Late Effects of Surgery, Staphylococcus Aureus, Surgical Site Infection
Conditions
Keywords
Daptomycin, Antibiotic Prophylaxis, Pharmacokinetics, Surgical Wound Infection, Staphylococcus aureus, Cardiopulmonary Bypass Surgery
Brief summary
This investigation is a prospective, open-label pharmacokinetic study of daptomycin prophylaxis in patients undergoing coronary artery bypass graft surgery without valvular replacement.
Detailed description
Cardiothoracic surgery is a commonly performed procedure in the United States. Many sites previously used cefazolin, an antibiotic, as standard prophylaxis to prevent surgical site infections. However, given most bacteria causing surgical site infections are now resistant to cefazolin, most center are using vancomycin, an alternative antibiotic, as surgical antibiotic prophylaxis. However, some patients cannot take vancomycin, and there are no well studied alternatives to vancomycin for surgical prophylaxis. Therefore, we are studying daptomycin, a newer United States Food and Drug Administration (FDA)-approved antibiotic, as prophylaxis against surgical site infections among patients undergoing cardiothoracic bypass (CPB) with coronary artery bypass graft surgery (CABG). Our study will not be powered to see if daptomycin is as effective as vancomycin at preventing surgical site infections. Instead, the purpose of this study is to validate that adequate levels of antibiotics are present in patients' blood during cardiothoracic bypass surgery. Study subjects in the intervention group will be followed from the time of enrollment in the study until their discharge from the hospital, or up to 7 days following administration of daptomycin, whichever comes first. The first 15 subjects enrolled will receive the intervention drug daptomycin as surgical antibiotic prophylaxis and the following 15 subjects will be enrolled as matched controls and will receive the standard of care surgical prophylaxis per the patient's treating physicians. The controls will undergo monitoring for the same safety outcomes that the patients who received daptomycin will undergo. Subjects enrolled in the intervention group will receive a single intravenous administration of daptomycin 8 milligram (mg)/kilogram (kg) 30-60 minutes prior to surgery (incision). Blood samples will be drawn by the Research Coordinator. A total of 85 (milliliters) mL of blood will be collected during the study. A total of 14 blood samples will be collected: 4 samples at the Pre-CPB phase, 4 samples during the CPB procedure, and 6 samples Post-CPB. Total plasma daptomycin concentrations will be determined utilizing standard high-performance liquid chromatography techniques. Plasma concentrations will be compared to the minimum inhibitory concentrations (MIC90) of the common pathogens involved in surgical site infections, specifically Staphylococcus aureus and coagulase negative Staphylococcus.
Interventions
DRUGdaptomycin
Subjects enrolled in the intervention group will receive a single intravenous administration of daptomycin 8 mg/kg 30-60 minutes prior to surgery (incision). The 500 mg vial will be reconstituted with 10 mL of 0.9% normal saline (NS) and further diluted in 50 mL of 0.9% NS to be given over a 30 minute infusion.
Sponsors
Cubist Pharmaceuticals LLC, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Hartford Hospital
Western University of Health Sciences
Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
19 Years to 74 Years
Healthy volunteers
No
Inclusion criteria
* Hospitalized patients, awaiting scheduled elective coronary artery bypass graft (CABG) surgery without valve replacement surgery * Age \> 18 years and \< 75 years * BMI between 18.5 and 35.0 kg/meters-squared * Crcl \> 50 ml/minute calculated based on Cockcroft Gault equation * No known active or suspected infection(s) * Ability to complete the informed consent process * Negative pregnancy test (for women of childbearing age)
Exclusion criteria
* History of allergic reaction to daptomycin or components of daptomycin * Receipt of daptomycin within 7 days prior to the surgery * Elevated CPK levels (defined as \> 3 times the upper limits of known normal) * History of myopathy or complaints consistent with myopathy * Current or planned use of mycophenolate mofetil, mycophenolic acid, or tobramycin during the subjects' current hospitalization (all of which are known to interact with daptomycin) * Inability to complete the informed consent process because of problems with mental capacity * Pregnancy and/or breast feeding
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Daptomycin Concentrations at 12, 18, 24, and 48 h | Hospital discharge or 7 days, whichever comes first | Mean daptomycin concentrations (mcg/ml) at 12, 18, 24, and 48 h |
Countries
United States
Participant flow
Recruitment details
From July 2008 to August 2010, we recruited subjects undergoing CABG surgery at Harbor-UCLA Medical Center, a 400-bed tertiary-care county hospital.
Participants by arm
| Arm | Count |
|---|---|
| Cases The first 15 subjects enrolled will receive the intervention drug daptomycin as surgical antibiotic prophylaxis. | 15 |
| Controls 15 subjects will be enrolled in the standard of care antibiotic group to serve as the controls. Controls will receive no experimental medications or treatments. The purpose of enrolling control patients was to serve as a reference group for intervention patients. Specifically cases and controls will be compared for changes in commonly collected hematologic parameters, creatinine, and CPK. Additionally, parameters collected during anesthesia will be compared. Controls will be matched to the intervention group by age (+/- 10 years), gender, and ethnicity. | 15 |
| Total | 30 |
Baseline characteristics
| Characteristic | Controls | Cases | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 3 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 12 Participants | 24 Participants |
| Age, Continuous | 57 years STANDARD_DEVIATION 8.7 | 56 years STANDARD_DEVIATION 8 | 56 years STANDARD_DEVIATION 7.4 |
| Region of Enrollment United States | 15 participants | 15 participants | 30 participants |
| Sex: Female, Male Female | 2 Participants | 3 Participants | 5 Participants |
| Sex: Female, Male Male | 13 Participants | 12 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 15 | 0 / 15 |
| serious Total, serious adverse events | 0 / 15 | 3 / 15 |
Outcome results
Primary
Mean Daptomycin Concentrations at 12, 18, 24, and 48 h
Mean daptomycin concentrations (mcg/ml) at 12, 18, 24, and 48 h
Time frame: Hospital discharge or 7 days, whichever comes first
Population: Based on sample sizes from previously published studies on antibiotic pk for CABG surgery.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cases | Mean Daptomycin Concentrations at 12, 18, 24, and 48 h | mean daptomycin concentration at 12 hours | 22.7 mcg/ml | Standard Deviation 9.7 |
| Cases | Mean Daptomycin Concentrations at 12, 18, 24, and 48 h | mean daptomycin concentration at 18 hours | 16.2 mcg/ml | Standard Deviation 8.2 |
| Cases | Mean Daptomycin Concentrations at 12, 18, 24, and 48 h | mean daptomycin concentration at 24 hours | 12.0 mcg/ml | Standard Deviation 4.7 |
| Cases | Mean Daptomycin Concentrations at 12, 18, 24, and 48 h | mean daptomycin concentration at 48 hours | 3.5 mcg/ml | Standard Deviation 2.3 |