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Optimal Doripenem Dosing Simulations in Critically Ill Nosocomial Pneumonia Patients With Obesity, Augmented Renal Clearance, and Decreased Bacterial Susceptibility*

Roberts, Jason A. PhD1,2,3; Lipman, Jeffrey FCICM, MD1,3

doi: 10.1097/CCM.0b013e31826ab4c4
Clinical Investigations

Objective: Doripenem is a valuable broad-spectrum antibiotic for empirical therapy in critically ill patients, although little data exist to guide effective dosing. We sought to describe the population pharmacokinetics of doripenem in critically ill patients with nosocomial pneumonia and then to use Monte Carlo dosing simulations to procure clinically relevant dosing recommendations for that population.

Design: Pharmacokinetic analysis of Phase III Trial data.

Setting: Critical care units at multiple centers.

Patients: Thirty-one critically ill adult patients with nosocomial pneumonia.

Interventions: Serial blood samples were taken on day 2 or 3 of treatment and used for population pharmacokinetic analysis with nonlinear mixed effects modelling and Monte Carlo simulation.

Measurements and Main Results: A two-compartment linear model was most appropriate. The mean values for doripenem clearance (20.4 ± 14.2 L/hr) and volume of distribution (45.9 ± 36.3 L) were larger than that observed in previous studies in noncritically ill patients. Doripenem clearance was correlated with creatinine clearance and peripheral volume of distribution with patient body weight. Administration by extended infusion negated much of the pharmacokinetic variability caused by different patient body weight and renal function and enabled achievement of concentrations associated with maximal bacterial killing.

Conclusions: This is the first article describing the pharmacokinetics/pharmacodynamics of doripenem solely in critically ill patients and emphasizes the effect of patient weight and creatinine clearance on pharmacokinetics. Use of extended infusions with this antibiotic should be encouraged as it maximizes the likelihood of achieving target blood concentrations.

1 Burns, Trauma, and Critical Care Research Centre, The University of Queensland, Brisbane, Australia.

2 Pharmacy Department, Royal Brisbane and Women’s Hospital, Brisbane, Australia.

3 Department of Intensive Care Medicine, Royal Brisbane and Women’s Hospital, Brisbane, Australia.

*See also p. 676.

Data were provided by Johnson and Johnson from a multicenter Phase III pharmacokinetic study. Dr. Roberts is responsible for this article and performed the population pharmacokinetic analysis and drafted the article. Dr. Lipman assisted with the drafting of this article. Dr. Roberts has previously provided consultancy to Astra Zeneca and Janssen-Cilag and has received honorarium from Pfizer, Astra Zeneca, and Johnson and Johnson. Dr. Roberts has received unrestricted grants from Janssen-Cilag, Astra Zeneca, and Novartis. Dr. Roberts is funded by a fellowship from the Australian National Health and Medical Research Council of Australia (Australian Based Health Professional Research Fellowship 569917). Dr. Lipman is a consultant to Astra Zeneca and Janssen-Cilag and has received an honorarium from Astra Zeneca, Janssen-Cilag, and Wyeth Australia. Dr. Lipman has received unrestricted grants from Janssen-Cilag, Astra Zeneca, and Novartis.

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© 2013 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins