Pharmacokinetic and Pharmacodynamic Evaluation of Doripenem in Critically Ill Trauma Patients with Sepsis

Background: Doripenem is approved by the Food and Drug Administration for the treatment of patients with complicated intra-abdominal infections and complicated urinary tract infections. While studies have described the pharmacokinetics/pharmacodynamics (PK/PD) of doripenem in the critically ill, no study has described the probability of target attainment profile among trauma patients with sepsis. Patients and Methods: This study was a prospective, open-label, pharmacokinetic study in the surgical intensive care unit (SICU) at Grady Health System. Thirty trauma patients with sepsis admitted to the SICU received doripenem 1g infused over 4hours every 8hours for three doses. Blood samples were taken just before and after the third dose. A two-compartment model was fit to the data using non-parametric population PK modeling software. Embedded with the final PK model, a Monte Carlo Simulations (MCS) was performed to determine the PK/PD profile of doripenem 1g, infused over 4hours, every 8hours after administration of the first and fourth doses. Results: Overall, the model fit the data well, and mean (standard deviation) clearance and volume of the central compartment were 16.9 (11.4) L/h and 28.5 (16.0) L, respectively. In the MCS analyses, doripenem 1g, infused over 4hours, administered every 8hours, conferred > 90% probabilities of achieving 30-50% time greater than the minimum inhibitory concentration (30-50% T > MIC) for MICs 2mg/L after infusion of both the first and fourth doses. The MCS indicated that more intensive doripenem dosing schemes should be considered for organisms with MIC values in excess of 2mg/L. Conclusions: This is the first study to describe the doripenem PK/PD in critically ill patients with trauma. Among these patients, the MCS analyses suggest that current dosing strategies may be ineffective when the MIC value for the infecting pathogen is expected to be above 2mg/L.