Colo-Pro Pilot: A Pilot Study to Compare Standard Single Dose Antibiotic Prophylaxis to Bolus-continuous Infusion Dosed Antibiotic Prophylaxis for the Prevention of Infections After Colorectal Surgery
Phase: PHASE2
Conditions: Surgical Site Infection
Sponsor: University of Leeds

 
Version 2.2 10/10/2016 
 
Medicinal Product Protocol Guidance and Template 
 
FULL TITLE OF THE TRIAL 
Colo-Pro Pilot: A pilot randomised controlled single blind trial to 
compare standard single dose antibiotic prophylaxis to antibiotic 
prophylaxis administered as a bolus-continuous infusion for the 
prevention of surgical site infections in adults undergoing colorectal 
surgery. 
 
SHORT STUDY TITLE  
Short title: Colo-Pro Pilot: A pilot study to compare standard single 
dose antibiotic prophylaxis to bolus-continuous infusion dosed 
antibiotic prophylaxis for the prevention of infections after colorectal 
surgery. 
Lay title: Colo-Pro Pilot: A pilot study to compare standard single dose 
antibiotic prophylaxis to higher dose antibiotic prophylaxis for the 
prevention of infections after colorectal surgery. 
 
 
This protocol has regard for the HRA guidance and order of content 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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RESEARCH REFERENCE NUMBERS 
Leeds Teaching Hospitals Trust R&I number: MB15/130 
The University of Leeds reference number: MB15/130 
 
TRIAL REGISTRY NUMBER AND DATE 
Clinical trials.gov: NCT02445859 
 
PROTOCOL VERSION NUMBER AND DATE 
Version 2.2. 10/10/2016 
 
SPONSOR  
The University of Leeds 
 

 
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RESEARCH REFERENCE NUMBERS 
 
REC Reference:  
15/YH/0260 
 
 
Clinical trials.gov Number:  
NCT02445859 
 
SPONSORS Number: 
MB15/130 
 
FUNDERS Number: 
Department of Microbiology, Leeds Teaching Hospitals 
NHS Trust. 
Reference number: Not applicable  
 
 

 
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SIGNATURE PAGE 
The undersigned confirm that the following protocol has been agreed and accepted and that the Chief 
Investigator agrees to conduct the trial in compliance with the approved protocol and will adhere to 
ICHGCP and research governance framework 2005  
I agree to ensure that the confidential information contained in this document will not be used for any 
other purpose other than the evaluation or conduct of the clinical investigation without the prior written 
consent of the Sponsor 
I also confirm that I will make the findings of the study publically available through publication or other 
dissemination tools without any unnecessary delay and that an honest accurate and transparent 
account of the study will be given; and that any discrepancies from the study as planned in this 
protocol will be explained. 
 
For and on behalf of the Study Sponsor 
Signature:  
...................................................................................................... 
 
Date: 
....../....../...... 
Name: 
 
 
 
Position: 
...................................................................................................... 
 
 
 
Chief Investigator 
Signature: 
...................................................................................................... 
 
Date: 
....../....../...... 
Name: Andrew Kirby 
 
 
 
Position: Associate clinical professor in microbiology 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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KEY TRIAL CONTACTS 
 
Chief Investigator 
Andrew Kirby 
Address: Old Medical School, Leeds General Infirmary, 
Leeds, LS1 3EX 
Telephone: 0113 3923929 
E-mail: a.kirby@leeds.ac.uk 
Trial Co-ordinator 
Andrew Kirby 
Address: Old Medical School, Leeds General Infirmary, 
Leeds, LS1 3EX 
Telephone: 0113 3923929 
E-mail: a.kirby@leeds.ac.uk 
Sponsor 
The University of Leeds 
Funder(s) and support in kind 
 
The University of Leeds 
Leeds Teaching Hospitals NHS Trust 
Department of Microbiology, Leeds Teaching Hospitals NHS 
Trust 
Department of Surgery, Leeds Teaching Hospitals NHS Trust 
The West Yorkshire Postgraduate Medical Deanery 
Clinical Trials Unit 
None 
Key Protocol Contributors 
Andrew Kirby 
Address: Old Medical School, Leeds General Infirmary, 
Leeds, LS1 3EX 
Telephone: 0113 3923929 
E-mail: a.kirby@leeds.ac.uk 
Eduardo Asín Prieto 
Pharmacokinetics, Nanotechnology and Gene Therapy Group 
Center of Investigation  
Lucio Lascaray (CIEA) Faculty of Pharmacy University of the 
Basque Country (UPV/EHU) C/Miguel de Unamuno, 3 01006 
- Vitoria-Gasteiz (Alava) Spain 
Tfn.:  (+34) 945 01 45 03 
E-mail: eduardo.asin@ehu.es 
Statistician 
Not applicable 
Trials pharmacist 
Not applicable 
Committees 
The Trial Steering group: This group will periodically review 

 
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safety data and liaise with the DMC regarding safety issues. 
Data (safety) monitoring group: This group will exist to ensure 
the trial protocol is followed and that any adverse events are 
investigated and reported 
 
Committees Contact 
Georgina Davis 
Old Medical School, Leeds General Infirmary, Leeds, LS1 
3EX 
Tel: 0113 3926814 
Fax: 0113 3922696  
E-mail: georgina.davis@nhs.net 
 
TRIAL SUMMARY 
 
Trial Title 
Colo-Pro Pilot: A pilot randomised controlled single blind trial to compare 
standard single dose antibiotic prophylaxis to antibiotic prophylaxis 
administered as a bolus-continuous infusion for the prevention of surgical 
site infections in adults undergoing colorectal surgery. 
Short title 
Colo-Pro Pilot: A pilot study to compare standard single dose antibiotic 
prophylaxis to bolus-continuous infusion dosed antibiotic prophylaxis for the 
prevention of infections after colorectal surgery. 
Clinical Phase  
Therapeutic exploratory trial including comparison with the standard 
treatment regimen (Phase II/III) 
Trial Design 
A randomised controlled single blind parallel group trial. 
Trial Participants 
Adults (>18 years) 
Undergoing colorectal surgery (incision, excision or anastomosis of the 
large bowel, including anastomosis of small to large bowel). 
Cefuroxime and metronidazole are suitable prophylactic antibiotics 
Expected duration of surgery > 2 hours 
Creatinine clearance > 40 ml/min 
Planned Sample Size 
90 
Treatment duration 
Duration of the surgical procedure up to 6 hours 
Follow up duration 
30 days 
Planned Trial Period 
12 months 
 
Objectives 
Outcome Measures 

 
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Primary 
 
To reduce by 50% the rate of surgical 
site infections after colorectal surgery.  
 
Surgical site infection within 30 
days of operation. 
 
Secondary 
 
To reduce the rate of all infections after 
colorectal surgery. 
 
To reduce antimicrobial consumption 
after colorectal surgery 
 
To reduce length of hospital stay after 
colorectal surgery 
 
To reduce mortality after colorectal 
surgery   
 
To reduce anastomotic leakage after 
colorectal surgery 
 
 
To improve quality of life after 
colorectal surgery 
 
 
To reduce the cost of healthcare 
treatment associated with colorectal 
surgery  
 
 
To investigate if pre-operative antibiotic 
resistance, as determined by antibiotic 
susceptibility testing of rectally 
colonising Enterobacteriaceae, is 
predictive of a patients risk of a post-
operative surgical site infection. 
 
To investigate the exposure-response 
relationship for antibiotic prophylaxis in 
the prevention of surgical site infection 
prevention after colorectal surgery.  
All infections within 30 days of 
operation. 
 
Antimicrobial consumption within 
30 days of operation. 
 
Length of hospital stay after 
operation 
 
Mortality after operation at one 
year. 
 
Radiological or clinically 
diagnosed anastomotic leakage 
 
 
Quality of life scores pre-
operatively and post operatively 
at 30 days.  
 
Cost of healthcare treatments 
after operation at 30 days. 
 
 
 
See Table 5 
 
 
 
 
 
See Table 5 

 
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Medicinal Product 
Cefuroxime 1.5g powder for solution for injection or infusion 
Formulation, Dose, 
Route of Administration 
Formulation 
Cefuroxime: Each vial contains, as the active ingredient, cefuroxime sodium 
for injection 1578mg equivalent to 1500mg of cefuroxime respectively 
Dose 
Standard treatment 
 
1.5 grams 4 hourly. 
Intervention treatment:  
 
A maximum loading dose of cefuroxime 2332 mg 
 
A maximum hourly dose on continuous infusion of 1226 mg/hour. 
These doses will be administered for a maximum of 6 hours. 
Route of administration 
Intravenous 
 
 
 
 
 

 
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FUNDING AND SUPPORT IN KIND 
FUNDER(S) 
FINANCIAL AND NON FINANCIALSUPPORT 
GIVEN 
The University of Leeds 
Employment of Dr Andrew Kirby 
Employment of Mr Dermot Burke 
Leeds Teaching Hospitals NHS Trust 
Employment of Dr Andrew Kirby 
Employment of Mr Dermot Burke 
Department of Microbiology, Leeds Teaching 
Hospitals NHS Trust 
Facilities/Funding for 
microbiological/pharmacological testing 
Leeds Teaching Hospitals Charitable funding to 
support microbiological testing at £12, 000 
Department of Surgery, Leeds Teaching 
Hospitals NHS Trust 
Facilities for recruitment and intervention 
The West Yorkshire Postgraduate Medical 
Deanery 
Employment of Academic Foundation Year 2 
doctor 
 
 
 
 

 
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ROLE OF STUDY SPONSOR AND FUNDER 
 
Neither study sponsor of funder has had any direct or indirect input into the study design. 
Neither study sponsor of funder will have any input into study conduct, data analysis or interpretation 
beyond ensuring governance arrangements for such procedures are appropriate. 
 
 
 
 

 
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ROLES AND RESPONSIBILITIES OF TRIAL MANAGEMENT COMMITEES/GROUPS & 
INDIVIDUALS 
 
The Trial Steering group 
This group will periodically review safety data and liaise with the DMC regarding safety 
issues. 
Chair: Dr Andrew Kirby 
Research doctor: Mr Dermot Burke 
Research doctor: Rotational academic FY2 doctor 
Administrator: Georgina Davis 
 
The Trial data (safety) monitoring group 
This group will exist to ensure the trial protocol is followed and that any adverse events are 
investigated and reported. The short nature of this pilot trial precludes the need for a 
committee only related to data monitoring or trial steering. 
Independent Chair: Dr Jonathan Sandoe 
Physician: Dr Damian Mawer 
Physician: Dr Sarah Drake  
Administrator: Georgina Davis 
 
 
 
 
 
 

 
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Protocol contributors 
Dr Andrew Kirby 
The sponsor was not directly involved in the design of the trial outside of the grant application review 
process. The funder will have no input into conduct, data analysis and interpretation, manuscript 
writing, or dissemination of results. The funder will not control the final decision regarding any of these 
aspects of the trial. 
The protocol will be reviewed by service users through the Leeds Patient and Public 
Involvement in Research Group 
 
KEY WORDS:  
Antibiotic; Prophylaxis; Surgical site infection; 
Pharmacodynamics. 
 

