SURGICAL INFECTIONS Volume 16, Number 3, 2015 ª Mary Ann Liebert, Inc. DOI: 10.1089/sur.2014.005

Surgical Infection Society Articles

Multi-Center Randomized Controlled Trial on the Effect of Triclosan-Coated Sutures on Surgical Site Infection after Colorectal Surgery Ilaria Mattavelli,1 Paola Rebora,2 Gianbattista Doglietto,3 Paolo Dionigi,4 Lorenzo Dominioni,5 Margherita Luperto,1 Angela La Porta,1 Mattia Garancini,1 Luca Nespoli,1 Sergio Alfieri,3 Roberta Menghi,3 Tommaso Dominioni,4 Lorenzo Cobianchi,4 Nicola Rotolo,5 Gabriele Soldini,5 Maria Grazia Valsecchi,2 Marco Chiarelli,6 Angelo Nespoli,1 and Luca Gianotti1

Abstract

Background: Surgical site infection (SSI) remains the most frequent complication after colorectal resection. The role of sutures coated with antimicrobial agents such as triclosan in reducing SSI is controversial. Methods: This was a multi-center randomized controlled trial with patients and outcome assessors blinded to treatment. The study was performed in four university referral hospitals. Patient candidates for elective colorectal resection were assigned randomly to abdominal incision closure with polyglactin 910 triclosan-coated sutures (triclosan group) or with polyglactin 910 without triclosan (control group). The primary outcome was the rate of SSI within 30 d after hospital discharge. The secondary outcomes were the overall rate of incision complications and length of hospital stay (LOS). Results: Two hundred eighty-one patients (triclosan group: 140; control group: 141) were analyzed after randomization. The rate of SSI was 12.9% (18/140) in the triclosan group versus 10.6% (15/141) in the control group (odds ratio: 1.24; 95% confidence interval: 0.60–2.57; p = 0.564). Secondary outcome analysis showed an overall incision complication rate of 38.3% in the control group versus 45.7% in the triclosan group (odds ratio: 1.36; 95% confidence interval: 0.84–2.18; p = 0.208). Median LOS was 11 d in both groups (p = 0.55). Conclusions: Surgical sutures coated with triclosan do not appear to be effective in reducing the rate of SSI.

S

urgical site infection (SSI) remains the most frequent complication after colorectal surgery [1–3]. Surgical site infections cause major discomfort for the patient, are potentially life-threatening events, prolong hospitalization stays, and increase direct and indirect costs with a significant overall financial burden for any health care system [4–6]. Therefore, any means to prevent SSI should be evaluated and tested thoroughly. Patient-related risk factors and potential strategies to reduce the risk of development of SSIs are well known [2,6–9]. Among the innovative approaches to reduce the risk of incision

infection is the ability to impregnate suture materials with antimicrobial substances. In fact, microbial adherence to the surface of sutures has been recognized as one of the reason for the development of incision infections [10–12]. To prevent microbial colonization of sutures, triclosan-coated materials have become available recently. Triclosan is an antiseptic that has been used in several pharmaceutical products over the past 30 years for its antiseptic properties and safety profile [13]. In vitro studies demonstrated that triclosan forms an inhibition zone around suture material and it is effective against the pathogens responsible most frequently for SSIs [14].

1

Department of Surgery and Translational Medicine, Milano-Bicocca University, San Gerardo Hospital, Monza, Italy. Department of Health Sciences, Centre of Biostatistics for Clinical Epidemiology, Milano-Bicocca University, Monza, Italy Department of Surgery, Policlinico Gemelli, Cattolica University, Rome, Italy. 4 Deparment of Surgery, Policlinico San Matteo, University of Pavia, Pavia, Italy. 5 Department of Surgical Sciences, Ospedale Circolo Fondazione Macchi, University of Insubria, Varese, Italy. 6 Department of Surgery, A. Manzoni Hospital, Lecco, Italy. The preliminary results of the present trial were presented at the Twenty-Fourth Annual Meeting of the Surgical Infection Society— Europe, Leon, Spain, May 25–28, 2011. 2 3

