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Pharmacokinetics and pharmacodynamics of meropenern in febrile neutropenic patients with bacteremia

Ariano, RE; Nyhlén, Anna LU ; Donnelly, JP; Sitar, DS; Harding, GKM and Zelenitsky, SA (2005) In Annals of Pharmacotherapy 39(1). p.32-38
Abstract
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... (More)
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. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
febrile neutropenia, meropenem
in
Annals of Pharmacotherapy
volume
39
issue
1
pages
32 - 38
publisher
Harvey Whitney Books Co
external identifiers
  • pmid:15598967
  • wos:000225919100005
  • scopus:11144239389
ISSN
1060-0280
DOI
10.1345/aph.1E271
language
English
LU publication?
yes
id
10d30234-5ac7-462f-b9da-b74a8c9c59a0 (old id 259057)
date added to LUP
2007-08-21 12:27:41
date last changed
2017-10-29 04:17:03
@article{10d30234-5ac7-462f-b9da-b74a8c9c59a0,
  abstract     = {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.},
  author       = {Ariano, RE and Nyhlén, Anna and Donnelly, JP and Sitar, DS and Harding, GKM and Zelenitsky, SA},
  issn         = {1060-0280},
  keyword      = {febrile neutropenia,meropenem},
  language     = {eng},
  number       = {1},
  pages        = {32--38},
  publisher    = {Harvey Whitney Books Co},
  series       = {Annals of Pharmacotherapy},
  title        = {Pharmacokinetics and pharmacodynamics of meropenern in febrile neutropenic patients with bacteremia},
  url          = {http://dx.doi.org/10.1345/aph.1E271},
  volume       = {39},
  year         = {2005},
}