Comparison of olanexidine versus povidone‐iodine as a preoperative antiseptic for reducing surgical site infection in both scheduled and emergency gastrointestinal surgeries: A single‐center randomized clinical trial

Abstract Aim Surgical site infection (SSI) is one of the most common postoperative complications in gastrointestinal surgery. To clarify the superiority of 1.5% olanexidine, we conducted a randomized prospective clinical trial that enrolled patients undergoing gastrointestinal surgery with operative wound classes II–IV. Methods To evaluate the efficacy of 1.5% olanexidine in preventing SSIs relative to 10% povidone‐iodine, we enrolled 298 patients in each group. The primary outcome was a 30‐day SSI, and the secondary outcomes were incidences of superficial and deep incisional SSI and organ/space SSI. In addition, subgroup analyses were performed. Results The primary outcome of the overall 30‐day SSI occurred in 38 cases (12.8%) in the 1.5% olanexidine group and in 53 cases (18.0%) in the 10% povidone‐iodine group (adjusted risk ratio: 0.716, 95% confidence interval: 0.495–1.057, p = 0.083). Organ/space SSI occurred in 18 cases (6.1%) in the 1.5% olanexidine group and in 31 cases (10.5%) in the 10% povidone‐iodine group, with a significant difference (adjusted risk ratio: 0.587, 95% confidence interval: 0.336–0.992, p = 0.049). Subgroup analyses revealed that SSI incidences were comparable in scheduled surgery (relative risk: 0.809, 95% confidence interval: 0.522–1.254) and operative wound class II (relative risk: 0.756, 95% confidence interval: 0.494–1.449) in 1.5% olanexidine group. Conclusion Our study revealed that 1.5% olanexidine reduced the 30‐day overall SSI; however, the result was not significant. Organ/space SSI significantly decreased in the 1.5% olanexidine group. Our results indicate that 1.5% olanexidine has the potential to prevent SSI on behalf of povidone‐iodine.


| INTRODUC TI ON
In gastrointestinal surgery, surgical site infection (SSI) is one of the most common postoperative complications. [1][2][3] In general, SSI prolongs hospitalization and increases medical costs for wound care, antibiotics, and interventions. The 2021 annual report of Japan Nosocomial Infections Surveillance (JANIS) showed that SSI incidence rates after upper gastrointestinal, colorectal, and hepatobiliary-pancreatic surgeries were 6.0%-16.7%, 8.5%-10.4%, and 6.3%-22.7%, respectively. 4 Multiple management protocols have been implemented to prevent SSI; among these, appropriate prophylactic antibiotics and preoperative skin antiseptics are the most important to minimize the risk of SSI. [1][2][3] In current clinical practice across the world, povidone-iodine and chlorhexidine are widely used as preoperative antiseptics.
Furthermore, povidone-iodine has been popularly used in daily clinical practice for more than 50 years. In contrast, some clinical trials have demonstrated that the application of chlorhexidine to patients before clean or clean-contaminated surgery is associated with lower SSI incidence relative to patients with povidone-iodine antisepsis. 5,6 Based on this evidence, chlorhexidine is the most widely used antiseptic in the United States and Europe. However, the quality of these studies is not sufficient to provide a strong recommendation for the choice of preoperative antiseptics.
Recently, 1.5% olanexidine (Olanedine; Otsuka Pharmatceutical Factory, Tokushima, Japan) has been commercially available as a preoperative antiseptic in Japan. In addition, some prospective and retrospective comparative studies have been conducted on gastrointestinal surgery. [7][8][9][10][11] However, the indications of all studies are limited to clean-contaminated (operative wound class II) gastrointestinal surgery. To clarify the true superiority of 1.5% olanexidine, we conducted a randomized prospective clinical trial to enroll patients undergoing gastrointestinal surgery with operative wound classes II-IV, including emergency surgery. Using the abovementioned clinical trials, the present study assessed the SSI-preventing effects of 1.5% olanexidine compared with 10% povidone-iodine.

