Pharmacokinetic and Pharmacodynamic Evaluation of Doripenem in Critically Ill Trauma Patients

Understanding the pharmacokinetic (PK)/pharmacodynamic (PD) characteristics of an antibiotic can provide insight into developing appropriate dosing regimens. It is even more imperative at the present time to maximize PK/PD parameters since there are no new novel antimicrobial agents to treat resistant gram-negative infections. This approach allows us to achieve superior PD parameters and treat bacteria that would have been resistant to standard dosing due to higher minimum inhibitory concentrations (MICs).

Doripenem exhibits time-dependent bactericidal activity and the pharmacodynamic parameter predicting clinical and bacteriologic outcomes is the percentage of the dosing interval that free drug concentrations remain above the minimum inhibitory concentration (T > MIC) of the infecting pathogen Sepsis is known to influence drug pharmacokinetics and pharmacodynamics as a result of changes in hemodynamics, capillary permeability, third spacing, acid-base status, serum proteins, and organ function. Moreover, trauma patients tend to be younger with fewer comorbidities. They are hypermetabolic and are often given aggressive fluid resuscitation resulting in increased renal clearance of drugs and a larger volume of distribution. As a consequence of these differences in PK parameters, the calculated PD parameters will likely differ resulting in sub-optimal T> MIC. For time-dependent antibacterial agents such as doripenem, the T > MIC is one of the most important pharmacodynamic parameters in predicting clinical efficacy, therefore it is imperative to evaluate the PK parameters in this particular population.

Inclusion criteria

• Patients are 18 years of age or older
• Admitted to Emory surgical intensive care unit (ICU) service
• Have a diagnosis of sepsis that requires empiric antimicrobial therapy
• Obtained written informed consent from the patient or a first-degree relative if the patient is unable to give informed consent due to his/her medical condition prior to initiation of any study procedure

Exclusion criteria

• Surgical ICU length of stay less than 24 hours
• Acute or chronic renal dysfunction (urine output less than 0.5 mL/kg/hr or calculated creatinine clearance of less than 50 mL/min)
• Pregnancy
• Known allergy to beta-lactam antibiotics
• Non-English-speaking patients