Standard Versus Prolonged Antibiotic Prophylaxis After Pancreatoduodenectomy (SPARROW)

Leiden University Medical Center (LUMC)

Status and phase: Enrolling; Phase 4

Conditions: Pancreatic Cancer

Treatments: Drug: Cefuroxime; Drug: Metronidazole

Study type: Interventional

Funder types: Other

Identifiers

NCT05784311

NL82304.058.22

Details and patient eligibility

About

The goal of this multicenter randomized controlled trial is to evaluate the additional value of pre-emptive antibiotic treatment on clinically relevant organ/space surgical site infections (OSIs) in patients undergoing pancreatoduodenectomy with a high risk for contaminated bile. The main objectives it aims to answer are:

• To evaluate the effect of pre-emptive antibiotic prophylaxis on clinically relevant OSIs in patients undergoing pancreatoduodenectomy with a high risk for contaminated bile
• To evaluate the effect of pre-emptive antibiotic prophylaxis on other postoperative outcomes (e.g. OSIs, superficial SSIs, POPF, PPH, major morbidity, ICU admission, readmission, length of hospital stay, and mortality).
• To evaluate concordance between perioperatively obtained bile cultures and postoperative cultures from infectious sites, and to evaluate antibiotic sensitivity patterns of the cultured microorganisms.

Participants will be randomized with a 1:1 allocation before surgery into the intervention or control group:

• Patients in the intervention group will receive perioperative prophylaxis (similar to the control group) followed by five days of 1500mg IV cefuroxime and 500mg IV metronidazole thrice daily.
• Patients in the control group will only receive perioperative prophylaxis (a single dose of 5-7mg/kg gentamicin followed by 2gr IV cefazolin and 500mg IV metronidazole every 4h of surgery), which will be discontinued after surgery.

Full description

Rationale: The additional value of pre-emptive antibiotic treatment after pancreatoduodenectomy is undetermined as previous research reported conflicting results regarding infectious complications. Prolonged antibiotic prophylaxis (formally pre-emptive antibiotic treatment) after pancreatoduodenectomy might reduce the rate of surgical site infections in patients with a high risk for contaminated bile (predominantly patients with preoperative biliary drainage or an ampullary malignancy). Current national and international guidelines lack clear recommendations regarding pre-emptive antibiotic treatment leading to substantially varying antibiotic prophylactic regimes between institutes.

Objective: This trial evaluates the additional value of pre-emptive antibiotic treatment on clinically relevant organ/space surgical site infections (OSIs) in patients undergoing pancreatoduodenectomy with a high risk for contaminated bile.

Study design: This multicenter, randomized controlled, superiority trial compares perioperative versus pre-emptive antibiotic treatment during five postoperative days after pancreatoduodenectomy in patients with a high risk for contaminated bile.

Study population: Adult patients undergoing pancreatoduodenectomy with a high risk for contaminated bile (patients with preoperative biliary drainage or an ampullary malignancy). Patients with a contraindication for the study antibiotics or a preoperative indication for antibiotics (e.g. cholangitis of preoperative abscesses) are excluded.

Intervention: Participants will be randomized to either perioperative prophylaxis (cefazolin, metronidazole and a single dose of 5-7mg/kg gentamicin, control arm) or additional cefuroxime and metronidazole for five postoperative days (experimental arm).

Main study endpoints: The primary endpoint are organ/space infections (OSIs) within 90 days after surgery requiring a therapeutic intervention. Secondary endpoints are OSIs, isolated OSIs, wound infections, postoperative pancreatic fistula, bile or enteric anastomotic leakage, post pancreatectomy hemorrhage, delayed gastric emptying, bacteremia, Clostridium difficile infection, major morbidity (Clavien-Dindo ≥III), reintervention, ICU admission, length of hospital stay, readmission, and in-hospital and 90-day mortality. Besides, switch of postoperative antibiotics, antibiotic sensitivity patterns and concordance between perioperative bile and postoperative surgical site cultures are analyzed.

Sample size: The sample size is calculated for superiority to achieve an OSI difference of 15% (40% vs 25%). With a 80% power (1-β) and a two-sided significance level (α) of 5.0%, a sample of 304 evaluable patients is required for superiority. Assuming a 3% non-resection rate due to metastatic disease and a 3% loss-of-follow-up rate, an expected number of 322 included patients are needed to reach the sample size of 304 evaluable patients to demonstrate superiority for the intervention.

Enrollment: 344 estimated patients

Sex: All

Ages: 18 to 90 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Patients undergoing elective pancreatoduodenectomy with a high risk for contaminated bile defined as patients with preoperative biliary drainage or an ampullary malignancy.
• Age >18 years

Exclusion criteria

• Pregnancy
• Contraindication for the study antibiotics (e.g. allergy or intolerance)
• Preoperative planned therapeutic antibiotic treatment (i.e. for cholangitis or liver abscesses)
• A reduced renal function, defined as an eGFR of <60 ml/min/1.73m2 measured on the closest timepoint prior to pancreatoduodenectomy

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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344 participants in 2 patient groups

Perioperative plus prolonged antibiotic prophylaxis

Experimental group

Description:

Prolonged prophylaxis: a single dose of 5-7mg/kg gentamicin followed by 2gr IV cefazolin and 500mg IV metronidazole every 4 hours of surgery (perioperative prophylaxis) followed by five days of 1500mg IV cefuroxime and 500mg IV metronidazole thrice daily

Treatment:

Drug: Metronidazole

Drug: Cefuroxime

Only perioperative prophylaxis

No Intervention group

Description:

Perioperative prophylaxis: a single dose of 5-7mg/kg gentamicin followed by 2gr IV cefazolin and 500mg IV metronidazole every 4 hours of surgery.