| Study design
We conducted a single-center, prospective, randomized, openendpoint trial to evaluate the efficacy of 1.5% olanexidine in preventing SSIs compared with the 10% povidone-iodine group in gastrointestinal surgery. This clinical trial was approved by the institutional ethics committee of Morioka Municipal Hospital (H30-1), here in accordance with the Declaration of Helsinki and the National Clinical Trials Registry (UMIN000033830) before patient recruitment. As a prospective randomized controlled trial, the study strategy was constructed following the CONSORT 2010 statement. 12

| Eligibility criteria
Eligible participants were aged 20 years or above and underwent either classes II-IV scheduled or emergency gastrointestinal, hepatobiliary, or pancreatic surgery. In the present study, surgical procedures with intestinal resections were defined as eligible surgical procedures; therefore, cholecystectomy, splenectomy, and hepatectomy without intestinal resections were excluded. In contrast, appendectomy, perforated peritonitis, and other emergency surgical procedures with intestinal resection were also included as class III or IV surgeries. All patients provided written informed consent before randomization.
Exclusion criteria were as follows: (1) allergy to olanexidine gluconate or povidone-iodine, (2) antimicrobial therapy the day before surgery, and (3) patients who were deemed by surgeons to be inappropriate for participation.

| Randomization and sample size setting
We employed three adjustment factors for randomization: age, gender, and type of surgery. Both olanexidine and povidone-iodine were recognized by color after antisepsis; therefore, blinding was not employed.
Regarding the sample size, an enrollment ratio was set at 1:1, and 298 patients for each group were required to follow the backgrounds and calculations. The average SSI incidence rate for gastrointestinal surgery was 3.7%-22.7% (average 10.9%), according to the 2021 SSI open report of JANIS. 4 Previous reports revealed that the SSI incidence of contaminated and infected abdominal surgery was about 15%-20% 13,14 ; hence, the SSI incidence rate for povidoneiodine was set as 18% by including contaminated and infected surgeries. We assumed that olanexidine can reduce the SSI incidence rate to 10%, with a power of 80% and an alpha error of 5%.

| Study protocol
A preoperative culture of the umbilicus was routinely performed after final preoperative bathing. Culture sampling was performed after bed bathing the patients who required an emergency operation. Following the induction of general anesthesia, hair removal was performed using a clipper, if necessary. Surgical skin antisepsis with 1.5% olanexidine or 10% povidone-iodine was then administered to cover the entire surgical site. In the present study, the entire surgical site was defined as the area from the level of the papilla to the upper thighs. Antiseptics were allowed to dry for 3 min, and we then began to perform the surgery.
We used other procedures to prevent SSI along with bundles as follows: (1) Antibiotic prophylaxis was administered within 60 min before incision via intravenous dripping. A repeated dose of antibiotic prophylaxis was administered 3 h after starting the surgery. We used cefazoline for upper gastrointestinal surgery, cefmetazole for colorectal surgery, and a combination of cefoperazone and sulbactam for hepatobiliary and pancreatic surgery. (2) We routinely employed the double gloves technique and changed gloves before closure. After abdominal wall closure, we checked the intraoperative culture of the wound to evaluate the causative bacteria of the SSIs.
Wound irrigation was performed with 500 mL of sterilized normal saline before skin closure, and skin closure was routinely performed using absorbable monofilament buried sutures for laparoscopic surgery and a barbed suture device for open surgery.

| Evaluation of SSI
Regarding usual wound checking, responsible surgeons examined the presence or absence of SSI daily during the hospital stay and at every outpatient visit until 30 days after surgery. The wound condition was diagnosed as superficial SSI when it satisfied all the following criteria: (1) infection must be confirmed within 30 days after surgery; (2) the extent of the infection is limited within the skin and subcutaneous tissue; and (3) organisms were isolated from an aseptically obtained culture of fluid or tissue from the superficial incision, and purulent discharge (with or without laboratory confirmation), signs of infection (pain, tenderness, localized swelling, redness, and heat), and a superficial incision, which was deliberately opened by the surgeon unless the incision was culture-negative, were observed.
In contrast, organ/space SSI was also diagnosed by the following criteria: (1) infection should be confirmed within 30 days after surgery, (2) organisms were isolated from an aseptically obtained culture of fluid or tissue from the organ/space infection site, and (3) the infection site, including the abscess cavity, must be detected in the operative area by multimodal diagnostic tools. When organ/space SSI and other wound complications were found in the same patient, we counted as organ/space SSI; therefore, duplicated count of every SSI incidence was strictly avoided.

