Evidence review for application of intraoperative topical antiseptics and antibiotics before wound closure

Evidence review for application of intraoperative topical antiseptics and antibiotics before wound closure

Surgical site infections: prevention and treatment

Evidence review C

NICE Guideline, No. 125

London: National Institute for Health and Care Excellence (NICE); 2019 Apr.

ISBN-13: 978-1-4731-3394-5

Effectiveness of intraoperative topical antiseptics and antibiotics before wound closure in the prevention of surgical site infection

Review question

Is the application of intraoperative topical antiseptics/antimicrobials before wound closure clinically effective in reducing surgical site infection rates?

It became apparent during the development of this update that the question above carried forward from the original guideline should specifically state antiseptics and antibiotics instead of the term ‘antimicrobials’. This decision was based on committee input during the development of the review protocol. The committee noted that the term ‘antimicrobials’ would encompass both antiseptics and antibiotics. The committee also agreed that term ‘operative field’ would be more appropriate as the application of the interventions included in this review can vary. Hence, the review question answered in this update (and to be carried forward in any future updates) was:

Is the application of antiseptics and antibiotics in the operative field before wound closure clinically effective in reducing surgical site infection rates?

Introduction

Surgical site infections (SSIs) are serious postoperative complications. Antiseptics and antibiotics can be applied to the operative field before wound closure to reduce the risk of SSIs.

The 2008 NICE guideline on the prevention and treatment of surgical site infection recommended against the use of intraoperative skin re-disinfection or topical cefotaxime in abdominal surgery to reduce surgical site infection. This decision was driven by the evidence which demonstrated that the instillation of cefotaxime into wounds prior to closure appears to have no effect on SSI incidence after surgery for peritonitis.

The topic was reviewed in 2017 by NICE surveillance team and new evidence was identified which examined the use of topical antiseptics and antimicrobials before wound closure for the reduction in SSI, and thus prompted a partial update to review new evidence.

The review aimed to evaluate the effective application of intraoperative antiseptics and antibiotics to the operative field before wound closure in the prevention of SSI.

This review identified studies that fulfilled the conditions specified in PICO table. For full details of the review protocol, see appendix A.

Table 1

PICO: Is the application of antiseptics and antibiotics in the operative field before wound closure clinically effective in reducing surgical site infection rates?

Methods and process

This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual (2014). Methods specific to this review question are described in the review protocol in appendix A and the methods section in appendix B.

Declarations of interest were recorded according to NICE’s 2018 conflicts of interest policy.

A search strategy was used to identify all studies that examined the effectiveness of intraoperative topical antiseptics and antibiotics (outlined in Table 1) applied to the operative field before wound closure to reduce the risk of SSIs. RCTs and systematic reviews of RCTs were considered for inclusion. The review protocol specified that in the event of less than 5 RCTs being identified, quasi randomised trials would also be considered for inclusion.

The search strategies used in this review are detailed in appendix C.

Studies were also excluded if they:

Included patients undergoing a surgical procedure that does not involve a visible incision and therefore does not result in the presence of a conventional surgical wound
Were not in English
Were not full reports of the study (for example, published only as an abstract)

Data on overall SSI was extracted. Where possible, data on superficial, deep and organ/space SSI were also examined. According to the Centres for Disease Control and Prevention (CDC) a SSI is defined as an infection occurring within 30 days after operation. A deep SSI is defined as an infection which occurs within 30 days after the operation if no implant is left in place, or within 1 year if implant is placed. Therefore SSI within 30 days and 1 year were prioritised in this review.

Studies included in the review explored a number of different follow up periods. Two studies [Andersson 2010 and Collin 2013] reported outcomes at various time points. Therefore analysis was stratified by different follow up periods.

A number of different surgical procedures were explored in the studies included in the review. Where possible subgroup analysis was conducted based on surgical procedure. Furthermore, surgical procedures and wounds can be classified as the following:

Clean–incision in which no inflammation is encountered in a surgical procedure, without a break in sterile technique, and during which the respiratory, alimentary and genitourinary tracts are not entered.
Clean-contaminated – an incision through which the respiratory, alimentary or genitourinary tract is entered under controlled conditions but with no contamination encountered.
Contaminated – an incision undertaken during an operation in which there is a major break in sterile technique or gross spillage from the gastrointestinal tract, or an incision in which acute, non-purulent inflammation is encountered. Open traumatic wounds that are more than 12–24 hours old also fall into this category
Dirty or infected – an incision undertaken during an operation in which the viscera are perforated or when acute inflammation with pus is encountered during the operation (for example, emergency surgery for faecal peritonitis), and for traumatic wounds where treatment is delayed, and there is faecal contamination or devitalised tissue present.

Data on surgical wound classification was also extracted and subgroup analysis was conducted.

Clinical evidence

Included studies

From a database of 1,982 studies, 129 studies were identified from the literature search as being potentially relevant. Five additional studies were identified as being potentially relevant; 1 study from the 2008 NICE guideline on the prevention and treatment of surgical site infection, 1 study from the surveillance review and 3 additional studies from a systematic review [Konstantelias 2016]. Altogether, 134 studies were identified as being potentially relevant. Following full text review of the 134 studies, 30 RCTs were included.

For the search strategy, see appendix C. For clinical evidence study selection flowchart, see appendix D.

The included RCTS examined the following interventions:

Gentamicin collagen sponges
Povidone iodine spray
Povidone iodine solution
Vancomycin powder
Cefotaxime
Cephaloridine
Antibiotic loaded bone cement (erythromycin and colistin loaded bone cement)
Ampicillin powder
Iodine solution (2.5% iodine in 70% ethanol)

Excluded studies

List of papers excluded at full text, with reasons for exclusion, is given in Appendix K.

Summary of clinical studies included in the evidence review

The included studies are summarised in Table 2 below. See appendix E for full evidence tables.

Table 2

Summary of included studies.

See appendix D for full evidence tables.

Quality assessment of clinical studies included in the evidence review

All studies included in the review were RCTs. The quality of the evidence was started at high. A number of studies demonstrated unclear blinding of participants however these studies were not downgraded in this domain. Studies were mainly downgraded for unclear random sequence generation, allocation concealment and blinding of outcome assessment.

Studies included in the review classified infections using different criteria including the Centres for Disease Control and Prevention (CDC) SSI criteria. Studies which did not explicitly describe criteria used for the classification of infection were downgraded for serious indirectness.

Outcomes at a number of different follow-up periods were reported in the studies included. Studies which did not specify a follow-up period were downgraded for serious indirectness. In such studies the follow-up period was assumed be the postoperative phase.

See evidence tables in appendix E for quality assessment of individual studies and appendix G for full GRADE tables.

Economic evidence

Included studies

A literature search was conducted to identify cost–utility analyses comparing strategies for the intraoperative use of antibiotics or antiseptics prior to wound closure. Standard health economic filters were applied to a clinical search, returning a total of 1,344 citations. Following review of all titles and abstracts, 11 studies were identified as being potentially relevant to this decision problem, and were ordered for full review. After reviewing the full texts, 2 studies were included as economic evidence for nasal decontamination. Both evaluated the cost-effectiveness of antibiotic-impregnated bone cement for use in hip surgery.

Graves et al. (2016)

Graves et al. (2016) developed a lifetime economic model comparing 9 infection control strategies in total hip replacement (THR) surgery, comprising the use or absence of: systemic antibiotics, antibiotic-impregnated bone cement, and novel ventilation techniques. For the purpose of this review, strategies that are identical except for plain cement compared with antibiotic cement are relevant. Baseline deep infection rates were from a multicentre RCT of operating theatre ventilation (3.4% in 2.5 years). A cohort of 77,321 THR patients progressed through a daily 9-state Markov model, including the risk of a deep SSI (up to 1 year), followed by treatment with debridement, 1 or 2-stage revision, or permanent resection, and death. Time-dependent transition probabilities between states were calculated by linking data from 5 databases: NHS Hospital Episode Statistics, Office for National Statistics, SSI Surveillance Service, National Joint Registry, and NHS England patient-report outcome measures data. Mortality was captured using national UK life tables. Relative effectiveness was identified by a systematic review and mixed treatment comparison with meta-regression, containing 12 studies (6 RCTs) and 123,788 THRs. Probability ratios for deep SSI, compared with the reference treatment of no systematic antibiotics, plain cement and standard ventilation, ranges from 0.22 (best) to 0.61.

Costs included components of each intervention and of treatments following SSI. Plain cement was £68 per THR, with antibiotic-impregnated cement at £95. Utility values were not based on EQ-5D, and were informed by published evidence as the NHS England data did not capture quality of life specifically following SSI or subsequent treatment. All outcomes were discounted by 3% per year.

With no systemic antibiotics and conventional ventilation, antibiotic-impregnated cement generated 0.001 additional QALYs and saved £60 per patient. It was 96% likely to be cost-saving from 1,000 probabilistic model runs, and gained QALYs in 62% of runs. With systemic antibiotics, antibiotic cement generated 0.001 additional QALYs and saved £14 per patient. The value of antibiotic-impregnated cement was reduced significantly when both systemic antibiotics and laminar airflow ventilation were used, generating 0.0001 additional QALYs and a higher cost of £26 per patient compared with plain cement. The resulting ICER is in excess of £300,000 per QALY gained.

Cummins et al. (2009)

Cummins et al. (2009) also evaluated the cost-effectiveness of antibiotic-impregnated bone cement, for use in primary hip arthroplasty in the US. A lifetime Markov model composed of 4 health states was developed, capturing the primary procedure, septic and aseptic revision, and death. Septic and aseptic revision rates were informed by the Norwegian Arthroplasty Registry (1987–2004), with a relative risk of septic revision using plain cement of 1.8 (p = 0.01), and 1.3 for aseptic revision (p = 0.02). While this is not randomised evidence, it represents a rich data source (22,170 procedures over 14 years) and included a Cox regression to account for heterogeneity between patients (e.g. use of systemic antibiotic prophylaxis, theatre characteristics, age and sex). Operative mortality was 0.23%, otherwise mortality was informed by national US life tables.

Direct costs included the primary procedure and acute hospitalisation, antibiotic-impregnated cement (+£422), septic revision (£67,500) and aseptic revision (£24,500), from various published sources. Utility inputs, loosely informed by a study using the SF-36 questionnaire, applied a 10% utility loss for aseptic revision and a 20% loss for a septic revision. All outcomes were discounted by 3% per year.

When only differences in septic revisions were included, antibiotic cement gained 0.009 QALYs and had an additional cost of £141 per patient, compared with plain cement, producing an ICER around £15,600 per QALY gained. When the observed effect of reducing the risk of aseptic revisions was also captured, antibiotic cement was found to be dominant. Results were found to be relatively sensitive to cost inputs, and to the age of the patient, being more likely to be cost-effective in younger patients who are at risk of revision for longer than older patients due to age-related mortality. However, these were evaluated against US cost-effectiveness benchmark of $50,000 (£35,000), which has limited applicability to the UK setting. Probabilistic analysis was not reported.

Excluded studies

Studies that were excluded upon full review are listed in Appendix J, including the primary reason for exclusion. Among the excluded studies is a cost–utility analysis by some of the authors of the included Graves et al. (2016) study, which used the same model structure and much of the same data but was in the Australian setting (Merollini et al., 2013). Inputs such as baseline infection rates and costs were therefore less applicable to the NHS setting. Its conclusions regarding antibiotic cement versus plain cement, alongside systemic antibiotics, were consistent with Graves et al. (2016). As such, this study was selectively excluded to avoid presenting the same evidence twice, in favour of only including the more applicable and more recent UK study.

Economic model

New economic modelling for this topic was not prioritised by the guideline development committee, therefore no model was developed.

Summary of studies included in the economic evidence review

A summary of the 2 studies included as economic evidence is provided below. Full economic evidence tables for each study are provided in Appendix H. A summary economic evidence profile is provided in Appendix I.

Evidence statements

The format of the evidence statements is explained in the methods in appendix B. Evidence statements were also stratified by follow up period and were formulated to reflect the surgical procedure and surgical wound classification.

Clinical evidence

Erythromycin and colistin loaded bone cement

Outcomes at 1 year after surgery

Low to very low quality evidence from 1 RCT, including 2,948 knees, could not differentiate the following outcomes between people who received erythromycin and colistin loaded bone cement during total knee arthroplasty and those who received bone cement without antibiotic:
- SSI
- Superficial SSI
- Deep SSI

Vancomycin powder

Outcomes at 3 months after surgery

Very low quality evidence from 1 RCT, including 907 people, could not differentiate the following outcomes between people who received vancomycin powder before wound closure during spinal surgery and those who did not receive additional antibiotic powder:
- SSI
- Superficial SSI
- Deep SSI.
These results were also consistent in the following subgroups:
- Instrumented spinal surgery
- Non-instrumented spinal surgery

Ampicillin powder

Outcomes at 3 weeks after surgery

Moderate quality evidence from 1 RCT, including 130 people, indicated that people who received ampicillin powder before wound closure during appendicectomy had a lower incidence of SSI compared to those who received a placebo.

Topical cefotaxime

Outcomes at 1 month after surgery

Very low quality evidence from 1 RCT, including 177 people, could not differentiate the following outcomes between people who received topical cefotaxime before wound closure during abdominal surgeries and those who did not receive topical antibiotic:
- SSI
- Septicaemia
- Mortality post-surgery
These results were also consistent in the following subgroups:
- appendectomy
- biliary surgery
- colonic surgery
- drainage of intra-abdominal abscess

Topical cephaloridine

Outcomes at 1 month after surgery

Moderate quality evidence from 1 RCT, including 401 people, indicated that people who received topical cephaloridine before wound closure had a lower incidence of SSI compared to those who did not receive topical antibiotic.
This result was also consistent in the following subgroups:
- clean surgery
- contaminated surgery

Topical povidone iodine spray

Outcomes at 2 weeks after surgery

Moderate quality evidence from 1 RCT, including 153 people, indicated that people who received topical povidone iodine spray before wound closure during abdominal surgery had a lower incidence of SSI compared to those who did not receive topical antiseptic spray.
Moderate quality evidence from 1 RCT, including 153 people, could not differentiate postoperative antibiotic use between people who received topical povidone iodine spray before wound closure during abdominal surgery and those who did not receive topical antiseptic spray.

Outcomes at 1 month after surgery

Moderate quality evidence from 2 RCTs, including 702 people, indicated that people who received topical povidone iodine spray before wound closure had a lower incidence of SSI compared to those who did not receive topical antiseptic spray.
This result was also consistent in the following subgroups:
- clean surgery
- clean/contaminated surgery
- contaminated surgery
- dirty surgery
Very low quality evidence from 1 RCT, including 100 people, could not differentiate SSI between people who received topical povidone iodine spray before wound closure during appendectomy and those who received ampicillin powder.

Povidone iodine solution

Outcomes during postoperative period

Very low quality evidence from 1 RCT, including 107 people, could not differentiate SSI between people who received povidone iodine solution before wound closure during gastric and colorectal surgery and those who did not receive antiseptic solution.

2.5% Iodine in 70% ethanol

Outcomes at 2 weeks after surgery

Low quality evidence from 1 RCT, including 662 people, could not differentiate SSI between people who received topical 2.5% iodine in 70% ethanol as well as drapes before wound closure during Caesarean section and those who did not receive topical antiseptics.
Low quality evidence from 1 RCT, including 678 people, could not differentiate SSI between people who received topical 2.5% iodine in 70% ethanol and no drapes before wound closure during Caesarean section and those who did not receive topical antiseptics.

Gentamicin collagen sponge

Outcomes at 1 week after surgery

Very low quality evidence from 2 RCTs, including 301 people, could not differentiate SSI between people who received gentamicin collagen sponge before wound closure and those who did not receive a gentamicin collagen sponge. This result was also consistent in abdominoperineal resection alone.
- Very low quality from 1 RCT, including 200 people, indicated that people who received gentamicin collagen sponge before wound closure during hidradenitis suppurativa surgery had lower incidence of SSI compared to people who did not receive a gentamicin collagen sponge.

Outcomes at 2 weeks after surgery

Very low quality evidence from 1 RCT, including 159 people, could not differentiate SSI between people who received gentamicin collagen sponge before wound closure during pilonidal sinus surgery and those who did not receive a gentamicin collagen sponge.

