Standard Versus Prolonged Antibiotic Prophylaxis After Pancreatoduodenectomy (SPARROW) (SPARROW)

October 17, 2024 updated by: J.S.D. Mieog, MD PhD, Leiden University Medical Center

Standard Versus Pre-emptive Antibiotic Treatment to Reduce the Rate of Infectious Outcomes After Whipple's Procedure (SPARROW): a Multicenter, Randomized Controlled Trial

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed 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.

Study Type

Interventional

Enrollment (Estimated)

344

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Netherlands
      • Amsterdam, Netherlands
        • Recruiting
        • Amsterdam University Medical Center
        • Contact:
          • Marc GH Besselink, Prof. Dr
        • Contact:
          • Marc GH Besselink, Prof. Dr.
      • Breda, Netherlands
        • Recruiting
        • Amphia Ziekenhuis
        • Contact:
          • Jan H Wijsman, MD PhD
      • Den Bosch, Netherlands
        • Not yet recruiting
        • Jeroen Bosch Ziekenhuis
        • Contact:
          • Koop Bosscha, MD
      • Eindhoven, Netherlands
        • Recruiting
        • Catharina Ziekenhuis
        • Contact:
          • Misha DP Luyer, MD PhD
      • Enschede, Netherlands
        • Recruiting
        • Medisch Spectrum Twente
        • Contact:
          • Daan J Lips, MD PhD
      • Groningen, Netherlands
        • Recruiting
        • Groningen University Medical Center
        • Contact:
          • Frederik JH Hoogwater, MD PhD
      • Maastricht, Netherlands
        • Recruiting
        • Maastricht University Medical Center
        • Contact:
          • Stefan AW Bouwense, MD PhD
      • Nijmegen, Netherlands
        • Recruiting
        • Radboud University Medical Center
        • Contact:
          • Martijn Stommel, MD PhD
      • Rotterdam, Netherlands
        • Recruiting
        • Erasmus MC Cancer Institute
        • Contact:
          • Bas Groot Koerkamp, Prof. Dr.
      • Utrecht, Netherlands
        • Recruiting
        • Regional Academic Cancer Center Utrecht
        • Contact:
          • Hjalmar C van Santvoort, Prof. Dr
        • Contact:
          • Hjalmar C van Santvoort, Prof. Dr.
    • Zuid Holland
      • Leiden, Zuid Holland, Netherlands, 2333 ZA
        • Recruiting
        • Leiden University Medical Center
        • Contact:
        • Contact:
          • Daphne HM Droogh, MD
        • Contact:
          • J. Sven D. Mieog, MD PhD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 90 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Perioperative plus prolonged antibiotic prophylaxis
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
Drug: Cefuroxime
1500mg IV cefuroxime thrice daily during five days.
Other Names:
  • Zinacef
Drug: Metronidazole
500mg IV metronidazole thrice daily during five days.
Other Names:
  • Flagyl
No Intervention: Only perioperative prophylaxis
Perioperative prophylaxis: a single dose of 5-7mg/kg gentamicin followed by 2gr IV cefazolin and 500mg IV metronidazole every 4 hours of surgery.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Rate of clinically relevant organ/space surgical site infection (OSI) between patients with perioperative versus prolonged antibiotic prophylaxis
Time Frame: 90 days after surgery

A clinically relevant OSI is defined by the following criteria:

  • A deep surgical site infection involving any part of the abdomen (e.g. organs and/or spaces) other than the surgical incision within 90 days after surgery.
  • AND Requires radiological, endoscopic or surgical intervention OR therapeutic antibiotics required for an episode of sepsis, defined as two or more SIRS criteria.
  • AND Organisms isolated from an aseptically obtained culture.
90 days after surgery

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The rate of organ/Space Infection (OSI) between patients with perioperative versus prolonged antibiotic prophylaxis
Time Frame: 90 days

An OSI is defined by the CDC definition:

o The infection appears to be related to the operative procedure and infection involves any part of the anatomy (e.g., organs or spaces) other than the incision opened or manipulated during the operative procedure, and at least one of the following is present:

  1. Purulent drainage from a drain that is placed into the organ/space.
  2. Organisms isolated from an aseptically obtained culture of fluid or tissue in the organ/space.
  3. An abscess or other evidence of infection involving the organ/space on direct examination, during reoperation, or by histopathologic or radiologic examination.
  4. Diagnosis of an organ/space SSI by a surgeon or attending physician."
90 days
The rate of isolated OSI between patients with perioperative versus prolonged antibiotic prophylaxis
Time Frame: 90 days
Isolated OSI is defined as an OSI without concurrent anastomotic leakage (pancreatojejunostomy, hepaticojejunostomy or gastrojejunostomy). The concept of an isolated OSI is used to separately classify abdominal infections without concurrent anastomotic leakage.
90 days
The rate of superficial incisional SSI between patients with perioperative versus prolonged antibiotic prophylaxis
Time Frame: 90 days

A superficial surgical site infection after surgery which involves superficial or deep soft tissue (skin, muscle or fascia, but no intra-abdominal tissue), and at least one of the following criteria is present:

  • Purulent drainage from the incision or subcutaneous tissue.
  • Isolation of microorganisms from an aseptically obtained culture of fluid or tissue from the superficial incision of subcutaneous tissue.
  • Superficial infections of the skin or subcutaneous tissue which is deliberately opened by a surgeon or attending physician OR at least one of the following signs are present: localizes pain, tenderness, swelling, heat or fever >38 degrees).
90 days
The rate of clinically relevant postoperative pancreatic fistula between patients with perioperative versus prolonged antibiotic prophylaxis
Time Frame: 90 days

Grade B or C postoperative pancreatic fistula (POPF) defined by the International Study Group of Pancreatic Surgery definition:

Grade A: Amylase >3 times upper limit of the institutional normal serum amylase value

Grade B: Grade A + persistant drainage >3 weeks, clinically relevant change in management of POPF, percutaneous or endoscopic drainage, angiographic procedures for bleeding, or signs of infection without organ failure.

