Sepsis
Conditions
Keywords
Pharmacokinetics, Pharmacodynamics, Doripenem, Trauma, sepsis, Trauma patients with sepsis
Brief summary
The study hypothesis is to measure how the drug doripenem is cleared from the body of critically ill trauma patients. The investigators will measure blood drug concentrations and calculate how much the drug distributes in the body and how fast it is removed from the body. There is little information on how drugs are cleared in critically ill patients and the wrong dose of a drug could make it ineffective. The investigators will use this information to predict the most reasonable dose to treat infections effectively in these patients.
Detailed description
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.
Interventions
DRUGDoripenem
Doripenem 1 gm administered over 4 hours X 3 doses
Sponsors
Ortho-McNeil Janssen Scientific Affairs, LLC
Emory University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Volume of Distribution (Vd) | After 3rd dose of study medication | The Volume of distribution is the calculated volume that the given amount of drug is uniformly distributed in the body to achieve a particular concentration |
| Clearance (CL) | After 3rd dose of study medication | Clearance is the volume of drug removed from the body per unit of time (hrs). |
| Elimination Constant (ke) | after 3rd dose of study drug | The elimination rate constant of a drug from the central compartment |
Countries
United States
Participant flow
Recruitment details
Patients recruited from April 2010 to July 2011. All patients were admitted to the Surgical ICU during the study period
Participants by arm
| Arm | Count |
|---|---|
| Doripenem Group Patients will receive doripenem 1 gm IV over 4 hours X 3 doses for the empiric treatment of an infection | 30 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Protocol Violation | 1 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Doripenem Group |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 5 Participants |
| Age, Categorical Between 18 and 65 years | 25 Participants |
| Age, Continuous | 43.6 years STANDARD_DEVIATION 15 |
| Region of Enrollment United States | 30 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 30 |
| serious Total, serious adverse events | 8 / 30 |
Outcome results
Primary
Clearance (CL)
Clearance is the volume of drug removed from the body per unit of time (hrs).
Time frame: After 3rd dose of study medication
Population: Patients that completed the study and did not have atypical variations in the measurement of serum concentrations were included in the final evaluation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Doripenem Group | Clearance (CL) | 16.94 liters per hour | Standard Deviation 11.4 |
Primary
Elimination Constant (ke)
The elimination rate constant of a drug from the central compartment
Time frame: after 3rd dose of study drug
Population: Patients that completed the study and did not have atypical variations in the measurement of serum concentrations were included in the final evaluation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Doripenem Group | Elimination Constant (ke) | 1.47 per hour | Standard Deviation 2.24 |
Primary
Volume of Distribution (Vd)
The Volume of distribution is the calculated volume that the given amount of drug is uniformly distributed in the body to achieve a particular concentration
Time frame: After 3rd dose of study medication
Population: Patients that completed the study and did not have atypical variations in the measurement of serum concentrations were included in the final evaluation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Doripenem Group | Volume of Distribution (Vd) | 28.52 liters | Standard Deviation 16.01 |