Continuous Antibiotic Prophylaxis in Colorectal Surgery

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.

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.

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.