 
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LIST of CONTENTS 
GENERAL INFORMATION 
Page No. 
TITLE PAGE  
 
RESEARCH REFERENCE NUMBERS 
 
 
SIGNATURE PAGE 
 
TRIAL SUMMARY 
 
 
FUNDING 
 
 
KEY TRIAL CONTACTS 
 
 
ROLE OF SPONSOR AND FUNDER 
 
ROLES & RESPONSIBILITIES OF TRIAL MANAGEMENT COMMITTEES, GROUPS AND 
INDIVIDUALS  
 
 
LIST of CONTENTS  
 
LIST OF ABBREVIATIONS 
 
TRIAL FLOW CHART 
 
SECTION  
1. BACKGROUND 
 
 
2. RATIONALE 
 
 
3. OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS  
 
4. TRIAL DESIGN 
 
5. STUDY SETTING 
 
6. ELIGIBILITY CRITERIA 
 
7. TRIAL PROCEDDURES 
 
8. TRIAL MEDICATION 
 
9. PHARMACOVIGILANCE 
 
10. STATISTICS AND DATA ANALYSIS 
 
11. DATA HANDLING 
 
12. MONITORING, AUDIT & INSPECTION 
 
13. ETHICAL AND TRIAL ADMINISTRATION 
 
14. DISSEMINATION POLICY 
 
15. REFERENCES 
 
16. APPENDICIES 
 
 
 
 

 
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LIST OF ABBREVIATIONS 
Define all unusual or ‘technical’ terms related to the trial.  Add or delete as appropriate to your trial.  
Maintain alphabetical order for ease of reference. 
AE 
Adverse Event 
AR 
Adverse Reaction 
CA 
Competent Authority 
CI 
Chief Investigator 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CTA 
Clinical Trial Authorisation 
CTIMP 
Clinical Trial of Investigational Medicinal Product  
DMC 
Data Monitoring Committee 
DSUR 
Development Safety Update Report 
EC 
European Commission 
EMEA 
European Medicines Agency 
EU 
European Union 
EUCTD 
European Clinical Trials Directive 
EudraCT 
European Clinical Trials Database 
EudraVIGILANCE 
European database for Pharmacovigilance 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice  
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation of technical 
requirements for registration of pharmaceuticals for human 
use. 
IDMC 
Independent Data Monitoring Committee 
IMP 
Investigational Medicinal Product 
IMPD 
Investigational Medicinal Product Dossier 
ISF 
Investigator Site File 
ISRCTN 
International Standard Randomised Controlled Trials 
 
Number 
MA 
Marketing Authorisation 
MHRA 
Medicines and Healthcare products Regulatory Agency 
MP 
Medicinal Product 
MS 
Member State 

 
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NHS R&D 
National Health Service Research & Development   
NIMP 
Non-Investigational Medicinal Product 
PI 
Principal Investigator 
PIC 
Participant Identification Centre 
PIS 
Participant Information Sheet 
QA 
Quality Assurance 
QC 
Quality Control 
QP 
Qualified Person  
RCT 
Randomised Control Trial 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SDV 
Source Data Verification 
SOP 
Standard Operating Procedure  
SmPC 
Summary of Product Characteristics  
SSI 
Site Specific Information 
SUSAR 
Suspected Unexpected Serious Adverse Reaction  
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 
TMF 
Trial Master File 
 
 
 
 
 

 
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TRIAL FLOW CHART 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Standard treatment: Single dose 
antibiotic prophylaxis during surgery 
Clinical agreement for a patient to 
undergo colorectal surgery 
Intervention treatment: Continuous 
infusion antibiotic prophylaxis during 
surgery 
Patient invitation to research study 
Patient provides consent for research 
study 
Patient randomised 
Pre-operative rectal swab collected 
and quality of life questionnaire 
completed. 
Research team identify eligible 
patient 
Intra-operative collection of blood 
samples: 4 x 6ml samples. 
Questionnaire day 30 post operation 
(questionnaire relating to quality of 
life and surgical wound infection) 
Surgical site infection assessment at 
approximately day 5 post operation 

 
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STUDY PROTOCOL 
 
Title: Colo-Pro Pilot: A pilot randomised controlled single blind trial to compare standard single dose 
antibiotic prophylaxis to antibiotic prophylaxis administered as a bolus-continuous infusion for the 
prevention of surgical site infections in adults undergoing colorectal surgery 
 
 
1 
BACKGROUND 
 
Review of published literature 
Surgical site infection (SSI) following colorectal surgery 
20,000 patients annually undergo elective colorectal surgery in England with approximately 22% 
developing a surgical site infection (SSI). SSIs after colorectal surgery have been associated with a 
4.6% increase in 30 day mortality, increase hospital stay and cost £5000 per SSI (Jenks 2014).  
Colorectal surgery is a common surgical procedure for conditions such as colonic cancer, ulcerative 
colitis and Crohn’s disease.  Following surgery, patients undergoing colorectal surgery have a high 
rate of surgical site infection (SSI), higher than all other types of surgery (Health Protection Agency 
2014). SSIs include infections of the site site which encompasses infection of the skin and/or deep 
tissues (superficial and deep SSIs, as well as infections within the abdomen (organ space SSIs). For 
the purposes of this study we will refer to superficial and deep SSIs as SSIs (i.e. excluding organ 
space SSIs). Post operative SSIs in colorectal patients are associated with increased length of 
hospital stay, increased health care costs (£5000 per SSI) and in the case of organ space SSIs, are 
associated with an increase in post operative mortality (Coello, 2005, Kirby 2015a). 
Antibiotic prophylaxis to prevent SSI – current practice and limitations. 
In an attempt to prevent SSIs antibiotics are usually given just before an operation, this is called 
antibiotic prophylaxis. Antibiotic prophylaxis is effective. When initially introduced antibiotic prophylaxis 
reduced SSI rates from 40% to 10% (Nelson 2014). Currently, published evidence suggests SSI rates 
after elective colorectal surgery occur in over > 10% of patients (Kirby 2015a, Petrosillo 2008, Smith 
2004, Tanner 2009, Wick 2008). The reasons for the higher rate of SSIs now are unclear, but it may 
represent different definitions (SSI includes organ space infections, SSI does not), more aggressive 
treatment e.g. pre-operative radiotherapy, or that antibiotic prophylaxis is less effective.  In patients 
undergoing emergency procedures SSI rates are higher than for elective procedures (Morikane 2014). 
Most SSIs (90%) occur within 14 days of the operation (Kirby 2015a). These infections are commonly 
caused by bacteria that live in the human bowel. The types of bacteria from the bowel which are 
believed to cause SSIs are called Enterobacteriaceae, commonly referred to as “coliforms” (e.g. E. 
coli) and anaerobes.  
Antibiotic prophylaxis is currently prescribed to patients at doses similar to those used to treat 
infections such as pneumonia. It is not known if these are the best doses to prevent infections after 
colorectal surgery. There has only been one study which compared different antibiotic doses for the 

 
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prevention of SSI after colorectal surgery.  In this study two different dosing regimens were compared 
(Gentamicin: 4.5kmg/kg and 1.5 mg/kg) in 146 patients. The study determined that the higher dose 
regimen had a lower SSI rate (22%) than the low dose regimen (55%) (Zelenitsky 2000). Unfortunately 
other studies have not been completed to further investigate if new, non-treatment based dosing 
regimens, are better at preventing post-operative SSIs when compared to dosing used for the 
treatment of infections.  
There is increasing concern over the efficacy of antibiotic prophylaxis in the United Kingdom, as well 
as internationally, because of increasing rates of resistance to antibiotics (McGregor 2013). Some 
clinical evidence suggests that pre-operative identification of antimicrobial resistant (AMR) coliforms in 
patients undergoing liver transplants and prostate biopsies is associated with an increased rate of post 
operative infections (Roberts 2014, Lübbert 2104). There is currently no evidence relating AMR to 
SSIs in colorectal surgery. In addition, increasing rates of obesity mean higher antibiotic doses are 
likely to be needed to obtain the same benefits; twenty five percent of adults are now obese, 
compared to 15% 20 years ago. Data have been reported which does show obesity (BMIs over 30) 
are associated with a higher SSI rates (Itani 2008). These concerns over the efficacy of antibiotic 
prophylaxis may be justified because a significant increasing trend of colorectal SSIs has been 
reported by Public Health England (2014). There is also evidence, based on pharmacological 
modelling, that suggests patients with good renal function, who excrete antibiotics quickly, are another 
risk group for SSIs (Asín-Prieto 2015).   
Ways to improve prophylaxis 
AMR bacteria are normally identified in patients with infection, and so resistance rates are reported for 
defined infections. Similar data are not available for patients who are about to undergo surgery as they 
are not normally sampled. To understand if patients admitted to the hospital for colorectal surgery 
were colonised with resistant bacteria pre-operatively we completed a feasibility study. In 63 patients 
due for colorectal surgery, rectal swabs were collected pre-operatively.  Enterobacteriaceae (e.g. 
E.coli) underwent antimicrobial susceptibility testing. It was found that 18.2% of patients with 
Enterobacteriaceae cultured (10/55) were colonised with cefuroxime resistant Enterobacteriaceae 
(Kirby 2015b). The antibiotic susceptibilities of these Enterobacteriaceae are presented in Table 1 by 
MIC value. A Minimum Inhibitory Concentration (MIC) is the lowest concentration that inhibits the 
growth of a bacterium. MICs are used to define bacteria as sensitive or resistant to an antibiotic i.e. as 
likely to be effectively treated by an antibiotic or not.  Cefuroxime resistance in Enterobacteriaceae is 
defined as an Enterobacteriaceae which requires >8mg/L to inhibit overnight growth.  
 
Table 1: The Minimum Inhibitory Concentration of rectally colonising Enterobacteriaceae to cefuroxime 
in participants planned to undergo elective colorectal surgery (Kirby 2015b) (resistance highlighted in 
bold).  
 
Enterobacteriacea MICs to cefuroxime (%) 
MIC 
(mg/L) 
<=2 
7.3 
4 
70.9 

 
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8 
3.6 
16 
7.3 
>=32 
10.9 
 
It is not known how MICs relate to treatment outcome when using antibiotics for surgical prophylaxis. 
Expert publications have suggested that the time during the operation that the free (non protein 
bound) serum drug level is above the MIC is most likely to be predictive of treatment success (Moine 
2013). By using clinical data on drug levels we can compare serum drug levels achieved throughout 
an operation in patients receiving standard doses of antibiotics to the antibiotic susceptibility of 
Enterobacteriaceae. A summary measure of Enterobacteriaceae susceptibility is the MIC90. The 
MIC90 is the MIC value which includes 90% of a bacterial population. For the data provided in Table 1 
the MIC90 is 16mg/L. These data suggest that treatment doses of antibiotics commonly used an 
antibiotic prophylaxis for surgery, e.g. cefuroxime (1.5g), does not reach blood levels which would 
inhibit the growth of 90% of bacteria for much beyond one hour of an operation (Table 2). These data 
should also be considered in relation to the variation in drug levels seen in a population of patients. In 
pharmacological models which take account of this variation, in patients with normal renal function, 
less than 40% of patients are predicted to have free serum drug levels of 8mg/l at 4 hours of surgery 
(Asín-Prieto 2015).  
  
Table 2: Known and estimated cefuroxime serum drug concentrations after intravenous administration 
in relation to E. coli MIC90. 
Drug 
 
Drug concentration at 1 hour time intervals (mg/L) 
after a single intravenous dose 
Reference 
1hr 
2hr 
3hr 
4hr 
Cefuroxime 
1.5g  
Free drug: 
50% of total 
drug 
21.5 
12.15 
7.8 
4 
Estimated 
from Kucers’ 
2010 
Cefuroxime MIC90 (mg/L) 
16 
 
 
Table 2 shows that many patients do not achieve drug levels throughout surgery that are predicted to 
prevent infections. One way of maintaining drug levels at desired concentrations is by dosing 
differently. Currently, single doses of antibiotic are administered pre-operatively. An alternative 
strategy is to dose continuously throughout surgery. Continuous infusion offers the opportunity to 
maintain targeted drug concentrations for the duration of an operation. This could also be achieved by 
administering antibiotics with long serum half lives, Table 3. The antibiotics with long serum half lives 
are ceftriaxone and ertapenem. Ceftriaxone has been assessed in relation to other cephalosporins 
with shorter half lives and been found to be more effective. For abdominal surgery ceftriaxone is more 
effective these other cephalosprins, having an odds ratio of 0.5 (Woodfield 2009). And ertapenem, 
when compared to ceftriaxone has been shown to be equally effective (Leng 2014). The 
disadvantages of these antibiotics are that they have been written out of antibiotic prophylaxis 

 
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guidelines by microbiologists due to concerns over antibiotic resistance and Clostridium difficile 
infection. Third generation cephalosporins (e.g. ceftriaxone) and carbapenems are antibiotics that are 
usually reserved for the treatment of antibiotic resistant infections in hospitalised patients. Widespread 
use for antibiotic prophylaxis would be a concern as antibiotic consumption is known to relate to 
antibiotic resistance. In addition, the use of antibiotics with a long half-life would expose bacteria to 
antibiotics over a relatively long period of time, and to relatively low concentrations of antibiotics for a 
long time (i.e. a long tail). Ceftriaxone use has been dramatically reduced in the UK given it 
association with C. difficile infection. Therefore it is unlikely a strategy of prophylaxis using ceftriaxone, 
despite its improved efficacy, would be accepted within the NHS. 
 
Table 3: Ceftriaxone and ertapenem antibiotic serum drug concentrations after intravenous 
administration in relation to E. col MIC90. 
 
 
 
 
 
 
 
 
The problem of low drug levels when administering short half life antibiotics during surgery could be 
addressed by continuous infusion of these antibiotics. There is concern, and evidence (Zelenitsky 
2000) that these low levels which can occur during surgery are associated with antibiotic prophylaxis 
failures. This strategy, continuous infusion of short half life antibiotics, limits the post operative 
antibiotic exposure and so potentially reduces risks of C. difficile infection and antibiotic resistance.  
 
