Piperacillin-Tazobactam Compared With Cefoxitin as Antimicrobial Prophylaxis for Pancreatoduodenectomy
Authors: D’Angelica Michael I. , Ellis Ryan J. , Liu Jason B. , Brajcich Brian C. , Gönen Mithat , Thompson Vanessa M. , Cohen Mark E. , Seo Susan K. , Zabor Emily C. , Babicky Michele L. , Bentrem David J. , Behrman Stephen W. , Bertens Kimberly A. , Celinski Scott A. , Chan Carlos H. F. , Dillhoff Mary , Dixon Matthew E. B. , Fernandez-del Castillo Carlos , Gholami Sepideh , House Michael G. , Karanicolas Paul J. , Lavu Harish , Maithel Shishir K. , McAuliffe John C. , Ott Mark J. , Reames Bradley N. , Sanford Dominic E. , Sarpel Umut , Scaife Courtney L. , Serrano Pablo E. , Smith Travis , Snyder Rebecca A. , Talamonti Mark S. , Weber Sharon M. , Yopp Adam C. , Pitt Henry A. , Ko Clifford Y. 
Published: April 2023

Importance

Despite improvements in perioperative mortality, the incidence of postoperative surgical site infection (SSI) remains high after pancreatoduodenectomy. The effect of broad-spectrum antimicrobial surgical prophylaxis in reducing SSI is poorly understood.

Objective

To define the effect of broad-spectrum perioperative antimicrobial prophylaxis on postoperative SSI incidence compared with standard care antibiotics.

Design, Setting, and Participants

Pragmatic, open-label, multicenter, randomized phase 3 clinical trial at 26 hospitals across the US and Canada. Participants were enrolled between November 2017 and August 2021, with follow-up through December 2021. Adults undergoing open pancreatoduodenectomy for any indication were eligible. Individuals were excluded if they had allergies to study medications, active infections, chronic steroid use, significant kidney dysfunction, or were pregnant or breastfeeding. Participants were block randomized in a 1:1 ratio and stratified by the presence of a preoperative biliary stent. Participants, investigators, and statisticians analyzing trial data were unblinded to treatment assignment.

Intervention

The intervention group received piperacillin-tazobactam (3.375 or 4 g intravenously) as perioperative antimicrobial prophylaxis, while the control group received cefoxitin (2 g intravenously; standard care).

Main Outcomes and Measures

The primary outcome was development of postoperative SSI within 30 days. Secondary end points included 30-day mortality, development of clinically relevant postoperative pancreatic fistula, and sepsis. All data were collected as part of the American College of Surgeons National Surgical Quality Improvement Program.

Results

The trial was terminated at an interim analysis on the basis of a predefined stopping rule. Of 778 participants (378 in the piperacillin-tazobactam group [median age, 66.8 y; 233 {61.6%} men] and 400 in the cefoxitin group [median age, 68.0 y; 223 {55.8%} men]), the percentage with SSI at 30 days was lower in the perioperative piperacillin-tazobactam vs cefoxitin group (19.8% vs 32.8%; absolute difference, −13.0% [95% CI, −19.1% to −6.9%];P &amp;lt; .001). Participants treated with piperacillin-tazobactam, vs cefoxitin, had lower rates of postoperative sepsis (4.2% vs 7.5%; difference, −3.3% [95% CI, −6.6% to 0.0%];P = .02) and clinically relevant postoperative pancreatic fistula (12.7% vs 19.0%; difference, −6.3% [95% CI, −11.4% to −1.2%];P = .03). Mortality rates at 30 days were 1.3% (5/378) among participants treated with piperacillin-tazobactam and 2.5% (10/400) among those receiving cefoxitin (difference, −1.2% [95% CI, −3.1% to 0.7%];P = .32).

Conclusions and Relevance

In participants undergoing open pancreatoduodenectomy, use of piperacillin-tazobactam as perioperative prophylaxis reduced postoperative SSI, pancreatic fistula, and multiple downstream sequelae of SSI. The findings support the use of piperacillin-tazobactam as standard care for open pancreatoduodenectomy.

Trial Registration

ClinicalTrials.gov Identifier:NCT03269994