Outcomes at 1 month after surgery

Low quality from 4 RCTs, including 1,063 people, could not differentiate SSI between people who received gentamicin collagen sponge before wound closure and those who did not receive a gentamicin collagen sponge. This result was also consistent in the following subgroups:
- abdominoperineal resection
- splenectomy
- colorectal surgery
- hip arthroplasty
Low quality evidence from 2 RCTs, including 878 people, could not differentiate superficial SSI between people who received gentamicin collagen sponge before wound closure and those who did not receive a gentamicin collagen sponge. This result was also consistent in the following subgroups:
- Hip arthroplasty
- Colorectal surgery
Low quality evidence from 2 RCTs, including 878 people, could not differentiate deep SSI between people who received gentamicin collagen sponge before wound closure and those who did not receive a gentamicin collagen sponge. This result was also consistent in hip arthroplasty alone.
Moderate quality evidence from 2 RCTs, including 902 people, could not differentiate mortality post-surgery between people who received gentamicin collagen sponge before wound closure and those who did not receive a gentamicin collagen sponge. This result was also consistent in the following subgroups:
- hip arthroplasty
- colorectal surgery
Moderate quality evidence from 1 RCTs, including 684 people, could not identify a difference in mean length of stay between people who received gentamicin collagen sponge before wound closure during hip arthroplasty and those who did not receive a gentamicin collagen sponge.
Very low quality evidence from 2 RCTs, including 800 people, indicated that people who received gentamicin collagen sponge before wound closure had lower incidence of SSI compared to people who received a placebo. This result was also consistent in loop-ileostomy alone.
- Very low quality evidence from 1 RCT, including 720 people, indicated that people who received gentamicin collagen sponge before wound closure during cardiac surgery had a lower incidence of SSI compared to those who received a placebo.
Very low quality evidence from 3 RCTs, including 993 people, could not identify a difference in superficial SSI between people who received gentamicin collagen sponge before wound closure and those who received a placebo. This result was also consistent in the following subgroups:
- loop-ileostomy
- cardiac surgery
- colorectal surgery
Very low quality evidence from 3 RCTs, including 993 people, indicated that people who received gentamicin collagen sponge before wound closure had a lower incidence of deep SSI compared to those who received a placebo. This result was also consistent in cardiac surgery alone.
- Low quality evidence from 1 RCT, including 80 people, could not identify a difference in deep SSI between people who received gentamicin collagen sponge before wound closure during loop-ileostomy and those who received a placebo

Outcomes at 2 months after surgery

Very low quality evidence from 3 RCTs, including 2,649 people, could not differentiate SSI between people who received gentamicin collagen sponge before wound closure and those who did not receive a gentamicin collagen sponge. This result was also consistent in abdominoperineal resection alone.
- High quality evidence from 1 RCT, including 1,950 people, indicated that people who received gentamicin collagen sponge before wound closure during cardiac surgery had a lower incidence of SSI compared to those who did not receive a gentamicin collagen sponge.
- Moderate quality evidence from 1 RCT, including 602 people, indicated that people who did not receive a gentamicin collagen sponge before colorectal surgery lower incidence of SSI compared to those who did receive a gentamicin collagen sponge.
Very low quality evidence from 3 RCTs, including 2,649 people, could not differentiate superficial SSI between people who received gentamicin collagen sponge before wound closure and those who did not receive a gentamicin collagen sponge. This result was also consistent in abdominoperineal resection alone.
- High quality evidence from 1 RCT, including 1,950 people, indicated that people who received gentamicin collagen sponge before wound closure during cardiac surgery had a lower incidence of superficial SSI compared to those who did not receive a gentamicin collagen sponge.
- Moderate quality evidence from 1 RCT, including 602 people, indicated that people who did not receive a gentamicin collagen sponge before colorectal surgery lower incidence of superficial SSI compared to those who did receive a gentamicin collagen sponge.
Very low quality evidence from 3 RCTs, including 2,649 people, could not differentiate deep SSI between people who received gentamicin collagen sponge before wound closure and those who did not receive a gentamicin collagen sponge. This result was also consistent in the following subgroups:
- abdominoperineal resection
- cardiac surgery
- colorectal surgery
Moderate to low quality evidence from 1 RCT, including 602 people, could not differentiate the following outcomes between people who received gentamicin collagen sponge before wound closure during colorectal surgery and those who did not receive a gentamicin collagen sponge:
- Organ space SSI
- Hospital readmission
Low quality evidence from 1 RCT, including 1,950 people, could not differentiate the following outcomes between people who received gentamicin collagen sponge before wound closure during cardiac surgery and those who did not receive a gentamicin collagen sponge:
- Hospital mortality
- Mortality post-surgery

Outcomes at 3 months after surgery

Moderate quality evidence from 5 RCTs, including 2,473 people, could not differentiate SSI between people who received gentamicin collagen sponge before wound closure and those who did not receive a gentamicin collagen sponge. This result was also consistent in the following subgroups:
- cardiac surgery
- colorectal surgery
- abdominoperineal resection
- pilonidal sinus surgery
Low quality evidence from 2 RCT, including 2,044 people, could not differentiate superficial SSI between people who received gentamicin collagen sponge before wound closure during cardiac surgery and those who did not receive a gentamicin collagen sponge.
Very low quality evidence from 1 RCT, including 171 people, could not differentiate superficial/deep SSI between people who received gentamicin collagen sponge before wound closure during colorectal surgery and those who did not receive a gentamicin collagen sponge.
Low quality evidence from 2 RCT, including 2,044 people, could not differentiate deep SSI between people who received gentamicin collagen sponge before wound closure during cardiac surgery and those who did not receive a gentamicin collagen sponge.
Moderate quality evidence from 2 RCT, including 2,044 people, could not differentiate organ/space SSI between people who received gentamicin collagen sponge before wound closure during cardiac surgery and those who did not receive a gentamicin collagen sponge.
Low quality evidence from 1 RCT, including 542 people, could not differentiate mortality post-surgery between people who received gentamicin collagen sponge before wound closure during cardiac surgery and those who did not receive a gentamicin collagen sponge.
Low quality evidence from 1 RCT, including 1,502 people, could not differentiate hospital readmission between people who received gentamicin collagen sponge before wound closure during cardiac surgery and those who did not receive a gentamicin collagen sponge.

Outcomes at 6 months after surgery

Low quality evidence from 2 RCTs, including 621 people, could not differentiate SSI between people who received gentamicin collagen sponge before wound closure and those who did not receive a gentamicin collagen sponge. This result was also consistent in the following subgroups:
- prosthetic repair of groin hernias
- abdominoperineal resection
Moderate quality evidence from 1 RCT, including 44 people, indicated that people who received gentamicin collagen sponge before wound closure during abdominoperineal resection had a shorter mean length of hospital stay compared to those who did not receive a gentamicin collagen sponge.

Outcomes during postoperative phase

Low quality evidence from 1 RCT, including 221 people, indicated that people who received gentamicin collagen sponge before wound closure during colorectal surgery had lower incidence of SSI compared to people who did not receive a gentamicin collagen sponge.

Economic evidence

Antibiotic-impregnated bone cement

Two partially applicable cost–utility analyses with potentially serious limitations compared antibiotic-impregnated bone cement with plain bone cement for use in primary hip replacement surgery. A UK study found that antibiotic cement is likely to be dominant, unless its benefit is eroded by the presence of other infection control interventions such as a combination of systemic antibiotics and laminar airflow theatre ventilation. A US study found that antibiotic cement is dominant if its effect on all types of hip revision are considered, but its ICER is around £16,000 per QALY gained if only septic revisions are considered.

The committee’s discussion of the evidence

Interpreting the evidence

The outcomes that matter most

The committee identified SSI including superficial SSI, deep SSI and organ space SSI as outcomes of interests. Studies included in the review captured outcomes at a number of different follow up periods. Furthermore, 2 studies were identified [Andersson 2010 and Collins 201], that reported outcomes at various time points during the study period. Due to this, data was stratified based on different follow up periods. While the committee took into all the outcomes at different follow up periods into consideration, based on the CDC definition of SSI, the committee identified outcomes up to 30 days and 1 year to be important.

The quality of the evidence

Overall, the committee noted that the studies ranged from moderate to very low quality evidence. Study locations also varied, with 5 studies being identified, which were conducted in the UK. Furthermore, studies also ranged in sample sizes. The largest evidence base was identified for gentamicin collagen implants and sample sizes ranged from 50 participants to 1,950 participants.

The committee noted that a number of studies included in the review were conducted before the year 2000. Furthermore, the majority of the evidence identified for 2.5% iodine in 70% alcohol [Cordtz 1989] cephaloridine [Evans 1974], povidone iodine [Sherlock 1984, Gray 1981, Walsh 1981 and Parker 1985], cefotaxime [Moesgaard 1989] and ampicillin [Rickett 1969] were conducted before the 1990s. The committee discussed that practice is too far removed from the time these studies were conducted. Furthermore, products such as cephaloridine can no longer be found on the market. Therefore, with no new evidence for these interventions, the committee could not make recommendations based on outdated evidence.

Studies included in the review classified SSIs using different criteria. Ten studies were identified which classified SSIs based on the Centres of Disease Control and Prevention (CDC) criteria. A number of studies were identified which based the classification of SSIs on purulent discharge with and without the inclusion of bacteriological confirmation. Nine studies were found which did not define criteria used for the classification on infections. These studies were downgraded for serious indirectness, as it was unclear if these infections were classified in a similar manner to the other included studies.

During committee discussions, the importance of identifying SSIs up to 30 days after surgery and 1 year after orthopaedic surgery were discussed. In this review, evidence on outcomes at different follow up periods post-surgery was identified. In order to adequately assess the outcomes, data was stratified, based on follow up period. However, 2 studies [Harihara 2006 and Rutten 1997] included in the review did not state the period in which the outcomes were followed up. For the purpose of this review, it was assumed that these studies followed up outcomes during the postoperative phase. However, as follow up was unclear, these studies were downgraded for serious indirectness.

Benefits and harms

It was discussed that SSIs result in poor patient outcomes and increased costs. In terms of the use of gentamicin sponges, 19 studies were identified which explored the use of the sponges in a number of different types of surgery. Evidence demonstrated that the gentamicin implants were effective in cardiac surgery which is considered a high risk surgery. Therefore, it was noted that the use of gentamicin collagen implants may aid in reducing the risk of infection in people undergoing cardiac surgery.

As part of this review, adverse events such as kidney toxicity and anaphylaxis were examined. No studies were identified which explored these outcomes. It was noted that nephrotoxicity is a side effect with the use of all aminoglycosides. In adults, it occurs more commonly in the elderly and also occurs most commonly in children with renal failure. The committee discussed this potential harm and noted that manufacturers of the gentamicin collagen implants state that the use of the implants is associated with low systemic concentrations of the antibiotic.

The committee also discussed that studies involving the use of gentamicin collagen implants tend to not include patients with reduced renal function, therefore it is difficult to ascertain side effects associated with the use of the implants in this patient population. However, the committee noted that caution must be taken when considering use of the implants in people with poor renal function. Furthermore, the research recommendation developed also includes organ toxicity as an important outcome of interest.

Antimicrobial resistance is a major concern with the use of antibiotics and antiseptics. The committee discussed that during surgery, along with receiving skin antiseptics, people may also receive additional peri-operative antimicrobial prophylaxis as part of the standard protocol. This raises the risk of multidrug resistance and it also means that identifying antimicrobial resistance to a single intervention is difficult.

Based on the evidence, the committee recommended gentamicin collagen implants to be considered in cardiac surgery. However, no evidence was identified that which examined the antimicrobial resistance associated with the use of these implants. Additionally, as the evidence on other antiseptics and antibiotics were poor, the committee made an additional recommendation for the use of antiseptics and antibiotics to only be considered as part of a clinical trial.

While this recommendation should reduce the misuse of these interventions and in turn reduce the risk of antimicrobial resistance, the committee noted that more evidence is required to examine the risk of antimicrobial resistance. Therefore, the committee made a research recommendation to further examine the effectiveness intraoperative antiseptics and antibiotics, in which antimicrobial resistance is an important outcome.

Cost effectiveness and resource use

The committee discussed the 2 published cost-effectiveness analyses identified in the economic literature review. Both studies evaluated the use of antibiotic-impregnated bone cement for use during total hip replacement, compared with using plain bone cement. The UK study (Graves et al., 2016) found in favour of antibiotic bone cement, unless there were other infection control measures in place; namely, antibiotic prophylaxis and laminar airflow theatre ventilation. The committee advised that laminar airflow is routinely used in orthopaedic surgery in the NHS, and antibiotic prophylaxis use is not uncommon, such that it is unclear whether the Graves et al. study provides evidence that antibiotic-impregnated bone cement is cost effective. Further, the committee advised that it is routine practice to avoid using bone cement in primary joint replacement surgery, if possible; therefore, even the UK study might have limited applicability to the NHS setting. The committee also agreed that the clinical evidence underpinning both models is of insufficient quality to support recommendations regarding antibiotic-impregnated bone cement. The Graves et al. study was based on a network meta-analysis of 12 studies, of which 6 were RCTs; however, none of the RCTs compared antibiotic-impregnated bone cement with plain bone cement. This comparison was therefore informed by direct observational studies and indirect evidence from the wider network, which the committee agreed was weak evidence to inform an economic evaluation. The second study (Cummins et al., 2009) was agreed to be less applicable to NHS practice, being a US analysis based on long-term Norwegian registry data. Although an attempt had been made to account for potential confounding factors in the clinical evidence, the committee agreed that this is weak evidence to inform an economic evaluation.

The committee discussed the use of gentamicin-collagen sponges in cardiac surgery. It agreed that the most compelling evidence for the effectiveness of gentamicin-collagen sponges is in cardiac surgery, and noted that the original CG74 committee also made this comment. However, no cost-effectiveness evidence regarding their use was identified. The committee advised that the cost of gentamicin-collagen sponges varies by hospital, ranging from around £20 to £90 per sponge. The committee estimated that around 25,000 cardiac surgery procedures occur annually in the NHS; therefore, the use of gentamicin-collagen sponges in all cardiac surgery would have resource implications. If the typical cost per sponge is £55 – the midpoint of the committee’s range – this would imply a resource impact of £1,375,000; however, the committee advised that these sponges are often used in NHS cardiac surgery already, as they are perceived to reflect best practice. If they are already in use the resource impact of full adoption would be lower that the above figure; for example, £962,500 if they are currently used in 30% of cardiac surgery procedures. This resource impact estimate does not capture cost savings associated with a reduction in the incidence of SSI that would occur as a result of using gentamicin-collagen sponges. A UK hospital SSI surveillance study (Jenks et al., 2014) estimated a mean SSI cost of £11,003 in cardiac surgery patients, higher than SSIs in most other surgical categories. Avoiding 91 SSIs across 25,000 annual cardiac surgical procedures would therefore save £1 million in SSI treatment costs. Based on the economic model developed for this guideline evaluating nasal decontamination of S. aureus, the committee was aware that infection control tends to be cost-effective, particularly when the cost impact of a SSI is high, like in the case of cardiac surgery. The committee was therefore satisfied that a recommendation to consider the use of gentamicin-collagen sponges in cardiac surgery, where its clinical evidence is the most supportive, is likely to be a cost-effective used of NHS resources.

Other factors the committee took into account

The number of studies identified for each intervention varied. While single studies were found which explored the clinical effectiveness of antibiotic loaded bone cement, 2.5% iodine in 70% alcohol, cefotaxime, cephaloridine, ampicillin and vancomycin, 5 studies explored the effectiveness of povidone iodine and 19 studies investigated the effectiveness of gentamicin collagen implants. These studies also explored a number of different surgical procedures.

Studies which examined the effectiveness of povidone iodine mainly involved people undergoing abdominal procedures such as gastric surgery and colorectal surgery. While topical povidone iodine did demonstrate a significant reduction in SSI at 2 weeks in people undergoing abdominal surgery, no significant results were identified in people undergoing various other clean, contaminated or dirty abdominal procedures.

Studies examining the effectiveness of gentamicin collagen implants included people undergoing cardiac, colorectal and hidradenitis suppurativa surgery as well as arthroplasty, pilonidal sinus excision, prosthetic repair of groin hernias, abdominoperineal resection, mastectomy and closure of loop-ileostomy. Gentamicin collagen implants demonstrated a significant reduction in SSIs at 1 week after surgery in people undergoing hidradenitis suppurativa surgery as well as a reduction in SSIs at 1 month and 2 months after surgery in people undergoing cardiac surgery.

Conflicting data was identified on the clinical effectiveness of the implants in people undergoing colorectal surgery. Two studies [Nowacki 2006 and Pochhammer 2015] were identified which demonstrated a non-significant reduction in SSIs, as well as superficial SSIs, in people undergoing colorectal surgery. One partially applicable study [Rutten 1997] further demonstrated a significant reduction in SSIs. However, one study [Bennett-Gurerro 2010a] demonstrated a significant risk of SSI at 2 months associated with the use of gentamicin implants in people undergoing colorectal surgery.

The authors of the paper did hypothesis that the presence of sponge mass may have created a mechanical barrier to early wound healing that promoted infection, however such significant results were not replicated in any other study identified. Furthermore, the study which demonstrated a significant reduction had a small sample size and did not state the follow-up period. Due to the lack of conclusive evidence on the use of gentamicin collagen implants in colorectal surgery, no recommendations were made for this surgery type.

The committee noted that the application of antiseptics and antibiotics vary. While gentamicin collagen sponges are implanted into the wound cavity for the purpose of wound disinfection, topical antiseptics are generally used for skin re-disinfection. Antibiotics can also be applied topically, but usually in the form of powders, as reflected in the evidence identified. The committee wanted to make a clear distinction between wound disinfection and peri-wound skin re-disinfection. With regards to wound disinfection, evidence was mainly identified for the use of gentamicin collagen implants. Based on the evidence identified the committee recommended for the gentamicin collagen implants to be considered in cardiac surgery.

No new evidence was identified which demonstrated the clinical effectiveness of skin re-disinfection using antiseptics before would closure in reducing the incidence of SSI. Due to the lack of evidence, the committee discussed the need for further research. Therefore, no recommendations were made for the use of antiseptic in practice, but a research recommendation was made to promote further research.

Questions were also raised on the availability of interventions. Evidence was identified which suggested that cephaloridine demonstrated a significant reduction in SSIs in people undergoing contaminated surgical procedures. However, the committee noted that while this intervention is effective, this product is no longer available on the market.

Additionally, it was noted that studies included in the review did not provide evidence on children. Due to the lack of evidence in this population, specific recommendations for children could not be made. Caution must be taken when considering use in children with renal failure.

Appendices

Appendix A. Review protocols

Review protocol for application of intraoperative antiseptics and antibiotics before wound closure

Download PDF (1.2M)

Appendix B. Methods

Priority screening

The reviews undertaken for this guideline all made use of the priority screening functionality with the EPPI-reviewer systematic reviewing software. This uses a machine learning algorithm (specifically, an SGD classifier) to take information on features (1, 2 and 3 word blocks) in the titles and abstract of papers marked as being ‘includes’ or ‘excludes’ during the title and abstract screening process, and re-orders the remaining records from most likely to least likely to be an include, based on that algorithm. This re-ordering of the remaining records occurs every time 25 additional records have been screened.

As an additional check to ensure this approach did not miss relevant studies, the included studies lists of included systematic reviews were searched to identify any papers not identified through the primary search.

