Evaluation of Cefuroxime and Metronidazole in Reducing Infectious Complications Post-Pancreatoduodenectomy in High-Risk Patients: A Randomized Controlled Trial

The primary objective of this study is to evaluate the occurrence of a clinically relevant **organ/space infection (OSI)** following pancreatoduodenectomy, specifically within 90 days post-surgery. This is defined by the presence of a deep surgical site infection involving any part of the abdomen other than the surgical incision, necessitating radiological, endoscopic, or surgical intervention, or requiring therapeutic antibiotics for an episode of sepsis, characterized by two or more systemic inflammatory response syndrome (SIRS) criteria, with organisms isolated from an aseptically obtained culture. This objective is clinically significant as it addresses the potential for serious postoperative complications that can impact patient recovery and healthcare resources.

Secondary objectives include: - OSI defined by the CDC definition within 90 days after surgery. - Isolated OSI without concurrent anastomotic leakage. - Superficial incisional surgical site infection (SSI) as per CDC definition. - Rate of clinically relevant postoperative pancreatic fistula (grade B or C). - Rate of bile and enteric leakage. - Rate of postpancreatectomy hemorrhage. - Rate of delayed gastric emptying. - Rate of chyle leak. - Rate of postoperative bacteraemia. - Rate of **Clostridium difficile** infection. - Rate of major complications (Clavien-Dindo score ≥III). - Reintervention during admission. - ICU admission within 90 days after surgery. - Length of hospital stay. - Readmission within 90 days after surgery. - In-hospital and 90-day mortality. - Switch of postoperative antibiotics and reasons for deviation. - Antibiotic sensitivity patterns in bile and surgical site cultures. - Concordance of microorganisms in bile and surgical site cultures.

The clinical trial involves participants undergoing elective **pancreatoduodenectomy** with a high risk for contaminated bile, specifically those with preoperative biliary drainage or an ampullary malignancy. The study population includes both male and female subjects aged over 18 years. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants. Participants were selected based on their surgical procedure and associated risk factors. No specific lifestyle considerations such as diet or physical activity are highlighted in the trial data.

The clinical trial is designed as a **randomized controlled trial** to evaluate the efficacy of pre-emptive antibiotic prophylaxis in reducing the rate of infectious outcomes following pancreatoduodenectomy in patients with a high risk for contaminated bile. The trial will involve the administration of **cefuroxime** and **metronidazole** as antimicrobial agents, delivered via infusion. The study is expected to commence on March 1, 2023, and conclude by July 31, 2025, with a maximum treatment period of 5 days for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as undergoing elective pancreatoduodenectomy and being over 18 years of age. Follow-up visits will be scheduled to monitor the occurrence of clinically relevant organ/space infections (OSIs) and other secondary endpoints, including rates of superficial surgical site infections, postoperative pancreatic fistula, and other complications. The end-of-study visit will evaluate the primary endpoint, which is the additional value of pre-emptive antibiotic prophylaxis on clinically relevant OSIs.

The expected length of participant involvement is approximately 90 days post-surgery, during which the primary endpoint will be assessed. Conditions that may lead to early termination from the study include withdrawal of consent, occurrence of adverse events that contraindicate continued participation, or any other medical reasons deemed necessary by the investigator. The trial will adhere to rigorous scientific standards to ensure the validity and reliability of the results, contributing valuable insights into the management of infectious outcomes in high-risk surgical patients.

The clinical trial involves the administration of **Cefuroxime**, marketed as Cefuroxim Hikma 1500 mg, which is provided in the form of a powder for solution for injection or infusion. This **antimicrobial agent** is chemically synthesized and is administered via infusion. The maximum daily dose is 4500 mg, with a total maximum dose of 4500 mg over a treatment period of up to 5 days. The product is manufactured by HIKMA FARMACÊUTICA (PORTUGAL), S.A. and is authorized for use in the Netherlands under the marketing authorization number RVG 20590. Participant compliance with the dosing schedule will be monitored throughout the trial.

Additionally, the trial includes the use of **Metronidazole**, marketed as Metronidazol 5 mg/ml Fresenius, in the form of a solution for infusion. This **antimicrobial agent** is also chemically synthesized and administered via infusion. The maximum daily dose is 1500 mg, with a total maximum dose of 1500 mg over a treatment period of up to 5 days. This product is manufactured by FRESENIUS KABI NEDERLAND B.V. and is authorized for use in the Netherlands under the marketing authorization number RVG 56005. As with Cefuroxime, participant compliance with the dosing schedule will be closely monitored during the trial.

The efficacy of the clinical trial titled "Standard versus Pre-emptive Antibiotic Treatment to Reduce the Rate of Infectious Outcomes after Whipple’s procedure (SPARROW)" will be assessed primarily by evaluating the occurrence of a clinically relevant **Organ/Space Infection (OSI)**. This primary endpoint is defined based on the CDC criteria and includes a deep surgical site infection involving any part of the abdomen other than the surgical incision within 90 days post-surgery. The infection must require radiological, endoscopic, or surgical intervention, or necessitate therapeutic antibiotics for an episode of sepsis, characterized by two or more SIRS criteria, with organisms isolated from an aseptically obtained culture.

Secondary endpoints for efficacy assessment include a comprehensive range of infection-related and postoperative outcomes. These include the rate of OSIs according to the CDC definition, isolated OSIs, superficial surgical site infections, clinically relevant postoperative pancreatic fistula, bile and enteric leaks, post-pancreatectomy hemorrhage, delayed gastric emptying, postoperative bacteremia, and **Clostridium difficile** infection. Additional parameters include the rate of major complications (Clavien-Dindo grade III or higher), reintervention rates, ICU admissions, length of hospital stay, readmission rates, mortality, and the switch of postoperative antibiotics. The study will also evaluate antibiotic sensitivity patterns in bile cultures and cultures from surgical sites, the concordance of microorganisms in bile and surgical site cultures, and the rate of chyle leak according to the ISGPS definition.