Pharmacokinetics of Daptomycin During Cardiopulmonary Bypass Surgery

This investigation is a prospective, open-label pharmacokinetic study of daptomycin prophylaxis in patients undergoing coronary artery bypass graft surgery without valvular replacement.

Study Overview

• Status: Completed
• Conditions: Staphylococcus Aureus; Surgical Site Infection; Late Effects of Surgery
• Intervention / Treatment: Drug: daptomycin

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.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • California
    • Torrance, California, United States, 90509
      • Harbor-UCLA Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 19 years to 74 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cases; The first 15 subjects enrolled will receive the intervention drug daptomycin as surgical antibiotic prophylaxis.	Drug: daptomycin; 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.; Other Names: Cubicin
No Intervention: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Daptomycin Concentrations at 12, 18, 24, and 48 h	Mean daptomycin concentrations (mcg/ml) at 12, 18, 24, and 48 h	Hospital discharge or 7 days, whichever comes first

Collaborators and Investigators

• Sponsor: Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center
• Collaborators: Western University of Health Sciences; Hartford Hospital; Cubist Pharmaceuticals LLC
• Investigators: Principal Investigator: Loren G Miller, M.D., M.P.H., Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center

Publications and helpful links

General Publications

• Nguyen MH, Eells SJ, Tan J, Sheth CT, Omari B, Flores M, Wang J, Miller LG. Prospective, open-label investigation of the pharmacokinetics of daptomycin during cardiopulmonary bypass surgery. Antimicrob Agents Chemother. 2011 Jun;55(6):2499-505. doi: 10.1128/AAC.01404-10. Epub 2011 Mar 28.

Helpful Links

• Free full text article

Study record dates

Study Major Dates

• Study Start: July 1, 2008
• Primary Completion (Actual): October 1, 2010
• Study Completion (Actual): October 1, 2010

Study Registration Dates

• First Submitted: June 17, 2008
• First Submitted That Met QC Criteria: June 18, 2008
• First Posted (Estimate): June 19, 2008

Study Record Updates

• Last Update Posted (Estimate): August 29, 2016
• Last Update Submitted That Met QC Criteria: July 19, 2016
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Staphylococcus aureus; Antibiotic Prophylaxis; Surgical Wound Infection; Daptomycin; Cardiopulmonary Bypass Surgery
• Additional Relevant MeSH Terms: Pathologic Processes; Infections; Postoperative Complications; Wound Infection; Surgical Wound Infection; Anti-Infective Agents; Anti-Bacterial Agents; Daptomycin
• Other Study ID Numbers: 12903-01; IIS 0003-07-2007 (Other Identifier: Cubist Pharmaceuticals)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Data may be shared upon written request to the principal investigator.