Clinical trial NCT02618720: Intravenous Versus Combined Oral and Intravenous Antimicrobial Prophylaxis for the Prevention of Surgical Site Infection in Elective Colorectal Surgery
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Elective Colorectal Surgery
Keywords: Antimicrobial prophylaxis
Colorectal surgery
Surgical Site Infection
Postoperative morbidity
Lead sponsor: University Hospital, Clermont-Ferrand
Sponsor class: OTHER
First posted: 2015-12-01
Enrollment: 920
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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.

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

Eligibility criteria: 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

Primary outcomes:
measure: occurrence of any SSI within 30 days after surgery.
timeFrame: 30 days after surgery
Secondary outcomes:
measure: Incidence of individual types of SSI according to the group of treatment
timeFrame: 30 days after surgery
measure: Number of postoperative complications
timeFrame: 30 days after surgery
measure: Number of surgical complications: anastomotic leakage and the need for abdominal reoperation and/or radiological intervention
timeFrame: 30 days after surgery
measure: Duration of hospital stay
timeFrame: 30 days after surgery
measure: All-cause mortality
timeFrame: 30 days after surgery
measure: All-cause mortality
timeFrame: 90 days after surgery
measure: Time to introduction of adjuvant chemotherapy related to SSI
timeFrame: 30 days after surgery
measure: Postoperative syndrome of systemic inflammatory response (Infectious complications)
timeFrame: 30 days after surgery
measure: Sepsis (Infectious complications)
timeFrame: 30 days after surgery
measure: Septic shock (Infectious complications)
timeFrame: 30 days after surgery
measure: Arrhythmia (Cardiovascular complications)
timeFrame: 30 days after surgery
measure: Myocardial infarction (Cardiovascular complications)
timeFrame: 30 days after surgery
measure: Acute cardiac failure (Cardiovascular complications)
timeFrame: 30 days after surgery
measure: Pneumonia (Respiratory complications)
timeFrame: 30 days after surgery
measure: Need for postoperative reventilation (Respiratory complications)
timeFrame: 30 days after surgery
measure: Renal dysfunction
timeFrame: 30 days after surgery
measure: Time to initiation of adjuvant chemotherapy
timeFrame: 30 days after surgery
measure: Need for hospital readmission
timeFrame: 30 days after surgery
measure: Unexpected admission to intensive care unit
timeFrame: 30 days after surgery
measure: Hospital free days
timeFrame: 30 days after surgery
Other outcomes:
Locations:
city: Clermont-Ferrand
country: France
facility: CHU Clermont-Ferrand
Study officials:
References:
citation: 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.
citation: 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.