Antibiotic prophylaxis and pharmacodynamics 
If it is accepted that maintaining the antibiotic levels above certain serum blood concentration targets 
(pharmacokinetic (PK) targets) is desirable during surgery, consideration is needed as to exactly what 
that target is. The desired PK target should take account of what antibiotic concentration profile is best 
able to prevent an infection (pharmacodynamic (PD) targets). PD targets are unfortunately unknown 
for prophylaxis. For treatment, the PD targets are most commonly the time unbound serum drug 
concentrations are above the MIC (fT>MIC), or the ratio of maximal serum concentration to MIC 
(CMAX/MIC) (MacGowan 2011). There are reasons these relationships may not be applicable to 
prophylaxis. Firstly, there is clinical evidence: A study of gentamicin prophylaxis showed that serum 
concentrations at the end of surgery were associated with efficacy, whereas treatment success with 
gentamicin is predicted by CMAX/MIC. In addition, serum drug levels below 3.5g//L were associated 
Drug 
 
Drug concentration at 1 hour time intervals (mgL)  
after a single intravenous dose 
Reference 
1hr 
2hrs 
3hrs 
4hrs 
 
Ceftriaxone 1g 
Fee drug:  
27 % 
1.74 
1.3 
0.98 
0.73 
Kucers’ 
Ceftriaxone MIC 90 mg/L 
0.125 
 
Ertapenem 1g 
Free drug: 
10% 
13.1 
11.4 
9.0 
8.0 
Kucers’ 
Ertapenem MIC 90 mg/L 
0.25 
 

 
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with an increased SSI rate (Zelenitsky 2000). Given the MIC90 of gentamicin is 1-2mg/L (estimate 
based on EUCAST data (http://www.eucast.org/)) this would suggest the effectiveness of gentamicin 
prophylaxis was reduced below fT>2-4xMIC90. Theoretical reasons why treatment exposure-response 
relationships may not be relevant to prophylaxis include: The site of surgery does not have an 
established immune response as it would in an infection, so blood/drug flows and immune responses 
at the surgical site are reduced. The bacterial challenge is numerically higher: The load of bacteria 
within the gastrointestinal tract is likely to be different, and higher, to that identified in an infection. The 
surgical process is traumatic and likely to result is tissue with reduced blood flow via damaged blood 
vessels. Antibiotic penetration may be reduced. Tissue damage is likely to result in the release of 
cellular protein. Antibiotics bind to protein and so, especially for long acting (high protein binding) 
antibiotics, free/active drug concentrations may be lower than predicted. Antibiotic prophylaxis is 
single dose, acting over a short time period, compared to treatment which is multi-dose over a number 
of days. On this basis it is not possible to design antibiotic dosing regimens for antibiotic prophylaxis in 
colorectal surgery which are based on high quality evidence. The absence of data on which to design 
the dosing regimen for this study is the weakness of the study, but it also is the basis on which the 
study is required.  
 
Free serum antibiotic concentrations vs tissue concentrations 
Tissue antibiotic concentrations, in relation to antibiotic activity, have been suggested as an alternative 
marker of outcomes than serum antibiotic concentrations. As described by Mouton et al, tissue 
concentrations are difficult to measure. Tissue homogenates are often assessed for drug 
concentration but these levels may not reflect the drugs true location e.g. extracellular vs intracellular. 
In addition, the time profile of tissue concentrations is different to serum concentrations so multiple 
samples require testing (Mouton 2008). Enterobacteriaceae which are being studied in this research 
are extracellular pathogens, and the extracellular fluid rapidly equilibrates with the serum 
concentrations. On this basis serum antibiotic concentrations have been chosen as the preferred 
biomarker over tissue concentrations.   
 
Systematic reviews 
 
 
Antibiotic resistance impact on SSIs 
 
In 2015 Kirby & Santoni published a review of the impact of antibiotic resistant Enterobacteriaceae on 
the efficacy of antibiotic prophylaxis for surgical site infections in colorectal surgery (Kirby 2015c). No 
clinical research data was identified to inform clinical practice. One ongoing research project was 
identified. The study (R-GNOSIS) is investigating the use of a rapid molecular test for antibiotic 
resistance with modification of antibiotic prophylaxis when resistance genes are detected.  
 
 
CDC systematic review into the prevention of surgical site infections. 

 
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In 2014 the Centre for Disease Control (CDC) in the USA published a systematic review into the 
prevention of SSIs (CDC 2014). They addressed questions identified by experts as the most important 
for SSI prevention. Two of those questions are relevant to this research. They asked if there was 
evidence for dose modifications based on patient weight, and the need to achieve higher intra-
operative antibiotic drug levels by intra-operative re-dosing. Both original articles were reviewed as 
well as clinical guidelines, so comparing evidence and practice recommendations.   
Weight based dosing: CDC “did not identify any randomised controlled trial or systematic review that 
evaluated weight-adjusted antimicrobial prophylaxis dosing and its impact on the risk of SSI”. They 
reviewed clinical guidelines and found: “Clinical practice guidelines based on a review of the evidence 
and expert opinion recommend increasing the single preoperative prophylactic antimicrobial agent 
dose for select prophylactic antimicrobial agents in obese and morbidly obese patients” 
Intraoperative redosing: Only one RCT was identified which compared single dose timentin (an 
antibiotic containing ticarcillin and clavulanic acid)) and timentin re-dosed at 2 hours after the first dose 
of antibiotic prophylaxis.  No differences in outcomes were reported. CDC reports this trial to be at 
moderate risk of bias. It is noted the trial was reported in 1991, when antibiotic resistance and BMIs 
were lower. The results were not subject to multivariate analysis. The half life of timentin is 
approximately 1 hour. The review reports: “Clinical practice guidelines based on a review of the 
evidence and expert opinion recommend prophylactic antimicrobial agent redosing in cases of 
prolonged procedures (when the procedure exceeds the half-life of the prophylactic antimicrobial 
agent or is longer than 3-4 hours) and in patients with major blood loss (>1500 ml) or extensive burns. 
Redosing should also be performed at intervals of 1-2 times the prophylactic antimicrobial agent half-
life, starting at the beginning of the pre-operative dose. No recommendations are provided for optimal 
prophylactic antimicrobial agent dosing in obese and morbidly obese patients when redosing.” 
CDC Recommendations 
No recommendation can be made regarding the safety and effectiveness of weight-adjusted dosing of 
parenteral prophylactic antimicrobial agents for the prevention of surgical site infection (No 
recommendation/unresolved issue) (Key Question 1C). 
No recommendation can be made regarding the safety and effectiveness of intraoperative redosing of 
parenteral prophylactic antimicrobial agents for the prevention of surgical site infection (No 
recommendation/unresolved issue) (Key Question 1D). 
 
 
Cochrane review of antibiotic prophylaxis for colorectal surgery 
 
In 2014 a Cochrane review of antibiotic prophylaxis in colorectal surgery determined that aerobic 
cover, in addition to anaerobic cover, reduced surgical site infection (SSI) rates (RR 0.44, 95% C.I. 
0.29 to 0.68) (Nelson 2014). This benefit obtained by addition of aerobic cover is the potential for 
surgical efficacy to be reduced if Enterobacteriaceae (aerobe) resistance impacts on the efficacy of 
antibiotic prophylaxis. No recommendations are made on antibiotic dosing.  

 
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 
Meta-analysis of ceftriaxone vs other antibiotics for antibiotic prophylaxis. 
 
Ceftriaxone, an antibiotic with a long half life, has been assessed in relation to other cephalosporins 
with shorter half lives and been found to be more effective. For abdominal surgery it is more effective, 
having an odds ratio of 0.5 (Woodfield 2009). 
 
Brief description of proposed study 
We propose to randomise patients due to undergo colorectal surgery to standard antibiotic prophylaxis 
or an interventional antibiotic prophylaxis regimen and assess surgical site infection (SSI) 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. 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 site 
infections after colorectal surgery. 
 
The rationale for this study design is based on the following rationale. An expert assessment is that 
fT>MIC is the measure most likely to be applicable to prophylaxis (Moine 2013). But as shown in table 
2, 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 (Macgowan). 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. Bolus-
Continuous infusion of antibiotic prophylaxis will ensure there is continuous targeting of this drug level 
throughout the operation.  
 
2 
RATIONALE  
 

 
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Research question: Does pharmacodynamic target (4x MIC90 free serum concentration) based 
continuous antibiotic dosing of antibiotic prophylaxis reduce the rate of surgical site infection after 
colorectal surgery when compared against standard antibiotic prophylaxis dosing regimens.  
 
Research hypothesis: Pharmacodynamic target (4x MIC90 free serum concentration) based 
continuous antibiotic dosing of antibiotic prophylaxis reduces the rate of surgical site infections after 
colorectal surgery by 50% when compared against standard antibiotic prophylaxis dosing regimens. 
 
Importance of research question 
 
Surgical site infections after colorectal surgery are an important post-operative complication.  
 
 
78,000 patients annually undergo elective colorectal surgery in England (Hospital Episode 
Statistics 2014) with approximately 22% (12%) developing an SSI. 9000 patients undergo 
emergency surgery, with approximately 30% developing an SSI.  
 
SSIs after colorectal surgery have been associated with an increased hospital stay (Kirby 
2015a) 
 
SSIs are recognised as a patient safety issue: The National Patient Safety website and the 
Patient Safety First campaign highlight that prevention of SSIs is an NHS patient safety priority. 
 
On average each SSI is treated with 8 days of antibiotics. Antibiotic consumption is associated 
with antibiotic resistance. 
 
It is recognised that antibiotic resistance threatens the viability of surgical procedures. Sally 
Davies, England’s Chief Medical Officer, has said “antibiotic resistance could routinely result in 
deaths from minor surgery”. If new antibiotics are developed they are unlikely to be used for 
routine prophylaxis.  We must therefore do better with the antibiotics we currently have. 
 
The English National Point Prevalence Survey of HCAIs identified 13.2% of antibiotics 
prescribed in hospital each day were for surgical prophylaxis. This is therefore an important 
area to dose correctly.  
 
Why closely related questions are not being answered 
 
Weight based dosing/intra-operative re-dosing. 
The CDC systematic review on the prevention of surgical site infections identified 10 key questions 
after consultation with expert sources. Five of these questions were related to antibiotic prophylaxis, 
three were answered with a recommendation, but two questions received no recommendation and 
were identified as an unresolved issue. These two questions relate to:  
1- The safety and effectiveness of weight-adjusted dosing of parenteral prophylactic antimicrobial 
agents for the prevention of surgical site infection. 
2- The safety and effectiveness of intraoperative redosing of parenteral prophylactic antimicrobial 
agents for the prevention of surgical site infection. 
Both these questions are essentially asking if dosing of antibiotic prophylaxis can be optimised. The 
Colo-Pro study will address both these questions in a single study of optimised dosing of antibiotic 
prophylaxis. PK analysis has shown that weight is not an important variable in an optimised regimen, 
but renal function is. PD target dosing includes renal function within the dose calculation, which PK 

 
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analysis suggests is more important than weight, and the continuous infusion addresses the aim of re-
dosing i.e. maintaining “therapeutic” drug levels through the operation.   
 
Individualised antibiotic prophylaxis  
An individual’s antibiotic prophylaxis could be modified based on antibiotic resistance testing of 
colonising Enterobacteriaceae. The challenges to this approach are 
1- Time delays involved in testing 
2- No established or defined sensitive/resistance testing protocols. Sensitive resistance 
classifications used for treatment may not be relevant to the prophylaxis setting. 
3- Logistics of individualising prophylaxis 
4- Excludes emergency surgical patients 
5- Excludes the possibility of reducing SSI rates in the majority of patients with sensitive 
Enterobacteriaceae (80%) who have a high rate of SSIs 
Rapid molecular testing could be completed, as per the R-GNOSIS study, which is using a rapid 
molecular test. In the UK we have low rates of ESBL infections, and detection of a resistance 
mechanism may not be informative with regard the expression of the resistance mechanism. Despite 
the limitations of this approach it is a potential avenue of research. We would explore the testing 
aspects of this approach within the Colo-Pro study. Rectal swabs would be collected pre-operatively 
and various biomarkers with regard to colonising Enterobacteriaceae (Species, Concentration, 
Antimicrobial susceptibility testing) would be determined and related to outcomes. This will allow a 
greater understanding of resistance in the prophylaxis setting, and what the best test of resistance 
testing and individualising antibiotic prophylaxis would be. 
 
Alternative antibiotic choice 
Another strategy to reducing SSI rates could be to compare alternative antibiotics. There are some 
new antibiotics e.g. tigecycline, and old antibiotics e.g. fosfomycin, that could be used for antibiotic 
prophylaxis. The use of these antibiotics could potentially help mitigate some of the impact of 
antibiotic resistance. They may not though be expected to reduce SSI rates for the majority of patients 
who have susceptible Enterobacteriaceae and so not answer questions identified by the CDC experts 
relating to weight based dosing and re-dosing. Nor the question set by this study of PD target driven 
dosing. Alternative antibiotics may also have limitations e.g. tigecycline has no activity against 
Morganella or Proteus spp. In settings of high resistance we think a strategy of alternative antibiotics 
should be explored and we would consider investigating it once more fundamental principles of 
antibiotic dosing for surgical prophylaxis have been established in the Colo-Pro study. 
 
Risk based approach to alternative regimens 
Another strategy to avoid treating patients colonised with resistant Enterobacteriaceae with antibiotics 
they were resistant to would be to create an antibiotic resistance risk prediction rule. In our Leeds 
study (Kirby 2015b) there were no factors which predicted colonisation with a resistant 
Enterobacteriaceae.   
 
