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