Triclosan coated sutures for prevention of surgical site infection: a health technology assessment
Health technology assessment|
We have summarized the efficacy and safety and assessed the health economic consequences of the use of triclosan-coated sutures compared to standard sutures for the prevention of surgical site infections.
We have summarized the efficacy and safety and assessed the health economic consequences of the use of triclosan-coated sutures compared to standard sutures for the prevention of sur-gical site infections. Triclosan is an antimicrobial agent associated with antibiotic resistance and environmental pollution. Therefore, we have also evaluated the potential impact of triclosan-coated sutures on antibiotic resistance and the environment. The certainty to the estimates of effect were assessed using the GRADE tool (high, moderate, low, or very low).
In the meta-analyses of the studies with low and moderate risk of bias, we found that the use of triclosan-coated sutures compared to standard sutures resulted in:
- no difference or possibly a small reduction in the risk of infections after gastrointestinal/abdominal surgeries. (GRADE: low).
- little or no difference after cardiovascular surgeries. (GRADE: low)
- uncertain results for orthopaedic surgeries, and both fewer and more infections may occur. The confidence interval was wide. (GRADE: very low).
- no difference or possibly a small reduction in the risk of infections after clean (non-infected) surgeries. Cardiovascular and orthopaedic surgeries are classified as clean. (GRADE: low)
For subgroup analyses of superficial infections, studies with low risk of bias, and studies with participant numbers over 1000, the confidence intervals crossed the line of no effect. We assessed the certainty of the evidence as moderate for studies with low risk of bias and low in the others. In these analyses, we did not differentiate between different surgical procedures.
In the health economic assessment, subgroup analyses within gastrointestinal and abdominal surgeries of laparoscopic colon surgery, open colon surgery, and laparoscopic gallbladder removal suggested that triclosan-coated sutures may provide both cost savings and additional costs. The results for all three analyses indicated a tendency that the use of triclosan-coated sutures potentially would lead to less cost savings the lower the infection incidence.
Triclosan can be linked to antibiotic resistance in several important pathogenic bacteria as well as environmental bacteria, and it can lead to increased transfer of antibiotic resistance genes between bacteria. One question is whether any benefit from the use of triclosan outweighs the risk of developing antibiotic resistance.
The amounts of triclosan expected to be released into the environment after use in sutures are low. Although the emission is undesirable, the impact on the environment is likely to be minimal. If the use of triclosan-coated sutures is a valuable, environmental considerations will probably not be an obstacle to their use.
If new studies are to be conducted, our experts from the field have proposed studies with a cluster-randomized design where infections after caesarean sections, gallbladder surgeries, and colon surgeries are registered.
One of the most common complications after surgery is surgical site infections. To prevent infections, absorbable sutures coated with the antimicrobial agent triclosan have been used. An antimicrobial agent inhibits the growth or kills microorganisms such as bacteria, fungi, and viruses. The term is often used interchangeably with antibiotics. However, triclosan can lead to environmental pollution and is associated with antibiotic resistance. Due to these undesirable properties, bans on triclosan have been implemented in many areas. Chlorhexidine is another antimicrobial agent used to prevent infections, but it is not used on sutures to the same extent as triclosan. Moreover, chlor-hexidine is not listed by Miljødirektoratet, the environmental directorate in Norway, as environmentally harmful substance that meet the PBT criteria (substances that are persistent, bioaccumulative, and toxic). A multidisciplinary team of experts from the fields of surgery, infectious diseases, antibiotic resistance, transplant medicine, infection control and environmental pollution have participated in the work of this report.
The research questions we aimed to address were:
- What is the efficacy and safety of triclosan-coated sutures compared to standard (uncoated) sutures in order to prevent surgical site infections?
- What studies can be found relating to the efficacy and safety of chlorhexidine-coated sutures compared to standard sutures in order to prevent surgical site infections?
- What are the economic consequences of using triclosan-coated sutures compared to standard sutures in order to prevent surgical site infections?
- Assess whether the use of triclosan-coated sutures can lead to the development of resistance, thereby reducing the effectiveness of clinically important antimicrobial agents.
- Evaluate whether the use of triclosan-coated sutures can impact the environment.
Clinical effectiveness and safety
We used the recently published report (2022) from the National Institute for Health and Care Excellence (NICE), hereafter referred to as the NICE report, as a basis for our search and presentation of results. We assessed the NICE report to have high methodological quality.
