Perioperative antibiotic prophylaxis in pancreatoduodenectomy: toward a new standard, but questions remain

Postoperative surgical site infections (SSIs) remain among the most significant contributors to morbidity following pancreatoduodenectomy (PD). While advances in operative technique, anesthesia, and postoperative care have lowered early mortality rates, major complication rates remain above 30%, with infectious complications representing the most common and clinically impactful category (1). SSIs, often associated with or compounded by postoperative pancreatic fistula (POPF), contribute to prolonged hospitalization, delayed return to baseline function, delayed adjuvant therapy initiation, and even worse long-term survival (2,3). These facts underscore why prevention of SSIs remains a major quality focus for high-volume pancreatic surgery centers. The burden of infectious complications after PD has far-reaching implications beyond the immediate postoperative course. Multiple large series and registry analyses have shown that SSIs, intra-abdominal abscesses, and cholangitis following PD are associated with increased hospital costs, more frequent intensive care utilization, and readmission rates exceeding 20% (4,5). These complications also delay the initiation of adjuvant chemotherapy in patients with pancreatic ductal adenocarcinoma, a factor independently associated with worse disease-specific survival (4,6). Therefore, perioperative antibiotic strategy in PD is not merely a technical or pharmacologic choice—it has direct implications for oncologic outcomes and healthcare resource allocation.

Harnoss et al. add to a growing body of evidence supporting the use of broad-spectrum, penicillin-based prophylaxis—specifically piperacillin-tazobactam—as the preferred perioperative antibiotic regimen for open PD (7). Their meta-analysis and systematic review includes 11 non-randomized clinical trials and the landmark ACS NSQIP randomized trial by D’Angelica et al., which demonstrated a 13% absolute reduction in SSI rates, along with reductions in POPF and sepsis, when using piperacillin-tazobactam instead of cefoxitin (8). Importantly, these benefits were observed in patients both with and without preoperative biliary stents, though the magnitude of benefit was greater among stented patients—likely reflecting improved coverage against organisms such as Enterococcus, Klebsiella, and Pseudomonas.

Why piperacillin-tazobactam makes sense for antibiotic prophylaxis in PD

It is also important to consider that the spectrum of organisms encountered in PD patients has shifted over time. Widespread preoperative stenting and more frequent endoscopic interventions have led to a higher prevalence of multidrug-resistant Gram-negative organisms and vancomycin-resistant Enterococcus in bile cultures. Several studies have highlighted that nearly half of bile cultures from stented patients show resistance to standard cephalosporin prophylaxis (9,10). This changing microbiologic landscape strengthens the argument for broader empiric coverage in this population.

The rationale for broad-spectrum coverage is rooted in the altered biliary microbiology of many PD patients. Preoperative biliary drainage—often performed to address jaundice or cholangitis—introduces enteric organisms into the biliary tree, leading to colonization with multidrug-resistant Gram-negative bacilli and Enterococcus species (11). Cephalosporin-based regimens, such as cefoxitin, offer suboptimal coverage for these organisms, whereas piperacillin-tazobactam provides reliable empiric coverage.

Observational studies have consistently shown that the pathogens cultured from bile at the time of PD are frequently resistant to standard cephalosporins (12). The NSQIP trial provided high-level evidence that empiric coverage with piperacillin-tazobactam translates into clinically meaningful reductions in SSI and POPF, and Harnoss et al. corroborate this in a broader real-world context. These findings mirror data from Steffani et al., who demonstrated that extended prophylaxis was associated with fewer major complications in stented patients when the intraoperative pathogens were fully covered by the prophylactic regimen (13). The question of prophylaxis duration is particularly pressing in the era of antimicrobial stewardship. While the standard ≤24-hour regimen is supported by multiple guidelines for clean-contaminated abdominal procedures, PD occupies a unique position because of its complex biliary-enteric reconstruction and high bacterial load in the operative field (14). Some centers have adopted a selective approach, using intraoperative bile cultures to tailor postoperative antibiotics for patients with resistant organisms, a strategy that could be tested in multicenter randomized trials.

