Editorial
April 20, 2023
Informing a Rational Approach to Antimicrobial Prophylaxis in Open Pancreatoduodenectomy
Anthony Charles, Preeti N. Malani
JAMA. 2023;329(18):1556-1557. doi:10.1001/jama.2023.6275
Despite numerous advances in perioperative care, surgical site infection (SSI) remains a frequent complication after major abdominal surgery, with gastrointestinal procedures among the highest risk for infection.1Besides the increased length of stay and overall costs of care, SSIs are the most common indication for readmission after surgery. Antimicrobial prophylaxis given during the perioperative period is an essential, evidence-based aspect of SSI prevention. The choice of prophylactic regimen in patients undergoing a surgical procedure should include an agent effective against the most likely infecting organisms.2
Pancreatoduodenectomy is a technically complex procedure with substantial associated morbidity and mortality. Infectious complications have been reported to occur in as many as 30% of patients following open pancreatoduodenectomy.3,4 Biliary colonization that arises from preoperative procedures for biliary drainage closely predicts infectious complications following pancreatoduodenectomy.5 Besides biliary intervention, nutritional reserve and biliary or pancreatic anastomotic leaks are common factors linked to developing infectious complications following pancreatoduodenectomy. Current guidelines recommend first- or second-generation cephalosporins for perioperative prophylaxis during pancreatoduodenectomy. However, given the unique risks of infection after pancreatoduodenectomy, there may be a role for using broader-spectrum agents for routine surgical prophylaxis.
In this issue of JAMA, D’Angelica and colleagues6 report the findings of an open-label, multicenter randomized trial that included 778 patients from 26 sites across the US and Canada between November 2017 and August 2021. Patients undergoing open pancreatoduodenectomy were randomized to receive either piperacillin-tazobactam (n = 378) or cefoxitin (current standard care; n = 400) for perioperative prophylaxis. The primary outcome was postoperative SSI within 30 days. The trial was terminated after an interim analysis based on a predefined stopping rule.
The results showed that the postoperative SSI rate was significantly reduced among patients receiving piperacillin-tazobactam as antimicrobial prophylaxis (75/378 [19.8%]) compared with cefoxitin (131/400 [32.8%]). The difference between groups remained when subdivided into superficial SSI (3.4% vs 9.5%; odds ratio [OR], 0.34 [95% CI, 0.20-0.58]) and organ/space SSI (14.3% vs 22.8%; OR, 0.57 [95% CI, 0.40-0.81]), but not deep incisional SSI (n = 2; 0.5% vs 0.5%). Patients treated with piperacillin-tazobactam, compared with cefoxitin, also had lower rates of postoperative sepsis (4.2% vs 7.5%; OR, 0.55 [95% CI, 0.32-0.92]), Clostridiodes difficile colitis (0.3% vs 3.5%; OR, 0.07 [95% CI, 0.01-0.63]), and postoperative pancreatic fistula (12.7% vs 19.0%; OR, 0.62 [95% CI, 0.40-0.96]). There was no significant difference in 30-day mortality between the 2 groups (1.3% in the piperacillin-tazobactam group and 2.5% in the cefoxitin group). The authors concluded that the results support the routine use of piperacillin-tazobactam for perioperative prophylaxis during open pancreatoduodenectomy.
Although the results reported by D’Angelica et al6 are practice-changing, the study also has several potential limitations. First, intraoperative and postoperative culture data were absent. Previous studies have noted that the most common organisms isolated from patients undergoing pancreatoduodenectomy were Enterococcus, Escherichia coli, and Klebsiella species.7 Other encountered organisms included Pseudomonas and Enterobacter species. Microbiological data could have provided further evidence for a causal link between the antimicrobial agent used for prophylaxis and decreased SSI risk. Second, the finding that the use of piperacillin-tazobactam significantly reduces clinically relevant postoperative pancreatic fistula is meaningful. However, the underlying mechanism for this finding proffered by the authors in which coverage against Enterococcus species, altering the microbial environment of the reconstruction and facilitating healing, is highly speculative. Third, the American College of Surgeons National Surgical Quality Improvement Program registry is subject to misclassification, particularly regarding reporting complications for patients undergoing pancreatectomy.8 The utility of National Surgical Quality Improvement Program is only as strong as the consistency, completeness, and fidelity of data entry across reporting sites. These limitations aside, the study is also a remarkable example of how an existing registry can be leveraged to help answer clinically relevant questions without a massive investment of additional resources, including external funding. In some regards, this may be the most notable long-term contribution of the work of D’Angelica and colleagues. Despite the significant disease burden, investment in resource-intensive infection prevention trials continues to lag. The current study should serve as a model for future investigations that can inform prevention approaches for other high-risk operations.
While the absolute risk reduction associated with piperacillin-tazobactam was large, the SSI rate among the intervention group was still nearly 20%. Although this study did not show a reduction in 30-day mortality based on the difference in SSI incidence, a difference may have been observed at a later point. Clinically, the deleterious effect of SSIs on postoperative quality of life and overall outcomes among this medically complex patient population cannot be overemphasized. Besides readmissions and the need for extended courses of parenteral antibiotics, infectious complications after open pancreatoduodenectomy may also delay the receipt of adjunctive cancer therapies in some patients.
Given the enormous adverse consequences of postoperative infections, prevention efforts grounded in the best evidence remain essential. The trial by D’Angelica and colleagues is an elegant addition to the evidence of how best to prevent SSIs after open pancreatoduodenectomy and a model for how other existing networks can inform clinical care.
