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Pharmacokinetics of Cefazolin and Vancomycin in Infants Undergoing Open-Heart Surgery With Cardiopulmonary Bypass

Ingrande, Jerry MD, MS*; Gutierrez, Kathleen MD; Lemmens, Hendrikus J. MD, PhD; Verma, Archana MD, MBBS; Nicolau, David P. PharmD§; Sutherland, Christina A. BS§; Ramamoorthy, Chandra MD

doi: 10.1213/ANE.0000000000003876
Pediatric Anesthesiology: Original Clinical Research Report
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BACKGROUND: Gram-positive bacteria account for nearly three-quarters of all surgical site infections. Antibiotic prophylaxis against these bacteria with cephalosporins or, in select circumstances, with vancomycin is considered standard of care for prevention of surgical site infections. There is little evidence to describe the optimal dosing regimen for surgical site infection prophylaxis in infants undergoing cardiac surgery, and a great deal of institutional variability exists in dosing prophylactic antibiotics. We designed this study to describe an optimal dose regimen for cephalosporin and vancomycin based on pharmacokinetic evidence for infant open-heart surgery on cardiopulmonary bypass.

METHODS: Two separate cohorts of infants undergoing cardiac surgery with cardiopulmonary bypass were evaluated. Plasma concentrations of vancomycin (cohort 1, N = 10) and cefazolin (cohort 2, N = 10) were measured, and mixed-effects pharmacokinetic models were constructed for each drug. Simulations of various dosing regimens were performed to describe an appropriate dosing regimen necessary to maintain antibiotic concentrations above the susceptibility cutoff for staphylococci.

RESULTS: Both cefazolin and vancomycin plasma concentration versus time profiles were characterized by a 2-compartment model. Subject weight was a significant covariate for V1 for vancomycin. Subject age was a significant covariate for V1 for cefazolin. Cardiopulmonary bypass did not influence concentration versus time profiles. Simulations demonstrated that a 1-hour vancomycin infusion (15 mg·kg−1), repeated every 12 hours and a 10-minute infusion of cefazolin (30 mg·kg−1), repeated every 4 hours maintained plasma concentrations above 4 μg·mL−1 and 16 μg·mL−1, for vancomycin and cefazolin, respectively. Both concentrations are above the minimum inhibitory concentration 90 for most susceptible staphylococci.

CONCLUSIONS: Prophylactic treatment of vancomycin 15 mg·kg−1 infused >1 hour with 12-hour redosing and cefazolin 30 mg·kg−1 infused >10 minutes with 4-hour redosing will maintain serum levels of each antibiotic above the susceptibility cut-offs for susceptible staphylococci in infants undergoing cardiac surgery. Cefazolin levels may be adequate for some, but not all, Gram-negative bacteria. The effect of cardiopulmonary bypass on pharmacokinetics is negligible.

From the *Department of Anesthesiology, University of California, San Diego School of Medicine, San Diego, California

Department of Pediatrics, Division of Infectious Diseases, Stanford University School of Medicine, Stanford, California

Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, California

§Center for Anti-Infective Research and Development, Hartford Hospital, Hartford, Connecticut

Department of Anesthesiology, Perioperative and Pain Medicine, Division of Pediatric Cardiac Anesthesia, Stanford University School of Medicine, Stanford, California.

Published ahead of print 19 September 2018.

Accepted for publication September 19, 2018.

Funding: None.

The authors declare no conflicts of interest.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website.

Clinical Trials Registry: NCT01619982.

Reprints will not be available from the authors.

Address correspondence to Jerry Ingrande, MD, MS, Department of Anesthesiology, University of California, San Diego School of Medicine, 402 Dickinson St, Hillcrest, CA 92103. Address e-mail to jingrande@ucsd.edu.

Copyright © 2018 International Anesthesia Research Society
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