Quality assessment

Individual systematic reviews were quality assessed using the ROBIS tool, with each classified into one of the following three groups:

High quality – It is unlikely that additional relevant and important data would be identified from primary studies compared to that reported in the review, and unlikely that any relevant and important studies have been missed by the review.
Moderate quality – It is possible that additional relevant and important data would be identified from primary studies compared to that reported in the review, but unlikely that any relevant and important studies have been missed by the review.
Low quality – It is possible that relevant and important studies have been missed by the review.

Each individual systematic review was also classified into one of three groups for its applicability as a source of data, based on how closely the review matches the specified review protocol in the guideline. Studies were rated as follows:

Fully applicable – The identified review fully covers the review protocol in the guideline.
Partially applicable – The identified review fully covers a discrete subsection of the review protocol in the guideline.
Not applicable – The identified review, despite including studies relevant to the review question, does not fully cover any discrete subsection of the review protocol in the guideline.

Using systematic reviews as a source of data

If systematic reviews were identified as being sufficiently applicable and high quality, and were identified sufficiently early in the review process (for example, from the surveillance review or early in the database search), they were used as the primary source of data, rather than extracting information from primary studies. The extent to which this was done depended on the quality and applicability of the review, as defined in Table . When systematic reviews were used as a source of primary data, any unpublished or additional data included in the review which is not in the primary studies was also included. Data from these systematic reviews was then quality assessed and presented in GRADE tables as described below, in the same way as if data had been extracted from primary studies. In questions where data was extracted from both systematic reviews and primary studies, these were cross-referenced to ensure none of the data had been double counted through this process.

Table 3. Criteria for using systematic reviews as a source of data

Evidence of effectiveness of interventions

Quality assessment

Individual RCTs were quality assessed using the Cochrane Risk of Bias Tool. Other study were quality assessed using the ROBINS-I tool. Each individual study was classified into one of the following three groups:

Low risk of bias – The true effect size for the study is likely to be close to the estimated effect size.
Moderate risk of bias – There is a possibility the true effect size for the study is substantially different to the estimated effect size.
High risk of bias – It is likely the true effect size for the study is substantially different to the estimated effect size.

Each individual study was also classified into one of three groups for directness, based on if there were concerns about the population, intervention, comparator and/or outcomes in the study and how directly these variables could address the specified review question. Studies were rated as follows:

Direct – No important deviations from the protocol in population, intervention, comparator and/or outcomes.
Partially indirect – Important deviations from the protocol in one of the population, intervention, comparator and/or outcomes.
Indirect – Important deviations from the protocol in at least two of the following areas: population, intervention, comparator and/or outcomes.

Methods for combining intervention evidence

Meta-analyses of interventional data were conducted with reference to the Cochrane Handbook for Systematic Reviews of Interventions (Higgins et al. 2011).

Where different studies presented continuous data measuring the same outcome but using different numerical scales (e.g. a 0–10 and a 0–100 visual analogue scale), these outcomes were all converted to the same scale before meta-analysis was conducted on the mean differences. Where outcomes measured the same underlying construct but used different instruments/metrics, data were analysed using standardised mean differences (Hedges’ g).

A pooled relative risk was calculated for dichotomous outcomes (using the Mantel–Haenszel method). Both relative and absolute risks were presented, with absolute risks calculated by applying the relative risk to the pooled risk in the comparator arm of the meta-analysis.

Fixed- and random-effects models (der Simonian and Laird) where appropriate, with the presented analysis dependent on the degree of heterogeneity in the assembled evidence. Fixed-effects models were the preferred choice to report, but in situations where the assumption of a shared mean for fixed-effects model were clearly not met, even after appropriate pre-specified subgroup analyses were conducted, random-effects results are presented. Fixed-effects models were deemed to be inappropriate if one or both of the following conditions was met:

Significant between study heterogeneity in methodology, population, intervention or comparator was identified by the reviewer in advance of data analysis. This decision was made and recorded before any data analysis was undertaken.
The presence of significant statistical heterogeneity in the meta-analysis, defined as I²≥50%.

In any meta-analyses where some (but not all) of the data came from studies at high risk of bias, a sensitivity analysis was conducted, excluding those studies from the analysis. Results from both the full and restricted meta-analyses are reported. Similarly, in any meta-analyses where some (but not all) of the data came from indirect studies, a sensitivity analysis was conducted, excluding those studies from the analysis.

Meta-analyses were performed in Cochrane Review Manager v5.3.

Minimal clinically important differences (MIDs)

The Core Outcome Measures in Effectiveness Trials (COMET) database was searched to identify published minimal clinically important difference thresholds relevant to this guideline. Identified MIDs were assessed to ensure they had been developed and validated in a methodologically rigorous way, and were applicable to the populations, interventions and outcomes specified in this guideline. In addition, the Guideline Committee were asked to prospectively specify any outcomes where they felt a consensus MID could be defined from their experience. In particular, any questions looking to evaluate non-inferiority (that one treatment is not meaningfully worse than another) required an MID to be defined to act as a non-inferiority margin.

No MIDs were identified. Therefore, a default MID interval for dichotomous outcomes of 0.8 to 1.25 was used.

When decisions were made in situations where MIDs were not available, the ‘Evidence to Recommendations’ section of that review should make explicit the committee’s view of the expected clinical importance and relevance of the findings. In particular, this includes consideration of whether the whole effect of a treatment (which may be felt across multiple independent outcome domains) would be likely to be clinically meaningful, rather than simply whether each individual sub outcome might be meaningful in isolation.

GRADE for pairwise meta-analyses of interventional evidence

GRADE was used to assess the quality of evidence for the selected outcomes as specified in ‘Developing NICE guidelines: the manual (2014)’. Data from all study designs was initially rated as high quality and the quality of the evidence for each outcome was downgraded or not from this initial point, based on the criteria given in Table 4.

Table 4. Rationale for downgrading quality of evidence for intervention studies

The quality of evidence for each outcome was upgraded if any of the following three conditions were met:

Data from non-randomised studies showing an effect size sufficiently large that it cannot be explained by confounding alone.
Data showing a dose-response gradient.
Data where all plausible residual confounding is likely to increase our confidence in the effect estimate.

Publication bias

Publication bias was assessed in two ways. First, if evidence of conducted but unpublished studies was identified during the review (e.g. conference abstracts, trial protocols or trial records without accompanying published data), available information on these unpublished studies was reported as part of the review. Secondly, where 10 or more studies were included as part of a single meta-analysis, a funnel plot was produced to graphically assess the potential for publication bias.

Evidence statements

Evidence statements for pairwise intervention data are classified in to one of four categories:

Situations where the data are only consistent, at a 95% confidence level, with an effect in one direction (i.e. one that is ‘statistically significant’), and the magnitude of that effect is most likely to meet or exceed the MID (i.e. the point estimate is not in the zone of equivalence). In such cases, we state that the evidence showed that there is an effect.
Situations where the data are only consistent, at a 95% confidence level, with an effect in one direction (i.e. one that is ‘statistically significant’), but the magnitude of that effect is most likely to be less than the MID (i.e. the point estimate is in the zone of equivalence). In such cases, we state that the evidence could not demonstrate a meaningful difference.
Situations where the data are consistent, at a 95% confidence level, with an effect in either direction (i.e. one that is not ‘statistically significant’) but the confidence limits are smaller than the MIDs in both directions. In such cases, we state that the evidence demonstrates that there is no difference.
In all other cases, we state that the evidence could not differentiate between the comparators.

For outcomes without a defined MID or where the MID is set as the line of no effect, evidence statements are divided into 2 groups as follows:

We state that the evidence showed that there is an effect if the 95% CI does not cross the line of no effect.
The evidence could not differentiate between comparators if the 95% CI crosses the line of no effect.

Health economics

Literature reviews seeking to identify published cost–utility analyses of relevance to the issues under consideration were conducted for all questions. In each case, the search undertaken for the clinical review was modified, retaining population and intervention descriptors, but removing any study-design filter and adding a filter designed to identify relevant health economic analyses. In assessing studies for inclusion, population, intervention and comparator, criteria were always identical to those used in the parallel clinical search; only cost–utility analyses were included. Economic evidence profiles, including critical appraisal according to the Guidelines manual, were completed for included studies.

Economic studies identified through a systematic search of the literature are appraised using a methodology checklist designed for economic evaluations (NICE guidelines manual; 2014). This checklist is not intended to judge the quality of a study per se, but to determine whether an existing economic evaluation is useful to inform the decision-making of the committee for a specific topic within the guideline.

There are 2 parts of the appraisal process. The first step is to assess applicability (that is, the relevance of the study to the specific guideline topic and the NICE reference case); evaluations are categorised according to the criteria in Table 1.

Table 1. Applicability criteria

In the second step, only those studies deemed directly or partially applicable are further assessed for limitations (that is, methodological quality); see categorisation criteria in Table 2.

Table 2. Methodological criteria

Studies were prioritised for inclusion based on their relative applicability to the development of this guideline and the study limitations. For example, if a high quality, directly applicable UK analysis was available, then other less relevant studies may not have been included. Where selective exclusions were made on this basis, this is noted in the relevant section.

Where relevant, a summary of the main findings from the systematic search, review and appraisal of economic evidence is presented in an economic evidence profile alongside the clinical evidence.

Appendix C. Literature search strategies

Table

The MEDLINE search strategy is presented below. This was translated for use in all of the other databases listed. The aim of the search was to identify evidence for the clinical question being asked. Randomised Controlled Trial and Systematic Review filters were used to identify the study designs specified in the Review Protocol.

Surgical Wound Infection/
Wound Infection/
SURGICAL WOUND DEHISCENCE/
Infection Control/
(infection adj4 control).tw.
Postoperative Complications/
((wound? or incision* or suture*) adj4 (infect* or sepsis or septic* or dehiscen* or site* or contamin* or disrupt* or rupture* or separat*)).tw.
(SSI or SSIs or SSTI or SSTIs).tw.
Bacterial Infections/pc [Prevention & Control]
exp Specialties Surgical/
exp Surgical Procedures, Operative/
surgery.fs.
(surger* or surgical* or operat* or procedure*).tw.
exp Minimally Invasive Surgical Procedures/
(arthroscopy* or laparoscop* or thoracoscop* or endoscop*).tw.
or/1–15
exp Anti-Infective Agents, Local/
Iodine/ or Iodine Compounds/
iodine*.tw.
((iod or iodide) adj4 derivative*).tw.
(iodinated adj4 compound*).tw.
(bioiodine or steribath or thysat or estroven or nasciodine or tcp).tw.
iodophor*.tw.
Povidone-Iodine/
((povidone adj4 iodine) or povidone-iodine).tw.
((povidine adj4 iodine) or povidine-iodine).tw.
(PVP-I or PVPI or PVP I or PVP-iodine or PVPiodine or pvp iodine or polyvinylpyrrolidoneiodine* or polyvinylpyrrolidone-iodine* or polyvinylpyrrolidone iodine*).tw.
(alphadine* or betadine* or betaisodona or betasept or “brush off” or “cold sore lotion” or disadine* or inadine or pharmadine* or povidine* or “savlon dry” or videne or codella).tw.
(octenisan or octenide or octenidine).tw.
Chlorhexidine/
chlorhexidine.tw.
(novalsan or tubulicid or “sebidan a” or mk 412a or mk-412a or mk412a).tw.
(acriflex or bacticlens or bactigras or “cx powder” or cepton or chlorasept or chlorohex or clorhexitulle or corsodyl or curasept or dispray or eczmol or elgydium or hibidil or hibiscrub or hibitane or hydrex or periochip or perioguard or rotersept or savlon or serotulle or spotoway or sterexidine or steripod or gluconate or uniscrub or unisept or “uriflex c” or phiso-med or CB12 or cetriclens or chloraprep or Clearasil or covonia or cyteal or dermol or eludril or germolene or germoloid* or hibi or hibicet or hibisol or instillagel or medi-swab or medi-wipe or mycil or nystaform* or quinoderm or savloclens or savlodil or sterets or steriwipe or tisept or torbetol or travasept or tri-ac or xylocaine).tw.
Disinfection/
exp Detergents/
exp Anti-Bacterial Agents/ or Antibiotic Prophylaxis/
(antimicrob* or anti microb* or antibiotic* or anti biotic*).tw.
((anti-infective* or antiinfective* or antibacterial* or anti-bacteria*) adj (agent* or drug*)).tw.
microbicide?.tw.
(bacteriocide? or bacteriocidal agent?).tw.
carbapenem*.tw.
exp Carbapenems/
exp Cephalosporins/
cephalosporin*.tw.
exp Cephamycins/
(cephamycin* or cefoxitin*).tw.
exp Monobactams/
monobactam*.tw.
exp Penicillins/
Penicillin*.tw.
exp Thienamycins/
Thienamycin*.tw.
exp Macrolides/
macrolide*.tw.
exp Fluoroquinolones/
Fluoroquinolone*.tw.
exp Sulfonamides/
Sulfonamide*.tw.
exp Tetracyclines/
Tetracycline*.tw.
exp Aminoglycosides/
Aminoglycoside*.tw.
Clindamycin/
(Clindamycin* or dalacin* or zindaclin or duac or refobacin or treclin).tw.
exp Nitroimidazoles/
Nitroimidazole*.tw.
exp Gentamicins/ or Cefuroxime/ or Metronidazole/ or exp Ciprofloxacin/ or Vancomycin/
(gentamicin* or cidomycin or garamycin or genticin or lugacin or collatemp or gentisone or palacos or refobacin or septocoll or septopal or vipsogal or cefuroxime* or aprokam or ximaract or zinacef or zinnat or metronidazole* or acea or anabact or elyzol or flagyl or metrogel or metrolyl or metrosa or metrotop or metrozol or nidazol or noritate or norzol or rosiced or rozex or vaginyl or zadstat or zidoval or zyomet or entamizole or helimet or ciprofloxacin* or cetraxal or ciloxan or ciproxin or cilodex or vancomycin* or vancocin).tw.
Antisepsis/
(antiseptic? or antisepsis).tw.
or/18–70
exp Skin/
skin.tw.
administration, topical/ or administration, cutaneous/
(skin or topical* or cutan* or dermal* or dermis* or local* or cutis or derma or epicutaneous).tw.
(transcutan* or percutan* or cutan*).tw.
Surgical wound/
(wound* or incision*).tw.
or/72–78
((before or prior to or previous to or preced*) adj4 (clos* or stitch* or stapl*)).tw.
(pre closure or preclosure or pre sutur* or presutur* or pre-suture*).tw.
Intraoperative care/ or Intraoperative Period/
(intraop* or intrawound*).tw.
or/80–83
71 and 79
17 or 85
16 and 86
84 and 87
(collagen adj4 (implant* or sponge* or bead* or gel*)).tw.
Surgical Sponges/ or Drug Implants/
Powders/
powder*.tw.
exp Bone Cements/
(bone adj4 cement*).tw.
or/89–94
16 and 71 and 95
88 or 96
animals/ not humans/
97 not 98
limit 99 to english language
Randomized Controlled Trial.pt.
Controlled Clinical Trial.pt.
Clinical Trial.pt.
exp Clinical Trials as Topic/
Placebos/
Random Allocation/
Double-Blind Method/
Single-Blind Method/
Cross-Over Studies/
((random$ or control$ or clinical$) adj3 (trial$ or stud$)).tw.
(random$ adj3 allocat$).tw.
placebo$.tw.
((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).tw.
(crossover$ or (cross adj over$)).tw.
or/101–114
Meta-Analysis.pt.
Network Meta-Analysis/
Meta-Analysis as Topic/
Review.pt.
exp Review Literature as Topic/
(metaanaly$ or metanaly$ or (meta adj3 analy$)).tw.
(review$ or overview$).ti.
(systematic$ adj5 (review$ or overview$)).tw.
((quantitative$ or qualitative$) adj5 (review$ or overview$)).tw.
((studies or trial$) adj2 (review$ or overview$)).tw.
(integrat$ adj3 (research or review$ or literature)).tw.
(pool$ adj2 (analy$ or data)).tw.
(handsearch$ or (hand adj3 search$)).tw.
(manual$ adj3 search$).tw.
or/116–129
115 or 130
100 and 131

Economic evaluations and quality of life data

Search filters to retrieve economic evaluations and quality of life papers were appended to the strategy listed above to identify relevant evidence. The MEDLINE economic evaluations and quality of life search filters are presented below. They were translated for use in MEDLINE in Process, Embase, The Cochrane Library, CINAHL and Econlit databases.

