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Antimicrobial Agents and Chemotherapy, September 2002, p. 3026-3030, Vol. 46, No. 9
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.9.3026-3030.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Antibiotic Pharmacodynamics in Surgical Prophylaxis: an Association between Intraoperative Antibiotic Concentrations and Efficacy

Sheryl A. Zelenitsky,^1,2,3,4* Robert E. Ariano,^1,2,3 Godfrey K. M. Harding,^2,4,5 and Richard E. Silverman^2,6

Faculties of Pharmacy,¹ Medicine, University of Manitoba,² Departments of Pharmacy,³ Infectious Diseases,⁴ Clinical Microbiology,⁵ Surgery, St. Boniface General Hospital, Winnipeg, Manitoba, Canada⁶

Received 24 September 2001/ Returned for modification 25 March 2002/ Accepted 18 June 2002

The objective of this study was to characterize the relationship between gentamicin concentrations during surgery and the development of wound infection following colorectal operations. Despite decades of research in surgical prophylaxis, the relationship between intraoperative antibiotic concentrations and postoperative infection and the concentrations required for effective prophylaxis have not been established. A pharmacodynamic analysis was conducted using data from a previous prospective, randomized, double-blind clinical study which compared two dosage regimens of gentamicin plus metronidazole for prophylaxis in connection with elective colorectal surgery. Univariate and multivariate analyses of risk factors for postoperative wound infection were conducted, and the relationship between intraoperative gentamicin concentrations and surgical outcome was characterized. The gentamicin concentration at the time of surgical closure was one of the strongest independent risk factors for infection (P = 0.02), along with the presence of diabetes mellitus (P = 0.02), stoma (P = 0.04), and advanced age (P = 0.05). Gentamicin concentrations at closure of less than 0.5 mg/liter were associated with an infection rate of 80% (representing 8 of 10 patients with concentrations below that level) (P = 0.003). Receiver operating characteristic curve analysis identified a critical closure concentration of 1.6 mg/liter for effective surgical prophylaxis (P = 0.002; sensitivity, 70.8%; specificity, 65.9%). This study provides new and important information on antibiotic pharmacodynamics in surgical prophylaxis. It demonstrates the critical effect of the antibiotic concentration at closure on wound infection and suggests a significant association between the concentration and other well-established risk factors, like the timing of preoperative antibiotic administration and surgery duration.

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* Corresponding author. Mailing address: Division of Clinical Sciences and Practice, Faculty of Pharmacy, University of Manitoba, Winnipeg, Manitoba, Canada R3T 2N2. Phone: (204) 474-8414. Fax: (204) 474-7617. E-mail: zelenits{at}ms.umanitoba.ca.

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Antimicrobial Agents and Chemotherapy, September 2002, p. 3026-3030, Vol. 46, No. 9
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.9.3026-3030.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

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