Grade C: Grade A or B requiring reoperation, resulting in organ failure or death.
90 days
The rate of bile leakage between patients with perioperative versus prolonged antibiotic prophylaxis
Time Frame: 90 days

Grade A, B or C defined by the ISGLS definition:

Grade A: Bile leakage requiring no or little change in patients' clinical management.

Grade B: Bile leakage requiring a change in patients clinical management (eg, additional diagnostic or interventional procedures) but manageable without relaparotomy, or a Grade A bile leakage lasting for >1 week.

Grade C: Bile leakage requiring relaparotomy
90 days
The rate of post pancreatectomy hemorrhage between patients with perioperative versus prolonged antibiotic prophylaxis
Time Frame: 90 days

Grade A, B or C defined by the ISGPS definition:

Grade A: Early (<24h after surgery), intra- or extraluminal, clinically mild.

Grade B: Early (<24h after surgery), intra- or extraluminal and clinically severe OR later (>24h after surgery), intra- or extraluminal and clincally mild.

Grade C: Late (>24h after surgery), intra- or extraluminal and clinically severe.
90 days
The rate of delayed gastric emptying between patients with perioperative versus prolonged antibiotic prophylaxis
Time Frame: 90 days

Grade A, B or C defined by the ISGPS definition:

Grade A: Until day 4-7 or replacement of feeding tube > 3 days after surgery

Grade B: Until day 8-14 or replacement of feeding tube > 7 days after surgery

Grade C: >day 14 or replacement of feeding tube > 14 after surgery
90 days
The rate of postoperative bacteremia between patients with perioperative versus prolonged antibiotic prophylaxis
Time Frame: 90 days
Defined as a positive blood culture obtained during a septic period (defined as two or more SIRS criteria)
90 days
The rate of Clostridium difficile infection between patients with perioperative versus prolonged antibiotic prophylaxis
Time Frame: 90 days
Defined by a positive fecal culture for Clostridium difficile
90 days
Rate of major complications between patients with perioperative versus prolonged antibiotic prophylaxis
Time Frame: 90 days

Major complications is defined by a Clavien-Dindo score of ≥III.

Clavien-Dindo classification of Surgical Complications:

Grade I: Any deviation from the normal postoperative course without the need for pharmacological treatment or surgical, endoscopic and radiological interventions.

Grade II: Requiring pharmacological treatment with drugs other than such allowed for grade I complications.

Grade IIIa: Requiring surgical, endoscopic or radiological intervention not under general anesthesia Grade IIIb: Requiring surgical, endoscopic or radiological intervention under general anesthesia

Grade IVa: Life-threatening complication (including CNS complications)* requiring IC/ICU-management with single organ dysfunction (including dialysis).

Grade IVb: Life-threatening complication (including CNS complications)* requiring IC/ICU-management with multi organ dysfunction.

Grade V: Death of a patient
90 days
The number of reinterventions in patients with perioperative versus prolonged antibiotic prophylaxis
Time Frame: 90 days
Reinterventions could be either radiological, surgical or endoscopic reinterventions
90 days
The number of ICU admission in patients with perioperative versus prolonged antibiotic prophylaxis
Time Frame: 90 days
ICU admission
90 days
Length of hospital stay in patients with perioperative versus prolonged antibiotic prophylaxis
Time Frame: 90 days
In days
90 days
The number of readmissions between patients with perioperative versus prolonged antibiotic prophylaxis
Time Frame: 90 days
Readmission into the hospital
90 days
Mortality
Time Frame: 90 days
In-hospital and 90-days mortality
90 days

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
The percentage of patients with a deviation from antibiotic study protocol
Time Frame: 5 days

Study protocol:

  • Control arm: Perioperative antibiotic prophylaxis (cefazolin, metronidazole and single-dose gentamicin).
  • Intervention arm: Perioperative plus prolonged antibiotics (cefuroxime and metronidazole for five postoperative days).
5 days
Antibiotic sensitivity patterns of microorganisms cultured from bile cultures and postoperative cultures from infectious sites between patients with perioperative versus prolonged antibiotic prophylaxis
Time Frame: 90 days
Rate of Antibiotic sensitivity patterns in bile cultures and cultures from surgical sites
90 days
The percentage of concordance of microorganisms in bile and cultures from infectious sites postoperatively
Time Frame: 90 days
Defined as the similarity of microorganisms between perioperative bile cultures and postoperative cultures from infectious sites.
90 days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Leiden University Medical Center

Investigators

  • Principal Investigator: J. Sven D. Mieog, MD PhD, Leiden University Medical Center

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 6, 2023

Primary Completion (Estimated)

July 1, 2025

Study Completion (Estimated)

January 1, 2026

Study Registration Dates

First Submitted

February 27, 2023

First Submitted That Met QC Criteria

March 22, 2023

First Posted (Actual)

March 24, 2023

Study Record Updates

Last Update Posted (Actual)

October 21, 2024

Last Update Submitted That Met QC Criteria

October 17, 2024

Last Verified

October 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NL82304.058.22

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

IPD Plan Description

Available upon request to the principal investigator

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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