We updated the search from the NICE report and included relevant randomized controlled trials (RCTs) using the machine learning tool EPPI-reviewer. We assessed the risk of bias in the included RCTs for research question 1. The primary outcomes were the incidence of surgical site infections in different subgroup analyses. In addition, we investigated the incidence of wound dehiscence.
According to our experts, it is unlikely that any potential effect of triclosan in one type of surgery can be extrapolated to others. Therefore, we performed (as described in the NICE report) subgroup analyses of the occurrence of infections categorized by surgical sites and for clean surgeries. Surgeries can be classified into different degrees of contamination. Other subgroup analyses included studies with low, moderate, and high risk of bias, studies with more than 1000 and more than 500 participants, studies conducted in countries with similar levels of antibiotic resistance to Norway, studies funded by co-panies and non-company-funded studies, as well as studies that exclusively included children. We calculated relative risks (RR) with 95% confidence intervals (CI). We assessed the certainty of the evidence, i.e. the extent to which we have confidence that the effect estimate is close to the true underlying effect, using the GRADE tool. The assess-ments are graded to high, moderate, low, or very low confidence.
For research question 2 regarding chlorhexidine-coated sutures, we included studies with a control group and presented the results from the articles in a table. We did not assess the certainty of the evidence of the studies or perform any analyses.
We included 31 studies comparing triclosan-coated sutures with standard sutures for the prevention of surgical site infections. Several studies had more than 1000 participants, and one study, the Falcon study published in 2021, had more than 5000 participants.
About half of the studies had a high risk of bias and few participants. In the meta-analyses, we only included studies with low and moderate risk of bias when the precision (number of adverse events) was not significantly reduced. This is recommended by Cochrane when studies with different risks of bias yield different results. The results for all studies (n = 31) are provided in the appendix.
In the meta-analyses of studies including all the different types of surgeries (n = 17 studies), we found an RR (risk ratio) of 0.87 (95% CI: 0.76 to 0.99) in favour of triclosan-coated sutures. However, when only studies with low risk of bias (n = 11) were included in the analysis, the confidence interval crossed the line of no effect (RR = 0.92, 95% CI: 0.80 to 1.06, GRADE: moderate). When analysing studies with moderate (n = 6) and high (n = 13) risk of bias separately, the effect estimates favoured triclosan-coated sutures. These results were uncertain, and we assessed the certainty of evidence as low (GRADE). For superficial infections, we found an RR of 0.95 (95% CI: 0.75 to 1.19), GRADE: low, while for deep infections, we found an RR of 0.86 (95% CI: 0.56 to 1.32), GRADE: very low. Only four studies were included in the analysis of wound dehiscence. The results were in favour of triclosan-coated sutures (RR = 0.75, [95% CI: 0.61 to 0.92], GRADE: moderate).
For gastrointestinal / abdominal surgeries, the confidence interval for the effect estimate included both a small effect in favour of triclosan and no effect (RR = 0.90, [95% CI: 0.77 to 1.06], GRADE: low). The result for orthopaedic surgeries was uncertain, with the possibility of both higher and lower risk of infections (RR = 0.72, [95% CI: 0.40 to 1.28], GRADE: very low). After cardiovascular surgeries, we found little or no difference in the risk of infections (RR = 0.96, [95% CI: 0.74 to 1.25], GRADE: low). For the analysis of clean surgeries regardless of the surgical procedure, the confidence interval for the effect estimate included both a small effect in favour of triclosan and no effect (RR = 0.91, [95% CI: 0.71 to 1.19], GRADE: low). Analyses of types of surgeries with other degrees of contamination were not possible to perform as surgeries with different degrees of contamination often occurred within the same study.
In the subgroup analyses of studies with over 1000 participants, the confidence interval crossed the line of no effect (RR = 0.87, [95% CI: 0.71 to 1.06], GRADE: low). The same applied to the analysis of studies from countries with low and medium-low levels of antibiotic resistance (RR = 0.82, [95% CI: 0.66 to 1.02], GRADE: low). This result was not significantly different from the studies from countries with medium, medium-high, and high resistance levels. The few studies that focused solely on children showed no ad-vantage for either triclosan-coated or standard sutures. The confidence interval was very wide, and the effect estimate was uncertain (RR = 0.74, [95% CI: 0.15 to 3.71], GRADE: very low). Furthermore, we found that the results favoured triclosan-coated sutures for studies funded by the manufacturer, Ethicon (RR = 0.81, [95% CI: 0.67 to 0.98]), while the confidence interval crossed the line of no effect for studies not funded by the company (RR = 0.89, [95% CI: 0.75 to 1.07]).
