title: Pharmacokinetic and Pharmacodynamic Evaluation of Doripenem in Critically Ill Trauma Patients with Sepsis.
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.
  
  
  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.
authors.affiliation: 1 University Medical Center of Southern Nevada , Las Vegas, Nevada.
authors.forename: Aryan J
authors.initials: AJ
authors.lastname: Rahbar
authors.affiliation: 2 Albany College of Pharmacy and Health Sciences , Albany, New York.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Lodise
authors.affiliation: 3 Grady Health System , Atlanta, Georgia .
authors.forename: Prasad
authors.initials: P
authors.lastname: Abraham
authors.affiliation: 4 Parkland Hospital and Health System , Dallas, Texas.
authors.forename: Alissa
authors.initials: A
authors.lastname: Lockwood
authors.affiliation: 2 Albany College of Pharmacy and Health Sciences , Albany, New York.
authors.forename: Manjunath P
authors.initials: MP
authors.lastname: Pai
authors.affiliation: 3 Grady Health System , Atlanta, Georgia .
authors.forename: John
authors.initials: J
authors.lastname: Patka
authors.affiliation: 3 Grady Health System , Atlanta, Georgia .
authors.forename: Marina
authors.initials: M
authors.lastname: Rabinovich
authors.affiliation: 5 Emory Saint Joseph's Hospital , Atlanta, Georgia .
authors.forename: Karen
authors.initials: K
authors.lastname: Curzio
authors.affiliation: 3 Grady Health System , Atlanta, Georgia .
authors.forename: Katleen
authors.initials: K
authors.lastname: Chester
authors.affiliation: 6 University of Texas Southwestern , Dallas, Texas.
authors.forename: Brian
authors.initials: B
authors.lastname: Williams
authors.affiliation: 7 Emory University School of Medicine , Atlanta, Georgia .
authors.forename: Bryan
authors.initials: B
authors.lastname: Morse
authors.affiliation: 8 Jersey City Medical Center , Jersey City, New Jersey.
authors.forename: Mitchell
authors.initials: M
authors.lastname: Chaar
authors.affiliation: 9 Midwestern University , Glendale, Arizona.
authors.forename: Vanthida
authors.initials: V
authors.lastname: Huang
authors.affiliation: 10 University of Arizona College of Medicine , Tucson, Arizona.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Salomone
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D015780:Carbapenems / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D016638:Critical Illness; D000077726:Doripenem; D005260:Female; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D011446:Prospective Studies; D018805:Sepsis / Q000150:complications / Q000188:drug therapy; D014947:Wounds and Injuries / Q000150:complications*
chemical_list: D000900:Anti-Bacterial Agents; D015780:Carbapenems; D000077726:Doripenem
keywords: carbapenem; doripenem; pharmacodynamics; pharmacokinetics; sepsis; trauma