Sources searched to identify economic evaluations:

Table

Economic evaluations

Economics/
exp “Costs and Cost Analysis”/
Economics, Dental/
exp Economics, Hospital/
exp Economics, Medical/
Economics, Nursing/
Economics, Pharmaceutical/
Budgets/
exp Models, Economic/
Markov Chains/
Monte Carlo Method/
Decision Trees/
econom$.tw.
cba.tw.
cea.tw.
cua.tw.
markov$.tw.
(monte adj carlo).tw.
(decision adj3 (tree$ or analys$)).tw.
(cost or costs or costing$ or costly or costed).tw.
(price$ or pricing$).tw.
budget$.tw.
expenditure$.tw.
(value adj3 (money or monetary)).tw.
(pharmacoeconomic$ or (pharmaco adj economic$)).tw.
or/1–25

Quality of Life

“Quality of Life”/
quality of life.tw.
“Value of Life”/
Quality-Adjusted Life Years/
quality adjusted life.tw.
(qaly$ or qald$ or qale$ or qtime$).tw.
disability adjusted life.tw.
daly$.tw.
Health Status Indicators/
(sf36 or sf 36 or short form 36 or shortform 36 or sf thirtysix or sf thirty six or shortform thirtysix or shortform thirty six or short form thirtysix or short form thirty six).tw.
(sf6 or sf 6 or short form 6 or shortform 6 or sf six or sfsix or shortform six or short form six).tw.
(sf12 or sf 12 or short form 12 or shortform 12 or sf twelve or sftwelve or shortform twelve or short form twelve).tw.
(sf16 or sf 16 or short form 16 or shortform 16 or sf sixteen or sfsixteen or shortform sixteen or short form sixteen).tw.
(sf20 or sf 20 or short form 20 or shortform 20 or sf twenty or sftwenty or shortform twenty or short form twenty).tw.
(euroqol or euro qol or eq5d or eq 5d).tw.
(qol or hql or hqol or hrqol).tw.
(hye or hyes).tw.
health$ year$ equivalent$.tw.
utilit$.tw.
(hui or hui1 or hui2 or hui3).tw.
disutili$.tw.
rosser.tw.
quality of wellbeing.tw.
quality of well-being.tw.
qwb.tw.
willingness to pay.tw.
standard gamble$.tw.
time trade off.tw.
time tradeoff.tw.
tto.tw.
or/1–30

Appendix D. Clinical evidence study selection

Appendix E. Clinical evidence tables

Appendix F. Forest plots

F.1. Erythromycin and colistin-loaded bone cement vs. bone cement without antibiotic

Outcomes at 1 year after surgery

SSI

Superficial SSI

Deep SSI

F.2. Vancomycin powder vs no vancomycin powder

Outcomes at 3 months

SSI

Superficial SSI

Deep SSI

F.3. Ampicillin powder vs placebo

Outcomes at 3 weeks after surgery

SSI

F.4. Topical cefotaxime vs. no topical antibiotic

Outcomes at 1 month after surgery

SSI

Septicaemia

Mortality post-surgery

F.5. Topical cephaloridine vs no topical antibiotic

Outcomes at 1 month after surgery

SSI

F.6. Topical povidone iodine spray vs no antiseptic spray

Outcomes at 2 weeks after surgery

SSI

Postoperative antibiotic use

Outcomes at 1 month after surgery

SSI

SSI (Analysis by wound category)

F.7. Povidone iodine spray vs ampicillin powder

Outcomes at 1 month after surgery

SSI

F.8. Povidone iodine solution vs no antibiotic solution

Outcomes during postoperative period

SSI

F.9. Topical 2.5% iodine in 70% ethanol vs no topical antiseptic

Outcomes at 2 weeks

SSI

F.10. Gentamicin collagen sponge vs no sponge

Outcomes at 1 week after surgery

SSI

Outcomes at 2 weeks after surgery

SSI

Outcomes at 1 month after surgery

SSI

Superficial SSI

Deep SSI

Mortality post-surgery

Mean length of stay during 1-month follow up

Outcomes at 2 months after surgery SSI

SSI

Superficial SSI

Deep SSI

Organ space SSI

Hospital mortality

Mortality post-surgery

Hospital readmission during 2 month follow up period

Outcomes at 3 months after surgery

SSI

Superficial SSI

Superficial/ deep SSI

Deep SSI

Organ space SSI

Mortality post-surgery

Hospital readmission during 3 month follow up period

Outcomes at 6 months after surgery

SSI

Length of stay

Outcomes during postoperative period

SSI

F.11. Gentamicin collagen sponge vs collagen sponge alone

Outcomes at 1 month after surgery

SSI

Superficial SSI

Superficial SSI-Sensitivity analysis (excluding high risk of bias studies)

Deep SSI

Deep SSI-Sensitivity analysis (excluding high risk of bias studies)

Appendix G. GRADE tables

G.1. Erythromycin and colistin loaded bone cement vs. bone cement without antibiotics

Outcomes at 1 year after surgery

Table

1 Hinarejos 2013

G.2. Vancomycin powder vs no vancomycin powder

Outcomes at 3 months

Table

1 Tubaki 2013

G.3. Ampicillin powder vs placebo

Outcomes at 3 weeks after surgery

Table

1 Rickett 1969

G.4. Topical cefotaxime vs no topical antibiotic

Outcomes at 1 month after surgery

Table

1 Moesgaard 1989

G.5. Topical cephaloridine vs no topical antibiotic

Outcomes 1 month after surgery

Table

1 Evans 1974

G.6. Topical povidone iodine spray vs no topical antiseptic spray

Outcomes at 2 weeks after surgery

Table

1 Gray 1981

Outcomes at 1 month after surgery

Table

2 Sherlock 1984

Povidone iodine spray vs ampicillin powder

Outcomes at 1 month after surgery

Table

G.7. Povidone iodine solution vs no antibiotic solution

Outcomes during postoperative period

Table

G.8. Topical 2.5% iodine in 70% ethanol vs no topical antiseptic

Outcomes at 2 week after surgery

Table

G.9. Gentamicin collagen sponge vs no sponge

Outcomes at 1 week after surgery

Table

2 Collin 2013

Outcomes at 2 weeks after surgery

Table

1 Andersson 2010

Outcomes at 1 month after surgery

Table

4 Collin 2013

Outcomes at 2 months after surgery

Table

3 Gruessner 2001 Frigberg 2005

Outcomes at 3 months after surgery

Table

Difference in medians: 0 days (non-significant according to Chi-square test)

Outcomes at 6 months after surgery

Table

Outcomes at 1 year

Table

Outcomes at 6–30 months

Table

Outcomes during postoperative period

Table

G.10. Gentamicin collagen sponge vs collagen sponge alone (placebo)

Outcomes at 1 month after surgery

Table

Difference in medians: 0.5 days (non-significant according to Kurskal-Wallis test)

Appendix H. Economic evidence study selection

Appendix I. Economic evidence tables

Download PDF (200K)

Appendix J. Excluded studies

Clinical studies

Table

Conference abstract Systematic review did not match review protocol

Economic studies

Table

Appendix K. Research recommendations

1. Is the application of antiseptics and antibiotics in the operative field before wound closure, clinically and cost effective in reducing surgical site infection rates?

30 RCTs were identified in this review which examined the clinical effectiveness of different topical antiseptics and antibiotics. This evidence ranged from moderate to very low quality and examined a number of different interventions including antibiotic loaded bone cement. Old and out-dated evidence suggested that interventions such as ampicillin, cephaloridine (which is no longer available on the market) and topical povidone iodine reduced the incidence of SSI. More recent data mainly suggests that gentamicin collagen implant are effective in reducing SSI in cardiac surgery and hidradenitis supperativa surgery.

As new interventions are being introduced into practice, further research is required, using a robust study design, to further explore the role of antibiotics and antiseptics in the reduction of SSI when applied intraoperatively. These studies should be adequately powered and should also further explore interventions such as antibiotic impregnated implants and antibiotic loaded bone cement. Further research should be based in the UK and take into account different surgical procedures. Research in this area is essential to inform future updates of key recommendations in this guidance which in turn can help improve patient outcomes.

Table

Population: People of any age undergoing any surgery, including minimally invasive surgery (arthroscopic, thoracoscopic and laparoscopic surgery)

Appendix L. References

Included studies

Andersson Roland E, Lukas Gudrun, Skullman Stefan, and Hugander Anders (2010) Local administration of antibiotics by gentamicin-collagen sponge does not improve wound healing or reduce recurrence rate after pilonidal excision with primary suture: a prospective randomized controlled trial. World journal of surgery 34(12), 3042–8 [PubMed: 20734046]
Bennett-Guerrero Elliott, Pappas Theodore N, Koltun Walter A, Fleshman James W, Lin Min, Garg Jyotsna, Mark Daniel B, Marcet Jorge E, Remzi Feza H, George Virgilio V, Newland Kerstin, Corey G R, and Group Swipe Trial (2010) Gentamicin-collagen sponge for infection prophylaxis in colorectal surgery. The New England journal of medicine 363(11), 1038–49 [PubMed: 20825316]
Bennett-Guerrero Elliott, Ferguson T Bruce, Jr, Lin Min, Garg Jyotsna, Mark Daniel B, Scavo Vincent A, Jr, Kouchoukos Nicholas, Richardson John B, Jr, Pridgen Renee L, Corey G R, and Group Swipe Trial (2010) Effect of an implantable gentamicin-collagen sponge on sternal wound infections following cardiac surgery: a randomized trial. JAMA 304(7), 755–62 [PubMed: 20716738]
Buimer Mathijs G, Ankersmit Miriam F. P, Wobbes Theo, and Klinkenbijl Jean H. G (2008) Surgical treatment of hidradenitis suppurativa with gentamicin sulfate: a prospective randomized study. Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.] 34(2), 224–7 [PubMed: 18093197]
Collin A, Gustafsson UM, Smedh K, Pahlman L, Graf W, and Folkesson J (2013) Effect of local gentamicin-collagen on perineal wound complications and cancer recurrence after abdominoperineal resection: a multicentre randomized controlled trial.. Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland 15(3), 341–6 [PubMed: 22889358]
Cordtz T, Schouenborg L, Laursen K, Daugaard H O, Buur K, Munk Christensen, B, Sederberg-Olsen J, Lindhard A, Baldur B, and Engdahl E (1989) The effect of incisional plastic drapes and redisinfection of operation site on wound infection following caesarean section. The Journal of hospital infection 13(3), 267–72 [PubMed: 2567756]
Eklund A M, Valtonen M, and Werkkala K A (2005) Prophylaxis of sternal wound infections with gentamicin-collagen implant: randomized controlled study in cardiac surgery. The Journal of hospital infection 59(2), 108–12 [PubMed: 15620444]
Evans C, Pollock A V, and Rosenberg I L (1974) The reduction of surgical wound infections by topical cephaloridine: a controlled clinical trial. British Journal of Surgery 61(2), 133–135 [PubMed: 4361233]
Friberg Orjan, Svedjeholm Rolf, Soderquist Bo, Granfeldt Hans, Vikerfors Tomas, and Kallman Jan (2005) Local gentamicin reduces sternal wound infections after cardiac surgery: a randomized controlled trial. The Annals of thoracic surgery 79(1), 153–2 [PubMed: 15620935]
Friberg Orjan (2007) Local collagen-gentamicin for prevention of sternal wound infections: the LOGIP trial. APMIS : acta pathologica, microbiologica, and et immunologica Scandinavica 115(9), 1016–21 [PubMed: 17931240]
Gray J G, and Lee M J (1981) The effect of topical povidone iodine on wound infection following abdominal surgery. The British journal of surgery 68(5), 310–3 [PubMed: 7013895]
Gruessner U, Clemens M, Pahlplatz PV, Sperling P, Witte J, and Rosen HR (2001) Improvement of perineal wound healing by local administration of gentamicin-impregnated collagen fleeces after abdominoperineal excision of rectal cancer.. American journal of surgery 182(5), 502–9 [PubMed: 11754859]
Haase O, Raue W, Bohm B, Neuss H, Scharfenberg M, and Schwenk W (2005) Subcutaneous gentamycin implant to reduce wound infections after loop-ileostomy closure: a randomized, double-blind, placebo-controlled trial. Diseases of the colon and rectum 48(11), 2025–31 [PubMed: 16228839]
Harihara Yasushi, Konishi Toshiro, Kobayashi Hiroyoshi, Furushima Kaoru, Ito Kei, Noie Tamaki, Nara Satoshi, and Tanimura Kumi (2006) Effects of applying povidone-iodine just before skin closure. Dermatology (Basel, and Switzerland) 212 Suppl 1, 53–7 [PubMed: 16490976]
Hinarejos Pedro, Guirro Pau, Leal Joan, Montserrat Ferran, Pelfort Xavier, Sorli M L, Horcajada J P, and Puig Lluis (2013) The use of erythromycin and colistin-loaded cement in total knee arthroplasty does not reduce the incidence of infection: a prospective randomized study in 3000 knees. The Journal of bone and joint surgery. American volume 95(9), 769–74 [PubMed: 23636182]
Migaczewski Marcin, Zub-Pokrowiecka Anna, Budzynski Piotr, Matlok Maciej, and Budzynski Andrzej (2012) Prevention of early infective complications after laparoscopic splenectomy with the Garamycin sponge. Wideochirurgia i inne techniki maloinwazyjne = Videosurgery and other miniinvasive techniques 7(2), 105–10 [PMC free article: PMC3516976] [PubMed: 23256010]
Moesgaard F, Nielsen M L, Hjortrup A, Kjersgaard P, Sorensen C, Larsen P N, and Hoffmann S (1989) Intraincisional antibiotic in addition to systemic antibiotic treatment fails to reduce wound infection rates in contaminated abdominal surgery. A controlled clinical trial. Diseases of the colon and rectum 32(1), 36–8 [PubMed: 2642790]
Musella M, Guido A, and Musella S (2001) Collagen tampons as aminoglycoside carriers to reduce postoperative infection rate in prosthetic repair of groin hernias.. The European journal of surgery = Acta chirurgica 167(2), 130–2 [PubMed: 11266253]
Nowacki Marek P, Rutkowski Andrzej, Oledzki Janusz, and Chwalinski Maciej (2005) Prospective, randomized trial examining the role of gentamycin-containing collagen sponge in the reduction of postoperative morbidity in rectal cancer patients: early results and surprising outcome at 3-year follow-up. International journal of colorectal disease 20(2), 114–20 [PubMed: 15375668]
Ozbalci Gokhan Selcuk, Tuncal Salih, Bayraktar Kenan, Tasova Volkan, Ali Akkus, and Mehmet (2014) Is gentamicin-impregnated collagen sponge to be recommended in pilonidal sinus patient treated with marsupialization? A prospective randomized study. Annali italiani di chirurgia 85(6), 576–82 [PubMed: 25711716]
Parker Mc, and Mathams A (1985) Systemic metronidazole combined with either topical povidone-iodine or ampicillin in acute appendicitis. Journal of hospital infection 6 Suppl A, 97–101 [PubMed: 2860183]
Pochhammer Julius, Zacheja Steffi, and Schaffer Michael (2015) Subcutaneous application of gentamicin collagen implants as prophylaxis of surgical site infections in laparoscopic colorectal surgery: a randomized, double-blinded, three-arm trial. Langenbeck’s archives of surgery 400(1), 1–8 [PubMed: 25172200]
Rickett J W, and Jackson B T (1969) Topical ampicillin in the appendicectomy wound: report of double-blind trial. British medical journal 4(5677), 206–7 [PMC free article: PMC1629853] [PubMed: 4900147]
Rutkowski A, Zajac L, Pietrzak L, Bednarczyk M, Byszek A, Oledzki J, Olesinski T, Szpakowski M, Saramak P, and Chwalinski M (2014) Surgical site infections following short-term radiotherapy and total mesorectal excision: results of a randomized study examining the role of gentamicin collagen implant in rectal cancer surgery. Techniques in coloproctology 18(10), 921–8 [PMC free article: PMC4185107] [PubMed: 24993838]
Rutten H J, and Nijhuis P H (1997) Prevention of wound infection in elective colorectal surgery by local application of a gentamicin-containing collagen sponge. The European journal of surgery. Supplement. : = Acta chirurgica. Supplement (578), 31–5 [PubMed: 9167147]
Schimmer Christoph, Ozkur Mehmet, Sinha Bhanu, Hain Johannes, Gorski Armin, Hager Benjamin, and Leyh Rainer (2012) Gentamicin-collagen sponge reduces sternal wound complications after heart surgery: a controlled, prospectively randomized, double-blind study. The Journal of thoracic and cardiovascular surgery 143(1), 194–200 [PubMed: 21885068]
Sherlock D J, Ward A, and Holl-Allen R T (1984) Combined preoperative antibiotic therapy and intraoperative topical povidone-iodine. Reduction of wound sepsis following emergency appendectomy. Archives of surgery (Chicago, and Ill. : 1960) 119(8), 909–11 [PubMed: 6378144]
Tubaki Vijay Ramappa, Rajasekaran S, and Shetty Ajoy Prasad (2013) Effects of using intravenous antibiotic only versus local intrawound vancomycin antibiotic powder application in addition to intravenous antibiotics on postoperative infection in spine surgery in 907 patients. Spine 38(25), 2149–55 [PubMed: 24048091]
Walsh JA, Watts JM, McDonald PJ, and Finlay-Jones JJ (1981) The effect of topical povidone-iodine on the incidence of infection in surgical wounds.. The British journal of surgery 68(3), 185–9 [PubMed: 7008894]
Westberg Marianne, Frihagen Frede, Brun Ole-Christian, Figved Wender, Grogaard Bjarne, Valland Haldor, Wangen Helge, and Snorrason Finnur (2015) Effectiveness of gentamicin-containing collagen sponges for prevention of surgical site infection after hip arthroplasty: a multicenter randomized trial. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 60(12), 1752–9 [PubMed: 25737375]
Yetim I, Ozkan O V, Dervisoglu A, Erzurumlu K, and Canbolant E (2010) Effect of local gentamicin application on healing and wound infection in patients with modified radical mastectomy: a prospective randomized study. The Journal of international medical research 38(4), 1442–7 [PubMed: 20926017]