Unanswered questions

While the evidence strongly supports piperacillin-tazobactam for perioperative prophylaxis in open PD, several important questions remain before its application can be considered universally resolved. The path to universal change will require both top-down and bottom-up efforts. National societies and infection-prevention bodies must be willing to update perioperative antibiotic guidelines to reflect high-quality PD-specific evidence. At the same time, individual institutions must engage their antimicrobial stewardship committees early to develop locally tailored protocols that integrate current evidence with local resistance patterns. Pilot implementation projects could use quality-improvement frameworks to monitor both SSI rates and resistance trends, providing real-world feedback that can guide sustained adoption.

Duration of prophylaxis

Both the Harnoss and NSQIP trials adhered to a ≤24-hour prophylaxis duration, consistent with current SCIP guidelines (7,8). Yet Steffani et al. and others have examined extended postoperative courses—particularly in stented patients—and found reductions in organ-space infections (13). However, meta-analyses indicate that such benefits may be limited to patients with preoperative stents, and gains must be balanced against the risk of fostering resistance, particularly among Enterococcus species.

Applicability to robotic and minimally invasive PD

The current high-level evidence applies exclusively to open PD. Robotic-assisted PD introduces different operative dynamics—longer operative times, pneumoperitoneum, and altered exposure—that may affect SSI risk and antibiotic pharmacokinetics. Without prospective data, it remains unclear whether the same prophylactic regimen and duration are optimal in this setting. Ultimately, the decision to adopt piperacillin-tazobactam as standard prophylaxis for PD should not be viewed as an isolated intervention but as part of a comprehensive perioperative infection-prevention strategy. This includes meticulous surgical technique, optimized glycemic control, early mobilization, and careful drain management. When embedded within such a multimodal strategy, antibiotic optimization has the potential to significantly reduce morbidity, shorten hospital stays, and improve long-term oncologic outcomes. The challenge for the hepatopancreatobiliary surgical community will be to translate this robust evidence base into consistent practice while remaining vigilant stewards of our most effective antimicrobial agents.

Universal adoption

Even with robust trial data, translating evidence into universal practice is challenging. Institutional inertia, antimicrobial stewardship concerns, local resistance patterns, and cost considerations all influence adoption speed. Tailoring empiric regimens to local microbiology may be necessary, especially in centers with high rates of piperacillin-tazobactam-resistant Enterococcus.

The way forward

Incorporating piperacillin-tazobactam into PD protocols—particularly for stented patients—represents a rational, evidence-based step forward. However, adoption should be accompanied by institutional protocols specifying appropriate timing (within 60 minutes of incision) and duration (≤24 hours, pending further evidence), with surveillance systems to track postoperative microbiology and resistance trends.

Future research priorities include

• Randomized trials to define optimal duration, particularly for high-risk subgroups, including the currently accruing SPARROW trial (NCT05784311).
• Dedicated studies assessing efficacy in robotic PD.
• Integration of microbiome and resistance surveillance into surgical quality collaboratives.
• Evaluation of cost-effectiveness and stewardship impact at the institutional and national levels.

Conclusions

The accumulating data make a persuasive case for broad-spectrum, penicillin-based perioperative prophylaxis in PD, especially for patients with preoperative biliary stents. While unanswered questions remain, particularly regarding optimal duration and application to minimally invasive PD, the weight of current evidence should prompt reconsideration of existing guidelines. As with any antimicrobial intervention, implementation must balance short-term gains in infectious outcomes with long-term stewardship goals to preserve antibiotic efficacy for future patients.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, HepatoBiliary Surgery and Nutrition. The article has undergone external peer review.

Peer Review File: Available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-604/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2025-604/coif). The authors have no conflicts of interest to declare.

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