| Outcome and data collection
The primary outcome was a 30-day SSI after surgery, here following the Centers of Disease Control and Prevention guidelines. 15 In the present study, incidences of superficial and deep incisional SSI and organ/space SSI were also analyzed as secondary outcomes.
We preoperatively collected the following laboratory data: serum albumin and white blood cell (WBC), a fraction of neutrophil, lymphocyte, and platelet counts. In addition, patient background, body mass index (BMI), prevalence of diabetes, smoking habit, physical status approved by the American Society of Anesthesiologists (ASA-PS), 16 timing of surgery (scheduled or emergent), types of surgery (upper gastrointestinal, lower gastrointestinal, hepatobiliary-pancreatic, and overlapping), types of approach (open or laparoscopy), risk index (0-3) approved by JANIS, 4 and operative wound class (II, III, and IV) were collected. Operative parameters, operating time, amount of blood loss, administration of intraoperative blood transfusion, and duration of hospital stay were also measured.
We performed wound cultures in all enrolled cases for a maximum of three times: umbilical skin culture before surgery, wound culture before skin closure during surgery, and SSI diagnosis.

| Statistical analysis
All data are presented as numbers for categorical variables and as means ± SD for continuous variables. Statistical analysis was performed using chi-square tests for categorical variables and Student's t-tests or Mann-Whitney U tests for continuous variables. We used All p values less than 0.05 using two-sided analyses were considered significant. All statistical analyses were performed using JMP statistical software version 15 (SAS Institute).

| Patient flowchart and characteristics
Between July 1, 2018, and December 31, 2020, we enrolled 596 patients at Morioka Municipal Hospital, and 298 patients were assigned to the 1.5% olanexidine group and 298 to the 10% povidone-iodine group. The patient flowchart of this study is shown in Figure 1. We excluded patients who did not meet the inclusion criteria; patients with an ASA-PS of 5 or a history of iodine allergy before enrollment were also excluded. Therefore, 298 patients in each group were included in the full-analysis set. We then used an intention-to-treat analysis. Table 1 shows the patient characteristics and operative out-

| Primary and secondary outcomes
The incidences of SSIs in each group and the statistical results are shown in Table 2. The primary outcome of the overall 30-day SSI assessed in the full-analysis set occurred in 38 cases (12.8%) in the 1.5% olanexidine group and in 53 cases (18.0%) in the 10% povidone-iodine group (odds ratio: 0.676, 95% confidence interval: 0.431-1.059, adjusted risk ratio: 0.716, 95% confidence interval: 0.495-1.057, p = 0.083).

| Subgroup analyses
The results of the subgroup analyses are shown in Figure 2. We analyzed whether SSI incidence was associated with both the type of antisepsis and other background characteristics. The overall SSI rate was low in the 1.5% olanexidine group.

| Comparison between SSI-causing bacteria and preoperative wound cultures
A positive bacterial culture of SSI was observed in 20 patients (52.6%) in the 1.5% olanexidine group and in 19 patients (39.6%) in the 10% povidone-iodine group. Table 3 Table 4 also shows the concordance rate between SSI-causing organisms F I G U R E 1 Patients flowchart of this study.
TA B L E 1 Baseline characteristics and operative outcomes.

| DISCUSS ION
The present randomized controlled trial presents two major results. First, 1.5% olanexidine reduced the overall SSI incidence relative to 10% povidone-iodine as a preoperative antisepsis; however, the result was not significant (p = 0.083). Second, 1.5% olanexidine

TA B L E 3
Concordance rate between SSI-causative organisms and preoperative or wound cultures in 1.5% olanexidine group.
significantly (p = 0.049) reduced organ/space SSI. In studies that have clarified the efficacy of antisepsis, the timing of surgery and operative wound class were considered to exclude selection biases; however, homogenization in clinical trials diverges from clinical practice.
To compensate for this discrepancy, we enrolled patients undergoing emergency surgery or/with higher operative wound class (contaminated and infected) for the present study. Subgroup analyses revealed that emergency surgery and operative wound class did

