BackgroundWe previously reported that an extended antibiotic mitigation pathway following pancreatoduodenectomy in patients with intermediate-/high-risk glands is associated with 83 % lower odds of clinically relevant postoperative pancreatic fistula (CR-POPF). We now describe associations between the pathway, resource utilization, and hospital charges. MethodsWe performed a retrospective cohort study of patients who underwent elective pancreatoduodenectomy with soft gland texture and fistula risk score (FRS) ≥3 who received standard or extended antibiotics. Hospital charges and resource utilization within 90 days of surgery were compared by CR-POPF status and antibiotic pathway. ResultsA total of 34 patients received extended antibiotics and 53 received standard antibiotics. In patients with CR-POPF, patients who received extended antibiotics had lower likelihood of surgical or percutaneous reintervention (75.0 % vs. 100.0 %, p = 0.022). Ninety-day postoperative charges associated with CR-POPF were higher than no CR-POPF ($60,527 vs. $25,631, p = 0.028). Our risk-based model predicted a $15,825 decrease in hospital charges per patient receiving extended antibiotics. ConclusionsCR-POPF is associated with higher 90-day hospital charges. Extended antibiotic therapy following pancreatoduodenectomy in patients with soft gland texture and FRS ≥3 is associated with fewer reinterventions in patients who develop CR-POPF. These outcomes will be formally tested in a randomized controlled trial (NCT05753735).