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INFECTIOUS DISEASES

Pharmacokinetics and Pharmacodynamics of Meropenem in Febrile Neutropenic Patients with Bacteremia

Anna Nyhlén, MD

Department of Infectious Diseases, University Hospital of Lund, Lund, Sweden

J Peter Donnelly, PhD

University Hospital St Radboud, Nijmegen, Netherlands

Daniel S Sitar, PhD

Clinical Pharmacology Section, Pharmacology and Therapeutics, Department of Medicine, University of Manitoba

Godfrey KM Harding, MD

Infectious Diseases Section, Department of Medicine, University of Manitoba

Sheryl A Zelenitsky, PharmD

Associate Dean, Faculty of Pharmacy, University of Manitoba

Reprints: Dr. Ariano, St. Boniface General Hospital, Winnipeg, Manitoba, Canada R2H-2A6, fax 204/235-1476, rariano{at}sbgh.mb.ca

BACKGROUND: Pharmacodynamic investigations with antimicrobials define the relationship between the infecting organism and achievable drug concentrations with clinical outcome.

OBJECTIVE: To examine this relationship for meropenem in a population of patients who are at high risk of infection-related morbidity and mortality.

METHODS: The study was a retrospective analysis of a multicenter, randomized, blinded clinical trial. A population-based predictive model was created using data from adults with febrile neutropenia and the nonparametric modeling program, NPEM. Patient age, body weight, and serum creatinine level were covariates in the model used to predict unbound concentrations for each patient. Pathogen susceptibility was estimated using product literature minimum inhibitory concentrations for effectiveness against 50% of microorganisms (MIC₅₀) for specific organisms. The pharmacodynamic index of percent time above MIC (% T>MIC) was analyzed for its association with clinical outcome.

RESULTS: A 2-compartment pharmacokinetic model using patient covariates of body weight and renal function best described the pharmacokinetics of meropenem in febrile neutropenic patients. Sixty patients with confirmed gram-positive or -negative bacteremia were studied. An average of 83% T>MIC was identified for the 42 clinical responders compared with 59% T>MIC for the 18 nonresponders (p = 0.04). An 80% clinical response rate was evident when the % T>MIC for meropenem exceeded 75% of the dosing interval (p = 0.01).

CONCLUSIONS: To our knowledge, this is the first published report of a relationship between a pharmacodynamic index and clinical outcome in a febrile neutropenic population. Based on this relationship, dosing with intravenous meropenem 500 mg every 6 hours is predicted to be comparable to the currently recommended 1 g every 8 hours for serious infections. Our model provides further justification for a prospective clinical trial to evaluate a pharmacodynamically targeted meropenem dosing schedule as to its ability to improve clinical outcome in these patients.

Key Words: febrile neutropenia, meropenem

Published Online, December 14, 2004. www.theannals.com, DOI 10.1345/aph.1E271

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