TA B L E 4
Concordance rate between SSI-causative organisms and preoperative or wound cultures in 10% povidone-iodine group.
not increase SSI incidence. The present study was the first singlecenter randomized prospective trial to investigate the efficacy of 1.5% olanexidine for SSI prevention relative to 10% povidone-iodine in patients undergoing clean-contaminated (class II), contaminated (class III), and infected (class IV) surgeries.
The bactericidal mechanism of olanexidine has a higher affinity However, this study could not demonstrate the superiority of 1.5% olanexidine compared to the 10% povidone-iodine group (1.80% vs. 2.38%, p = 0.500). 20 Orthopaedic surgery requires operative wound class I surgery because osteomyelitis and device-associated infection should be avoided; therefore, the usual SSI incidence is lower in orthopaedic surgery than in gastrointestinal surgery, and a significant difference in clean orthopaedic surgery is difficult to identify. confidence interval: 0.34-0.90, p = 0.020) relative to povidoneiodine. 5,6 However, these previous studies have heterogeneity in the concentrations of both chlorhexidine (0.5%-4.0%) and povidoneiodine (0.75%-10.0%), and the most suitable antisepsis has not been clearly established. Therefore, the results of the comparative studies of 1.5% olanexidine, including the present study, may provide a new interpretation for SSI prevention because the concentration of olanexidine in every study was the same, and 10% povidoneiodine was used as a control arm in four of the five studies. In Japan, povidone-iodine is mostly used as a preoperative antiseptic, not chlorhexidine, because chlorhexidine contains alcohol; therefore, it is flammable. The Pharmaceuticals and Medical Devices Agency, which is a Japanese regulatory agency that works together with the Ministry of Health, Labour, and Welfare, has strongly warned of the danger of the ignition of alcohol-based antisepsis because of the use of electric scalpels. 7 Because of this, we selected 10% povidoneiodine as the reference arm for this clinical trial.
Several factors have been previously reported as risk factors for SSI incidence. The known risk factors for SSI include ASA-PS, BMI, operating time, intraoperative blood transfusion, colorectal surgery, prevalence of diabetes, operative wound class, and nutritional status. [21][22][23] In the present study, the SSI incidence in the 10% povidone- Subgroup analyses revealed that emergent surgery and operative wound class III/IV did not significantly increase SSI incidence in 10% povidone-iodine group. Emergent surgeries are often a contaminated or infected condition in clinical practice, however, it is controversial whether an emergent surgery is a risk factor of SSI incidence or not. 24 Combinations of these factors might be confounding biases in 10% povidone-iodine group.
In this study, we did not adopt timing of surgery and operative wound class as adjustment factors; therefore, allocation of the en- organ resection were not considered as factors affecting SSI in patients with malignant diseases. Fourth, the present study was conducted as an investigator-initiated clinical trial, and we performed all the processes of this trial. Furthermore, the colors of 1.5% olanexidine and 10% povidone-iodine are clearly different; therefore, we could not conduct this study as a double-blinded clinical trial. Finally, the current comparative studies on olanexidine were from Japan, and almost all enrolled patients in these studies were Japanese.
Thus, the use of olanexidine should be expected to spread worldwide, and further studies of olanxidine are warranted to clarify its efficacy as a new antiseptic.

| CON CLUS IONS
This randomized prospective clinical trial revealed that 1.5% olanexidine reduced the 30-day overall SSI incidence relative to 10% povidone-iodine during gastrointestinal surgery with intestinal resection; however, the result was not significant. Our study demonstrated that 1.5% olanexidine was associated with significantly reducing organ/space SSI and subgroup analyses also revealed that emergency surgery and operative wound class did not increase SSI

ACK N OWLED G M ENTS
The authors thank Yu Ariyoshi, Shingo Yanari, Kenichiro Ikeda, Hiroyuki Nitta, and the staff at Morioka Municipal Hospital.

FU N D I N G I N FO R M ATI O N
This research did not receive any grant from funding agencies in the public, commercial, or not-for-profit sectors.

CO N FLI C T O F I NTER E S T S TATEM ENT
The authors declare no competing interests.