, Department of Pediatrics, University of Texas Southwestern Medical Center Dallas, Dallas, Texas

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Roberto P. Santos MD,

Corresponding Author

Roberto P. Santos MD

[email protected]

Division of Infectious Diseases, Department of Pediatrics, University of Texas Southwestern Medical Center Dallas, Dallas, Texas

Claude B. Prestidge MD,

Claude B. Prestidge MD

Cystic Fibrosis Care and Teaching Center, Children's Medical Center Dallas, Dallas, Texas

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Michael E. Brown MD,

Michael E. Brown MD

Cystic Fibrosis Care and Teaching Center, Children's Medical Center Dallas, Dallas, Texas

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Brenda Urbancyzk RN,

Brenda Urbancyzk RN

Cystic Fibrosis Care and Teaching Center, Children's Medical Center Dallas, Dallas, Texas

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Donald K. Murphey MD,

Donald K. Murphey MD

Cook Children's Medical Center, Fort Worth, Texas

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Christine M. Salvatore MD,

Christine M. Salvatore MD

Division of Infectious Diseases, Department of Pediatrics, University of Texas Southwestern Medical Center Dallas, Dallas, Texas

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Hasan S. Jafri MD,

Hasan S. Jafri MD

Division of Infectious Diseases, Department of Pediatrics, University of Texas Southwestern Medical Center Dallas, Dallas, Texas

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George H. McCracken Jr MD,

George H. McCracken Jr MD

Division of Infectious Diseases, Department of Pediatrics, University of Texas Southwestern Medical Center Dallas, Dallas, Texas

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Naveed Ahmad MD,

Naveed Ahmad MD

Research Department, Children's Medical Center Dallas, Dallas, Texas

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Pablo J. Sanchez MD,

Pablo J. Sanchez MD

Division of Infectious Diseases, Department of Pediatrics, University of Texas Southwestern Medical Center Dallas, Dallas, Texas

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Jane D. Siegel MD,

Jane D. Siegel MD

Division of Infectious Diseases, Department of Pediatrics, University of Texas Southwestern Medical Center Dallas, Dallas, Texas

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First published: 09 January 2009

https://doi.org/10.1002/ppul.20966

Citations: 39

^†

Presented in part at the 47th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), Chicago, Illinois, September 17–20, 2007 (A-781).

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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 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.

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Volume44, Issue2

February 2009

Pages 148-154

Pharmacokinetics and Pharmacodynamics of Linezolid in Children With Cystic Fibrosis^†

Abstract

Objectives

Hypotheses

Methods

Results

Conclusions

REFERENCES

Citing Literature

References

Information

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Pharmacokinetics and Pharmacodynamics of Linezolid in Children With Cystic Fibrosis†

Abstract

Objectives

Hypotheses

Methods

Results

Conclusions

REFERENCES

Citing Literature

References

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Pharmacokinetics and Pharmacodynamics of Linezolid in Children With Cystic Fibrosis^†