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TRICLOSAN-COATED SUTURES IN COLORECTAL SURGERY

Clinical experience with this material is still limited. Two recent meta-analyses [15,16] on the effect of triclosanimpregnated sutures on SSI reported conflicting results. A potential limitation of both analyses was the heterogeneity of the studies incorporated ranging from clean to dirty operations and different types of surgery. Until now, only three randomized controlled trials (RCTs) addressing the effect of triclosan-coated sutures in colorectal operations have been published, with inconsistent outcome. A Hungarian multicenter trial [17] failed to demonstrate any advantage of impregnated sutures on the overall rate of SSIs. Two recent single-center studies [18,19] showed a significant reduction of incision infection in patients undergoing open colorectal resection treated with triclosan-coated sutures. We sought to evaluate the effect of a triclosan-coated sutures on the incidence of SSIs after elective colorectal operations. Patients and Methods Study design

The present study was a multi-center, randomized, controlled trial carried out in four university referral hospitals in Italy. The protocol was approved by the ethical committees of all four centers. Written informed consent was obtained from all participants before randomization. The study was registered at www.clinical-trial.gov with identifier number NCT01869257. Study population

Patient enrollment took place between January 2010 and March 2013. Patients were eligible if they were candidates for elective colorectal resection with a clean-contaminated field. The exclusion criteria were younger than 18 y, pregnancy, emergency operations, ongoing infections, American Society of Anesthesiologists (ASA) score ‡ 3, any organ insufficiency, Karnofsky performance status < 70, intra-operative evidence of gross contamination of the surgical field, and denied written consent. Necessity of re-operation for any reason during the post-operative course resulted in patient dropout from the trial with no replacement. Random assignment and blinding

Patients were randomized during surgery after the colorectal resection was completed and just before beginning the closure of the abdominal wall. Treatment allocation was by means of a computerized randomization list with 1:1 ratio. Each center had an independent list. Assignment was done by sealed, opaque, numbered envelopes that were opened in sequence by a registered nurse not involved in the study. This was an independent, unsponsored study and each hospital purchased the sutures. Therefore, it was impossible for the organizers of the trial to receive blind suture packages. As a result, operating surgeons were not blinded to the material used for incision closure. To minimize the risk of bias, patients and outcome assessors were blinded to the allocation for the full period of evaluation. The surgical staff members were not allowed to communicate information about treatment allocation to patients or other staff during the duration of the study. Intervention

Patients were randomly allocated into two groups to receive either closure of the midline abdominal incision with

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triclosan-coated sutures (triclosan group) or a suture material without triclosan (control group). In the treated group the abdominal incision was sutured by a separate layer technique starting with the peritoneum with 0 Vicryl Plus (triclosancoated polyglactin 910; Ethicon Italia, Pratica di Mare, Italy), followed by the fascia with PDS Plus (triclosan-coated polydioxanone; Ethicon), and then the skin with 3/0 Vicryl Plus. The skin closure was by interrupted sutures, while the peritoneum and the fascia by a running suture. The identical technique was used in the control group using polyglactin (Vicryl; Ethicon) or polydioxanone suture without triclosan (PDS II; Ethicon). Suturing or not suturing the subcutaneous tissue layer was left to the preference of the operating surgeon. In cases of subcutaneous fat tissue closure, the technique was interrupted sutures with 3/0 Vicryl Plus or 3/0 Vicryl according to randomization. Bowel preparation with 3 L of an iso-osmotic solution was carried out only in patients who were candidates for rectal resection. Patients presenting with large bowel obstruction were treated with an endoscopic metallic stenting and operated on after a complete resumption of bowel function. Hair removal was performed the evening before operation or the morning of the operation with either an electric clipper or a razor blade. Skin disinfection before incision was done in all cases with a 10% povidone-iodine solution. Mechanical wound protectors were used only in case of laparoscopic resection during specimen extraction. All patients received antibiotic prophylaxis. The type of drug was left to the preference of the operating surgeons but within the limited choice based on national guidelines [20]. A single pre-operative dose, 30 min before skin incision (single dose), or a pre-operative dose followed by three consecutive doses every 8 h after the operation (multiple doses) was based on surgeon prescription. A second dose of antibiotic during surgery was administered in cases in which the duration of the operation was longer than 4 h, intra-operative contamination, or bleeding more than 500 mL. Prevention of intraoperative hypothermia was carried out by means of warming blankets and infusion of heated fluids. Data collection and follow-up

