Pharmacodynamics of doripenem in critically ill patients with ventilator-associated Gram-negative bacilli pneumonia.

Abstract

Several pathophysiological changes in critically ill patients are important in determining the therapeutic success of β-lactam antibiotics. The aim of this study was to assess the population pharmacokinetics and probabilities of target attainment (PTAs) of doripenem in patients with ventilator-associated pneumonia, comparing administration by 1-h and 4-h infusion. Patients were randomised into two groups: Group I received a 1-h infusion of 0.5 g every 8 h (q8h) for seven doses; and Group II received a 4-h infusion of 0.5 g q8h for seven doses. A Monte Carlo simulation was performed to determine the PTAs. PTAs of achieving 40% T(>MIC) [exposure time during which the free drug concentration remains above the minimum inhibitory concentration (MIC)] and 75% T(>MIC) are required for effective bactericidal activity of this agent in immunocompetent and immunocompromised hosts, respectively. Values of volume of distribution and total clearance of doripenem in these patients were 17.26±1.83 L and 24.89±1.63 L/h, respectively. For pathogens with a MIC of 1 μg/mL, the PTAs of achieving 40% T(>MIC) following administration of doripenem by a 1-h and 4-h infusion of 0.5 g q8h were 92.95% and 98.32%, respectively. For pathogens with a MIC of 2 μg/mL in immunocompromised hosts, the PTAs of achieving 80% T(>MIC) following administration of doripenem by 1-h and 4-h infusion of 2 g q8h were 56.57% and 91.21%, respectively. In conclusion, these findings indicated that higher than recommended doses in this patient population, particularly neutropenic patients, would be necessary to optimise the pharmacokinetics of doripenem.

• Authors: Sutep Jaruratanasirikul, Wibul Wongpoowarak, Narongdet Kositpantawong, Nanchanit Aeinlang, Monchana Jullangkoon
• Journal: International journal of antimicrobial agents (Int J Antimicrob Agents) Vol. 40 Issue 5 Pg. 434-9 (Nov 2012) ISSN: 1872-7913 [Electronic] Netherlands
• PMID: 22959555 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

Chemical References

• Anti-Bacterial Agents
• Carbapenems
• Doripenem

Topics

• Adult
• Aged
• Aged, 80 and over
• Anti-Bacterial Agents (administration & dosage, pharmacokinetics)
• Carbapenems (administration & dosage, pharmacokinetics)
• Critical Illness
• Doripenem
• Female
• Gram-Negative Bacterial Infections (drug therapy)
• Humans
• Infusions, Intravenous (methods)
• Male
• Microbial Sensitivity Tests
• Middle Aged
• Pneumonia, Ventilator-Associated (drug therapy)
• Time Factors