Non absorbable oral antibiotics 
The Cochrane review of antibiotic prophylaxis in colorectal surgery asked if oral (PO) non absorbable 
oral antibiotics given in addition to intravenous (IV) antibiotics for antibiotic prophylaxis were able to 

 
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reduce SSI risk. It was reported that combining these two regimens reduced SSI rates (RR 0.56 [0.43, 
0.74]) compared to IV therapy alone. These trials were carried out in an era of pre-operative bowel 
cleaning preparation. Pre-operative bowel preparation has not been associated with clinical benefit so 
is now not recommended, and it is not known if this will reduce the efficacy of non absorbable oral 
antibiotic prophylaxis. A number of trials in this meta-analysis were limited by including systemically 
absorbed PO antibiotics. In addition the PO regimens included regimens given for a number of days, 
which may increase the opportunity for selection of antibiotic resistance. There are large trials not 
included in the Cochrane review which do not show a benefit of oral antibiotic prophylaxis (Kobayashi 
2007). There is therefore clearly clinical equipoise in this area and it is suggested research is carried 
out. We suggest this should be carried out after the IV antibiotics have been assessed for optimisation 
given the increased chance of resistance associated with more prolonged courses of antibiotics. 
 
Long half life antibiotics 
See background section: Long half life antibiotics. 
 
Available treatments and their limitations 
 
In the UK three regimens are commonly recommended for antibiotic prophylaxis: 
1- Co-amoxiclav 1.2g IV 
2- Cefuroxime 1.5g IV and Metronidazole 400mg IV 
3- Amoxicillin 1g IV, Gentamicin (various doses), and Metronidazole 400mg IV 
 
There are a number of potential limitations to these treatments 
1- Dosing is fixed. This may result in antibiotic drug levels which are lower than intended, with an 
increased risk of antibiotic prophylaxis failure. 
2- Dosing is single dose, and the antibiotics have a short half-life, 1-2 hours. This can result in 
antibiotic drug levels which are lower than intended, with an increased risk of antibiotic 
prophylaxis failure. 
3- The dosing of these antibiotics has not been optimised. 
4- Antimicrobial resistance may be having an impact on the efficacy of prophylaxis 
5- Increasing antibiotic MICs, even within the susceptible range, may be having an effect on the 
efficacy of prophylaxis. 
6- If re-dosing is recommended, it is frequently forgotten by the surgical/anaesthetic team. 
 
The potential improvement of the Investigational Medicinal product (IMP) over the standard treatments 
is: 
1- Dosing is varied based on renal function, ensuring targeted drug levels are more likely to be 
achieved increasing the chance of antibiotic prophylaxis success. 
2- Dosing is continuous, avoiding the risk of low levels during the procedure.  
3- The dosing achieves MIC serum levels equal to 4x MIC90 throughout the operation, a level 
which will potentially provide an optimised antibiotic prophylaxis regimen. 
4- A continuous infusion will remove the need for a surgeon/anaesthetist to remember to provide 
recommended re-dosing during an operation. 
 

 
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The minimum clinically important difference 
From the patients perspective the receipt of antibiotic prophylaxis by single dose or continuous 
infusion is not important given they are anaesthetised for duration of antibiotic administration. And the 
dosing is not expected to increase the risk of side effects. Therefore any reduction in SSI rates will be 
acceptable to the patient. Though not expected, there are potential risks to patients e.g. increased risk 
of thrombophlebitis, vascular access related complications; larger overall doses of antibiotic may 
increase C. difficile risk and risk of antibiotic resistance. The alternative beta-lactam used in the UK for 
prophylaxis is co-amoxiclav. There is evidence that cefuroxime has a lower C. difficile infection risk 
than co-amoxiclav supporting the choice of cefuroxime (Slimings 2014). 
The additional cost of a continuous infusion regimen is likely to be minimal for an individual patient. 
There will be no additional cost beyond those associated with the infusion equipment and additional 
antibiotic costs. These are likely to be small in relation to the cost of £5000 per SSI i.e. only a 1 or 2 
percent reduction in SSI rates is likely to be cost effective.  
The study will therefore not be powered based on a minimally clinically important difference but will 
consider expected reductions in SSI rates. 
 
Justification for the dosage regimen and treatment duration 
Antibiotic prophylaxis at treatment doses is the most effective intervention for the prevention of SSIs. 
Despite this effective intervention a significant minority of patients, >10%, still suffer SSIs. Therefore, if 
it is possible to improve the efficacy of prophylaxis it is likely, given the limited benefits of other 
interventions aimed at reducing SSI rates, that this intervention would offer the most rewards in terms 
of reducing SSIs. To improve the efficacy of an antibiotic intervention it would be normal practice to 
design a dosing regimen using the known exposure-response relationship. An exposure-response 
relationship would define the most effective dosing regimen. Different exposure-response relationships 
have been identified in the treatment of infections. For example, aminoglycoside dosing is optimised 
by getting a high ratio of peak drug concentration/MIC. For beta-lactams the time the serum level is 
above the MIC is important. The exposure-response for antibiotics used for prophylaxis is unknown.  
We have therefore decided to investigate if a pharmacodynamic (PD) target based dosing approach, 
with a single target that covers a number of different exposure-response relationships, is more 
effective than standard antibiotic dosing regimens. The use of a PD target, as opposed to simply 
giving higher doses, means that we address issues highlighted as being important. These include 
obesity and the need to maintain antibiotic drug levels throughout the duration of surgery. A PD target 
of a free serum drug concentration of 4 x MIC 90 value has been chosen as up to this level bacterial 
killing is reported to increase (MacGowan 2011). This level equates to 64mg/L for and cefuroxime, 
which is below a level of 100mg/L. It has been suggested that a level of <100mg/L is a safe beta-
lactam target to aim for (Moriyama 2010). This level will potentially increase the killing of bacteria 
including those that are resistant (MIC>8mg/L). The PD target chosen, 4xMIC90, therefore addresses 
concerns that antibiotic resistance is impacting on the efficacy on standard dosing of antibiotic 
prophylaxis. 
 
Choice of control interventions: 
Intravenous cefuroxime 1.5 grams pre-operatively, and repeated at 4 hours will be the standard 
treatment, in combination with intravenous metronidazole 500mg as a single pre-operative dose. 
This equates to standard treatment. 
 

 
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2.1 
Assessment and management of risk 
 
Benefit analysis: The potential benefits from the IMP are a reduced SSI rate which is estimated to be 
in the order of a 50% reduction. SSIs are associated with increased length of hospital stay, increased 
cost and increased antibiotic consumption. 
 
Risk analysis 
Beta-lactam antibiotics are generally very well tolerated. The most serious potential risk is anaphylaxis 
which is reported in 1-5/10,000 doses.  As per usual clinical practise, patients will have their allergy 
status checked pre-operatively and those with a known relevant allergy excluded from the trial. For 
those included, we have no reason to believe that continuous infusion is any more likely to result in an 
allergic reaction than bolus dose. The risk above standard treatment with in this study protocol is the 
higher dose of cefuroxime required to achieve the target a serum level of 64mg/L for the duration of 
surgery (53% <3 hours, 95% < 6 hours). Cefuroxime levels above 64mg/L are surpassed after bolus 
administration of intravenous therapy. But due to cefuroxime’s short half life (1.5 hours) these levels 
normally fall over the following hours. Continuous infusions of beta-lactam antibiotics, in order to 
achieve continuously targeted serum concentrations of up to 100mg/L, have been administered for 
days of treatment without reported adverse events (Moriyama 2010). Other beta-lactams e.g. 
piperacillin, are given at 4g in a single dose (repeated 8 hourly). Cefuroxime can be dosed at higher 
doses (higher dose 3g 8 hourly, vs standard dose 1.5 g 8 hourly) for meningitis. This suggests 
targeting cefuroxime serum levels of 64mg/L for up to 6 hours is unlikely to result in dose related 
adverse events. See section 8.6 for full details of the study intervention dosing regimen.  
 
An assessment of adverse events associated with cefuroxime is provided in the products SPC: 
https://www.medicines.org.uk/emc/medicine/16929 
 
This study has been reviewed by the MHRA and assessed as not being a CTIMP. 
 
Risk minimisation/management 
 
Administration of doses: Anaesthetists/Research staff will administer antibiotics. They will use 
a programmable infusion pump to dose according to the protocol.  
 
Intravenous antibiotics can cause phlebitis, therefore antibiotic administration 
recommendations will be that where possible a 14G cannula/largest possible is used for 
administering antibiotic into a large peripheral vein.  
 
 
 
3 
OBJECTIVES AND OUTCOME MEASURES/ENDPOINTS 
 

 
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3.1 
Primary objective 
 
To determine if pharmacodynamic target (4xMIC90 free serum concentrations) based continuous 
antibiotic dosing of antibiotic prophylaxis reduces the rate of surgical site infections after colorectal 
surgery when compared against standard antibiotic prophylaxis dosing regimens. 
 
3.2 
Secondary objectives 
 
To determine if pharmacodynamic target (4xMIC90 free serum concentrations) based continuous 
antibiotic dosing of antibiotic prophylaxis reduces the rate of all in-patient infections after colorectal 
surgery when compared against standard antibiotic prophylaxis dosing regimens. 
 
To determine if pharmacodynamic target (4xMIC90 free serum concentrations) based continuous 
antibiotic dosing of antibiotic prophylaxis reduces the in-patient consumption of antibiotics after 
colorectal surgery when compared against standard antibiotic prophylaxis dosing regimens. 
 
To determine if pharmacodynamic target (4xMIC90 free serum concentrations) based continuous 
antibiotic dosing of antibiotic prophylaxis reduces the length of hospital stay after colorectal surgery 
when compared against standard antibiotic prophylaxis dosing regimens. 
 
To determine if pharmacodynamic target (4xMIC90 free serum concentrations) based continuous 
antibiotic dosing of antibiotic prophylaxis reduces mortality after colorectal surgery when compared 
against standard antibiotic prophylaxis dosing regimens.) 
 
To determine if pharmacodynamic target (4xMIC90 free serum concentrations) based continuous 
antibiotic dosing of antibiotic prophylaxis reduces anastomotic leak after colorectal surgery when 
compared against standard antibiotic prophylaxis dosing regimens. 
 
To determine if pharmacodynamic target (4xMIC90 free serum concentrations) based continuous 
antibiotic dosing of antibiotic prophylaxis improves quality of life after colorectal surgery when 
compared against standard antibiotic prophylaxis dosing regimens. 
 
To determine if pharmacodynamic target (4xMIC90 free serum concentrations) based continuous 
antibiotic dosing of antibiotic prophylaxis reduces the cost of healthcare treatment after colorectal 
surgery when compared against standard antibiotic prophylaxis dosing regimens. 
 
To determine if pre-operative antibiotic resistance, as determined by antibiotic susceptibility testing of 
rectally colonising Enterobacteriaceae,  is predictive of a patients risk of a post-operative surgical site 
infection. 
 

 
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To determine the exposure-response relationship for antibiotic prophylaxis in the prevention of surgical 
site infection prevention after colorectal surgery. 
 
3.3 
Outcome measures/endpoints 
 
3.4 
Primary endpoint/outcome 
Primary endpoint: Surgical site infection within 30 days of operation. 
Endpoint aggregation by percent. 
Timings of measurement: Day 5, Day 30. 
 
Rationale for the choice of trial endpoint/outcome 
The Centre for Disease Control’s (CDCs) National Nosocomial Infections Surveillance (NNIS) criteria 
for defining SSIs, to be used in this study, have been widely applied to SSI research studies. 
Application of these criteria has been shown to differentiate the effectiveness of SSI interventions in a 
number of studies e.g. antibiotic prophylaxis and surgical skin preparation. Whilst these criteria do 
have some limitations, principally the application involves a subjective assessment of the wound, we 
have agreed access to a SSI assessment training package developed for the ROSSINI trial (NIHR 
RfPB funded) to help standardise SSI assessment. 
 
3.5 
Secondary endpoints/outcomes 
• 
All in-patient infections within 30 days of operation 
• 
All in-patient antimicrobial consumption within 30 days of operation. 
• 
Length of hospital stay after operation 
• 
Mortality after operation at one year. 
•  
Anastomotic leak within 30 days of operation 
• 
Quality of life scores pre-operatively and at 30 days.  
• 
Cost of healthcare treatments after operation at 30 days. 
 
3.6 
Exploratory endpoints/outcomes  
 
Table 5: Exploratory endpoints 
Objectives 
Outcome Measures  
Timepoint(s) of evaluation of 
this outcome measure (if 
applicable) 
To explore the impact of the 
antibiotic susceptibility of 
rectally colonising 
Enterobacteriaceae on the 
Minimum Inhibitory 
Concentration of the 
Predominant 
Enterobacteriaceae 
Pre-operative 

 
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efficacy of antibiotic prophylaxis 
in patients receiving standard 
antibiotic dosing, and in patients 
receiving PD target based 
dosing. 
 
Minimum Inhibitory 
Concentration of the most 
resistant Enterobacteriaceae 
 
Minimum Inhibitory 
Concentration of the 
predominant E. coli.  
 