After the patients signed informed consent the following pre-operative baseline demographic characteristics and risk factors were recorded: Age, weight, height, body mass index [BMI], type of disease, ASA score, weight loss and its amount, smoking habit, diabetes mellitus, chemoradiation, steroid use, and laboratory parameters (blood glucose, albumin, pseudocholinesterase, lymphocyte count). During and after the operation the following data were recorded: Duration and type of surgery and technical details, use of peritoneal drainage, and blood transfusion. Independent, blinded trained observers checked the patients during the post-operative course twice per day and the incision every other day until hospital discharge. The observers performed data collection using standard paper case report forms and electronic databases. Using the U.S. Centers for Disease Control and Prevention (CDC) criteria of 1999 [21], they recorded the occurrence of and defined SSI and any other incision event. Superficial incisional SSI and deep incisional SSI were considered in this trial whereas organ/space SSIs were not included because suture coating should not have a role in the occurrence of intra-peritoneal collection.

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Superficial incisional SSI was defined as an infection occurring within 30 d after the operation and involving only skin or subcutaneous tissue of the incision and at least one of the following: Purulent drainage from the incision, pain or tenderness, localized swelling, redness, or heat. Deep incisional SSI was defined as an infection occurring within 30 d after the operation and involving deep soft tissues (e.g., fascial and muscle layers) of the incision and at least one of the following: Purulent drainage from the incision but not from the organ/space component of the surgical site; spontaneous dehiscence or deliberate incision opening by the surgeon with fever ( > 38C), localized pain or tenderness, or deep incisional abscess. In case of suspected SSI, microbiologic analysis and pus culture had to be performed. The occurrence of complications was monitored for 30 d after discharge with regular weekly visits by the same per-

FIG. 1.

sonnel. In case of any incision complication the assessor was required to ask for a second opinion to confirm the event. End points

The primary outcome measure was the overall rate of incisional SSI (superficial and deep incisional SSI). Secondary end points were length of hospital stay and overall incision complication rate, including skin swelling and redness, hematomas, and seromas. Statistics

When designing the study, the overall SSI rate was expected to be approximately 15%. This was based on the mean rate of SSI in the four participating centers in the years 2007– 2008. A relative reduction of 50% was considered clinically

CONSORT diagram for the trial.

TRICLOSAN-COATED SUTURES IN COLORECTAL SURGERY

229

Table 1. Baseline Characteristics and Risk Factors Control (n = 141) Male Age (y)a Body mass index (kg/m2)a Body mass index categories < 19 19–25 26–30 > 30 Weight loss > 10% Percent of weight lossa Smoking habit Diabetes mellitus Biochemistry Total lymphocytes (109/L)a Blood glucose (mg/dL)a Albumin (g/L)a Pseudocholinesterase (IU/L)a Cancer ASA 1 2 3 Steroid use Pre-operative radiochemotherapy Hair removal Day before surgery Same day as surgery Technique of hair removal Electric clipper Razor blade Antibiotic prophylaxis PPBLI Cefazolin Cefoxitin Piperacillin Other Metronidazole in combination Antibiotic dose Single Multiple Second intra-operative dose Type of surgery Right colectomy Transverse resection Left colectomy Anterior resection of rectum Abdominal–perineal resection Laparoscopy Type of anastomosis Manual Mechanical Side-to-side End-to-side End-to-end Protective stoma Duration of surgery (min)a Blood transfusion Use of drainage Subcutaneous tissue closure

74 ( 69 ( 24.8 (

52.4) 60 – 22.3 –

10 64 55 12 15 5.4 17 18

7.1) 45.4) 39.0) 8.5) 10.6) 3.6 – 12.1) 12.8)

1.83 98 39.0 6,989 118

( ( ( ( ( ( ( (

76) 27.1)

11.2)

( 1.37– 2.37) ( 88 – 112) ( 3.5 – 4.2) (5,292 –8,504) ( 83.7)

Triclosan (n = 140) 81 ( 69 ( 24.3 (

57.8) 60 – 22.6–

4 77 46 13 19 6.3 26 21

2.8) 55.0) 32.8) 9.3) 13.6) 5.4– 18.6) 15.0)

