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Comment
. 2023 May 9;329(18):1579-1588.
doi: 10.1001/jama.2023.5728.

Piperacillin-Tazobactam Compared With Cefoxitin as Antimicrobial Prophylaxis for Pancreatoduodenectomy: A Randomized Clinical Trial

Michael I D'Angelica  1 , Ryan J Ellis  1   2 , Jason B Liu  2   3 , Brian C Brajcich  2 , Mithat Gönen  1 , Vanessa M Thompson  2 , Mark E Cohen  2 , Susan K Seo  1 , Emily C Zabor  1 , Michele L Babicky  4 , David J Bentrem  5 , Stephen W Behrman  6 , Kimberly A Bertens  7 , Scott A Celinski  8 , Carlos H F Chan  9 , Mary Dillhoff  10 , Matthew E B Dixon  11 , Carlos Fernandez-Del Castillo  12 , Sepideh Gholami  13 , Michael G House  14 , Paul J Karanicolas  15 , Harish Lavu  16 , Shishir K Maithel  17 , John C McAuliffe  18 , Mark J Ott  19 , Bradley N Reames  20 , Dominic E Sanford  21 , Umut Sarpel  22 , Courtney L Scaife  23 , Pablo E Serrano  24 , Travis Smith  25 , Rebecca A Snyder  26 , Mark S Talamonti  27 , Sharon M Weber  28 , Adam C Yopp  29 , Henry A Pitt  2   30 , Clifford Y Ko  2   31   32
Affiliations
Comment

Piperacillin-Tazobactam Compared With Cefoxitin as Antimicrobial Prophylaxis for Pancreatoduodenectomy: A Randomized Clinical Trial

Michael I D'Angelica et al. JAMA. .

Abstract

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 < .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.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr McAuliffe reported receiving nonfinancial support from Loki Therapeutics for providing an advisory role in pancreas cancer therapy research during the conduct of the study and personal fees from Boston Scientific for providing an advisory and educator role outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Participant Flow in a Study of Piperacillin-Tazobactam vs Cefoxitin as Antimicrobial Prophylaxis for Pancreatoduodenectomy
aRandomization stratified by the presence or absence of preoperative biliary stent. Data on screened patients were not collected due to the unfunded, pragmatic nature of the trial. bOther reasons for exclusion in participants randomized to receive piperacillin-tazobactam included drug allergy (n = 2), preoperative steroid use (n = 3), operation changed to different resection (n = 8; 1 duodenal resection, 1 distal gastrectomy, 2 total pancreatectomy, 1 distal pancreatectomy, 1 Puestow procedure, 1 enucleation, 1 liver resection), and accrual closed (n = 2). cOther reasons for exclusion in participants randomized to receive cefoxitin included kidney insufficiency (n = 1), operation changed to different resection (n = 9; 2 total pancreatectomy, 2 distal pancreatectomy, 2 minimally invasive resection, 1 enucleation, 1 central pancreatectomy, 1 liver resection), and accrual closed (n = 2).
Figure 2.
Figure 2.. Risk of Surgical Site Infection for Participant Subgroups
The dotted vertical line represents no association, squares are subgroup-specific odds ratios, and whiskers represent 95% CIs.
See this image and copyright information in PMC

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