Surgical site infection rate within 
30 days of operation 
 
To determine exposure 
response relationships within 
patients treated with standard 
antibiotic dosing. 
Free serum drug levels  
MICs of colonising 
Enterobacteriaceae 
Exposure response 
relationships including: 
fT>MIC  
CMAX/MIC 
1,2,3 and 4 hours post initiation 
of antibiotic prophylaxis. 
 
 
4 
TRIAL DESIGN 
 
Colo-Pro Pilot: A pilot randomised controlled single blind trial to compare standard single dose of 
antibiotic prophylaxis to antibiotic prophylaxis administered as a continuous infusion for the prevention 
of surgical site infections in adults undergoing colorectal surgery. 
 
5 
STUDY SETTING 
 
Leeds Teaching Hospitals NHS Trust 
 
Interventions will be carried out by the following staff 
o Recruitment and allocation: Research nurse or research doctor 
o Intervention: Anaesthetist and surgeon, supported by a research nurse or research 
doctor. 
o Sample collection: Rectal swab and blood samples: Research nurse or research doctor 
o Outcome data collection: Research nurse or research doctor. 
 
 

 
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6 
ELIGIBILITY CRITERIA 
 
This study is pragmatic as it is intended that the intervention would be applied to all patients undergoing 
colorectal surgery, emergency and elective, with varied indications for surgery, and varied risks of surgical 
site infections. 
 
6.1 
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  
 
6.2 
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 an SSI at the time of study entry. 
 
STARR procedures 
 
Weight <30kg or >110kg 
 

 
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Duration of the risk mitigation measures: 24 hours  
MPs are not teratogenic 
 
7 
TRIAL PROCEDURES  
Schedule of procedures: Appendix 4. 
 
7.1 
Recruitment 
Participants who are screened for trial entry and are not randomised will have data collected for 
Consolidated Standards of Reporting Trials (CONSORT) reasons to allow reporting of the 
generalisability of the results. Anonymised information on participants who are not randomised for will 
include: Age, Gender, whether the patient is registered or not registered, the reason not eligible for 
trial participation, or if they are eligible but declined, the procedure they were due to undergo, if the 
procedure was elective or an emergency procedure and the ASA score. 
 
7.1.1 Patient identification 
Participant eligibility screening process 
Patients will be identified for trial entry by a number of methods including: 
- 
Notification by a member of the patient’s clinical team, to the research team, a patient is due to 
undergo colorectal surgery. This may happen after the patient has been seen: 
o In the outpatient setting 
o As a hospital in patient 
- 
Identification by a member of the research team a patient is due to undergo colorectal surgery 
by screening of hospital surgical theatre lists.  
 
Both the clinical team and the research staff will hold a contract, permanent or honorary, with their 
host hospital. All recruiting staff will therefore be part of the patient’s normal clinical staff. 
 
The research team will include medical and nursing staff. Eligibility will be confirmed by a medical 
practitioner. 
 
 
7.1.2 Screening 
 
No diagnostic testing is required to confirm eligibility 
 
Penicillin/cephalosporin allergy will be assessed  
 
7.2 Consent  
The Principal Investigator (PI) retains overall responsibility for the informed consent of participants at 
their site and will ensure that any person delegated responsibility to participate in the informed consent 
process is duly authorised, trained and competent to participate according to the ethically approved 
protocol, principles of Good Clinical Practice (GCP) and Declaration of Helsinki.  
Delegation of consent: 

 
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Informed consent will be obtained prior to the participant undergoing procedures specifically for the 
purposes of the trial  
The right of a participant to refuse participation without giving reasons will be respected.   
The participant will remain free to withdraw at any time from the trial without giving reasons and 
without prejudicing his/her further treatment and will be provided with a contact point where he/she 
may obtain further information about the trial.  
The PI takes responsibility for ensuring that all vulnerable subjects are protected and participate 
voluntarily in an environment free from coercion or undue influence 
Translation:  
To comply with the Welsh Language Act 1993, the Participant Information Sheets and Consent forms 
will be translated into Welsh or provided bilingually where this is requested by a participant at a 
research site. 
The protocol will fully describe the process which typically involves: 
Consenting protocol involved: 
 
Discussion between the potential participant or his/her legally acceptable representative and 
an individual knowledgeable about the research about the nature and objectives of the trial 
and possible risks associated with their participation 
 
The presentation of written material (Patient information leaflet and consent form, approved 
by the REC and in compliance with GCP, local regulatory requirements and legal 
requirements) 
 
The opportunity for potential participants to ask questions 
 
Assessment of capacity. Participants must be capable of giving consent for themselves. A 
capable person will:  
o understand the purpose and nature of the research  
o understand what the research involves, its benefits (or lack of benefits), risks and 
burdens  
o understand the alternatives to taking part  
o be able to retain the information long enough to make an effective decision. 
o be able to make a free choice  
o be capable of making this particular decision at the time it needs to be made (though 
their capacity may fluctuate, and they may be capable of making some decisions but 
not others depending on their complexity) 
o where participants are capable of consenting for themselves but are particularly 
susceptible to coercion, it is important to explain how their interests will be protected 
Where a participant is able to consent but later becomes incapacitated the participant would be 
withdrawn from the study. Identifiable data or tissue already collected with consent would be retained 
and used in the study. No further data or tissue would be collected or any other research procedures 
carried out on or in relation to the participant. 
 
7.2.1 Additional consent provisions for collection and use of participant data and biological 
specimens in ancillary studies, if applicable 

 
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 
Data and biological specimens including bacteria from rectal swabs and blood samples for 
antibiotic drug concentrations will be acquired and stored during the trial. 
 
Participation in the ancillary research is required for participation in trial. A single consent will 
be obtained for the use of rectal swabs samples and blood samples for antibiotic drug 
concentrations in planned and future research related to the clinical condition under study 
only. 
 
7.3 
The randomisation scheme 
 
Simple randomisation with a 1:1 allocation ratio will be used to allocate patients.  
 
7.3.1 Method of implementing the allocation sequence 
The allocation sequence will involve: 
- 
generation of an unpredictable allocation sequence  
- 
concealment of that sequence until assignment irreversibly occurs. 
The system to use be used a web based randomisation/treatment allocation system 
Research nurses and research doctors recruiting patients will access this at the research  
 The allocation system will provide sealed envelopes to be accessed upon a decision to allocate a 
participant to a treatment arm.   
 Documentation of the randomisation arm will be added to the patient notes in a sealed document 
holder for access in case of medical need only. 
 Documentation of the randomisation will be provided to a research database accessible to 
researchers.  
 
7.4 
Blinding 
 
The trial design is a single blinded trial. The trial participants will be blinded to their treatment.  
Staff present at the time of operation, and prophylaxis, will be unblinded.  
Health care staff not present at the time of operation will be blinded to treatment.  
Outcome assessors will be blinded to treatment. 
Final unbinding of all trial participants will occur after the creation of a locked analysis data set. 
Medical/Anaesthetic notes will not contain the patient’s treatment arm to limit unbinding.  
 
Blinding of all care providers is not possible because of logistics relating to the blinding of treatments at 
short notice for all trial participants e.g. emergency surgery participants.  
 
7.5 
Unblinding 
 

 
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The study code will only be broken for valid medical or safety reasons e.g. in the case of a severe 
adverse event where it is necessary for the investigator or treating health care professional to know which 
treatment the patient is receiving before the participant can be treated. Subject always to clinical need, 
where possible, members of the research team will remain blinded. Documentation of the blinding arm 
will remain in the patient’s notes to allow access as needed. If this information is accessed the person 
accessing the arm will be notified to inform the principal investigator. The PI will notify the study sponsor 
and relevant authorities.  
 
7.6 
Baseline data 
 
Data collection includes but is not limited to: 
Pre-operative data 
- 
Age 
- 
Sex 
- 
Height/Weight 
- 
Co-morbidities 
- 
Indication for surgery 
- 
Pre-operative blood tests e.g. haemoglobin 
- 
National Nosocomial Infection Score 
- 
MRSA colonisation status 
- 
Infection status. Defined by NNIS definitions 
- 
Pre-operative radiotherapy 
- 
Pre-operative chemotherapy 
- 
Pre-operative bowel preparation 
Intra-operative data: 
- 
Surgical skin preparation 
- 
Surgical procedure- Including OPSC code 
- 
Surgical duration 
- 
Surgical classification (Clean to dirty) 
- 
Surgeon status 
- 
Surgical drain use 
- 
Colonic perforation noted.  
Post-operative data 
- 
Adverse events 
- 
Infections: Defined by NNIS definitions 
- 
Antibiotic consumption 
 
7.7 
Trial assessments 
 
Pre-operative assessment-Visit 1 
- 
Medical history 
- 
Antibiotic history 

 
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- 
Rectal swab 
- 
QofL assessment 
Intra-operative assessment-Visit 2 
- 
Anaesthetic history 
- 
Surgical history 
- 
Antibiotic prophylaxis history 
- 
Antibiotic blood concentrations 
Post operative assessment-Visit 3, day 5 (approximately) post-operation, or day of discharge 
- 
Medical history 
- 
Antibiotic history 
- 
Surgical site assessment: Where possible the surgical wound will be inspected and an SSI 
specific evaluation will be completed 
- 
Infections assessed as per standard (HPA point prevalence survey) definitions 
Post-operative assessments-Visit 4 (4A, 4B etc) (72 hourly post visit 3 while in-patient) 
- 
Medical history 
- 
Antibiotic history 
- 
Surgical site assessment: Where possible the surgical wound will be inspected and an SSI 
specific evaluation will be completed 
- 
Infections assessed as per standard (HPA point prevalence survey) definitions 
 
Post-operative assessment-Visit 5, day 30-45 post-operation 
- 
This will normally be completed by postal or telephone assessment though when possible the 
30-day follow-up might be combined with a patients post-operative clinic follow-up.  
- 
Surgical site infection questionnaire relating to outpatient SSIs 
- 
Antibiotic history 
- 
QofL questionnaire 
 
7.8 
Long term follow-up assessments 
 
Duration of follow-up period: 1 year 
Assessments to be carried out: Mortality assessments at 1 year via electronic health records. 
Patients will be identified as ‘lost to follow-up if they are unable to be contacted or declined further 
follow up.  
Measures taken to obtain the information if visits or data collection time-points are missed:  Medical 
noted will be reviewed where appropriate, questionnaires sent to patients or telephone interviews 
conducted.  
 
7.9 
Withdrawal criteria  
 

 
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The intervention is a single intervention, so withdrawal criteria are not expected to result from issues of 
being in the trial over a long period of time. 
An acute event associated with the MP would therefore be the main medical reason for removal from 
the trial. An anticipated acute event e.g. recognition of allergy after enrolment, would also lead to 
removal from the trial. These cases should be discussed with a microbiologist to decide upon 
appropriate antibiotic prophylaxis if the surgical procedure is performed as planned. A microbiologist 
will want to know how much antibiotic has been administered prior to the allergy being recognised, 
and the expected duration of the procedure. 
If withdrawn in this setting the participant would be included in the trial assessments as part of 
obtaining a complete data set for an intention to treat analysis.  
Documentation to be completed on subject withdrawal (including recording reasons for withdrawal and 
any follow-up information collected with timing). 
Withdrawn subjects are not to be replaced  
 
 
7.11 
Storage and analysis of samples 
 
Criteria for the collection, analysis, storage and destruction of biological samples 
 
Rectal swab 
 
- 
Testing location: Old Medical School, Leeds General Infirmary.  
- 
Timings of testing: Pre-operative 
- 
Shipping details: Clinical transport system 
- 
Sample destruction: At the end of the laboratory studies have been completed, not expected to be 
> 1 year after date of the participant recruitment. 
- 
Sample storage 
o Conditions: 4 degrees Celsius +/- 5 degrees Celsius 
o Duration: As sample destruction 
o Location: as testing location 
o Long term storage: None 
- 
Laboratory manual: Available in the Old Medical School, Leeds General Infirmary 
 
Blood samples for antibiotic drug concentrations 
- 
Whole blood 
- 
6 ml 
- 
Blood tube: Serum separator tube 
- 
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- 
Timings of testing: 4 samples taken intra-operatively. One sample will be collected at 
approximately 10 minutes after antibiotic infusion. One sample will be collected prior to closing the 
surgical wound. The other two samples will be taken after the surgery is approximately 1/3rd and 
2/3rds complete. If a patient is re-dosed intra-operatively one of the these two samples can be 
moved to be taken prior to the re-dosing. 
- 
Shipping details: On ICE to Southmeads Antibiotic reference laboratory 
- 
Sample destruction: As per Southmeads local guidelines (not more than 7 days of result) 
- 
Sample storage 
o Conditions: Freezer (-20 or -80 degrees) 
o Duration: Until testing 
o Location: Leeds and Southmeads 
o Long term storage: None 
 
Responsibilities of the trial site in regard to samples:  The trial site to ensure that samples are appropriately 
labelled in accordance with the trial procedures to comply with the 1998 Data Protection Act. Biological 
samples collected from participants as part of this trial will be transported, stored, accessed and processed 
in accordance with national legislation relating to the use and storage of human tissue for research 
purposes and such activities shall at least meet the requirements as set out in the 2004 Human Tissue Act 
and the 2006 Human Tissue (Scotland) Act. 
 
