Intravenous Versus Combined Oral and Intravenous Antimicrobial Prophylaxis for the Prevention of Surgical Site Infection in Elective Colorectal Surgery (COMBINE)

Intravenous Versus Combined Oral and Intravenous Antimicrobial Prophylaxis for the Prevention of Surgical Site Infection in Elective Colorectal Surgery: A Double-blinded Multicenter Prospective Randomized Controlled Trial

To assess the effects of a combined antimicrobial prophylaxis using oral ornidazole (the day before surgery) and intravenous cephalosporin (before surgical incision) with that of intravenous cephalosporin alone (standard of care) in combination with oral placebo on the incidence of SSI within 30 days after elective colorectal surgery.

Study Overview

• Status: Completed
• Conditions: Elective Colorectal Surgery
• Intervention / Treatment: Drug: Placebo; Drug: ornidazole

Detailed Description

Surgical site infection (SSI) is a major cause of nosocomial infection in surgical patients, with the highest rates being reported (ranging from 15% to 30%) in colorectal surgery. SSI is an independent predictor of postoperative mortality and is associated with longer hospital stay, a 5-fold likelihood of postoperative readmission and a 2- to 3-fold increase in costs of care. Given the high prevalence and financial burden associated with SSI, American and European guidelines have been issued providing evidenced-based recommendations for the prevention of postoperative SSI. However, the prevalence of SSI remains high despite adherence to these guidelines and the application of evidence-based preventive measures.

Risk factors for SSI, whether modifiable or not, are mainly related to the patient condition (including age, severe comorbidity, diabetes, nutritional status, steroid use, smoking, and immunosuppression) and/or the surgical procedure (especially the surgical duration and skin disinfection). The prevention of SSI consists of several individual measures, and antibiotic prophylaxis covering aerobic and anaerobic bacteria is highly recommended in patients scheduled to elective colorectal resection, with French and European guidelines recommending the administration of intravenous cephalosporin within 30 minutes before surgical incision.

Recent data from retrospective studies and two meta-analyses of clinical trials provided compelling arguments that oral antibiotic administration before surgery in addition to conventional intravenous prophylaxis may be useful in further reducing by almost 75% the incidence of SSI (relative risk 0.55 [CI95%: 0.41 to 0.74]) after elective colorectal cancer surgery.

However, most of these studies have limitations precluding extrapolation of data into routine care, especially:

1. prolonged duration of intravenous antibiotic administration, which is no longer recommended in elective surgery;
2. the use of antibiotics for oral prophylaxis whose availability is limited;
3. only a few studies focused specifically on colorectal resection;
4. most studies did not include enhanced recovery after surgery (ERAS) programs, which was found to improve outcome following colorectal surgery, and
5. most studies have used mechanical bowel preparation, which is no longer recommended in colonic surgery while the issue still remains open for rectal surgery.

Investigators hypothesized that oral antibiotic prophylaxis using ornidazole, which has a spectrum of activity extended to most anaerobic bacteria and whose pharmacokinetic profile allows a single administration the day before surgery, in addition to intravenous antibiotic prophylaxis could be more effective than intravenous antibiotic prophylaxis alone using cephalosporin in reducing the incidence of SSI after elective colorectal surgery. Given the number of patients operated of colorectal surgery each year, the study is of significant clinical importance

• Study Type: Interventional
• Enrollment (Actual): 920
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Clermont-Ferrand, France, 63003
    • Chu Clermont-Ferrand

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age > 18
• Laparoscopic or non-laparoscopic elective colorectal surgery

Exclusion Criteria:

• Non elective colorectal surgery (emergent surgery and/or reintervention or revision of a previous colorectal procedure)
• Significant concomitant surgical procedure (e.g., liver resection for metastasis)
• Bacterial infection at the time of surgery or antimicrobial therapy up to 2 weeks before surgery
• Inflammatory bowel disease
• Severe obesity (defined as a BMI >35 kg/m2)
• Known history of hypersensitivity to β-lactams and imidazoles
• Preoperative severe impairment in renal function (creatinine clearance (MDRD) < 30 ml/min)
• Patients with known colonization with multidrug-resistant digestive bacteria, especially multidrug-resistant gram-negative bacteria (requiring specific infection control measures)
• Allergy to lactose, galactose intolerance, Lapp lactase deficiency or glucose/galactose malabsorption (rare metabolic disease)
• Pregnant women, breastfeeding women, women of childbearing age without effective contraceptive- Refusal to participate or inability to provide informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ornidazole; oral antibiotic prophylaxis using ornidazole, which has a spectrum of activity extended to most anaerobic bacteria and whose pharmacokinetic profile allows a single administration the day before surgery, in addition to intravenous antibiotic prophylaxis could be more effective than intravenous antibiotic prophylaxis alone using cephalosporin in reducing the incidence of SSI after elective colorectal surgery. Given the number of patients operated of colorectal surgery each year, the study is of significant clinical importance	Drug: ornidazole
Placebo Comparator: placebo; oral antibiotic prophylaxis using ornidazole, which has a spectrum of activity extended to most anaerobic bacteria and whose pharmacokinetic profile allows a single administration the day before surgery, in addition to intravenous antibiotic prophylaxis could be more effective than intravenous antibiotic prophylaxis alone using cephalosporin in reducing the incidence of SSI after elective colorectal surgery. Given the number of patients operated of colorectal surgery each year, the study is of significant clinical importance	Drug: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
occurrence of any SSI within 30 days after surgery.	The primary end point of the trial is the occurrence of any SSI within 30 days after surgery. SSI will be classified as superficial, deep and/or organ-space infection according to validated and well-defined criteria developed by the Centers for Disease Control and Prevention (CDC).	30 days after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of individual types of SSI according to the group of treatment	Incidence of individual types of SSI (superficial incision infection, deep incision infection and organ-space infection) according to the group of treatment, 30 days after surgery	30 days after surgery
Number of postoperative complications	Using the Dindo and Clavien classification	30 days after surgery
Number of surgical complications: anastomotic leakage and the need for abdominal reoperation and/or radiological intervention		30 days after surgery
Duration of hospital stay	Including hospital stay of patients who are readmitted after surgery	30 days after surgery
All-cause mortality		30 days after surgery
All-cause mortality		90 days after surgery
Time to introduction of adjuvant chemotherapy related to SSI		30 days after surgery
Postoperative syndrome of systemic inflammatory response (Infectious complications)	Number of Postoperative syndrome of systemic inflammatory responses, in each group	30 days after surgery
Sepsis (Infectious complications)	Number of Sepsis, in each group	30 days after surgery
Septic shock (Infectious complications)	Number of Septic shocks, in each group	30 days after surgery
Arrhythmia (Cardiovascular complications)	Number of arrhythmias, in each group	30 days after surgery
Myocardial infarction (Cardiovascular complications)	Number of myocardial infarctions, in each group	30 days after surgery
Acute cardiac failure (Cardiovascular complications)	Number of acute cardiac failures, in each group	30 days after surgery
Pneumonia (Respiratory complications)	Number of pneumonias, in each group	30 days after surgery
Need for postoperative reventilation (Respiratory complications)	Number of postoperative reventilations (intubation and/or non-invasive mechanical ventilation), in each group	30 days after surgery
Renal dysfunction	Number of Renal dysfunctions in each group. Defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) classification	30 days after surgery
Time to initiation of adjuvant chemotherapy	Comparaison of time to initiation of adjuvant chemotherapy between the 2 groups	30 days after surgery
Need for hospital readmission	Number of hospital readmissions, in each group	30 days after surgery
Unexpected admission to intensive care unit	Number of Unexpected admissions to intensive care unit, in each group	30 days after surgery
Hospital free days		30 days after surgery

Collaborators and Investigators

• Sponsor: University Hospital, Clermont-Ferrand

Publications and helpful links

General Publications

• Futier E, Jaber S, Garot M, Vignaud M, Panis Y, Slim K, Lucet JC, Lebuffe G, Ouattara A, El Amine Y, Couderc P, Dupre A, De Jong A, Lasocki S, Leone M, Pottecher J, Pereira B, Paugam-Burtz C; COMBINE study group. Effect of oral antimicrobial prophylaxis on surgical site infection after elective colorectal surgery: multicentre, randomised, double blind, placebo controlled trial. BMJ. 2022 Nov 3;379:e071476. doi: 10.1136/bmj-2022-071476.
• Vignaud M, Paugam-Burtz C, Garot M, Jaber S, Slim K, Panis Y, Lucet JC, Bourdier J, Morand D, Pereira B, Futier E; COMBINE trial management committee. Comparison of intravenous versus combined oral and intravenous antimicrobial prophylaxis (COMBINE) for the prevention of surgical site infection in elective colorectal surgery: study protocol for a multicentre, double-blind, randomised controlled clinical trial. BMJ Open. 2018 Apr 12;8(4):e020254. doi: 10.1136/bmjopen-2017-020254.

Study record dates

Study Major Dates

• Study Start (Actual): May 25, 2016
• Primary Completion (Actual): November 26, 2019
• Study Completion (Actual): June 30, 2020

Study Registration Dates

• First Submitted: November 5, 2015
• First Submitted That Met QC Criteria: November 27, 2015
• First Posted (Estimate): December 1, 2015

Study Record Updates

• Last Update Posted (Actual): July 7, 2022
• Last Update Submitted That Met QC Criteria: July 4, 2022
• Last Verified: July 1, 2020

More Information

Terms related to this study

• Keywords: Colorectal surgery; Surgical Site Infection; Postoperative morbidity; Antimicrobial prophylaxis
• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Wound Infection; Infections; Surgical Wound Infection; Anti-Infective Agents; Antiprotozoal Agents; Antiparasitic Agents; Amebicides; Antitrichomonal Agents; Ornidazole
• Other Study ID Numbers: CHU-0250; 2015-002559-84 (Registry Identifier: 2015-002559-84)