1.71 96 38.3 7,099 124

( ( ( ( ( ( ( (

( ( ( ( (

14.9) 69.5) 15.6) 3.5) 5.7)

17 95 28 4 17

( ( ( ( (

12.1) 67.8) 20.0) 2.8) 12.1)

108 33

( (

76.6) 23.4)

106 34

( (

75.7) 24.3)

87 54

( (

61.7) 38.3)

82 58

( (

58.6) 41.4)

25 54 45 11 6 98

( ( ( ( ( (

17.7) 38.3) 31.9) 7.8) 4.2) 69.5)

23 61 28 12 16 99

( ( ( ( ( (

16.4) 43.6) 20.0) 8.6) 11.4) 70.7)

37 104 19

( ( (

26.2) 73.7) 13.5)

41 99 26

( ( (

29.1) 70.7) 18.6)

49 9 55 23 5 26

( ( ( ( ( (

34.7) 6.4) 39.0) 16.3) 3.6) 18.4)

49 5 55 29 2 26

( ( ( ( ( (

35.0) 3.6) 39.3) 20.7) 1.4) 18.6)

( 51.8) ( 48.2) ( 43.2) ( 14.2) ( 42.6) ( 9.9) ( 100 – 220) ( 15.6) ( 91.5) ( 87.2)

66 74 61 21 58 10 145 20 128 121

9.6)

( 1.2– 2.19) ( 84 – 107) ( 3.4– 4.3) (5,518 –8,468) ( 88.6)

21 98 22 5 8

73 68 61 20 60 14 140 22 129 123

75) 27.2)

( 47.1) ( 52.8) ( 43.6) ( 15.0) ( 41.4) ( 7.1) ( 105 – 230) ( 14.3) ( 91.4) ( 86.4)

a Values are median (interquartile range). Values in parentheses are percentages unless indicated otherwise. ASA = American Society of Anesthesiologists physical status classification system; PPBLI = penicillins plus b-lactamase inhibitors.

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Table 2. Primary Study End Point

Overall SSI Deep incisional Superficial incisional

Control (n = 141)

Triclosan (n = 140)

Difference (95% CI)

OR (95% CI)

p

15 (10.6) 8 ( 5.7) 7 ( 4.7)

18 (12.9) 4 ( 2.9) 14 (10.0)

2.2 ( - 5.3– 9.7) - 2.8 ( - 7.5– 1.9) 5.0 ( - 1.1–11.2)

1.24 (0.60–2.57) 0.49 (0.14–1.66) 2.13 (0.83–5.44)

0.564 0.252 0.115

Values in parentheses are percentages unless indicated otherwise. SSI = surgical site infection; OR = odds ratio; CI = confidence interval.

significant. With the planned sample size of 140 patients per arm, the expected width of the two-sided 95% confidence interval for the difference in proportions was 0.17. A dropout rate of 7% for discontinuation of intervention was anticipated, therefore, the target was a total sample size of 300 patients. The primary outcome measure was evaluated by 95% confidence interval of the difference in the proportion of SSI and by the odds ratios (odds ratio, p value were obtained from w2 test with 1 df). The secondary end points based on proportions were evaluated by odd ratio and 95% confidence interval. To evaluate the influence of pre- and intra-operative variables on the incidence of SSI, the w2 test or Fisher exact test when appropriate and t-test were applied for categorical and continuous variables, respectively. A multivariable logistic model was applied including the treatment variable and evaluating the most important risk factors emerging from the literature in a one-step model. From this model, the predicted probabilities of SSI were estimated for hypothetical patients with relevant combinations of risk factors. Results