Excluded studies

Abdullah Kg, Mallela A, Richardson A, and Lucas Th (2017) Topical vancomycin reduces surgical-site infections after craniotomy: a prospective, controlled study. Clinical neurosurgery. Conference: 2017 annual meeting of the congress of neurological surgeons. United states 64(Supplement 1), 238
Anagnostakos Konstantinos (2017) Therapeutic Use of Antibiotic-loaded Bone Cement in the Treatment of Hip and Knee Joint Infections. Journal of bone and joint infection 2(1), 29–37 [PMC free article: PMC5423576] [PubMed: 28529862]
Anagnostakos Konstantinos, and Schroder Katrin (2012) Antibiotic-impregnated bone grafts in orthopaedic and trauma surgery: a systematic review of the literature. International journal of biomaterials 2012, 538061 [PMC free article: PMC3412111] [PubMed: 22899933]
Andreas Martin, Muckenhuber Moritz, Hutschala Doris, Kocher Alfred, Thalhammer Florian, Vogt Paul, Fleck Tatjana, and Laufer Guenther (2017) Direct sternal administration of Vancomycin and Gentamicin during closure prevents wound infection. Interactive cardiovascular and thoracic surgery 25(1), 6–11 [PubMed: 28402472]
Bakhsheshian Joshua, Dahdaleh Nader S, Lam Sandi K, Savage Jason W, and Smith Zachary A (2015) The use of vancomycin powder in modern spine surgery: systematic review and meta-analysis of the clinical evidence. World neurosurgery 83(5), 816–23 [PubMed: 25535069]
Benaerts P J, Ridler B M, Vercaeren P, Thompson J F, and Campbell W B (1999) Gentamicin beads in vascular surgery: long-term results of implantation. Cardiovascular surgery (London, and England) 7(4), 447–50 [PubMed: 10430529]
Bertazzoni Minelli, E, Benini A, Magnan B, and Bartolozzi P (2004) Release of gentamicin and vancomycin from temporary human hip spacers in two-stage revision of infected arthroplasty. The Journal of antimicrobial chemotherapy 53(2), 329–34 [PubMed: 14688051]
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Block Jon E, and Stubbs Harrison A (2005) Reducing the risk of deep wound infection in primary joint arthroplasty with antibiotic bone cement. Orthopedics 28(11), 1334–45 [PubMed: 16295192]
Bozzetti F, Doci R, Milani A, Orefice S, Rasponi A, and Vaglini M (1975) Topical ampicilin and local infectious complications in oncological surgery. Tumori 61(5), 425–432 [PubMed: 1209742]
Chang Wai Keat, Srinivasa Sanket, MacCormick Andrew D, and Hill Andrew G (2013) Gentamicin-collagen implants to reduce surgical site infection: systematic review and meta-analysis of randomized trials. Annals of surgery 258(1), 59–65 [PubMed: 23486193]
Chen Antonia F, and Parvizi Javad (2014) Antibiotic-loaded bone cement and periprosthetic joint infection. Journal of long-term effects of medical implants 24(2–3), 89–97 [PubMed: 25272207]
Chiang Hsiu-Yin, Herwaldt Loreen A, Blevins Amy E, Cho Edward, and Schweizer Marin L (2014) Effectiveness of local vancomycin powder to decrease surgical site infections: a meta-analysis. The spine journal : official journal of the North American Spine Society 14(3), 397–407 [PubMed: 24373682]
Chiu F Y, Lin C F, Chen C M, Lo W H, and Chaung T Y (2001) Cefuroxime-impregnated cement at primary total knee arthroplasty in diabetes mellitus. A prospective, randomised study. The Journal of bone and joint surgery. British volume 83(5), 691–5 [PubMed: 11476307]
Chiu Fang-Yao, Chen Chuan-Mu, Lin Chien-Fu Jeff, and Lo Wai-Hee (2002) Cefuroxime-impregnated cement in primary total knee arthroplasty: a prospective, randomized study of three hundred and forty knees. The Journal of bone and joint surgery. American volume 84-A(5), 759–62 [PubMed: 12004017]
Creanor S, Barton A, and Marchbank A (2012) Effectiveness of a gentamicin impregnated collagen sponge on reducing sternal wound infections following cardiac surgery: a meta-analysis of randomised controlled trials. Annals of the Royal College of Surgeons of England 94(4), 227–31 [PMC free article: PMC3957499] [PubMed: 22613298]
Culligan Patrick J, Kubik Kari, Murphy Miles, Blackwell Linda, and Snyder James (2005) A randomized trial that compared povidone iodine and chlorhexidine as antiseptics for vaginal hysterectomy. American journal of obstetrics and gynecology 192(2), 422–5 [PubMed: 15695981]
de Bruin, A F J, Gosselink M P, van der Harst, E, and Rutten H J. T (2010) Local application of gentamicin collagen implants in the prophylaxis of surgical site infections following gastrointestinal surgery: a review of clinical experience. Techniques in coloproctology 14(4), 301–10 [PMC free article: PMC2988990] [PubMed: 20585822]
de Bruin, Anton F J, Gosselink Martijn P, van der Harst, and Erwin (2012) Local application of gentamicin-containing collagen implant in the prophylaxis of surgical site infection following gastrointestinal surgery. International journal of surgery (London, and England) 10 Suppl 1, S21–7 [PubMed: 22659224]
Desmond Joel, Lovering Andy, Harle Chris, Djorevic Tatiana, and Millner Russell (2003) Topical vancomycin applied on closure of the sternotomy wound does not prevent high levels of systemic vancomycin. European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery 23(5), 765–70 [PubMed: 12754030]
Diefenbeck Michael, Muckley Thomas, and Hofmann Gunther O (2006) Prophylaxis and treatment of implant-related infections by local application of antibiotics. Injury 37 Suppl 2, S95–104 [PubMed: 16651078]
Donovan Tj, Friedrich I, Sino S, and Greber N (2018) Sternal application of vancomycin greatly reduces the incidence of sternal wound complications in patients undergoing cardiosurgical procedures. Thoracic and cardiovascular surgeon. Conference: 47th annual meeting of the german society for thoracic and cardiovascular surgery, and DGTHG 2018. Germany 66(Supplement 1) (no pagination),
Dunbar Michael J (2009) Antibiotic bone cements: their use in routine primary total joint arthroplasty is justified. Orthopedics 32(9), [PubMed: 19751021]
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Fleischman Andrew N, and Austin Matthew S (2017) Local Intra-wound Administration of Powdered Antibiotics in Orthopaedic Surgery. Journal of bone and joint infection 2(1), 23–28 [PMC free article: PMC5423570] [PubMed: 28529861]
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Guideline version (FINAL)

These evidence reviews were developed by NICE Guideline Updates Team

Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.

Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.

NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.

Bookshelf ID: NBK569836PMID: 33905191

Table 1PICO: Is the application of antiseptics and antibiotics in the operative field before wound closure clinically effective in reducing surgical site infection rates?

Population	People of any age undergoing any surgery, including minimally invasive surgery (arthroscopic, thoracoscopic and laparoscopic surgery)
Interventions	Different antibiotic classes used alone or included in bone cement during orthopaedic surgery (penicllins, cephalosporins, fluoroquinolones, aminoglycosides, monobactams, carbapanems, macrolides and vancomycin) Gentamicin collagen sponges, beads and gel Cefotaxime Chlorhexidine Iodine lodophors including povidone iodine.
Comparator	No skin antiseptics/antibiotics Different antiseptics/antibiotics Placebo
Outcomes	Surgical site infection (superficial, deep and organ/space SSI), including SSIs up to 30 days and 1 year, defined using appropriate criteria such as CDC SSI criteria. Mortality post-surgery Length of hospital stay Postoperative antibiotic use. Infectious complications such as septicaemia or septic shock Adverse events: Antimicrobial resistance Kidney toxicity Anaphylaxis

Table 2Summary of included studies

Short Title	Title	Study details	Interventions	Comparator	Outcome measure(s)
Andersson (2010)	Local administration of antibiotics by gentamicin-collagen sponge does not improve wound healing or reduce recurrence rate after pilonidal excision with primary suture: a prospective randomized controlled trial	Study location Sweden Study setting Multicentre (performed across 11 hospitals) Study dates March 2003 to November 2005 Duration of follow-up Up to 3 months Sources of funding Not reported	Gentamicin collagen sponge	No antibiotics No gentamicin collagen sponge was implanted.	SSI
Bennett-Guerrero (2010a)	Gentamicin-collagen sponge for infection prophylaxis in colorectal surgery	Study location US Study setting Department of Surgery. Study dates February 2008 and March 2009 Duration of follow-up 60 days from surgery. Sources of funding Supported by Innocoll Technologies.	Gentamicin collagen sponge	No antibiotics No gentamicin collagen sponge was placed in the control group.	SSI Superficial SSI Deep SSI Organ/space SSI Length of hospital stay Hospital readmission
Bennett-Guerrero (2010b)	Effect of an implantable gentamicin-collagen sponge on sternal wound infections following cardiac surgery: a randomized trial	Study location US Study setting Not specified. Study dates 21st December 2007 to 11th March 2009 Duration of follow-up 90 days from surgery. Sources of funding Study was sponsored by Innocoll Technologies Ltd.	Gentamicin collagen sponge	No antibiotics The control group did not receive gentamicin collagen sponges.	SSI Superficial SSI Deep SSI Length of hospital stay Hospital readmission
Buimer (2008)	Surgical treatment of hidradenitis suppurativa with gentamicin sulfate: a prospective randomized study	Study location The Netherlands Study setting Medical Centre Study dates Not reported. Duration of follow-up 1 week Sources of funding Not specified.	Gentamicin collagen sponge	No antibiotics Hidradenitis suppurativa lesions were excised with primary closure of the wound without enclosure of antibiotics.	SSI
Collin (2013)	Effect of local gentamicin-collagen on perineal wound complications and cancer recurrence after abdominoperineal resection: a multicentre randomized controlled trial.	Study location Sweden Study setting University hospital Study dates February 2000 to April 2003 Duration of follow-up 1, 3 and 12 months. Sources of funding Not specified.	Gentamicin collagen sponge	No antibiotics Patients underwent surgery alone (no sponge implanted).	SSI
Cordtz (1989)	The effect of incisional plastic drapes and redisinfection of operation site on wound infection following caesarean section	Study location Denmark Study setting Hospital setting Study dates Not reported. Duration of follow-up 2 weeks Sources of funding Not reported	2.5% Iodine in 70% ethanol	No antiseptics For pre-operative skin disinfection 2.5% iodine in 70% ethanol was used. The patients were randomised to receive no disinfection.	SSI
Eklund (2005)	Prophylaxis of sternal wound infections with gentamicin-collagen implant: randomized controlled study in cardiac surgery	Study location Finland Study setting University hospital Study dates July 1998 and September 1999 Duration of follow-up 3 months Sources of funding The study was supported by grants from Helsinki University Central Hospital and Schering Plough Corporation.	Gentamicin collagen sponge	No antibiotics The controls’ sternums were closed in a routine manner with steel wires, without gentamicin implants.	SSI Superficial SSI Deep SSI Organ/space SSI Mortality post-surgery
Evans (1974)	The reduction of surgical wound infections by topical cephaloridine: a controlled clinical trial	Study location UK Study setting Hospital setting. Study dates Not specified. Duration of follow-up 4 weeks. Sources of funding Glaxo Laboratories Ltd provided the cephaloridine (Ceporin).	Cephaloridine	No antibiotics No antibiotics were used before wound closure.	SSI
Friberg (2005) Friberg (2007)	Local gentamicin reduces sternal wound infections after cardiac surgery: a randomized controlled trial	Study location Sweden Study setting Cardiothoracic centres Study dates September 2000 to September 2002 Duration of follow-up 2 months postoperatively Sources of funding Study financed by grants from the Research Committee of Orebro County Council and from Schering-Plough, who also provided free Collamtamp-G.	Gentamicin collagen sponge	No antibiotics In the control group the wound was closed in a conventional way.	SSI Superficial SSI Deep SSI Mortality post-surgery
Gray (1981)	The effect of topical povidone iodine on wound infection following abdominal surgery	Study location UK Study setting Surgical Department Study dates Not specified Duration of follow-up 2 weeks Sources of funding Not specified.	Povidone Iodine	No antiseptics	SSI Postoperative antibiotic use
Gruessner (2001)	Improvement of perineal wound healing by local administration of gentamicin-impregnated collagen fleeces after abdominoperineal excision of rectal cancer.	Study location Germany Study setting Not specified. Study dates Not specified. Duration of follow-up 8 weeks Sources of funding Not specified.	Gentamicin collagen sponge	No antibiotics Control group received complete closure of the pelvic floor, mandatory insertion of a sacral overflow drain, and multiple-layer primary wound management.	SSI
Haase (2005)	Subcutaneous gentamycin implant to reduce wound infections after loop-ileostomy closure: a randomized, double-blind, placebo-controlled trial	Study location Germany Study setting Department of General, visceral and thoracic surgery Study dates May 2000 to June 2003 Duration of follow-up within 30 days Sources of funding Not specified.	Gentamicin collagen sponge	Placebo The collagen implant was placed subcutaneously	SSI Superficial SSI Deep SSI
Harihara (2006)	Effects of applying povidone-iodine just before skin closure	Study location Japan Study setting Department of surgery. Study dates July 2004 and December 2004 Duration of follow-up Not specified. Sources of funding No specified .	Povidone Iodine	No antiseptics No antiseptic was used before skin closure .	SSI
Hinarejos (2013)	The use of erythromycin and colistin-loaded cement in total knee arthroplasty does not reduce the incidence of infection: a prospective randomized study in 3000 knees	Study location Spain Study setting Departments of Orthopaedic Surgery and Infectious Diseases. Study dates September 2005 to April 2010. Duration of follow-up 12 months. Sources of funding Not specified.	Erythromycin and colistin-loaded cement	No antibiotics Prosthesis was cemented with Simplex cement without antibiotic.	SSI Superficial SSI Deep SSI
Migaczewski (2012)	Prevention of early infective complications after laparoscopic splenectomy with the Garamycin sponge	Study location Poland Study setting not specified Study dates September 2007 to December 2009 Duration of follow-up 1 month (30 days) Sources of funding not reported	Gentamicin collagen sponge	No antibiotics Following laparoscopic splenectomy, no sponge was left at the splenic site.	SSI
Moesgaard (1989)	Intraincisional antibiotic in addition to systemic antibiotic treatment fails to reduce wound infection rates in contaminated abdominal surgery. A controlled clinical trial	Study location Denmark Study setting Department of surgical gastroenterology Study dates April 1983 to January 1986 Duration of follow-up One month Sources of funding Not specified	Cefotaxime	No antibiotics No antibiotics were used before skin closure.	SSI Organ/space SSI Infectious complication: septicaemia
Musella (2001)	Collagen tampons as aminoglycoside carriers to reduce postoperative infection rate in prosthetic repair of groin hernias.	Study location Italy Study setting University Hospital Study dates January 1991 to January 1999 Duration of follow-up 6 months Sources of funding Not specified.	Gentamicin collagen sponge	No antibiotics Patients in the control group had a standard surgical treatment.	SSI
Nowacki (2005)	Prospective, randomized trial examining the role of gentamycin-containing collagen sponge in the reduction of postoperative morbidity in rectal cancer patients: early results and surprising outcome at 3-year follow-up	Study location Poland Study setting not specified Study dates January 1997 to April 1999 Duration of follow-up 1 month (30 days) Sources of funding not reported	Gentamicin collagen sponge	No antibiotics No sponge was used.	SSI
Ozbalci (2014)	Is gentamicin-impregnated collagen sponge to be recommended in pilonidal sinus patient treated with marsupialization? A prospective randomized study	Study location Turkey Study setting Department of general Surgery Study dates January 2011 and December 2012 Duration of follow-up 6–30 months Sources of funding Not specified	Gentamicin collagen sponge.	No antibiotics Patients in this group did not receive gentamicin sponge.	SSI
Parker (1985)	Systemic metronidazole combined with either topical povidone-iodine or ampicillin in acute appendicitis	Study location UK Study setting Hospital setting Study dates Not specified. Duration of follow-up 1 month Sources of funding Napp laboratories supplied materials for study.	Povidone Iodine	Different antibiotics Ampicillin powder	SSI
Pochhammer (2015)	Subcutaneous application of gentamicin collagen implants as prophylaxis of surgical site infections in laparoscopic colorectal surgery: a randomized, double-blinded, three-arm trial	Study location Germany Study setting Single centre Study dates July 2008 to July 2010 Duration of follow-up 1 month (30 days) Sources of funding Authors reported that medical device manufacturers provided gentamicin-collagen and collagen-only sponges and no further funding was given.	Gentamicin collagen sponge	Placebo A collagen sponge without any antibiotics was inserted subcutaneously after closing the peritoneum and aponeurosis separately with a running polyglactin suture at the bowel extraction site No antibiotics No sponge was placed at the surgical site.	Superficial SSI Deep SSI Length of hospital stay
Rickett (1969)	Topical ampicillin in the appendectomy wound: report of double-blind trial	Study location UK Study setting Not specified. Study dates May and September 1968. Duration of follow-up 3 weeks after surgery. Sources of funding Beecham Research Laboratories supplied specially packaged phials of ampicillin and placebo.	Vancomycin powder	Placebo A phial (500mg) of placebo (lactose powder) was emptied into the muscle layers after closing peritoneum.	SSI
Rutkowski (2014)	Surgical site infections following short-term radiotherapy and total mesorectal excision: results of a randomized study examining the role of gentamicin collagen implant in rectal cancer surgery	Study location Poland Study setting Department of Oncological gastroenterology Study dates January 2008 to September 2011. Duration of follow-up 90 days after operation. Sources of funding Grant from the Ministry of Science and Higher Education Republic of Poland.	Gentamicin collagen sponge	No antibiotics In comparator group, no gentamicin collagen sponge was placed.	SSI Superficial and/or deep incisional SSI. Organ/space SSI
Rutten (1997)	Prevention of wound infection in elective colorectal surgery by local application of a gentamicin-containing collagen sponge	Study location The Netherlands Study setting Department of Gastrointestinal surgery Study dates May 1992 and May 1994 Duration of follow-up Not specified. Sources of funding Not specified.	Gentamicin collagen sponge	No antibiotics No gentamicin sponge	SSI
Schimmer (2012)	Gentamicin-collagen sponge reduces sternal wound complications after heart surgery: a controlled, prospectively randomized, double-blind study	Study location Germany Study setting Single centre Study dates June 2009 to June 2010 Duration of follow-up 1 month (30 days) Sources of funding Authors stated that the study was supported by medical device manufacturers: RESORBAW Wundversorgung GmbH & Co KG	Gentamicin collagen sponge	Placebo After complete adaption of the pericardium and preliminary placement of the sternal wiring, a placebo sponge, identical to the intervention sponge, was implanted retrosternally, without premoistening	SSI Superficial SSI Deep SSI
Sherlock (1984)	Combined preoperative antibiotic therapy and intraoperative topical povidone-iodine. Reduction of wound sepsis following emergency appendectomy	Study location UK Study setting Department of surgery. Study dates Not reported Duration of follow-up 4 weeks Sources of funding Not specified.	Povidone Iodine	No antiseptics No antiseptic was added before skin closure.	SSI
Tubaki (2013)	Effects of using intravenous antibiotic only versus local intrawound vancomycin antibiotic powder application in addition to intravenous antibiotics on postoperative infection in spine surgery in 907 patients	Study location India. Study setting Department of Orthopaedics and Spine Surgery. Study dates June 2011 to December 2012. Duration of follow-up 12 weeks. Sources of funding Ganga Orthopaedic Research and Education Foundation.	Vancomycin powder	No antibiotics	SSI Superficial SSI Deep SSI
Walsh (1981)	The effect of topical povidone-iodine on the incidence of infection in surgical wounds.	Study location Australia Study setting Department of surgery and clinical microbiology. Study dates Not specified. Duration of follow-up 1 month. Sources of funding F.H Faulding and Company for financial support and supplies of povidone iodine (Betadine).	Povidone Iodine	No antiseptics	SSI
Westberg (2015)	Effectiveness of gentamicin-containing collagen sponges for prevention of surgical site infection after hip arthroplasty: a multicenter randomized trial	Study location Norway Study setting Multicentre (performed across 4 district general hospitals and 1 university hospital) Study dates February 2011 to July 2013 Duration of follow-up 1 month (4 weeks) Sources of funding not reported	Gentamicin collagen sponge.	No antibiotics Following hemiarthroplasty, no collagen sponges were placed as investigators believed that they could theoretically act as a medium for bacterial growth.	Superficial SSI Deep SSI Mortality post-surgery Length of hospital stay
Yetim (2010)	Effect of local gentamicin application on healing and wound infection in patients with modified radical mastectomy: a prospective randomized study	Study location Turkey Study setting Department of General Surgery. Study dates June 2006 and June 2009. Duration of follow-up 6 months after surgery Sources of funding Not specified.	Gentamicin collagen sponge	No antibiotics Group 2 underwent modified radical mastectomy without the application of the Gentacoll.	SSI Length of hospital stay

: See appendix D for full evidence tables.