7.12 
End of trial 
The date of the last visit/data item of the last patient undergoing the trial is the trial end definition 
The study PI will notify REC of the end of the trial. 
 
8 
TRIAL MEDICATION 
 
8.1 
Name and description of medicinal product 
 
Comparators 
The comparator regimen is:  
Cefuroxime  
• 
Each vial contains, as the active ingredient, cefuroxime sodium for injection 1578mg equivalent 
to 1500mg of cefuroxime respectively 
Metronidazole 
• 
Metronidazole 5 mg/ml Solution 
Medicinal Products 
Cefuroxime  

 
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• 
Each vial contains, as the active ingredient, cefuroxime sodium for injection 1578mg equivalent 
to 1500mg of cefuroxime respectively 
Metronidazole 
• 
Metronidazole 5 mg/ml Solution  
Route of administration 
 
Intravenous 
 
8.2 
Legal status of the drug  
 
Cefuroxime 
- 
Licensed at 1.5g 8 hourly dosing and 3g 8 hourly (meningitis) 
- 
Indication: No BNF indication for surgical prophylaxis, although BNF provides dosing 
information for Surgical prophylaxis, 1.5 g by intravenous injection up to 30 minutes before the 
procedure. 
 
8.3 
Summary of Product Characteristics (SmPC) 
A Summary of Product Characteristics (SmPC) will be used in this trial. 
Updated versions will be incorporated into the trial after submission to the study sponsor, the National 
Research Ethics Committee (as appropriate).  
 
8.4 
Drug storage and supply 
 
The MPs will be supplied from normal hospital stock. 
 
The drug should be stored as per manufacturers guidelines 
 
8.5  
Preparation and labelling of Medicinal Product 
Preparation: Cefuroxime sodium will be diluted in water for injection. A dose of 1.5 grams will be 
diluted in 50ml’s of water for injection. Infusion will be according to Table 6 Labelling of infusion will be 
with infusion volume, drug concentration and infusion rate.  
Of note: The NHS Injectable Medicines Guide Group (2015) state that there is evidence of Y-site 
compatibility for atracurium and cefuroxime (in glucose 5%). This information is reflected in the 
Handbook of Injectable Drugs by Trissel (2015). 
 
8.6 
Dosage schedules 
Comparator 
 
Cefuroxime 1.5g 4 hourly throughout surgery. First dose given pre-operatively. 
 
Intervention 

 
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The MPs are to be administered to achieve a steady state blood concentration of free serum 
concentrations of 4xMIC90 for the duration of an operation, up to a total duration of 6 hours.  
In the intervention group, if surgery lasts for more than 6 hours, the infusion will be stopped and the 
dosing regimen will revert to 4-hourly bolus dose. 
Antibiotics will be administered initially with a loading dose, intravenously as is standard practice for 
antibiotic prophylaxis, in order that drug concentrations can be reliably achieved for the start of an 
operation. 
After the loading dose drug will be administered by continuous intravenous infusion. 
Timing of each dose: Loading dose will be within the hour before surgery, with initiation of the 
continuous infusion before surgery.  
To achieve this, the following calculations will be used to determine the bolus dose and the hourly 
dose. 
Loading dose (mg) =Cpeak(mg/L) x Vd(L/kg) x weight (kg) 
Maintenance infusion rate (mg/h)=Css (mg/L) x Cltotal (L/h) 
Maintenance infusion rate in renal impairment (mg/h) 
=maintenance infusion rate x (CrCl/100) 
Cltotal (L/h)=Ke(h-1)x Vd(L/kg) x weight (kg) 
Ke(h-1)=0.693/t1/2 
Cpeak=target peak concentration 
Vd=volume of distribution 
Css=target mean steady state concentration 
Cltotal=total body clearance 
Ke=elimination rate constant 
t1/2=half life 
CrCl=Creatanine clearance 
 
 
Cefuroxime dosing recommendations are provided below, Table 7. 
 
Table 7: Cefuroxime dosing guidelines 
 Weight 
(kg) 
Loading dose 
(mg) 
Continuous infusion dose: Based on creatinine clearance 
(ml/min) 
40-50 
50-60 
60-70 
70-80 
80-90 
>90 
30-40 
617 
128 
157 
185 
214 
242 
285 
40-50 
793 
165 
202 
238 
275 
312 
367 
50-60 
970 
202 
246 
291 
336 
381 
448 

 
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60-70 
1146 
238 
291 
344 
397 
450 
529 
70-80 
1322 
275 
336 
397 
458 
519 
611 
80-90 
1499 
312 
381 
450 
519 
589 
692 
90-100 
1675 
348 
426 
503 
580 
658 
774 
100-
110 
1851 
385 
470 
556 
641 
727 
855 
 
Maximum dosing 
A maximum loading dose of cefuroxime 2332 mg 
A maximum hourly dose of continuous infusion of 1226 mg/hour. 
These doses will be administered for a maximum of 6 hours. 
 
Route of administration: Intravenous 
 
8.7 
Dosage modifications  
Dose modifications: Dosages will be modified according to renal function as described in section 8.6.  
Stopping rules: Acute adverse event, duration of surgery 6 hours. 
Procedures in the event of toxicity reactions: Antibiotic treatment will be stopped.  
 
8.8 
Known drug reactions and interaction with other therapies 
 
The cefuroxime SPC reports: “Cephalosporin antibiotics at high dosage should be given with caution 
to patients receiving potent diuretics or aminoglycosides, as these combinations are suspected of 
adversely affecting renal function. Clinical experience has shown that this is not likely to be a problem 
at the recommended dose levels.” 
Given the short duration of treatment, and so low total drug amounts administered compared to daily 
treatment regimes, we will allow patients on diuretics (principally furosemide) and aminoglycosides to 
enter the study.  
 
8.9 
Concomitant medication 
 
Predictable concomitant agents include the anaesthetic medication administered intra-operatively.  
Anaesthetic medications: An exhaustive list of anaesthetic agents is not provided. Common anaesthetic 
agents are provided below: 
Anaesthetic agent: Propofol 
Analgesic/anaesthetics: Alfentanil, fentanyl, remifentanil 
Anaesthetic agents: Suxamethonium, atracurium, vecuronium, rocuronium 

 
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Analgesia: Morphone, tramadol, paracetamol, NSAID, oxycodone 
Anti-emetics: Ondansetron, dexamethasone, cyclizine, metocloprmamide 
Vasoconstictors: Metaraminol, ephedrine, noradrenaline 
 
Cephalosporins are not recognised as interacting with any anaesthetic agents.  
 
 
8.10 
Trial restrictions  
No contraindications whilst on the active phase of the trial. 
Contraception needs not be used.  
 
8.11 
Assessment of compliance 
Patient compliance is not applicable to this trial. 
Drug administration will be documented on research forms. 
 

 
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9 
PHARMACOVIGILANCE 
9.1 
Definitions 
Term 
Definition 
Adverse Event (AE) 
Any untoward medical occurrence in a participant to whom a 
medicinal product has been administered, including occurrences 
which are not necessarily caused by or related to that product.  
Adverse Reaction 
(AR) 
 
An untoward and unintended response in a participant to an 
medicinal product which is related to any dose administered to that 
participant. 
The phrase "response to an medicinal product" means that a causal 
relationship between a trial medication and an AE is at least a 
reasonable possibility, i.e. the relationship cannot be ruled out. 
All cases judged by either the reporting medically qualified 
professional or the Sponsor as having a reasonable suspected causal 
relationship to the trial medication qualify as adverse reactions. 
Serious Adverse 
Event (SAE) 
A serious adverse event is any untoward medical occurrence that: 
 results in death 
 is life-threatening 
 requires inpatient hospitalisation or prolongation of existing 
hospitalisation 
 results in persistent or significant disability/incapacity 
 consists of a congenital anomaly or birth defect 
Other ‘important medical events’ may also be considered serious if 
they jeopardise the participant or require an intervention to prevent 
one of the above consequences. 
NOTE: The term "life-threatening" in the definition of "serious" refers 
to an event in which the participant was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe. 
Serious Adverse 
Reaction (SAR) 
An adverse event that is both serious and, in the opinion of the 
reporting Investigator, believed with reasonable probability to be due 
to one of the trial treatments, based on the information provided. 
Suspected 
Unexpected Serious 
Adverse Reaction 
(SUSAR) 
A serious adverse reaction, the nature and severity of which is not 
consistent with the information about the medicinal product in 
question set out: 
 in the case of a product with a marketing authorisation, in the summary 
of product characteristics (SmPC) for that product 
 in the case of any other medicinal product, in the investigator’s 
brochure (IB) relating to the trial in question 
 
NB: to avoid confusion or misunderstanding of the difference between the terms “serious” and 
“severe”, the following note of clarification is provided: “Severe” is often used to describe intensity of a 

 
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specific event, which may be of relatively minor medical significance. “Seriousness” is the regulatory 
definition supplied above. 
 
9.2 
Operational definitions for (S)AEs  
(S)AEs will be defined according to standard definitions, section 9.1. 
 
9.3 
Recording and reporting of SAEs AND SUSARs  
The period of time over which AEs, ARs, SAEs, SARs and SUSARs are to be monitored start at and 
finish at: 
 
For AEs / SAEs – 1st MP dose to day 30 post operation 
 
For ARs / SARs and SUSARs – 1st MP dose to day 30 post operation 
 
SAEs occurring in a research participant should be reported to the main REC/Sponsor where in 
the opinion of the Chief Investigator (CI) the event was: 
 
Related – that is, it resulted from administration of any of the research procedures, and 
 
Unexpected – that is, the type of event is not listed in the protocol as an expected 
occurrence. 
Adverse events which are expected occurrences and relevant to the study population includes 
but is not limited to (multiple post-operative complications occur routinely in this cohort 
undergoing extensive colorectal surgery): 
 
Those listed in the Summary of Product Characteristics 
 
Surgical site infections 
 
All other infections including respiratory, urinary and skin infections (including fungal 
infections).  
 
Vascular events e.g. emboli, thrombosis, haemorrhage 
 
Failure of the surgical procedure e.g. anastomotic breakdown, fistulation 
 
Procedures i.e. urinary catheterisation, venous access device.  
 
SUSARs occurring from the time of randomisation until 30 days post cessation of trial 
treatment must be recorded on the AE form and faxed to the Sponsor within one working day of 
the research staff becoming aware of the event. Once all resulting queries have been resolved, 
the Sponsor will request the original form should also be posted to the Sponsor and a copy to 
be retained on site. 
 
For each SUSARs the following information will be collected: 
 
full details in medical terms and case description 
 
event duration (start and end dates, if applicable) 
 
action taken 
 
outcome 

 
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 
seriousness criteria 
 
causality (i.e. relatedness to trial drug / investigation), in the opinion of the investigator 
 
whether the event would be considered expected or unexpected. 
 
Any change of condition or other follow-up information should be faxed to the Sponsor as soon 
as it is available or at least within one working day of the information becoming available.  
SUSARs will be reported to the REC using the online reporting form within 15 days. Events will 
be followed up until the event has resolved or a final outcome has been reached, or 30 days 
have passed. The data monitoring committee will also be given a combined report of all the 
AEs, SAEs, ARs, SARs and SUSARs at the meeting. Any AEs with rates higher than expected 
will reported to the REC and sponsor.  
 
All SUSARs and will be subject to expedited reporting to the Medicines and Healthcare 
Products Regulatory Agency (MHRA). The PI or delegate will inform the MHRA, the REC and 
the Sponsor of SUSARs within the required expedited reporting timescales. 
 
9.4 
Responsibilities 
 
Principal Investigator (PI):  
Checking for AEs and ARs when participants attend for treatment / follow-up. 
1. Using medical judgement in assigning seriousness, causality and expectedness using 
the Reference Safety Information approved for the trial. 
2. Ensuring that all planned recording and reporting procedures for SAEs AND SUSARs as 
detailed in section 9.3 are adhered to. Ensuring that SUSARs are chased with Sponsor if 
a record of receipt is not received within 2 working days of initial reporting.  
 
Chief Investigator (CI) / delegate or independent clinical reviewer: 
1. Clinical oversight of the safety of patients participating in the trial, including an ongoing 
review of the risk / benefit. 
2. Using medical judgement in assigning seriousness, causality and expectedness of SAEs 
where it has not been possible to obtain local medical assessment. 
3. Using medical judgement in assigning expectedness. 
4. Immediate review of all SUSARs.  
5. Review of specific SAEs and SARs in accordance with the trial risk assessment and 
protocol as detailed in the Trial Monitoring Plan. 
 
Trial Steering Committee (TSC):  
In accordance with the Trial Terms of Reference for the TSC, periodically reviewing safety data 
and liaising with the DMC regarding safety issues. 
 