Three hundred eighty-seven patients were screened for eligibility for the study and 300 patients were enrolled. One hundred fifty subjects were allocated in the triclosan arm and 150 in the control arm. After randomization, 19 patients (9 in the control arm and 10 in the triclosan arm) underwent relaparotomy with discontinuation of intervention. This left 141 patients in the control arm and 140 in the triclosan arm for the final analysis (Fig. 1). No patient was lost for followup. Table 1 describes the demographic and baseline characteristics, surgical details, and the risk factors for SSI of the two groups. The two groups were well balanced for all the variables considered. The overall incidence of SSI was 11.7% (33/281), lower than what was expected. The evaluation of the primary end point showed that there was no statistically significant dif-

ference in the overall rate of SSI between treated and control groups (difference: 2.2; 95% CI ( - 5.3–9.7); odds ratio: 1.24; 95% CI: 0.60–2.57; p = 0.56). Similar results were obtained when SSI were divided between superficial and deep (Table 2). Among the 33 SSIs, 11 (33.3%) appeared after hospital discharge (4 in the triclosan group and 7 in the control group). Secondary outcome analysis showed that the overall wound complication rate was 45.7% in the triclosan group versus 38.3% in control group (odds ratio: 1.36; 95% CI: 0.84–2.18; p = 0.21; Table 3). The patients treated with triclosan-coated sutures had significantly more wound hematomas than the control group (9.3% vs. 2.1% respectively; odds ratio: 4.71; 95% CI: 1.31–16.91; p = 0.02), while no significant differences were observed for skin swelling, redness, or wound seroma. Duration of hospitalization was similar between groups (p = 0.546). Table 4 shows the results of the univariate analysis of single risk factors on the occurrence of SSI. Antibiotic prophylaxis with a single dose was the only parameter that was associated with a significant reduction of SSI compared with multiple doses. Other variables such as BMI < 30, the use of penicillins plus b-lactamase inhibitors (PPBLI) for prophylaxis, and not suturing the subcutaneous fat tissue did not reach statistical significance. The multivariable logistic regression analysis (Table 5) provided an estimate of the treatment effect (OR: 1.26, 95% CI: 0.59; 2.69). Regarding risk factors, results showed that giving multiple antibiotic doses was significantly associated with a fourfold increased risk of SSI compared with single dose (p = 0.01), after adjusting for type of antibiotics, BMI, and whether the patients had or did not have a subcutaneous tissue suture. Moreover, compared with PPBLI, other antibiotics were related to a sixfold increase in the odds of developing an SSI, although this did not reach statistical significance (p = 0.098). By constructing a statistical model we evaluated the potential combinations of factors increasing the likelihood of

Table 3. Secondary Study End Points Control (n = 141) Incision hematoma Incision swelling Incision redness Incision seroma Overall incision complications Length of stay (d) Mean – SD Median (interquartile range)

3 20 38 31 54

( 2.1) (14.2) (26.9) (22.1) (38.3)

13.5 – 10.4 11 (9–15)

Values in parentheses are percentages unless indicated otherwise. OR = odds ratio; CI = confidence interval; SD = standard deviation.

Triclosan (n = 140) 13 26 43 32 64

( 9.3) (18.6) (30.7) (22.9) (45.7)

12.3 – 6.5 11 (9–15)

OR (95% CI) 4.71 1.38 1.20 1.05 1.36

( ( ( ( (

1.31–16.91) 0.73– 2.61) 0.71– 2.02) 0.60– 1.84) 0.84– 2.18) - 1.22 ( - 5.24– 2.83)

p 0.018 0.322 0.486 0.861 0.208 0.546

TRICLOSAN-COATED SUTURES IN COLORECTAL SURGERY

Table 4. Univariate Analysis of Risk Factors for Surgical Site Infection

Table 4. (Continued) p p

Overall SSI Center Monza Pavia Rome Varese Gender Female Male Age BMI categories < 19 19–25 25–30 > 30 Weight loss No Yes Smoking habit No Yes Diabetes mellitus No Yes Total lymphocyte count (109/L) Blood glucose (mg/dL) Albumin (g/L) Pseudocholinesterase (U/L) Disease Cancer Non-cancer ASA score 1 2 3 Steroid use No Yes Preoperative radiochemotherapy No Yes Hair removal Day before surgery Same day of surgery Technique of hair removal Electric clipper Razor blade Antibiotic prophylaxis PPBLI Cefazolin Cefoxitin Piperacillin Other Metronidazole in combination No Yes Antibiotic dose Single Multiple