Table 3Criteria for using systematic reviews as a source of data

Quality	Applicability	Use of systematic review
High	Fully applicable	Data from the published systematic review were used instead of undertaking a new literature search or data analysis. Searches were only done to cover the period of time since the search date of the review.
High	Partially applicable	Data from the published systematic review were used instead of undertaking a new literature search and data analysis for the relevant subsection of the protocol. For this section, searches were only done to cover the period of time since the search date of the review. For other sections not covered by the systematic review, searches were undertaken as normal.
Moderate	Fully applicable	Details of included studies were used instead of undertaking a new literature search. Full-text papers of included studies were still retrieved for the purposes of data analysis. Searches were only done to cover the period of time since the search date of the review.
Moderate	Partially applicable	Details of included studies were used instead of undertaking a new literature search for the relevant subsection of the protocol. For this section, searches were only done to cover the period of time since the search date of the review. For other sections not covered by the systematic review, searches were undertaken as normal.

Table 4Rationale for downgrading quality of evidence for intervention studies

GRADE criteria	Reasons for downgrading quality
Risk of bias	Not serious: If less than 33.3% of the weight in a meta-analysis came from studies at moderate or high risk of bias, the overall outcome was not downgraded. Serious: If greater than 33.3% of the weight in a meta-analysis came from studies at moderate or high risk of bias, the outcome was downgraded one level. Very serious: If greater than 33.3% of the weight in a meta-analysis came from studies at high risk of bias, the outcome was downgraded two levels. Outcomes meeting the criteria for downgrading above were not downgraded if there was evidence the effect size was not meaningfully different between studies at high and low risk of bias.
Indirectness	Not serious: If less than 33.3% of the weight in a meta-analysis came from partially indirect or indirect studies, the overall outcome was not downgraded. Serious: If greater than 33.3% of the weight in a meta-analysis came from partially indirect or indirect studies, the outcome was downgraded one level. Very serious: If greater than 33.3% of the weight in a meta-analysis came from indirect studies, the outcome was downgraded two levels. Outcomes meeting the criteria for downgrading above were not downgraded if there was evidence the effect size was not meaningfully different between direct and indirect studies.
Inconsistency	Concerns about inconsistency of effects across studies, occurring when there is unexplained variability in the treatment effect demonstrated across studies (heterogeneity), after appropriate pre-specified subgroup analyses have been conducted. This was assessed using the I² statistic. N/A: Inconsistency was marked as not applicable if data on the outcome was only available from one study. Not serious: If the I² was less than 33.3%, the outcome was not downgraded. Serious: If the I² was between 33.3% and 66.7%, the outcome was downgraded one level. Very serious: If the I² was greater than 66.7%, the outcome was downgraded two levels. Outcomes meeting the criteria for downgrading above were not downgraded if there was evidence the effect size was not meaningfully different between studies with the smallest and largest effect sizes.
Imprecision	If an MID other than the line of no effect was defined for the outcome, the outcome was downgraded once if the 95% confidence interval for the effect size crossed one line of the MID, and twice if it crosses both lines of the MID. If the line of no effect was defined as an MID for the outcome, it was downgraded once if the 95% confidence interval for the effect size crossed the line of no effect (i.e. the outcome was not statistically significant), and twice if the sample size of the study was sufficiently small that it is not plausible any realistic effect size could have been detected. Outcomes were downgraded 1 level if presented as difference in medians without measure of spread. Evidence was further downgraded 1 level if the outcome was not statistically significant. Outcomes were downgraded 2 levels if effect size could not be calculated. Outcomes meeting the criteria for downgrading above were not downgraded if the confidence interval was sufficiently narrow that the upper and lower bounds would correspond to clinically equivalent scenarios.

Table 1Applicability criteria

Level	Explanation
Directly applicable	The study meets all applicability criteria, or fails to meet one or more applicability criteria but this is unlikely to change the conclusions about cost effectiveness
Partially applicable	The study fails to meet one or more applicability criteria, and this could change the conclusions about cost effectiveness
Not applicable	The study fails to meet one or more applicability criteria, and this is likely to change the conclusions about cost effectiveness. These studies are excluded from further consideration

Table 2Methodological criteria

Level	Explanation
Minor limitations	Meets all quality criteria, or fails to meet one or more quality criteria but this is unlikely to change the conclusions about cost effectiveness
Potentially serious limitations	Fails to meet one or more quality criteria and this could change the conclusions about cost effectiveness
Very serious limitations	Fails to meet one or more quality criteria and this is highly likely to change the conclusions about cost effectiveness. Such studies should usually be excluded from further consideration

Databases	Date searched	Version/files
Cochrane Central Register of Controlled Trials (CENTRAL)	03/05/2018	Issue 3 of 12, March 2018
Cochrane Database of Systematic Reviews (CDSR)	03/05/2018	Issue 5 of 12, May 2018
Database of Abstracts of Reviews of Effect (DARE)	03/05/2018	Issue 2 of 4, April 2015
HTA	03/05/2018	Issue 4 of 4, October 2016
Embase (Ovid)	03/05/2018	1974 to 2018 May 02
MEDLINE (Ovid)	03/05/2018	1946 to Present with Daily Update
MEDLINE In-Process (Ovid)	03/05/2018	May 02, 2018
MEDLINE Epub Ahead of Print ^a	03/05/2018	May 02, 2018
CINAHL Plus with full text (EBSCO)	03/05/2018	-
MHRA – Drug Safety Alerts	03/05/2018	-

Databases	Date searched
Embase (Ovid)	04/05/2018
MEDLINE (Ovid)	04/05/2018
MEDLINE In-Process (Ovid)	04/05/2018
EconLit (Ovid)	04/05/2018
NHS Economic Evaluation Database (NHS EED) (legacy database)	04/05/2018
Health Technology Assessment (HTA Database)	04/05/2018
CINAHL Plus with Fulltext (EBSCO)	04/05/2018

No. of studies	Study design	Sample size	Effect size (95% CI)	Absolute risk: control ^*	Absolute risk: intervention (95% CI)	Risk of bias	Indirectness	Inconsistency	Imprecision	Quality
SSI - RR <1 favours erythromycin and colistin loaded bone cement
1 Hinarejos 2013	RCT	2948 knees;	RR 1.22 (95% CI: 0.80, 1.86)	3 per 100 knees	3 per 100 knees (2,5)	Serious¹	Not serious	NA²	Very serious³	Very low
Superficial SSI - RR <1 favours erythromycin and colistin loaded bone cement
1 Hinarejos 2013	RCT	2948 knees	RR: 1.48 (95% CI: 0.82, 2.68)	1 per 100 knees	2 per 100 knees (1,3)	Serious¹	Not serious	NA²	Serious⁴	Low
Deep SSI - RR <1 favours erythromycin and colistin loaded bone cement
1 Hinarejos 2013	RCT	2948 knees	RR: 0.99 (95% CI: 0.53, 1.83)	1 per 100 knees	1 per 100 knees (1,2)	Serious¹	Not serious	NA²	Very serious³	Very low

1: Downgrade 1 level for serious risk of bias. Study demonstrated unclear allocation concealment and blinding of outcome assessment.

2: Inconsistency not applicable

3: 95% confidence interval crosses both ends of a defined MID interval (0.8, 1.25). Downgrade 2 levels.

4: 95% confidence interval crosses one end of a defined MID interval (0.8, 1.25). Downgrade 1 level.

*: Derived by taking the overall number of event/ total number of participants and multiplying by 100

No. of studies	Study design	Sample size	Effect size (95% CI)	Absolute risk: control ^*	Absolute risk: intervention (95% CI)	Risk of bias	Indirectness	Inconsistency	Imprecision	Quality
SSI (all surgeries) - RR <1 favours vancomycin powder
1 Tubaki 2013	RCT	907	RR 0.96 (95% CI: 0.35, 2.62)	2 per 100 people	2 per 100 people (1,4)	Serious¹	Serious²	NA³	Very serious⁴	Very low
SSI (instrumented surgery) - RR <1 favours vancomycin powder
Tubaki 2013	RCT	606	RR 1.01 (95% CI: 0.33, 3.09)	2 per 100 people	2 per 100 people (1,6)	Serious¹	Serious²	NA³	Very serious⁴	Very low
SSI (non-instrumented surgery) - RR <1 favours vancomycin powder
Tubaki 2013	RCT	301	RR 0.65 (95% CI: 0.06, 7.08)	1 per 100 people	1 per 100 people (1,8)	Serious¹	Serious²	NA³	Very serious⁴	Very low
Superficial SSI (all surgeries) - RR <1 favours vancomycin powder
Tubaki 2013	RCT	907	RR 0.55 (95% CI: 0.05, 6.01)	4 per 1000 people^**	2 per 1000 people (0, 25)^**	Serious¹	Serious²	NA³	Very serious⁴	Very low
Deep SSI (all surgeries) - RR <1 favours vancomycin powder
Tubaki 2013	RCT	907	RR 1.09 (95% CI: 0.36, 3.37)	1 per 100 people	1 per 100 people (1, 4)	Serious¹	Serious²	NA³	Very serious⁴	Very low

1: Downgrade 1 level for serious risk of bias. Study demonstrated unclear allocation concealment and blinding of outcome assessment.

2: Study did not specify criteria used for classification of surgical site infections. Downgrade 1 level for serious indirectness.

3: Inconsistency not applicable

4: 95% confidence interval crosses both ends of a defined MID interval (0.8, 1.25). Downgrade 2 levels.

*: Derived by taking the overall number of event/ total number of participants and multiplying by 100

**: Derived by taking the overall number of event/ total number of participants and multiplying by 1000

No. of studies

Study design

Sample size

Effect size (95% CI)

Absolute risk: control ^*

Absolute risk: intervention (95% CI)

Risk of bias

Indirectness

Inconsistency

Imprecision

Quality

SSI - RR <1 favours ampicillin powder

Rickett 1969

RCT

130

RR 0.13 (95% CI: 0.03, 0.54)

24 per 100 people

3 per 100 people (1, 13)

Serious¹

Not serious

NA²

Not serious

Moderate

1: Downgrade 1 level for serious risk of bias. Study demonstrated unclear random sequence generation and blinding of outcome assessment.

2: Inconsistency not applicable

*: Derived by taking the overall number of event/ total number of participants and multiplying by 100

No. of studies	Study design	Sample size	Effect size (95% CI)	Absolute risk: control ^*	Absolute risk: intervention (95% CI)	Risk of bias	Indirectness	Inconsistency	Imprecision	Quality
SSI (all abdominal surgeries) - RR <1 favours topical cefotaxime
1 Moesgaard 1989	RCT	177	RR 1.11 (95% CI: 0.57, 2.16)	16 per 100 people	17 per 100 people (9, 34)	Serious¹	Not serious	NA²	Very Serious³	Very low
SSI (appendectomy) - RR <1 favours topical cefotaxime
1 Moesgaard 1989	RCT	91	RR 1.34 (95% CI: 0.44, 4.08)	10 per 100 people	14 per 100 people (5, 43)	Serious¹	Not serious	NA²	Very Serious³	Very low
SSI (biliary surgery) - RR <1 favours topical cefotaxime
1 Moesgaard 1989	RCT	20	RR 1.23 (95% CI: 0.26, 5.82)	22 per 100 people	27 per 100 people (6, 129)	Serious¹	Not serious	NA²	Very Serious³	Very low
SSI (colonic surgery) - RR <1 favours topical cefotaxime
1 Moesgaard 1989	RCT	40	RR 0.45 (95% CI: 0.09, 2.20)	21 per 100 people	9 per 100 people (2, 46)	Serious¹	Not serious	NA²	Very Serious³	Very low
SSI (drainage of intra-abdominal abscess through an abdominal incision) - RR <1 favours topical cefotaxime
1 Moesgaard 1989	RCT	26	RR 1.56 (95% CI: 0.43, 5.61)	21 per 100 people	33 per 100 people (9, 120)	Serious¹	Not serious	NA²	Very Serious³	Very low
Septicaemia (all abdominal surgeries) - RR <1 favours topical cefotaxime
1 Moesgaard 1989	RCT	177	RR 0.78 (95% CI: 0.18, 3.37)	4 per 100 people	3 per 100 people (1, 15)	Serious¹	Not serious	NA²	Very Serious³	Very low
Mortality post-surgery (all abdominal surgeries) - RR <1 favours topical cefotaxime
1 Moesgaard 1989	RCT	177	RR: 1.45 (95% CI: 0.48, 4.39)	6 per 100 people	8 per 100 people (3, 24)	Serious¹	Not serious	NA²	Very Serious³	Very low

1: Downgrade1 level for serious risk of bias. Study demonstrated unclear random sequence generation and allocation concealment.

2: Inconsistency not applicable

3: 95% confidence interval crosses both ends of a defined MID interval (0.8, 1.25). Downgrade 2 levels.

*: Derived by taking the overall number of event/ total number of participants and multiplying by 100

No. of studies	Study design	Sample size	Effect size (95% CI)	Absolute risk: control ^*	Absolute risk: intervention (95% CI)	Risk of bias	Indirectness	Inconsistency	Imprecision	Quality
SSI - RR <1 favours Topical cephaloridine
1 Evans 1974	RCT	401	RR 0.41 (95% CI: 0.24, 0.69)	22 per 100 people	9 per 100 people (5, 15)	Serious¹	Not serious	NA²	Not serious	Moderate
SSI (clean) - RR <1 favours Topical cephaloridine
1 Evans 1974	RCT	186	RR 0.68 (95% CI: 0.17, 2.63)	6 per 100 people	4 per 100 people (1,15)	Serious¹	Not serious	NA²	Very serious³	Very low
SSI (contaminated) - RR <1 favours Topical cephaloridine
1 Evans 1974	RCT	215	RR: 0.33 (95% CI: 0.19, 0.57)	39 per 100 people	13 per 100 people (7, 22)	Serious¹	Not serious	NA²	Not serious	Moderate

1: Downgrade 1 level for serious risk of bias. Study demonstrated unclear allocation concealment and other sources of bias.

2: Inconsistency not applicable

3: 95% confidence interval crosses both ends of a defined MID interval (0.8, 1.25). Downgrade 2 levels.

*: Derived by taking the overall number of event/ total number of participants and multiplying by 100

No. of studies	Study design	Sample size	Effect size (95% CI)	Absolute risk: control ^*	Absolute risk: intervention (95% CI)	Risk of bias	Indirectness	Inconsistency	Imprecision	Quality
SSI-RR <1 favours topical povidone iodine spray
1 Gray 1981	RCT	153	RR 0.40 (95% CI: 0.18, 0.90)	24 per 100 people	10 per 100 people (4, 22)	Not serious	Not serious	NA¹	Serious²	Moderate
Postoperative antibiotic use - RR <1 favours topical povidone iodine spray
1 Gray 1981	RCT	153	RR 1.62 (95% CI: 0.90, 2.89)	18 per 100 people	30 per 100 people (16, 53)	Not serious	Not serious	NA¹	Serious²	Moderate

1: Inconsistency not applicable

2: 95% confidence interval crosses one end of a defined MID interval (0.8, 1.25). Downgrade 1 level.