 
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Data Monitoring Committee (DMC): 
In accordance with the Trial Terms of Reference for the DMC, periodically reviewing unblinded 
overall safety data to determine patterns and trends of events, or to identify safety issues, which 
would not be apparent on an individual case basis.  
 
 
 

 
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9.6 
Pregnancy reporting  
Pregnancy will not reported in this trial 
 
9.7      Overdose  
Overdose will be reported by the anaesthetist as this person is the only person to be administering 
drug. The anaesthetist will be provided contact details for the PI to be notified. Any overdosed patients 
will be withdrawn from the trial 
 
9.8 
Reporting urgent safety measures  
If any urgent safety measures are taken the CI/Sponsor shall immediately and in any event no later 
than 3 working days from the date the measures are taken, inform the relevant REC of the measures 
taken and the circumstances giving rise to those measures. 
 
9.9 
The type and duration of the follow-up of subjects after adverse events. 
Follow-up care for subjects following an adverse drug reaction will be one week. 
Adverse events will be identified by review of patient’s medical notes. 
 
10 
STATISTICS AND DATA ANALYSIS 
 
10.1 
Sample size calculation 
This study is a pilot study intending to recruit 90 patients.  We require 60 patients with blood samples 
collected for pharmacokinetic analysis. In approximately 30% of patients it is not possible to obtain blood 
samples for intra-operative technical reasons.  
The full study sample size will be based on the following data: 
 
 
Alternative hypothesis: Pharmacodynamic target (4xMIC90 free serum concentrations) based 
continuous antibiotic dosing of antibiotic prophylaxis reduces the rate of surgical site infection 
after colorectal surgery by 50% when compared against standard antibiotic prophylaxis 
dosing regimes. 
Justification: Ceftriaxone reduces surgical site infection in colorectal surgery by 39% 
compared to other cephalosporin regimes (odds ration 0.61). It is believed this benefit is 
achieved by obtaining optimal PD targets. The PD target approach to antibiotic prophylaxis 
investigated in this study is attempting to obtain an equivalent benefit seen from ceftriaxone, 
without using ceftriaxone.  We expect this 39% benefit to be restricted to patients who have 
operations over 2 hours. As 73% of patients have operations over 2 hours we expect the 
reduction in SSIs to be 53% (39/73).   
Treatment Effect or Alternative Hypothesis: is this the smallest size of effect that would be of 
clinical interest- how is this justified in the form of appropriate references, pilot data or clinical 
arguments.  

 
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 
Null Hypothesis: Pharmacodynamic target (4xMIC90 free serum concentrations) based 
continuous antibiotic dosing of antibiotic prophylaxis does not reduce the rate of surgical site 
infection after colorectal surgery when compared against standard antibiotic prophylaxis 
dosing regimes i.e. there is an absolute difference in response rates between arms of zero.  
 
Significance level: 0.05. 
 
Power: 90% 
 
Adjustments to sample size based on interim analysis(es)  
 
SSI rate in standard treatment group (operations > 2 hours) 
o 16.5% (estimated from elective patients only) 
 
SSI rate in investigation group: 50% of standard group=8.25% 
 
10.2 
Planned recruitment rate 
 
This pilot study plans to recruit 1 patient per week. 
 
10.3 
Statistical analysis plan 
 
10.3.1 Summary of baseline data and flow of patients 
 
 
Variables to be used to assess baseline comparability of the randomised groups 
o Age 
o Sex 
o Smoker 
o BMI 
o Charlson Comorbidity Index 
o Respiratory tract disease 
o Urinary tract disease 
o Diabetes 
o Most recent colorectal surgery 
o Previous hospital stay 
o Indication for surgery 
o Haemoglobin 
o eGFR 
o Albumin 
o MRSA status 
o ASA score 
o NNIS score 
 
A consort flow diagram (http://www.consort-statement.org/) will be produced, as per the figure below. 
 

 
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CONSORT 2010 Flow Diagram 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessed for eligibility (n=  ) 
Excluded  (n=   ) 
   Not meeting inclusion criteria (n=  ) 
   Declined to participate (n=  ) 
Other reasons (n= )
Analysed  (n=  ) 
 Excluded from analysis (give reasons) (n=  ) 
Lost to follow-up (give reasons) (n=  ) 
Discontinued intervention (give reasons) (n=  ) 
Allocated to intervention (n=  ) 
 Received allocated intervention (n=  ) 
 Did not receive allocated intervention (give 
reasons) (n=  ) 
Lost to follow-up (give reasons) (n=  ) 
Discontinued intervention (give reasons) (n=  ) 
Allocated to intervention (n=  ) 
 Received allocated intervention (n=  ) 
 Did not receive allocated intervention (give 
reasons) (n=  ) 
Analysed  (n=  ) 
 Excluded from analysis (give reasons) (n=  ) 
Allocation 
Analysis 
Follow-Up 
Randomized (n= )
Enrollment 

 
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10.3.2 Primary outcome analysis 
 Statistical analyses of the primary outcome: 
 
Surgical site infection within 30 days of colorectal surgery will be analysed by comparing 
proportions. 
 
10.3.3 Secondary outcome analysis 
Secondary outcomes will be analysed by comparing proportions. 
 
10.4 
Subgroup analyses 
Not applicable  
 
10.5 
Adjusted analysis 
 
Not applicable 
 
10.6 
Interim analysis and criteria for the premature termination of the trial 
 
Not applicable 
 
10.7 
Subject population 
 
Any subject randomised into the study that received at least one dose of study drug will be subjected 
to the study analysis. 
  
10.8 Procedure(s) to account for missing or spurious data  
 
Strategies to maximise follow-up will be employed including telephone follow up and postal follow up  
No strategies are being planned for missing data. 
 
10.9 
Other statistical considerations. 
 
None 
 
 
 

 
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10.11 Economic evaluation 
None 
 
11 
DATA HANDLING 
11.1 
Data collection tools and source document identification 
 
Data collection will be by paper case report forms (CRFs) 
CRFs will be created to document 
 
Surgical history, including antibiotic prophylaxis and blood collection timings 
 
Day 5 surgical site infection assessment 
 
Post operative medical history including antibiotic consumption within 30 days of surgery, 
infection diagnoses and length of hospital stay 
 
End of study form including mortality data 
 
Quality of Life questionnaires (EQ5-D) 
 
Surgical site infection questionnaire.  
 
Records of all participating patients (sufficient information to link records e.g., CRFs, hospital records 
and samples), all original signed informed consent forms and copies of the CRF pages will be kept. 
 
Records will be stored in a locked room at the Old Medical School, Leeds General Infirmary, Leeds. 
All research forms will be labelled with a patients study number. 
To maximise data collection, telephone assessments and postal questionnaires will be used where 
patients are unable to attend in person for assessments. 
 
11.2 
Data handling and record keeping 
 
Data entry: Data will be added to an excel database stored on Leeds Teaching Hospitals 
NHS Trust. 
 
Data quality audit will be completed at the end of the study. 
 
Data will be stored on paper and online. 
 
Data will be pseudonymised. 
 
Data entry will be by a clinical researcher (clinical research nurse or research doctor) 
 
The PI will be responsible for data entry, quality and analysis. 
 
Arrangements to pseudonymise the data: Samples and data (case report forms) will be 
given a study number at the time of collection. A database linking study numbers to patients 
will be created and be separate to the data and samples. Both paper and electronic records 
will be kept as part of a data disaster recovery plan. 

 
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11.3 
Access to Data 
Direct access will be granted to authorised representatives from the Sponsor, host institution and the 
regulatory authorities to permit trial-related monitoring, audits and inspections. 
 
11.4 
Archiving 
Archiving will be authorised by the Sponsor following submission of the end of study report 
The research group will be responsible for archiving all research data collected. 
Paper archiving will be for 5 years from the end of the study and be based in a locked room in the Old 
Medical School, Leeds General Infirmary. 
 
12 
MONITORING, AUDIT & INSPECTION 
 
A Trial Monitoring Plan will be developed and agreed by the Trial Management Group (TMG) 
and TSC based on the trial risk assessment which may include on site monitoring 
 
It is not anticipated this pilot study will be monitored or inspected.  
 
Any authorised body will be supported by the trial site to in monitoring the study. These may 
include hosting site visits, providing information for remote monitoring, or putting procedures 
in place to monitor the study internally 
 
13  
ETHICAL AND REGULATORY CONSIDERATIONS 
13.1  Research Ethics Committee (REC) review& reports 
 
Before the start of the trial, approval will be sought from a REC for the trial protocol, 
informed consent forms and other relevant documents. 
 
Substantial amendments that require review by REC will not be implemented until the REC 
grants a favourable opinion for the study (and/or NHS R&D departments before they can be 
implemented in practice at sites) 
 
All correspondence with the REC will be retained in the Trial Master File/Investigator Site 
File  
 
An annual progress report (APR) will be submitted to the REC within 30 days of the 
anniversary date on which the favourable opinion was given, and annually until the trial is 
declared ended 
 
It is the Chief Investigator’s responsibility to produce the annual reports as required. 
 
The Chief Investigator will notify the REC of the end of the study 
 
If the study is ended prematurely, the Chief Investigator will notify the REC, including the 
reasons for the premature termination 
 
Within one year after the end of the study, the Chief Investigator will submit a final report 
with the results, including any publications/abstracts, to the REC 
 
13.2  
Peer review 

 
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High quality peer review  
Peer review has been completed by Dr Jon Sandoe, Consultant Microbiologist, Leeds Teaching 
Hospitals NHS Trust.  
 
13.3  
Public and Patient Involvement 
The involvement of Patients and Public in the research includes 
 
A previous design of this study was presneted to the Leeds Cancer PPIR group. This 
resulted in a recommnedation for an interventional trial as per this study. 
 
This study design (Colo-Pro)  is due to be presented to this group again in June 2015. 
 
 
13.4 
 
Protocol compliance  
Accidental protocol deviations will be adequately documented on the relevant forms and reported to 
the sponsor immediately.  
 
13.7  Data protection and patient confidentiality  
All investigators and trial site staff will comply with the requirements of the Data Protection Act 1998 
with regards to the collection, storage, processing and disclosure of personal information and will 
uphold the Act’s core principles.  
This includes: 
The creation of coded, depersonalised data where the participant’s identifying information is replaced 
by an unrelated sequence of characters 
Secure maintenance of the data and the linking code in separate locations using encrypted digital files 
within password protected folders and storage media 
Limiting access to the minimum number of individuals necessary for quality control, audit, and analysis 
The PI is the data custodian 
 
13.8  Financial and other competing interests for the chief investigator, PIs at each site and 
committee members for the overall trial management  
None to declare 
13.9  Indemnity 
The University of Leeds is providing  
1. Insurance and/or indemnity to meet the potential legal liability of the sponsor for harm to 
participants arising from the management of the research. 
2. Insurance and/ or indemnity to meet the potential legal liability of the sponsor or employer for 
harm to participants arising from the design of the research. 
The NHS is providing 

 
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3. Insurance and/ or indemnity to meet the potential legal liability of investigators/collaborators 
arising from harm to participants in the conduct of the research. 
 
The sponsor has not made arrangements for payment of compensation in the event of harm to the 
research participants where no legal liability arises. 
 
13.10  Amendments  
 
Amendments will be agreed by the Trial management and data (safety) monitoring group. The Trial 
management and data (safety) monitoring group will decide if amendments are substantial.  
An amendment history will be maintained in the trial master file. 
HRA guidance on reporting of amendments (non CTIMP reporting) will be followed.  
http://www.hra.nhs.uk/resources/during-and-after-your-study/progress-and-safety-reporting/ 
 
 

 
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13.11  Post trial care 
No post trial care is planned, or relevant to this trial. 
 
13.12  Access to the final trial dataset 
The trial management and data (safety) monitoring group will have access to the final data set.   
 
14  
DISSEMINIATION POLICY 
14.1  
Dissemination policy 
Consort Guidelines will be reviewed prior to generating any publications for the trial to ensure they 
meet the standards required for submission to high quality peer reviewed journals. 
The data will be owned by The University of Leeds.  
On completion of the trial, the data will be analysed and tabulated and a Final Study Report prepared 
where the full study report can be accessed 
We plan to notify the participants of the outcome of the trial, by provision of the publication, and via a 
specifically designed newsletter. 
 
14.2  Authorship eligibility guidelines and any intended use of professional writers 
Authorship will include 
On the final trial report: The Trial Steering Committee 
For individually named authors: According to The International Committee of Medical Journal Editors 
definitions for authorship criteria for manuscripts submitted for publication. 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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15 
REFERENCES 
Asín-Prieto E, Soraluce A, Trocóniz IF, Campo Cimarras E, Sáenz de Ugarte Sobrón J, Rodríguez-
Gascón A, Isla A. 
Population pharmacokinetic models for cefuroxime and metronidazole used in combination as 
prophylactic agents in colorectal surgery: Model-based evaluation of standard dosing regimens. 
Int J Antimicrob Agents. 2015;45:504–511 
 
Barbour A, Schmidt S, Rout WR, Ben-David K, Burkhardt O, Derendorf H. Soft tissue penetration of 
cefuroxime determined by clinical microdialysis in morbidly obese patients undergoing abdominal 
surgery. Int J Antimicrob Agents. 2009;34(3):231-5.  
 
