Population pharmacokinetics and dosing simulations of imipenem in serious bacteraemia in immunocompromised patients with febrile neutropenia

J Pharmacol Sci. 2015 Feb;127(2):164-9. doi: 10.1016/j.jphs.2014.12.003. Epub 2014 Dec 11.

Abstract

The aims of this study were to i) reveal the population pharmacokinetics; and ii) assess the probability of target attainment (PTA) and cumulative fraction of response (CFR) (defined as the expected population PTA for a specific drug dose and a specific population of microorganisms) of imipenem in febrile neutropenic patients with bacteraemia. Ten patients were randomised into two groups: Group I received a 0.5-h infusion of 0.5 g of imipenem every 6 h (q6h) for 8 doses; and Group II received a 4-h infusion of 0.5 g q6h for 8 doses. A Monte Carlo simulation was performed to determine the PTA. The volume of distribution and total clearance of imipenem were 20.78 ± 1.35 l and 23.19 ± 1.34 l/h, respectively. Only a 4-h infusion of 1 g q6h regimen achieved a PTA >93% for 80% T>MIC for a MIC of 2 μg/ml. A 4-h infusion of all simulated regimens and a 0.5-h infusion of 0.5 g q6h and 1 g q6h achieved targets (CFR ≥ 90%) against Escherichia coli and Klebsiella spp. However, against Pseudomonas aeruginosa and Acinetobacter spp., no regimens achieved their targets. In conclusion, the results indicate that a higher than manufacturer's dosage recommendation is required to maximize the activity of imipenem.

Keywords: Febrile Neutropenia; Imipenem; Pharmacodynamics; Pharmacokinetics/pharmacodynamics; Population pharmacokinetics.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acinetobacter / drug effects
  • Adult
  • Aged
  • Anti-Bacterial Agents / administration & dosage
  • Anti-Bacterial Agents / pharmacokinetics*
  • Anti-Bacterial Agents / pharmacology
  • Bacteremia / complications
  • Bacteremia / drug therapy*
  • Bacteremia / microbiology*
  • Dose-Response Relationship, Drug
  • Drug Resistance, Bacterial
  • Escherichia coli / drug effects
  • Febrile Neutropenia / complications
  • Febrile Neutropenia / drug therapy*
  • Female
  • Humans
  • Imipenem / administration & dosage
  • Imipenem / pharmacokinetics*
  • Imipenem / pharmacology
  • Immunocompromised Host*
  • Infusions, Intravenous
  • Klebsiella / drug effects
  • Male
  • Middle Aged
  • Monte Carlo Method
  • Pseudomonas aeruginosa / drug effects
  • Severity of Illness Index
  • Young Adult

Substances

  • Anti-Bacterial Agents
  • Imipenem