We identified four studies which compared chlorhexidine-coated sutures to standard sutures for the prevention of surgical site infections. Three were randomized controlled studies, and one was a non-randomized prospective study. The number of participants in each study ranged from 30 to 150. The types of surgery were soft tissue surgery in one study, urological surgery in one, and dental and periodontal surgery in two studies. The infection incidence was very low, and therefore, we have no relevant results.
We conducted cost-consequence analyses of triclosan-coated sutures compared to standard sutures for the prevention of surgical site infections. We developed a decision tree model that included the probability of developing a deep or superficial infection, the costs associated with treating the infection, and the relative risk of using triclosan-coated sutures versus standard sutures. We performed an analysis of all surgeries in Norway (approximately 413,000 surgical procedures based on figures from the Directorate of Health for 2021), using the effect estimate from the meta-analysis across all studies with different types of surgery (N = 17). We also conducted three subgroup analyses specifically for laparoscopic colon surgery, open colon surgery, and laparoscopic gallbladder removal. For these analyses, we used the effect estimate from the meta-analysis of gastrointestinal/abdominal surgeries (N = 8).
The analysis of all surgeries in Norway suggested that triclosan-coated sutures may potentially lead to cost savings and fewer infections. However, there is significant uncertainty associated with this result because the overall effect estimate from the different types of surgery (N=17) cannot be directly transferred to an analysis of all surgeries in Norway. The cost to treat a superficial infection is approximately 2,300 Norwegian kroner and to treat a deep infection approximately 65,000 Norwegian kroner. The subgroup analyses of the three gastrointestinal / abdominal surgeries suggested that triclosan-coated sutures could provide both cost savings and additional costs, as both more and fewer infections may occur. Though the potential savings outweigh the additional costs in all three analyses. These results are however associated with considerable uncertainty. The findings from all four analyses indicated a trend/tendency that the use of triclosan-coated sutures may potentially result in smaller cost savings as the incidence of infection decreases. The additional cost of using triclosan-coated sutures is approximately 10 Norwegian kroner per suture. Typically, 1 to 3 sutures are used per operation. Treating a superficial infection may cost around 2,300 Norwegian kroner, while treating a deep infection may cost approximately 65,000 Norwegian kroner.
A project member, Kristin Hegstad, formulated the chapter and conducted a literature search in PubMed using the keywords a) triclosan, antibiotic, and cross-resistance, b) triclosan, antibiotic, and co-resistance, c) triclosan, antibiotic, and horizontal gene transfer, and d) triclosan, antibiotic, and spread. The review articles identified in these searches were used to find original articles that did not appear in the searches. The main research question was whether the effect of clinically important antimicrobial agents is reduced due to development of resistance when triclosan-coated sutures are used. The sub-questions were:
- Is triclosan resistance linked to antibiotic resistance? Describe any known concurrent resistance to triclosan and antibiotics in pathogenic bacteria (disease-causing bacteria) and environmental bacteria, and their occurrence.
- Does the use of triclosan contribute to increased horizontal gene transfer and thus the spread of antibiotic resistance? (The spread of resistance through horizontal gene transfer can occur when bacteria acquire resistance genes from other bacteria that are already resistant to antimicrobial agents).
- What concentrations of triclosan are expected locally in the patient, and is this sufficient to affect the development of antibiotic resistance?
Triclosan can be associated with antibiotic resistance in several important pathogenic bacteria as well as in environmental bacteria, and low concentrations of triclosan can lead to increased transfer of antibiotic resistance genes between bacteria. The use of triclosan in sutures will result in minimal triclosan increase in the environment compared to other sources of triclosan. Regarding local resistance development in the patient, it has been shown that certain bacterial species can tolerate high concentrations of triclosan while triclosan contributes to the development of antibiotic resistance. This has been described, for example, for P. aeruginosa and ciprofloxacin (an antibiotic). Therefore, simultaneous use of ciprofloxacin and sutures with triclosan should be avoided when P. aeruginosa infections are associated with such procedures. One question is whether the risk of developing antibiotic resistance with the use of triclosan-coated sutures is outweighed by the potential benefits of its’ use.
A project collaborator, Marius Gudbrandsen, formulated this chapter. Risk assessments from the European Chemicals Agency were used as a starting point, with supporting literature searches on specific topics, and the documentation was reviewed to find information on whether the use of triclosan-coated sutures could impact the environment. The questions related to the topic were as follows:
- What amounts of triclosan can be expected to be released into the environment if triclosan-coated sutures are used?
- Can these amounts contribute to risks of adverse effects in the environment?
- Can metabolites of triclosan pose a risk?
