Broad-Spectrum Antibiotic Prophylaxis May Improve Outcomes After Pancreatoduodenectomy: Annals of Surgery, March 2026

Introduction

Pancreatoduodenectomy (Whipple procedure) is a complex surgical operation performed for pancreatic and periampullary diseases. Despite advances in surgical techniques and perioperative care, the procedure continues to carry significant postoperative morbidity, largely driven by infectious complications. Surgical site infections (SSI), intra-abdominal infections, and sepsis frequently arise from postoperative pancreatic fistula (POPF) or biliary contamination, particularly in patients who undergo preoperative biliary drainage. Bacterial colonisation of bile ducts—commonly involving Enterococcus, Klebsiella, and Enterobacter species—increases the risk of postoperative infection and subsequent mortality.

Because infection remains a major contributor to postoperative mortality after pancreatoduodenectomy, perioperative antibiotic prophylaxis is routinely recommended. Traditionally, cephalosporins have been used as standard prophylaxis. However, emerging evidence suggests that these antibiotics may inadequately cover the spectrum of pathogens present in contaminated bile, especially in patients with biliary stents. This has led to increasing interest in broad-spectrum penicillin-based antibiotics, such as piperacillin–tazobactam, which provide enhanced coverage against Gram-negative organisms and Enterococcus species.

Summary of the Meta-analysis

This systematic review and meta-analysis evaluated whether broad-spectrum penicillin-based antibiotics (BS-AB) improve outcomes compared with cephalosporin-based prophylaxis (CE-AB) in patients undergoing pancreatoduodenectomy. The analysis included 12 studies (1 randomized controlled trial and 11 nonrandomized studies) encompassing 12,469 patients, of whom 35.3% received BS-AB and 64.7% received CE-AB.

Broad-spectrum prophylaxis was associated with significantly improved postoperative outcomes. The incidence of surgical site infections was markedly reduced with BS-AB (OR 0.53; 95% CI 0.32–0.86). Similarly, the risk of postoperative pancreatic fistula was lower (OR 0.62; 95% CI 0.47–0.81). Mortality was also significantly reduced in the BS-AB group (OR 0.56; 95% CI 0.34–0.95). Patients receiving broad-spectrum prophylaxis experienced a trend toward shorter hospital stays, approximately 2 days less than those receiving cephalosporins.

Subgroup analysis demonstrated even stronger benefits among patients with preoperative biliary drainage, where broad-spectrum antibiotics significantly reduced SSI, POPF, and mortality.

Conclusion

Broad-spectrum penicillin-based antibiotic prophylaxis appears to reduce infectious complications, pancreatic fistula, and mortality after pancreatoduodenectomy, particularly in patients with biliary stents. These findings suggest that broad-spectrum regimens may represent a new standard for perioperative prophylaxis in pancreatic surgery, though further high-quality randomized trials are needed to confirm these results and balance benefits against risks such as antimicrobial resistance.