Continuous Antibiotic Prophylaxis in Colorectal Surgery

NCT ID: NCT02445859

Last Updated: 2019-10-10

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 90 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-08-31
• Study Completion Date: 2017-05-31

Brief Summary

We propose to randomise patients due to undergo colorectal surgery to standard antibiotic prophylaxis or an interventional antibiotic prophylaxis regimen and assess surgical wound infection rates. Standard antibiotic prophylaxis is a pre-operative injection of cefuroxime, repeated every 4 hours. The intervention regimen is a loading dose of cefuroxime followed by a continuous infusion of cefuroxime until the end of surgery. The intervention regimen dosing will be calculated using a patient's renal function and body weight. The intervention regimen will target a free serum drug concentration of 64mg/L. This serum level is 4x the MIC90 for colonising Enterobacteriaceae. The rational for this dosing regimen is summarised below. The primary objective of the study is to reduce by 50% the rate of surgical wound infections after colorectal surgery.

Detailed Description

An expert assessment is that fT>MIC is the measure most likely to be applicable to prophylaxis. But this measure is not achieved by standard prophylaxis regimens. Neither do clinical data suggest this target achieves optimal prophylaxis. Therefore there is an opportunity to optimise antibiotic prophylaxis dosing. As the exposure response-relationship (pharmacodynamic target) is unknown we could either complete a number of studies exploring different relationships, or compare standard treatment to a single regimen which included a number of exposure-response relationships. The two most common exposure-response relationships are the CMAX/MIC ratio and the fT>MIC. And it has been reported that killing, as opposed to inhibition used in MIC values, is optimised by achieving 4 times an MIC value. An antibiotic prophylaxis regimen which achieved drug concentrations of 4xMIC for the duration of surgery would therefore achieves a high CMAX/MIC ratio, high T>MIC, and optimise bacterial killing. Therefore, standard dose antibiotic prophylaxis will be compared against a PD target dosed antibiotic prophylaxis regimen. The PD target will be a free serum antibiotic concentration of 4xMIC90 for Enterobacteriaceae against cefuroxime. Continuous infusion of antibiotic prophylaxis will ensure there is continuous targeting of this drug level throughout the operation.

Conditions

Surgical Site Infection

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: SINGLE

Study Groups

Standard regimen

Cefuroxime 1.5grams pre-operatively Repeated every 4 hours

Group Type: ACTIVE_COMPARATOR

Cefuroxime 4 hourly bolus

Intervention Type: DRUG

Cefuroxime loading dose followed by a continuous infusion dosed according to renal function. Dosed to target a serum concentration of 64mg/L.

Interventional regimen

Cefuroxime continuous infusion targeting 64mg/l serum concentrations.

Group Type: EXPERIMENTAL

Cefuroxime 4 hourly bolus

Intervention Type: DRUG

Cefuroxime loading dose followed by a continuous infusion dosed according to renal function. Dosed to target a serum concentration of 64mg/L.

Interventions

Cefuroxime 4 hourly bolus

Cefuroxime loading dose followed by a continuous infusion dosed according to renal function. Dosed to target a serum concentration of 64mg/L.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Undergoing colorectal surgery (incision, excision or anastomosis of the large bowel, including anastomosis of small to large bowel)
• Age >18.
• Expected duration of surgery > 2hours
• Creatinine clearance > 40 ml/min
• Cefuroxime/metronidazole are appropriate antibiotic prophylaxis regimens.
• Patient capable of giving informed consent
• Patients undergoing colorectal surgery plus additional surgery e.g. plastic surgery, urological surgery, gynaecological surgery.
• If it is not possible to obtain intra-operative blood samples e.g. difficult vascular access, or pre-operative swabs e.g. anatomy makes it difficult to obtain, patients will be included and this information treated as missing data. Patients on antibiotic treatment for an existing infection (except SSIs) can be included in the study

Exclusion Criteria

• Unable to consent
• Pregnancy
• Expected duration of surgery <2hours
• Creatinine clearance <40ml/min
• Individual level microbiological advice for non cefuroxime based prophylaxis
• Cephalosporin allergy
• Penicillin allergy (hypersensitivity reaction only)
• Coumarin (warfarin and acenocoumarol) treatment
• Active blood borne virus infection e.g. HIV, hepatitis.
• Seizure history
• Concurrent use of probenecid
• Current participation in a research project aimed at reducing SSIs
• Antibiotics for treatment of a systemic Gram negative infection within 2 hours of initiation of surgery (Vancomycin, Teicoplanin, Daptomycin, Linezolid, Flucloxacillin. Nitrofurantoin and Clarithromycin would be permissible antibiotics without systemic Gram negative antibiotics).
• A current diagnosis of a SSI at the time of study entry.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Leeds

OTHER

Sponsor Role: lead

Responsible Party

Andrew Kirby

Associate clinical professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Andrew Kirby

Role: PRINCIPAL_INVESTIGATOR

The University of Leeds

Locations

Leeds Teaching Hospitals NHS Trust

Leeds, West Yorkshire, United Kingdom

Countries

United Kingdom

References

Kirby A, Asin-Prieto E, Burns FA, Ewin D, Fatania K, Kailavasan M, Nisar S, Pericleous A, Troconiz IF, Burke D. Colo-Pro: a pilot randomised controlled trial to compare standard bolus-dosed cefuroxime prophylaxis to bolus-continuous infusion-dosed cefuroxime prophylaxis for the prevention of infections after colorectal surgery. Eur J Clin Microbiol Infect Dis. 2019 Feb;38(2):357-363. doi: 10.1007/s10096-018-3435-z. Epub 2018 Dec 5.

Reference Type: DERIVED

PMID: 30519893 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Document Type: Informed Consent Form

View Document

Other Identifiers

MB15/130

Identifier Type: -

Identifier Source: org_study_id