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

Aryan J. Rahbar, Thomas P. Lodise, Prasad Abraham, Alissa Lockwood, Manjunath P. Pai, John Patka, Marina Rabinovich, Karen Curzio, Katleen Chester, Brian Williams, Bryan Morse, Mitchell Chaar, Vanthida Huang, Jeffrey Salomone

Research output: Contribution to journalArticle

1 Scopus citations

Abstract

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 1 g infused over 4 hours every 8 hours 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 1 g, infused over 4 hours, every 8 hours 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 1 g, infused over 4 hours, administered every 8 hours, conferred >90% probabilities of achieving 30-50% time greater than the minimum inhibitory concentration (30-50% T>MIC) for MICs ≤2 mg/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 2 mg/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 2 mg/L.

Original languageEnglish (US)
Pages (from-to)675-682
Number of pages8
JournalSurgical Infections
Volume17
Issue number6
DOIs
Publication statusPublished - Dec 1 2016

    Fingerprint

Keywords

  • carbapenem
  • doripenem
  • pharmacodynamics
  • pharmacokinetics
  • sepsis
  • trauma

ASJC Scopus subject areas

  • Surgery
  • Microbiology (medical)
  • Infectious Diseases

Cite this

Rahbar, A. J., Lodise, T. P., Abraham, P., Lockwood, A., Pai, M. P., Patka, J., ... Salomone, J. (2016). Pharmacokinetic and Pharmacodynamic Evaluation of Doripenem in Critically Ill Trauma Patients with Sepsis. Surgical Infections, 17(6), 675-682. https://doi.org/10.1089/sur.2015.113