The amounts of triclosan expected to be released into the environment as a result of its use in sutures are low. Therefore, it is not expected that this use will pose a risk of adverse effects in the environment. However, the use will lead to an increase in emissions, which is undesirable as the substance is listed on the Environmental Directorate in Norway's (Miljødirektoratet) list of environmentally hazardous substances, and its use should be reduced. If it is concluded that the use of triclosan-containing sutures is a valuable tool in medicine, it is still difficult to argue that environmental considerations should hinder such use.
We only included studies with low and moderate risk of bias in our meta-analyses. Although assessments of the risk of bias evaluate the quality of the studies systematically, these assessments are still dependent on subjective judgments. All studies that we considered to have a high risk of bias were also assessed as having a high risk in the NICE report. Furthermore, our team of experts believed that extrapolating any potential effect of triclosan from one type of surgery to another cannot be done easily. The analyses that we placed the most emphasis on, i.e. the meta-analysis of the risk of infection for each of the different types of surgery and studies with low and moderate risk of bias, therefore differ from the main analyses in the NICE report and a systematic review from 2019. They assessed the overall effect estimate for all studies with different types of surgery and study quality. As a result, we arrive at different main conclusions regarding the effect of triclosan. A recently published systematic review from 2022, conducted by the same research group as the Falcon study (NIHR), only included studies with low risk of bias. They found that triclosan-coated sutures showed little or no difference in the risk of infections compared to standard sutures and concluded that global and national guidelines should be reassessed and recommendations for routine use should be removed.
The health economic analyses for colon surgery (open and laparoscopic) and gallbladder removal are associated with uncertainty because the results from the meta-analysis of gastrointestinal / abdominal surgeries encompass all operations within the field and not specific operations like gallbladder and colon surgeries. There is significant uncertainty regarding the outcome of the analysis for all surgeries because a combined effect estimate from various types of surgeries cannot be directly applied to an analysis of "all surgeries." This is because there is a significant difference in risk of infection associated with different types of surgeries and which organ being operated on.
Over half of the studies in this assessment were evaluated to have a high risk of bias. New studies with a mixture of patients and types of surgeries will probably not contribute to further clarification of the essential issues/research questions. We have carried out analyses of each of the different types of operations as well as of all the studies that concerning clean operations. Studies and analyses of operations with different degrees of contamination, however, could be beneficial to investigate further. The input from the experts is that the conclusion in this health technology assessment is so uncertain that it may be beneficial to carry out more studies. One proposal is to conduct studies in Norway and other countries where there are good registries for surgical site infections, for example studies on caesarean sections, gallbladder operations and colon surgery. With a cluster-randomized design over for example two years, this can be carried out with a sufficient number of patients and, in addition provide the opportunity to analyse according to degrees contamination and types of surgery. Results from such cluster-randomised studies would be able to support and complement results from the other randomised controlled studies.
The external experts who participated in this health technology assessment have emphasised that the results of the analyses of the effect of triclosan-coated sutures cannot be extrapolated from one type of surgery to another. The need was therefore to investigate the difference in risk of infection when using triclosan-coated sutures and standard sutures in different types of surgery and different degrees of contaminations of the surgeries separately.
We found no difference, or possibly a small reduction in the risk of surgical site infections after gastrointestinal/abdominal and after clean operations using triclosan-coated sutures compared to standard sutures. It is uncertain whether a possible reduction is of clinical relevance, particularly in countries such as Norway where infection rates are low. For the other types of surgery, we found little or no difference in the risk of infections between the suture types, but these results were limited by a low number of participants and are therefore uncertain. If further studies are to be conducted, it has been suggested to perform studies with a cluster-randomized design. Registration of infections after caesarean sections, gallbladder surgeries, and colorectal surgeries could be relevant. Comparison of chlorhexidine-coated sutures with standard sutures has not been investigated much, and it was therefore not possible to assess whether chlorhexidine-coated sutures had an effect on the incidence of infections compared to standard sutures. The additional cost of using triclosan-coated sutures is very low, while treating surgical site infections is resource demanding. Whether triclosan-coated sutures can result in cost savings will largely depend on whether they have an effect on the risk of infection. There seems to be a trend indicating that triclosan-coated sutures may potentially provide smaller cost savings as the incidence of infections decreases. Triclosan in sutures will have a minimal environmental impact but is associated with antibiotic resistance in several important pathogenic bacteria as well as environmental bacteria and can contribute to increased transfer of antibiotic resistance genes between bacteria. A question remains whether any potential benefits of using triclosan outweigh the risk of development antibiotic resistance.