33/281 (11.7) 0.081 12/ 11/ 3/ 7/

76 64 66 75

(15.8) (17.2) ( 4.5) ( 9.3) 0.233

18/126 (14.3) 15/155 ( 9.7) 0.546 0.193 2/ 14 16/140 9/101 6/ 25

231

(14.3) (11.4) ( 8.9) (24.0) 0.997

29/247 (11.7) 4/ 34 (11.8) 0.980 28/238 (11.8) 5/ 43 (11.6) 0.280x 31/242 (12.8) 2/ 39 ( 5.1) 0.147 0.402 0.780 0.399 0.822 28/242 (11.6) 5/ 39 (12.8) 0.937 5/ 38 (13.1) 23/196 (11.7) 5/ 47 (10.6)

Second intra-operative dose No Yes Type of surgery Right colectomy Transverse resection Left colectomy Anterior resection of rectum Abdominal-perineal amputation Laparoscopy No Yes Type of anastomosis Manual Mechanical Side-to-side End-to-side End-to-end Protective stoma No Yes Duration of surgery Blood transfusion No Yes Use of drainage No Yes Subcutaneous tissue closure No Yes

0.386 26/236 (11.0) 7/ 45 (15.5) 0.198 13/ 98 3/ 14 9/110 7/ 52 1/ 7

(13.3) (21.4) ( 8.2) (13.5) (14.2) 0.597

28/229 (12.2) 5/ 52 ( 9.6) 0.519 18/138 15/142 17/122 4/ 41 12/116

(13.0) (10.6) (13.9) ( 9.7) (10.3) 0.287

29/260 (11.2) 4/ 24 (16.7) 0.756 0.797 29/239 (12.1) 4/ 42 ( 9.5) 0.503 4/ 24 (16.7) 29/256 (11.3) 0.096 1/ 37 ( 2.7) 32/243 (13.2)

Values in parentheses are percentages unless indicated otherwise. SSI = surgical site infection; BMI = body mass index; ASA = American Society of Anesthesiologists physical status classification system; PPBLI = penicillins plus b-lactamase inhibitors;

0.286 31/272 (11.4) 2/ 9 (22.2) 0.330 32/256 (12.5) 1/ 25 ( 4.0) 0.072 21/214 ( 9.8) 12/ 67 (17.9) 0.233 23/169 (13.6) 10/112 ( 8.9) 0.107 1/ 48 17/115 8/ 73 4/ 23 3/ 22

( 2.1) (14.8) (10.9) (17.4) (13.6) 0.204

13/ 84 (15.5) 20/197 (10.2) 0.033 4/ 78 ( 5.1) 29/203 (14.3) (continued)

developing SSI in patients with certain characteristics (Fig. 2). Obese patients receiving multiple prophylactic antibiotic doses with drugs other than PPBLI and having subcutaneous tissue sutured had a probability of SSI of 34.1% in the triclosan group and 29.1% in the control group. These probabilities decreased to 18.9% and 15.5%, respectively, in non-obese patients with the same characteristics. In contrast, when none of the above variables were present, the chance of an SSI was 1.3% in the triclosan group and 1.1% in the control group. Table 6 presents the details of the bacteria isolated from the incisions in the patients who developed infections. The results show that in the vast majority of patients, gramnegative Enterobacteriaceae were the most frequent isolates, followed Pseudomonas aeruginosa. Only occasionally were gram-positive such as enterococci and Staphylococcus aureus identified. No difference was observed between groups. Discussion

There is justification for assuming that the use of sutures impregnated with triclosan may reduce the risk of SSI. Triclosan has demonstrated antiseptic properties primarily against gram-positive pathogens [22,23], but its effect against various E. coli strains was also proved in orthopedic operations

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Table 5. Logistic Regression Analysis of Risk Factors for Surgical Site Infection

Control vs. triclosan BMI > 30 vs. £ 30 All other antibiotics vs. PPBLI Multiple vs. single antibiotic dose Subcutaneous suture (yes vs. no)

OR

(95% CI)

p

1.26 2.23 6.16 4.22 2.77

(0.59– 2.69) (0.79– 6.28) (0.72–53.07) (1.41–12.57) (0.31–24.75)

0.545 0.131 0.098 0.010 0.361

OR = odds ratio; CI = confidence interval; BMI = body mass index; PPBLI = penicillins plus b-lactamase inhibitors.