*: Derived by taking the overall number of event/ total number of participants and multiplying by 100

No. of studies	Study design	Sample size	Effect size (95% CI)	Absolute risk: control ^*	Absolute risk: intervention (95% CI)	Risk of bias	Indirectness	Inconsistency	Imprecision	Quality
SSI - RR <1 favours topical povidone iodine spray
2 Sherlock 1984 Walsh 1981	RCT	702	RR 0.65 (95% CI: 0.43, 0.97)	15 per 100 people	10 per 100 people (6, 14)	Not serious	Not serious	Not serious	Serious²	Moderate
SSI (clean) - RR <1 favours topical povidone iodine spray
1 Walsh 1981	RCT	122	RR 0.36 (95% CI: 0.07, 1.69)	10 per 100 people	3 per 100 people (1, 16)	Not serious	Not serious	NA¹	Very serious³	Low
SSI (clean/contaminated) - RR <1 favours topical povidone iodine spray
1 Walsh 1981	RCT	464	RR 0.84 (95% CI: 0.48, 1.46)	11 per 100 people	9 per 100 people (5, 16)	Not serious	Not serious	NA¹	Very serious³	Low
SSI (contaminated) - RR <1 favours topical povidone iodine spray
1 Sherlock 1984	RCT	75	RR 0.43 (95% CI: 0.18,1.00)	36 per 100 people	16 per 100 people (7, 36)	Not serious	Not serious	NA¹	Serious²	Moderate
SSI (dirty wounds) - RR <1 favours topical povidone iodine spray
1 Walsh 1981	RCT	41	RR 0.78 (95% CI: 0.32, 1.93)	38 per 100 people	29 per 100 people (12, 72)	Not serious	Not serious	NA¹	Very serious³	Low

1: Inconsistency not applicable

2: 95% confidence interval crosses one end of a defined MID interval (0.8, 1.25). Downgrade 1 level.

3: 95% confidence interval crosses both ends of a defined MID interval (0.8, 1.25). Downgrade 2 levels.

*: Derived by taking the overall number of event/ total number of participants and multiplying by 100

No. of studies	Study design	Sample size	Effect size (95% CI)	Absolute risk: control ^*	Absolute risk: intervention (95% CI)	Risk of bias	Indirectness	Inconsistency	Imprecision	Quality
SSI (appendectomy) - RR <1 favours povidone iodine spray
Parker 1985	RCT	100	RR 0.75 (95% CI: 0.28, 2.00)	16 per 100 people	12 per 100 people (4, 32)	Very Serious¹	Not serious	NA²	Very serious³	Very low

1: Downgrade 2 levels for very serious risk of bias. Study demonstrates unclear random sequence generation and allocation concealment. Furthermore, interim outcomes were reported were reported by patients, unclear if patients were blinded.

2: Inconsistency not applicable

3: 95% confidence interval crosses both ends of a defined MID interval (0.8, 1.25). Downgrade 2 levels.

*: Derived by taking the overall number of event/ total number of participants and multiplying by 100

No. of studies	Study design	Sample size	Effect size (95% CI)	Absolute risk: control ^*	Absolute risk: intervention (95% CI)	Risk of bias	Indirectness	Inconsistency	Imprecision	Quality
SSI - RR <1 favours povidone iodine solution
Harihara 2006	RCT	107	RR 0.98 (95% CI: 0.40, 2.42)	15 per 100 people	15 per 100 people (6, 37)	Serious¹	Serious²	NA³	Very serious⁴	Very low

1: Downgrade 1 levels for serious risk of bias. Study demonstrates unclear random sequence generation, allocation concealment and blinding outcome assessment.

2: Downgrade 1 level for serious indirectness. Study did not specify length of follow up.

3: Inconsistency not applicable

4: 95% confidence interval crosses both ends of a defined MID interval (0.8, 1.25). Downgrade 2 levels.

*: Derived by taking the overall number of event/ total number of participants and multiplying by 100

No. of studies	Study design	Sample size	Effect size (95% CI)	Absolute risk: control^*	Absolute risk: intervention (95% CI)	Risk of bias	Indirectness	Inconsistency	Imprecision	Quality
SSI (drapes) - RR <1 favours topical 2.5% iodine in 70% ethanol
Cordtz 1989	RCT	662	RR 0.73 (95% CI: 0.51, 1.06)	17 per 100 people	13 per 100 people (9, 18)	Serious¹	Not serious	NA²	Serious³	Low
SSI (no drapes) - RR <1 favours topical 2.5% iodine in 70% ethanol
Cordtz 1989	RCT	678	RR 0.79 (95% CI: 0.51, 1.22)	12 per 100 people	10 per 100 people (6, 15)	Serious¹	Not serious	NA²	Serious³	Low

1: Downgrade 1 levels for serious risk of bias. Study demonstrates unclear random sequence generation, allocation concealment and blinding of outcome assessment.

2: Inconsistency not applicable

3: 95% confidence interval crosses one end of a defined MID interval (0.8, 1.25). Downgrade 1 level.

*: Derived by taking the overall number of event/ total number of participants and multiplying by 100

No. of studies	Study design	Sample size	Effect size (95% CI)	Absolute risk: control ^*	Absolute risk: intervention (95% CI)	Risk of bias	Indirectness	Inconsistency	Imprecision	Quality
SSI - RR <1 favours gentamicin collagen sponge
2 Collin 2013 Buimer 2008	RCT	301	RR 0.60 (95% CI: 0.35, 1.04)	18 per 100 people	11 per 100 people (6, 19)	Serious¹	Serious²	Not serious	Serious³	Very low
SSI (Abdominoperineal resection) - RR <1 favours gentamicin collagen sponge
1 Collin 2013	RCT	101	RR 0.94 (95% CI 0.33, 2.73)	12 per 100 people	12 per 100 people (4, 33)	Serious⁵	Not serious	NA4	Very serious⁶	Very low
SSI (Hidradenitis suppurativa surgery) - RR <1 favours gentamicin collagen sponge
1 Buimer 2008	RCT	200	RR 0.50 (95% CI 0.26, 0.96)	22 per 100 people	11 per 100 people (6, 21)	Serious⁷	Serious⁸	NA4	Serious³	Very low

1: Downgrade 1 level for serious risk of bias. Greater than 33.3% of the weight in meta-analysis came from with studies of moderate risk of bias due to unclear random sequence generation, allocation concealment as well as unclear or no blinding of outcome assessment.

2: Downgrade 1 level for serious indirectness. Greater than 33.3% of the weight in meta-analysis came from a partially direct study. Buimer (2008) did not specify criteria used to classify surgical site infection.

3: 95% confidence interval crosses one end of a defined MID interval (0.8, 1.25). Downgrade 1 level.

4: Inconsistency not applicable

5: Downgrade 1 level for serious risk of bias. Study demonstrates no blinding of outcome assessment.

6: 95% confidence interval crosses both ends of a defined MID interval (0.8, 1.25). Downgrade 2 levels.

7: Downgrade 1 level for serious risk of bias. Study demonstrates unclear random sequence generation, allocation concealment and blinding of outcome assessment.

8: Buimer (2008) did not specify criteria used to classify surgical site infections. Downgrade 1 level for serious indirectness.

*: Derived by taking the overall number of event/ total number of participants and multiplying by 100

No. of studies

Study design

Sample size

Effect size (95% CI)

Absolute risk: control ^*

Absolute risk: intervention (95% CI)

Risk of bias

Indirectness

Inconsistency

Imprecision

Quality

SSI - RR <1 favours gentamicin collagen sponge

Andersson 2010

RCT

159

RR 0.85 (95% CI: 0.48, 1.47)

26 per 100 people

22 per 100 people (12, 38)

Not serious

Serious¹

NA²

Very serious³

Very low

1: Andersson (2010) did not explicitly specify criteria used for the classification of surgical site infections. Downgrade 1 level for serious indirectness.

2: Inconsistency not applicable

3: 95% confidence interval crosses both ends of a defined MID interval (0.8, 1.25). Downgrade 2 levels.

*: Derived by taking the overall number of event/ total number of participants and multiplying by 100

No. of studies	Study design	Sample size	Effect size (95% CI)	Absolute risk: control ^*	Absolute risk: intervention (95% CI)	Risk of bias	Indirectness	Inconsistency	Imprecision	Quality
SSI - RR <1 favours gentamicin collagen sponge
4 Collin 2013 Migaczewski 2010 Nowacki 2006 Westberg 2015	RCT	1,063	RR 0.81 (95% CI: 0.53, 1.24)	8 per 100 people	6 per 100 people (4, 10)	Serious¹	Not serious	Not serious	Serious²	Low
SSI (abdominoperineal resection) - RR <1 favours gentamicin collagen sponge
1 Collin 2013	RCT	101	RR 0.67 (95% CI 0.33, 1.37)	29 per 100 people	19 per 100 people (9, 39)	Serious³	Not serious	NA⁴	Very serious⁵	Very low
SSI (splenectomy) - RR <1 favours gentamicin collagen sponge
1 Migaczewski 2012	RCT	60	RR 5.00 (95% CI: 0.25, 99.95)	Not calculable¹¹	Not calculable¹¹	Serious⁶	Serious⁷	NA⁴	Very serious⁵	Very low
SSI (colorectal surgery) - RR <1 favours gentamicin collagen sponge
1 Nowacki 2006	RCT	218	RR 0.63 (95% CI: 0.24, 1.68)	9 per 100 people	6 per 100 people (2, 15)	Serious⁶	Serious⁷	NA4	Very serious⁵	Very low
SSI (hip arthroplasty) - RR <1 favours gentamicin collagen sponge
1 Westberg 2015	RCT	684	RR 0.91 (95% CI: 0.48, 1.74)	5 per 100 people	5 per 100 people (3, 9)	Not serious	Not serious	NA⁴	Very Serious⁵	Low
Superficial SSI - RR <1 favours gentamicin collagen sponge
2 Westberg 2015 Pochammer 2015	RCT	878	RR 0.85 (95% CI: 0.50, 1.47)	6 per 100 people	5 per 100 people (3, 9)	Not serious	Not serious	Not serious	Very serious⁵	Low
Superficial SSI (Hip arthroplasty) - RR <1 favours gentamicin collagen sponge
1 Westberg 2015	RCT	684	RR 0.94 (95% CI: 0.47, 1.90)	5 per 100 people	4 per 100 people (2, 9)	Not serious	Not serious	NA⁴	Very serious⁵	Low
Superficial SSI (colorectal surgery) - RR <1 favours gentamicin collagen sponge
1 Pochammer 2015	RCT	194	RR 0.73 (95% CI: 0.31, 1.73)	11 per 100 people	8 per 100 people (4, 20)	Not serious	Not serious	NA⁴	Very serious⁵	Low
Deep SSI - RR <1 favours gentamicin collagen sponge
2 Westberg 2015 Pochammer 2015	RCT	878	RR 0.72 (95% CI: 0.12, 4.28)	1 per 100 people	1 per 100 people (0, 2)	Not serious	Not serious	Not serious	Very serious⁵	low
Deep SSI (hip arthroplasty) - RR <1 favours gentamicin collagen sponge
1 Westberg 2015	RCT	684	RR 0.72 (95% CI: 0.12, 4.28)	1 per 100 people	1 per 100 people (0, 2)	Not serious	Not serious	NA⁴	Very serious⁵	low
Deep SSI (colorectal surgery) - RR <1 favours gentamicin collagen sponge
1 Pochammer 2015	RCT	194	RR not estimable due to no occurrence of event in either study arm.			Not serious	Not serious	NAM⁴	Very Serious⁸	Low
Mortality post-surgery - RR <1 favours gentamicin collagen sponge
2 Westberg 2015 Nowacki 2006	RCT	902	RR 0.70 (95% CI: 0.42, 1.17)	7 per 100 people	5 per 100 people (3, 9)	Not serious	Not serious	Not serious	Serious²	Moderate
Mortality post-surgery (Hip arthroplasty) - RR <1 favours gentamicin collagen sponge
1 Westberg 2015	RCT	684	RR 0.71 (95% CI: 0.42, 1.20)	9 per 100 people	6 per 100 people (4, 11)	Not serious	Not serious	NA⁴	Serious²	Moderate
Mortality post-surgery (colorectal surgery) - RR <1 favours gentamicin collagen sponge
1 Nowacki 2006	RCT	218	RR 0.53 (95% CI: 0.05, 5.74)	2 per 100 people	1 per 100 people (0, 10)	Serious⁶	Serious⁷	NA⁴	Very serious⁵	Very low
Mean length of stay – effect size below zero favours gentamicin collagen sponge
1 Westberg 2015	RCT	684	MD: 0.40 (95% CI: −0.37, 1.17)	-	-	Not serious	Not serious	NA⁴	Serious⁹	Moderate
Length of stay – effect size below zero favours gentamicin collagen sponge
1 Pochammer 2015	RCT	194	Difference in medians: 0 days (non-significant according to Kurskal-Wallis test)			Not serious	Not serious	NA⁴	Very serious¹⁰	Low

1: Downgrade 1 level for serious risk of bias. Greater than 33.3% of the weight in meta-analysis came from with studies of moderate risk of bias due to unclear random sequence generation, allocation concealment as well as unclear or no blinding of outcome assessment.

2: 95% confidence interval crosses one end of a defined MID interval (0.8, 1.25). Downgrade 1 level.

3: Downgrade 1 level for serious risk of bias. Study demonstrates no blinding of outcome assessment.

4: Inconsistency not applicable

5: 95% confidence interval crosses both ends of a defined MID interval (0.8, 1.25). Downgrade 2 levels.

6: Downgrade 1 level for serious risk of bias. Study demonstrates unclear random sequence generation, allocation concealment and blinding of outcome assessment.

7: Study did not specify criteria used to classify surgical site infections. Downgrade 1 level for serious indirectness.

8: Unable to calculate effect size. Downgrade 2 levels

9: Non-significant result. Downgrade 1 level.

10: Downgrade 2 levels for no measure of spread and non-significant results.

11: The absolute risk was not calculable as there were no events in the control arm.

*: Derived by taking the overall number of event/ total number of participants and multiplying by 100

No. of studies	Study design	Sample size	Effect size (95% CI)	Absolute risk: control ^*	Absolute risk: intervention (95% CI)	Risk of bias	Indirectness	Inconsistency	Imprecision	Quality
SSI - RR <1 favours gentamicin collagen sponge
3 Gruessner 2001 Frigberg 2005 Bennett-Guerrero 2010	RCT	2,649	RR 0.65 (95% CI: 0.25, 1.69)	12 per 100 people	8 per 100 people (3, 21)	Not serious	Not serious	Very serious¹	Very serious²	Very Low
SSI (abdominoperineal resection) - RR <1 favours gentamicin collagen sponge
1 Gruessner 2001	RCT	97	RR 0.29 (95% CI: 0.09, 1.00)	21 per 100 people	6 per 100 people (2, 21)	Serious³	Serious⁴	NA⁵	Serious⁶	Very low
SSI (cardiac surgery) - RR <1 favours gentamicin collagen sponge
1 Frigberg 2005	RCT	1950	RR 0.47 (95% CI: 0.33, 0.68)	9 per 100 people	4 per 100 people (3, 6)	Not serious	Not serious	NA⁵	Not serious	High
SSI (colorectal surgery) - RR <1 favours gentamicin collagen sponge
1 Bennett-Guerrero 2010	RCT	602	RR 1.44 (95% CI: 1.09, 1.90)	21 per 100 people	30 per 100 people (23, 40)	Not serious	Not serious	NA⁵	Serious⁶	Moderate
Superficial SSI - RR <1 favours gentamicin collagen sponge
3 Gruessner 2001 Frigberg 2005 Bennett-Guerrero 2010	RCT	2,649	RR 0.56 (95% CI: 0.15, 2.05)	8 per 100 people	4 per 100 people (1, 16)	Not serious	Not serious	Very serious¹	Very serious²	Very Low
Superficial SSI (abdominoperineal resection) - RR <1 favours gentamicin collagen sponge
1 Gruessner 2001	RCT	97	RR 0.20 (95% CI: 0.02, 1.62)	10 per 100 people	2 per 100 people (0, 17)	Serious³	Serious⁴	NA⁵	Very serious²	Very low
Superficial SSI (cardiac surgery) - RR <1 favours gentamicin collagen sponge
1 Frigberg 2005	RCT	1950	RR 0.34 (95% CI: 0.20, 0.57)	6 per 100 people	2 per 100 people (1, 3)	Not serious	Not serious	NA⁵	Not serious	High
Superficial SSI (colorectal surgery) - RR <1 favours gentamicin collagen sponge
1 Bennett-Guerrero 2010	RCT	602	RR 1.50 (95% CI: 1.04, 2.15)	14 per 100 people	20 per 100 people (14, 29)	Not serious	Not serious	NA⁵	Serious⁶	Moderate
Deep SSI - RR <1 favours gentamicin collagen sponge
3 Gruessner 2001 Frigberg 2005 Bennett-Guerrero 2010	RCT	2,649	RR 0.88 (95% CI: 0.48, 1.62)	4 per 100 people	4 per 100 people (2, 7)	Not serious	Not serious	Serious⁷	Very serious²	Very low
Deep SSI (abdominoperineal resection) - RR <1 favours gentamicin collagen sponge
1 Gruessner 2001	RCT	97	RR 0.39 (95% CI: 0.08, 1.92)	10 per 100 people	4 per 100 people (1, 20)	Serious³	Serious⁴	NA⁵	Very serious²	Very low
Deep SSI (cardiac surgery) - RR <1 favours gentamicin collagen sponge
1 Frigberg 2005	RCT	1950	RR 0.71 (95% CI: 0.42, 1.20)	3 per 100 people	2 per 100 people (1, 4)	Not serious	Not serious	NA⁵	Serious⁶	Moderate
Deep SSI (colorectal surgery) - RR <1 favours gentamicin collagen sponge
1 Bennett-Guerrero 2010	RCT	602	RR 1.40 (95% CI: 0.78, 2.51)	6 per 100 people	8 per 100 people (5, 7)	Not serious	Not serious	NA⁵	Very serious²	Low
Organ space SSI - RR <1 favours gentamicin collagen sponge
1 Bennett-Guerrero 2010	RCT	602	RR 1.01 (95% CI: 0.25, 3.99)	1 per 100 people	1 per 100 people (0, 5)	Not serious	Not serious	NA⁵	Very serious²	Low
Hospital mortality - RR <1 favours gentamicin collagen sponge
1 Frigberg 2005	RCT	1950	RR 1.08 (95% CI: 0.46, 2.54)	1 per 100 people	1 per 100 people (0, 3)	Not serious	Not serious	NA⁵	Very serious²	Low
Mortality post-surgery - RR <1 favours gentamicin collagen sponge
1 Frigberg 2005	RCT	1950	RR 1.10 (95% CI: 0.57, 2.10)	2 per 100 people	2 per 100 people (1, 4)	Not serious	Not serious	NA⁵	Very serious²	Low
Hospital readmission - RR <1 favours gentamicin collagen sponge
1 Bennett-Guerrero 2010	RCT	602	RR 1.63 (95% CI: 0.83, 3.19)	4 per 100 people	7 per 100 people (4, 14)	Not serious	Not serious	NA⁵	Serious⁶	Moderate
Length of stay – effective size below zero favours gentamicin collagen sponge
1 Bennett-Guerrero 2010	RCT	602	Difference in medians: 0 days (non-significant according to Chi-square test)			Not serious	Not serious	NA⁵	Very serious⁸	Low

1: Downgrade 2 levels for very serious inconsistency. I² was greater than 66.7%.

