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

Several pathophysiological changes in critically ill patients are important in determining the therapeutic success of beta-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 mu g/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 mu g/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. (C) 2012 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.