[24,25]. Moreover, the coating provides prolonged protection against colonization of the tissue around the sutures because its effects last for approximately 1 mo [14,26]. This makes the use of triclosan-coated sutures even more attractive because of the considerable proportion of SSI presenting late after surgery [27]. Preliminary clinical results from a large retrospective analysis [28] were quite promising on the ability of triclosancoated materials to prevent the occurrence of SSI but most of the subsequent RCTs [15], even if conducted in heterogeneous cohorts, failed to demonstrate clear benefits on incision infection and complication rates. Colorectal surgery may represent a favorable clinical model to evaluate the effect of sutures impregnated with triclosan because of the high incidence of SSI and thus limiting the trial sample size and the polymicrobial origin of SSI allowing an in vivo appraisal of the antimicrobial spectrum of triclosan.

The results of the present RCT do not support the hypothesis that triclosan-coated sutures decrease the rate of post-operative SSI. Our findings are consistent with the results of Baracs et al. [17], who showed in a similar population of 385 patients undergoing comparable surgical procedures an overall rate of incision infection of 12.5% with no significant difference between the group treated with triclosancoated sutures (12.2%) and uncoated sutures (12.2%). As in our study, they used a running triclosan-coated polydioxanone to close the abdominal fascia; peritoneum and subcutaneous layer closure was optional and the rate of implementation was not reported. Our data are in contrast to those reported in a single-center RCT conducted in Japan [19]. The authors found that suturing the abdominal wall with triclosan-coated polyglactin 910 was significantly effective in reducing the incidence of incision infection in patients undergoing colorectal resection. The incidence of SSI in their study group was 4.3% (9/206), and 9.3% (19/204) in the control group (p = 0.047). This difference was mainly because of infections occurring in patients who underwent open surgery. The potential differences in the study design, such as type of suture, interrupted sutures, single-layer abdominal closure, and skin closure may partially explain the conflicting results. Probably more important in interpreting the discrepancies of results among trials is the composition of the colonic microbiota that differs substantially in different populations mainly according to alimentary habits and environmental conditions [29–31]. Because the main source of SSI after colorectal resection is the intestinal flora, different bacterial strains harboring the

FIG. 2. Predicted probabilities of SSI and 95% confidence intervals estimated from the multivariate model for hypothetical patients with relevant combinations of risk factors (dots and continuous lines). Dashed line reports the overall incidence of SSI. SSI = surgical site infection; C = control group; T = triclosan group; Y = yes; N = no.

TRICLOSAN-COATED SUTURES IN COLORECTAL SURGERY

Table 6. Bacteria Isolated from Infected Incisions Patient random number

Group

7 12

Control Control

31

Control

44 52 69 80

Control Control Control Control

88 93

Control Control

113 116 125 128 133 139 2

Control Control Control Control Control Control Triclosan

9 15 18 27 36 40 55 60

Triclosan Triclosan Triclosan Triclosan Triclosan Triclosan Triclosan Triclosan

72 85 90 101 110 129

Triclosan Triclosan Triclosan Triclosan Triclosan Triclosan

130 137 140

Triclosan Triclosan Triclosan

Microorganism ND Pseudomonas aeruginosa, Enterobacter cloacae Klebsiella pneumoniae, Escherichia coli ND E. coli ND Staphylococcus aureus, Bacteroides fragilis E. cloacae, E. coli Enterococcus faecium, Candida albicans ND P. aeruginosa ND Morganella morganii ND ND E. coli, E. faecalis, E. avium ND Citrobacter koseri E. coli ND S. aureus E. cloacae, M. morganii ND P. aeruginosa, Proteus vulgaris ND E. faecalis E. cloacae ND K. oxytoca, B. fragilis E. coli, Streptococcus anginosus, P. vulgaris ND ND E. cloacae

ND = not determined.

