Lack of Pharmacokinetic Basis of Weight-Based Dosing and Intra-Operative Re-Dosing with Cefazolin Surgical Prophylaxis in Obese Patients: Implications for Antibiotic Stewardship.

Abstract

Traditionally, there have been uniform antibiotic dosing guidelines for prophylaxis for clean-clean-contaminated surgery in both non-obese and obese adults. All other factors predisposing to surgical site infections (SSIs) being equal, over time, the preferred drug is cefazolin. The usual dose, given immediately pre-procedure, has been 1\u2009g intravenously (IV) in non-penicillin-allergic patients, which has been highly effective, Recently, it has become common practice to use high-dose cefazolin; i.e., 3\u2009g IV, in obese patients. This article reviews the literature on high-dose cefazolin prophylactic regimens in the obese from a pharmacokinetic (PK) point of view. There are no comparative studies to support this approach, which is based largely on the theory more must be better. Weight-based dosing of cefazolin in the obese is flawed, because it does not take into account PK factors, which are critical in the obese. Cefazolin is a water-soluble (hydrophilic) antibiotic that does not penetrate adipose tissue regardless of IV dose. Importantly, adipose tissue is not a valid target tissue in clean-clean-contaminated SSI prophylaxis, as it does not become infected. Higher doses result in proportionately higher serum/non-adipose tissue concentrations, but adipose tissue concentrations are unaffected. Cefazolin displays time-dependent killing kinetics so that as long as serum/tissue concentrations are above the minimum inhibitory concentration (MIC) of SSI pathogens, there is no enhanced killing with higher concentrations relative to concentration-dependent antibiotics. Taking into account PK principles, a cefazolin 1\u2009g IV bolus results in peak serum concentrations of ∼185\u2009mcg/mL, provides at least six hours of intra-operative protection, aside from any post-antibiotic effects, and eliminates any rationale for intra-operative re-dosing for procedures lasting six hours or less. Some have argued that a cefazolin 3\u2009g IV dose in the obese does not matter, as more must necessarily be better. However, from an antibiotic stewardship program (ASP) perspective, unneeded antibiotics are unnecessary. Moreover, the costs of cefazolin 1\u2009g (IV push) at $0.75 versus 2\u2009g (IV piggyback) at $ 6.83 can be significant in large centers using cefazolin prophylaxis for cardiothoracic, orthopedic, obstetric/gynecology, and bariatric surgery. Excessive antibiotics also expose the patient to potential adverse effects; i.e., Clostridium difficile. There is no dose-dependent or duration of exposure effect on resistance with one or two pre-operative or intra-operative doses. Well-done PK-based studies in obese patients clearly demonstrate the lack of benefit of using a 3-g dose or intra-operative re-dosing and show no incremental increase in adipose tissue concentrations with high doses. From an ASP point of view, antibiotic dosing recommendations should be reviewed and revised on the basis of PK principles that indicate that weight-based dosing has no basis for pre-operative prophylaxis in obese patients.