Coello R, Charlett A, Wilson J, Ward V, Pearson A, Borriello P.  
Adverse impact of surgical site infections in English hospitals.  
J Hosp Infect  2005;60:93-103. 
 
CDC 
Draft Guideline for the Prevention of Surgical Site Infection 
2014 
 
Health Protection Agency 
Surveillance of Surgical Site Infections in NHS Hospitals in England 
2013/14 
 
Itani KM, Jensen EH, Finn TS, Tomassini JE, Abramson MA.  
Effect of body mass index and ertapenem versus cefotetan prophylaxis on surgical site infection in 
elective colorectal surgery. 
Surg Infect (Larchmt). 2008;9:131-7. 
 
Jenks PJ, Laurent M, McQuarry S, Watkins R. Clinical and economic burden of surgical site infection 
(SSI) and predicted financial consequences of elimination of SSI from an English hospital. J Hosp 
Infect. 2014 ;86 (1):24-33.  
 
Kirby A, Burnside G, Bretsztajn L, Burke D. (a) 
Post-operative infections following colorectal surgery in an English teaching hospital.  
Journal of Infectious Diseases 2015: At peer review. 
 
Kirby A, Bretsztajn L, Santoni N, Patel H, Burke D, Horner C. (b) 
Microbiological prediction of surgical site infection risk after colorectal surgery: a feasibility study. 
J Hosp Infect  2015; In press 

 
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Kirby A, Santoni N. (c) 
Antibiotic resistance in Enterobacteriaceae: what impact on the efficacy of antibiotic prophylaxis in 
colorectal surgery?  
J Hosp Infect. 2015;89:259–263. 
 
Kobayashi M, Mohri Y, Tonouchi H, Miki C, Nakai K, Kusunoki M.  
Randomized clinical trial comparing intravenous antimicrobial prophylaxis alone with oral and 
intravenous antimicrobial prophylaxis for the prevention of a surgical site infection in colorectal cancer 
surgery.  
Surg Today. 2007;37:383-8. 
 
M Lindsay Grayson, Suzanne M Crowe, James S McCarthy, John Mills, Johan W Mouton, S Ragnar 
Norrby, David L Paterson, Michael A Pfaller. Kucers' The Use of Antibiotics Sixth Edition: A Clinical 
Review of Antibacterial, Antifungal and Antiviral Drugs. 2010, CRC Press. 
 
Leng XS, Zhao YJ, Qiu HZ, Cao YK, Zhu WH, Shen JF, Paschke A, Dai WM, Caldwell N, Wang J. 
Ertapenem prophylaxis of surgical site infections in elective colorectal surgery in China: a multicentre, 
randomized, double-blind, active-controlled study.  
J Antimicrob Chemother. 2014;69:3379-86. 
 
Lübbert C, Becker-Rux D, Rodloff AC, Laudi S, Busch T, Bartels M, Kaisers UX.  
Colonization of liver transplant recipients with KPC-producing Klebsiella pneumoniae is associated 
with high infection rates and excess mortality: a case-control analysis. 
Infection. 2014;42:309-16. 
 
MacGowan A. Revisiting Beta-lactams - PK/PD improves dosing of old antibiotics. Curr Opin 
Pharmacol. 2011;11:470-6. 
 
McGregor JC, Elman MR, Bearden DT et al. Sex-and age-specific trends in antibiotic resistance 
patterns of Escherichia coli urinary isolates from outpatients. BMC Fam Pract 2013; 22; 14:25. 
 
Moine P, Fish DN. Pharmacodynamic modelling of intravenous antibiotic prophylaxis in elective 
colorectal surgery. Int J Antimicrob Agents 2013 ;41:167-73. 
 
Morikane K, Honda H, Yamagishi T, Suzuki S, Aminaka M. 
Factors associated with surgical site infection in colorectal surgery: the Japan nosocomial infections 
surveillance.  
Infect Control Hosp Epidemiol. 2014;35:660-6.  
 
Moriyama B, Henning SA, Childs R, Holland SM, Anderson VL, Morris JC, Wilson WH, Drusano GL, 
Walsh TJ. High-dose continuous infusion beta-lactam antibiotics for the treatment of resistant 
Pseudomonas aeruginosa infections in immunocompromised patients. Ann Pharmacother. 2010; 
44:929-35.  
 
Mouton JW, Theuretzbacher U, Craig WA, Tulkens PM, Derendorf H, Cars O. Tissue concentrations: 
do we ever learn? J Antimicrob Chemother. 2008;61(2):235-7. 
 
Nelson RL, Gladman E, and Barbateskovic M.  
Antimicrobial prophylaxis for colorectal surgery.  
The Cochrane database of systematic reviews. 2014; 5: CD001181. 

 
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Roberts MJ, Williamson DA, Hadway P, Doi SA, Gardiner RA, Paterson DL.  
Baseline prevalence of antimicrobial resistance and subsequent infection following prostate biopsy 
using empirical or altered prophylaxis: A bias-adjusted meta-analysis.  
Int J Antimicrob Agents. 2014;43:301-9. 
 
Tanner J, Khan, D, Aplin C, Ball J, Thomas, M, and Bankart J.  
Post-discharge surveillance to identify colorectal surgical site infection rates and related costs.   
J Hosp Infect 2009;72:243-50. 
 
Petrosillo N, Drapeau CM, Nicastri E, Martini, L., Ippolito, G. & Moro, M. L. 2008.  
Surgical site infections in Italian Hospitals: a prospective multicenter study.  
BMC Infect Di. 2008;8:4. 
 
Slimings C, Riley TV. Antibiotics and hospital-acquired Clostridium difficile infection: update of 
systematic review and meta-analysis. J Antimicrob Chemother. 2014;69(4):881-91. 
 
Smith RL, Bohl JK, Mcelearney ST, Friel CM, Barclay MM., Sawyer RG, Foley EF. 
Wound infection after elective colorectal resection.  
Ann Surg, 2004;239:599-605. 
 
Wick EC, Gibbs L, Indorf LA, Varma MG, Garcia-Aguilar  
J.Implementation of quality measures to reduce surgical site infection in colorectal patients.  
Dis Colon Rectum. 2008;51:1004-9. 
 
Woodfield JC, Beshay N, van Rij AM. A meta-analysis of randomized, controlled trials assessing the 
prophylactic use of ceftriaxone. A study of wound, chest, and urinary infections. World J Surg. 2009 
Dec;33(12):2538-50. 
 
Zelenitsky SA, Silverman RE, Duckworth H, Harding GK.  
A prospective, randomized, double-blind study of single high dose versus multiple standard dose 
gentamicin both in combination with metronidazole for colorectal surgical prophylaxis.  
J Hosp Infect. 2000;46:135-40. 
 
 
16.  
APPENDICIES 
16.1  Appendix 1-Risk 
Risks associated with trial interventions 
 LOW ≡ Comparable to the risk of standard medical care 
 MODERATE ≡ Somewhat higher than the risk of standard medical care 
 HIGH ≡ Markedly higher than the risk of standard medical care 
 
 

 
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Justification:  Briefly justify the risk category selected and your conclusions below  (where the table is 
completed in detail the detail need not be repeated, however a summary should be given): 
 
The intervention antibiotic prophylaxis is an evidence based intervention. 
The method of administering the intervention, continuous infusion, is an established method of 
intervention, and used routinely in many health care systems. 
The maximum loading dose of cefuroxime recommended in this study, 2332 mg, is below the SPC single 
dose recommended for dosing cefuroxime of 3000mg. 
The maximum total dose of cefuroxime recommended in this study, 9688mg over 6 hours, is comparable 
to that in the drug SPC for treating meningitis, 3000mg 8 hourly (6000mg infused in an 8 hour period). 
Beta-lactam therapy is established as a safe treatment. High dose beta-lactam therapy is routinely 
administered e.g. 2400mg benzylpenicillin 4 hourly for treatment of endocarditis, amoxicillin 2000mg four 
hourly for endocarditis, flucloxacillin 2000mg 4 hourly for endocarditis, piperacillin 4000mg 8 hourly for 
severe infections. 
What are the key risks related to therapeutic 
interventions you plan to monitor in this trial? How will these risks be minimised? 
MP/Intervention  
Body system/Hazard 
Activity 
Frequency 
Comments 
Cefuroxime  
Gastrointestinal 
tract/Clostridium 
difficile associated 
diarrhoea 
Routine clinical 
assessment 
Continuous 
while a 
hospital in-
patient 
 
Cefuroxime  
Hepatobiliary 
disorders 
Liver function test 
(blood) 
Clinically 
driven 
testing 
 
Cefuroxime  
Blood and lymphatic 
system disorders 
Full blood count 
Clinically 
driven 
testing 
 
Cefuroxime  
Skin and 
subcutaneous tissue 
disorders 
Routine clinical 
assessment 
Continuous 
in-patient 
assessment 
 
Cefuroxime  
Renal and urinary 
disorders 
Renal function 
monitoring (blood 
tests) 
Clinically 
driven 
testing 
 
Cefuroxime 
General disorders 
and administration 
site conditions 
Injection site 
reactions which may 
include pain and 
thrombophlebitis 
Routine 
clinical 
assessment 
 
Outline any other processes that have been put in place to mitigate risks to participant safety (e.g. DMC, 
independent data review, etc.) 
MHRA assessment of the trial protocol 
Trial oversight committees 

 
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Independent protocol review 
National Research Ethics Committee 
Maximum dosing levels defined 
Exclusion of patients at risk of adverse events e.g. patients with known history of seizures. 
Advice that cefuroxime may affect the gut flora (as with most antibiotics), leading to lower oestrogen 
reabsorption and reduced efficacy of combined oral contraceptives. 
 
 
 

 
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16.2  Appendix 2 - Study management / responsibilities  
 
16.2.1  Patient registration/randomisation procedure  
No part of the trial coordination is outsourced. 
 
16.2.2  Data management  
 
No outsourcing of data management is planned. 
The PI is responsible for data management. 
CRF will be data checked, and the online database will facilitate this process. 
 
16.2.3 Preparation and submission of amendments  
No part of the trial coordination is outsourced.  
 
16.2.4 Preparation and submission of Annual Safety Report/Annual 
No part of the trial coordination is outsourced. 
 
16.2.5 Data protection/confidentiality  
No part of the trial coordination is outsourced. 
 
16.2.6 Trial documentation and archiving  
No part of the trial coordination is outsourced. 
 
16.3  Appendix 3 – Authorisation of participating sites  
 
Not applicable: single site study. 
 
 
 
 
 
 
 
 

 
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16.4  Appendix 4 – Schedule of Procedures 
 
Time (Specify months/ weeks/ days) 
  
0 
Day 5 
Day 8-30 
  
30 days 
  
  
Preoperative/Pre-assessment clinic* 
Surgery 
Day 5 (+/- 48 hours) or earlier if discharge at less than 5 days. 
72 hourly post initial assessment 
Discharge  
30 days post surgery/End of trial 
Premature withdrawal 
Informed consent 
X 
  
  
  
  
  
  
Assessment of Eligibility Criteria 
X 
  
  
  
  
  
  
Review of Medical History 
X 
  
X 
X 
X 
X 
  
Review of Concomitant Medications  
X 
  
  
  
  
  
  
Registration 
X 
  
  
  
  
  
  
Physical Exam - Complete 
  
  
No 
No 
No 
No 
  
Physical Exam - Surgical site 
  
  
X 
No 
No 
No 
  
Documentation of surgical practices e.g. 
antibiotic prophylaxis 
  
X 
  
  
  
  
  
Review of clinical notes including antibiotic 
prescribing 
X 
  
X 
X 
X 
X 
  
Patient questionnaire 
X 
  
X 
  
  
X 
  
Height 
X 
  
  
  
  
  
  
Weight 
X 
  
  
  
  
  
  
Heart rate, respiratory rate, blood pressure 
  
  
  
  
  
  
  
Rectal swab 
X 
  
  
  
  
  
  
Wound swab 
  
  
  
  
  
  
  
Study intervention (antibiotics) and 
documentation of surgical practices 
  
X 
  
  
  
  
  
Assessment of Adverse Events 
  
  
X 
X 
X 
X 
X 
 
 
 

 
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16.6 
Appendix 5 – Amendment History 
Amendment 
No. 
Protocol 
version no. 
Date issued 
Author(s) of 
changes 
Details of changes made 
1 
1.1 
 
 
AE/SAE event reporting updated 
2 
2.1 
 
AK 
Dosing regimen updated 
3 
2.2 
10/101/2016 
AK 
Dosing regimen returned to original 
regimen 
 
Protocol amendments will be submitted to the Sponsor for approval prior to submission to the REC 
committee.