gut and their susceptibility to the antimicrobial properties of triclosan may account for the inconsistent results among trials conducted in different countries. In fact, in the study by Nakamura et al. [19], enterococci were by far the most frequent isolates (54%), and the second most common infections was caused by Bacteroides species (36%). In our series, enterococci was present in fewer than 20% of the cases and gram-negative enterobacteriaceae (Escherichia, Klebsiella, Proteus, Enterobacter, Citrobacter, Morganella) and Pseudomonas aeruginosa were the most common isolates accounting for more than 80% of the infections. This partially confirms the limited in vivo efficacy of triclosan on several species of gram-negative bacteria [32]. However, in our series 42% of the incision infections were not confirmed by microbiologic and culture analysis. These data might be explained by the fact that one-third of the infections were evident after hospital discharge. Our health care system does not

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provide reimbursement for outpatient laboratory tests; the cost of the analysis was to be paid entirely by the patient, who declined it. Safety studies on triclosan have been performed in the past, mainly focusing on systemic toxicity and local adverse reactions. Overall, these studies showed that systemic concentrations of triclosan are low when applied topically [13]. Although triclosan is relatively non-toxic in classic toxicologic terms, negative effects such as dermatitis, skin irritation, and allergic reactions have been described [33]. The safety of use in suture materials has been proved repeatedly although a recent study by Deliaert et al. [34] reported a negative effect on incision healing after breast reduction surgery. Our results showed that in patients treated with triclosan-coated sutures there was an increase of wound hematomas. Such local side effects were not reported previously. The reason is unknown and difficult to explain on the basis of the identified safety reports. It can be speculated that the release of triclosan in the incision may interfere with some local coagulation pathways or platelet function. This minor side effect might be attributed to the broad use of triclosan-coated sutures in our study. In fact, we utilized four sutures to close peritoneum, fascia, subcutaneous fat tissue, and skin while previous similar trials used only one or two sutures. Using a multiple logistic regression analysis we investigated four key variables for SSI. The use of PPBLI for antibiotic prophylaxis and a single dose of antibiotics were the most protective factors against the development of SSI but also BMI < 30 and not suturing the subcutaneous tissues were related to a lesser risk. Taken singularly these elements have not been identified commonly as relevant variables for the occurrence of postoperative infections. Obesity is a wellrecognized risk factor [35], whereas the role of PPBLI versus other drugs as prophylactic agent [36], a single dose versus repeated antibiotic doses [37], and suturing versus not suturing of the subcutaneous layer [38] have been reported as comparable for the risk of SSI. The description of the SSI risk according to different combinations of the these variables showed that when all risk factors were present (obesity, suture of subcutaneous tissue, multiple antibiotic doses, and not using PPBLI) the risk was approximately 30% and only when obesity was not present was the risk reduced by 50% regardless the type of suture used. On the contrary, when all these variables were absent the risk of SSI almost disappeared (*1%). These results may have clinical relevance because the use of subcutaneous tissue sutures may increase infection risk in obese patients, perhaps by adding foreign material. Our trial has several methodologic limitations. The operating surgeon was not blinded to the intervention despite random assignment being done after the colorectal resection was completed and both patients and assessors being unaware of the randomization arm. Moreover, the randomization was not balanced for important and known patient and operative risk factors for SSIs. Despite prevention of intra-operative hypothermia being performed routinely, body temperature was not recorded in the database. Therefore, we could not assess the role of hypothermia on the occurrence of SSI. In our study there was no predefined prophylactic antibiotic regimen and dosing, and 40% of the reported SSI was not confirmed by positive culture although a second assessor had to confirm the event. Our

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univariate and multivariable analyses may have suffered from the small number of events potentially leading to variability in treatment effects due to a type II error. Furthermore, a multi-center trial may introduce bias linked to the heterogeneity of surgical techniques, sanitary behaviors of the personnel, and judgment practices among centers. Conclusions

The present trial failed to demonstrate a protective effect of triclosan-coated sutures on the occurrence of SSI. Our data suggest that the extensive use of such sutures have some local side effects. Given the conflicting results in the literature on the benefit and harm of triclosan-impregnated materials on incision healing, further large RCTs are needed before introducing it in a routine clinical use. Acknowledgment

This trial was funded by a research grant of the University of Milano-Bicocca. Author Disclosure Statement

No competing financial interests exist. References

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Address correspondence to: Prof. Luca Gianotti Department of Surgery San Gerardo Hospital Via Pergolesi 33 20900 Monza Italy E-mail: [email protected]