Prospective, Open-Label Investigation of the Pharmacokinetics of Daptomycin during Cardiopulmonary Bypass Surgery

Abstract

As methicillin-resistant Staphylococcus aureus (MRSA) becomes more prevalent, vancomycin is becoming increasingly used as a prophylaxis against surgical-site infections for cardiothoracic surgeries. However, vancomycin administration can be challenging, and the pharmacokinetics of alternative antibiotics in this setting are poorly understood. The primary objective of this investigation was to describe the pharmacokinetics of daptomycin in patients undergoing coronary artery bypass graft surgery. We enrolled 15 patients undergoing coronary artery bypass surgery requiring cardiopulmonary bypass. Each subject was administered a single open-label dose of daptomycin (8 mg/kg of body weight) for surgical prophylaxis. Fourteen daptomycin plasma samples were collected. Safety outcomes between subjects who received daptomycin and 15 control subjects who received the standard-of-care antibiotic were compared. The mean maximal concentration of daptomycin (C max ) was 84.4 ؎ 27.1 g/ml; the mean daptomycin concentration during the cardiopulmonary bypass procedure was 33.2 ؎ 11.4 g/ml and was 30.9 ؎ 12.7 g/ml at sternum closure. Mean daptomycin concentrations at 12, 18, 24, and 48 h were 22.7 ؎ 9.7, 16.2 ؎ 8.2, 12.0 ؎ 4.7, and 3.5 ؎ 2.3 g/ml, respectively. Mean daptomycin concentrations were consistently above the MIC at which 90% of the tested isolates are inhibited (MIC 90 ) for S. aureus and S. epidermidis during the cardiopulmonary bypass procedure. Daptomycin was not associated with surgical-site infections or differences in adverse events compared to findings for control subjects. We found that a single dose of daptomycin at 8 mg/kg was well tolerated and achieved adequate plasma concentrations against common pathogens associated with surgical-site infections after cardiothoracic surgery. Daptomycin may be considered an alternative surgical prophylaxis antibiotic for patients undergoing cardiothoracic bypass surgery who are unable to receive vancomycin.

Study Protocol for a Pilot, Open-Label, Prospective, and Observational Study to Evaluate the Pharmacokinetics of Drugs Administered to Patients during Extracorporeal Circulation; Potential of In Vivo Cytochrome P450 Phenotyping to Optimise Pharmacotherapy

“…Therefore, pharmacokinetics (PK) and pharmacodynamics (PD) of administered drugs can be significantly affected in setting of an extracorporeal circuit. Multiple studies conducted in patients undergoing CPB have reported on altered drug disposition [12,13,14,15]. During cardiac surgeries using CPB, patients undergo major physiological changes including hypothermia, haemodilution, reduced blood flow and pressure, release of stress-reactant hormones, fluid and electrolyte shifts, as well as release of cytokines and nitric oxide.…”