2: 95% confidence interval crosses both ends of a defined MID interval (0.8, 1.25). Downgrade 2 levels.

3: Downgrade 1 level for serious risk of bias. Study demonstrates unclear random sequence generation, allocation concealment and blinding of outcome assessment.

4: Study did not specify criteria used for the classification of surgical site infections. Downgrade 1 level for partial indirectness.

5: Inconsistency not applicable

6: 95% confidence interval crosses one end of a defined MID interval (0.8, 1.25). Downgrade 1 level.

7: Downgrade 1 level for serious inconsistency. I² was between 33.3% and 66.7%

8: Downgrade 2 levels for no measure of spread and non-significant results.

*: Derived by taking the overall number of event/ total number of participants and multiplying by 100

No. of studies	Study design	Sample size	Effect size (95% CI)	Absolute risk: control^*	Absolute risk: intervention (95% CI)	Risk of bias	Indirectness	Inconsistency	Imprecision	Quality
SSI - RR <1 favours gentamicin collagen sponge
5 Bennett-Guerrero 2010, Eklund 2005, Rutkowski 2014, Collin 2013, Andersson 2010	RCT	2473	RR 0.87 (95% CI: 0.67, 1.13)	9 per 100 people	8 per 100 people (6, 10)	Not serious	Not serious	Not serious	Serious¹	Moderate
SSI (cardiac surgery) - RR <1 favours gentamicin collagen sponge
2 Bennett-Guerrero 2010, Eklund 2005	RCT	2044	RR 0.91 (95% CI: 0.67, 1.23)	8 per 100 people	7 per 100 people (5, 10)	Not serious	Not serious	Not serious	Serious¹	Moderate
SSI (colorectal surgery) - RR <1 favours gentamicin collagen sponge
1 Rutkowski 2014	RCT	171	RR 0.72 (95% CI: 0.41, 1.27)	26 per 100 people	19 per 100 people 11, 33)	Serious³	Not serious	NA²	Very serious⁴	Very low
SSI (Abdominoperineal resection) - RR <1 favours gentamicin collagen sponge
1 Collin 2013	RCT	99	RR 2.28 (95% CI: 0.30, 26.22)	2 per 100 people	6 per 100 people (1, 55)	Serious⁵	Not serious	NA²	Very serious⁴	Very low
SSI (Pilonidal sinus surgery) - RR <1 favours gentamicin collagen sponge
1 Andersson 2010	RCT	159	RR 0.19 (95% CI: 0.01, 3.85)	3 per 100 people	0 per 100 people (0, 10)	Not serious	Serious⁶	NA²	Very serious⁴	Low
Superficial SSI - RR <1 favours gentamicin collagen sponge
2 Bennett-Guerrero 2010, Eklund 2005	RCT	2,044	RR 1.01 (95% CI: 0.70, 1.46)	5 per 100 people	5 per 100 people (4, 8)	Not serious	Not serious	Not serious	Very serious⁴	Low
Superficial/deep SSI - RR <1 favours gentamicin collagen sponge
1 Rutkowski 2014	RCT	171	RR 0.71 (95% CI: 0.23, 2.14)	8 per 100 people	6 per 100 people (2, 18)	Serious³	Not serious	NA²	Very serious⁴	Very low
Deep SSI - RR <1 favours gentamicin collagen sponge
2 Bennett-Guerrero 2010, Eklund 2005	RCT	2,044	RR 0.76 (95% CI: 0.40, 1.44)	2 per 100 people	2 per 100 people (1, 3)	Not serious	Not serious	Not serious	Very serious⁴	Low
Organ space SSI-RR <1 favours gentamicin collagen sponge
2 Bennett-Guerrero 2010, Eklund 2005	RCT	2,044	RR 0.63 (95% CI: 0.34, 1.18)	6 per 100 people	4 per 100 people (2, 7)	Not serious	Not serious	Not serious	Serious¹	Moderate
Mortality post-surgery - RR <1 favours gentamicin collagen sponge
1 Eklund 2005	RCT	542	RR 2.98 (95% CI: 0.31, 28.45)	0 per 100 people	1 per 100 people (0, 11)	Not serious	Not serious	NA²	Very serious⁴	Low
Hospital readmission - RR <1 favours gentamicin collagen sponge
1 Bennett-Guerrero 2010	RCT	1,502	RR 0.95 (95% CI: 0.54, 1.67)	3 per 100 people	3 per 100 people (3, 5)	Not serious	Not serious	NA²	Very serious³	Low
Length of stay
1 Bennett-Guerrero 2010	RCT	1,502	Difference in medians: 0 days (non-significant according to Chi-square test)			Not serious	Not serious	NA²	Very serious⁷	Low

1: 95% confidence interval crosses one end of a defined MID interval (0.8, 1.25). Downgrade 1 level.

2: Inconsistency not applicable

3: Downgrade 1 level for serious risk of bias. Study demonstrates unclear random sequence generation and blinding of outcome assessment.

4: 95% confidence interval crosses both ends of a defined MID interval (0.8, 1.25). Downgrade 2 levels.

5: Downgrade 1 level for serious risk of bias. Study demonstrates no blinding of outcome assessment.

6: Study did not explicitly specify criteria used for the classification of surgical site infections. Downgrade 1 level for serious indirectness.

7: Downgrade 2 levels for no measure of spread and non-significant results.

*: Derived by taking the overall number of event/ total number of participants and multiplying by 100

No. of studies	Study design	Sample size	Effect size (95% CI)	Absolute risk: control^*	Absolute risk: intervention (95% CI)	Risk of bias	Indirectness	Inconsistency	Imprecision	Quality
SSI (all surgeries) - RR <1 favours gentamicin collagen sponge
2 Musella 2001, Yetim 2010	RCT	621	RR 0.14 (95% CI: 0.03, 0.76)	3 per 100 people	0 per 100 people (0, 2)	Serious¹	Serious²	Not serious	Not serious	Low
SSI (Prosthetic repair of groin hernias) - RR <1 favours gentamicin collagen sponge
1 Musella 2001	RCT	577	RR 0.16 (95% CI: 0.22, 1.33)	2 per 100 people	0 per 100 people (0, 3)	Serious³	Serious⁴	NA5	Very serious⁶	Very low
SSI (abdominoperineal resection) - RR <1 favours gentamicin collagen sponge
1 Yetim 2010	RCT	44	RR 0.11 (95% CI: 0.01, 1.95)	18 per 100 people	2 per 100 people (0, 35)	Serious⁷	Serious⁴	NA⁵	Very serious⁶	Very low
Mean length of stay
1 Yetim 2010	RCT	44	MD: −4.68 (95% CI: −5.49, −3.87)	-	-	Serious⁷	Not serious	NA⁵	Not serious	Moderate

1: Downgrade 1 level for serious risk of bias. Greater than 33.3% of the weight in meta-analysis came from studies of moderate risk of bias due to unclear random sequence generation, allocation concealment and blinding of outcome assessment.

2: Greater than 33.3% of the weight in meta-analysis came from study partially direct study. Studies did not specify criteria used to classify surgical site infection. Downgrade 1 level for serious indirectness.

3: Downgrade 1 level for serious risk of bias. Study demonstrates unclear random sequence generation and allocation concealment.

4: Study did not specify criteria used to classify surgical site infection. Downgrade 1 level for serious indirectness.

5: Inconsistency not applicable

6: 95% confidence interval crosses both ends of a defined MID interval (0.8, 1.25). Downgrade 2 levels.

7: Downgrade 1 level for serious risk of bias. Study demonstrates unclear random sequence generation, allocation concealment and blinding of outcome assessment.

*: Derived by taking the overall number of event/ total number of participants and multiplying by 100

No. of studies	Study design	Sample size	Effect size (95% CI)	Absolute risk: control	Absolute risk: intervention (95% CI)	Risk of bias	Indirectness	Inconsistency	Imprecision	Quality
SSI - RR <1 favours gentamicin collagen sponge
1 Collin 2013	RCT	91	RR not estimable due to no occurrence of event in either study arm.			Serious¹	Not serious	NA²	Very serious³	Very low

1: Downgrade 1 level for serious risk of bias. Study demonstrates no blinding of outcome assessment.

2: Inconsistency not applicable

3: Unable to calculate effect size. Downgrade 2 levels for very serious imprecision.

No. of studies	Study design	Sample size	Effect size (95% CI)	Absolute risk: control*	Absolute risk: intervention (95% CI)	Risk of bias	Indirectness	Inconsistency	Imprecision	Quality
SSI-RR <1 favours gentamicin collagen sponge
1 Ozbalci 2014	RCT	50	RR not estimable due to no occurrence of event in either study arm.			Serious¹	Serious²	NA³	Very serious⁴	Very low

1: Downgrade 1 level for serious risk of bias. Study demonstrates unclear random sequence generation, allocation concealment and blinding of outcome assessment.

2: Downgrade 1 level for partial indirectness. Study did not specify criteria used to classify surgical site infection.

3: Inconsistency not applicable

4: Unable to calculate effect size. Downgrade 2 levels for very serious imprecision.

No. of studies	Study design	Sample size	Effect size (95% CI)	Absolute risk: control^*	Absolute risk: intervention (95% CI)	Risk of bias	Indirectness	Inconsistency	Imprecision	Quality
SSI - RR <1 favours gentamicin collagen sponge
1 Rutten 1997	RCT	221	RR 0.30 (95% CI: 0.13, 0.73)	18 per 100 people	6 per 100 people (2, 13)	Serious¹	Serious²	NA³	Not serious	Low

1: Downgrade 1 level for serious risk of bias. Study demonstrates unclear random sequence generation and blinding of outcome assessment.

2: Study did not specify follow up period. Downgrade 1 level for serious indirectness.

3: Inconsistency not applicable

*: Derived by taking the overall number of event/ total number of participants and multiplying by 100

No. of studies	Study design	Sample size	Effect size (95% CI)	Absolute risk: control^*	Absolute risk: intervention (95% CI)	Risk of bias	Indirectness	Inconsistency	Imprecision	Quality
SSI - RR <1 favours gentamicin collagen sponge
2 Haase 2005, Schimmer 2012	RCT	800	RR 0.48 (95% CI: 0.25, 0.91)	7 per 100 people	3 per 100 people (2, 6)	Very serious¹	Not serious	Not serious	Serious²	Very low
SSI (loop-ileostomy) - RR <1 favours gentamicin collagen sponge
1 Haase 2005	RCT	80	RR 1.00 (95% CI: 0.27, 3.72)	10 per 100 people	10 per 100 people (3, 37)	Not serious	Not serious	NA3	Very serious²	Low
SSI (cardiac surgery) - RR <1 favours gentamicin collagen sponge
1 Schimmer 2012	RCT	720	RR 0.39 (95% CI: 0.18, 0.83)	7 per 100 people	3 per 100 people (1, 5)	Very serious⁴	Not serious	NA3	Serious⁵	Very low
Superficial SSI - RR <1 favours gentamicin collagen sponge
3 Haase 2005, Schimmer 2012, Pochammer 2015	RCT	993	RR 0.74 (95% CI: 0.42, 1.31)	5 per 100 people	4 per 100 people (2, 7)	Very Serious⁶	Not serious	Not serious	Very serious²	Very low
Sensitivity analysis (excluding studies at high risk of bias) Superficial SSI - RR <1 favours gentamicin collagen sponge
2 Haase 2005, Pochammer 2015	RCT	273	RR: 0.79 (95% CI: 0.39, 1.63)	11 per 100 people	9 per 100 people (4,18)	Not serious	Not serious	Not serious	Very serious²	Low
Superficial SSI (loop-ileostomy) - RR <1 favours gentamicin collagen sponge
1 Hasse 2005	RCT	80	RR 2.00 (95% CI: 0.39, 10.31)	5 per 100 people	10 per 100 people (2, 52)	Not serious	Not serious	NA³	Very serious²	Low
Superficial SSI (cardiac surgery) - RR <1 favours gentamicin collagen sponge
1 Schimmer 2012	RCT	720	RR 0.66 (95% CI: 0.26, 1.69)	3 per 100 people	2 per 100 people (1, 5)	Very serious⁴	Not serious	NA³	Very serious²	Very low
Superficial SSI (colorectal surgery) - RR <1 favours gentamicin collagen sponge
1 Pochammer 2015	RCT	193	RR 0.61 (95% CI: 0.26, 1.40)	14 per 100 people	8 per 100 people (4, 19)	Not serious	Not serious	NA³	Very serious²	Low
Deep SSI - RR <1 favours gentamicin collagen sponge
3 Haase 2005, Schimmer 2012, Pochammer 2015	RCT	993	RR 0.17 (95% CI: 0.04, 0.63)	3 per 100 people	1 per 100 people (0, 2)	Very serious¹	Not serious	Not serious	Very serious²	Very low
Sensitivity analysis (excluding studies at high risk of bias) Deep SSI - RR <1 favours gentamicin collagen sponge
Haase 2005, Pochammer 2015	RCT	272	RR 0.20 (95% CI: 0.01, 4.04)	15 per 1000 people^**	3 per 1000 people (0,59)^**	Not serious	Not serious	Not serious	Very serious²	Low
Deep SSI (loop-ileostomy) - RR <1 favours gentamicin collagen sponge
1 Hasse 2005	RCT	80	RR 0.20 (95% CI: 0.01, 4.04)	5 per 100 people	1 per 100 people (0, 20)	Not serious	Not serious	NA³	Very serious²	Low
Deep SSI (cardiac surgery)
1 Schimmer 2012	RCT	720	RR 0.16 (95%CI: 0.04, 0.70)	4 per 100 people	1 per 100 people (0, 2)	Very serious⁴	Not serious	NA³	Very serious²	Very low
Deep SSI (colorectal surgery) - RR <1 favours gentamicin collagen sponge
1 Pochammer 2015	RCT	193	RR not estimable due to no occurrence of event in either study arm.			Not serious	Not serious	NA³	Very serious⁶	Low
Length of stay
1 Pochammer 2015	RCT	193	Difference in medians: 0.5 days (non-significant according to Kurskal-Wallis test)			Not serious	Not serious	NA³	Very serious⁷	Low

1: Downgrade 2 levels for very serious risk of bias. Greater than 33.3% of the weight in meta-analysis came from study of high risk of bias due to unclear random sequence generation, allocation concealment and blinding of outcome assessment. Furthermore, intention to treat analysis was not performed.

2: 95% confidence interval crosses both ends of a defined MID interval (0.8, 1.25). Downgrade 2 levels.

3: Inconsistency not applicable

4: Downgrade 2 levels for very serious risk of bias. Study demonstrates unclear random sequence generation, allocation concealment and blinding of outcome assessment. Furthermore, intention to treat analysis was not conducted.

5: 95% confidence interval crosses one end of a defined MID interval (0.8, 1.25). Downgrade 1 level.

6: Unable to calculate effect size. Downgrade 2 levels for very serious imprecision.

7: Downgrade 2 levels for no measure of spread and non-significant results.

*: Derived by taking the overall number of event/ total number of participants and multiplying by 100

**: Derived by taking the overall number of event/ total number of participants and multiplying by 1000

Short Title	Title
Abdullah (2017)	Topical vancomycin reduces surgical-site infections after craniotomy: a prospective, controlled study	Conference abstract
Anagnostakos (2012)	Antibiotic-impregnated bone grafts in orthopaedic and trauma surgery: a systematic review of the literature	Systematic review did not match review protocol
Anagnostakos (2017)	Therapeutic Use of Antibiotic-loaded Bone Cement in the Treatment of Hip and Knee Joint Infections	Review article but not a systematic review
Andreas (2017)	Direct sternal administration of Vancomycin and Gentamicin during closure prevents wound infection	Not a relevant study design Before and after study.
Bakhsheshian (2015)	The use of vancomycin powder in modern spine surgery: systematic review and meta-analysis of the clinical evidence	Systematic review did not contain new relevant papers
Benaerts (1999)	Gentamicin beads in vascular surgery: long-term results of implantation	Not a relevant study design Prospective observational study.
Bertazzoni (2004)	Release of gentamicin and vancomycin from temporary human hip spacers in two-stage revision of infected arthroplasty	Study not relevant to RQ Study did not examine SSI.
Birgand (2013)	Does a gentamicin-impregnated collagen sponge reduce sternal wound infections in high-risk cardiac surgery patients?	Not a relevant study design Before and after study.
Block (2005)	Reducing the risk of deep wound infection in primary joint arthroplasty with antibiotic bone cement	Systematic review did not contain new relevant papers
Bozzetti (1975)	Topical ampicilin and local infectious complications in oncological surgery	Study not reported in English
Chang (2013)	Gentamicin-collagen implants to reduce surgical site infection: systematic review and meta-analysis of randomized trials	Systematic review did not contain new relevant papers
Chen (2014)	Antibiotic-loaded bone cement and periprosthetic joint infection	Review article but not a systematic review
Chiang (2014)	Effectiveness of local vancomycin powder to decrease surgical site infections: a meta-analysis	Systematic review did not contain new relevant papers
Chiu (2001)	Cefuroxime-impregnated cement at primary total knee arthroplasty in diabetes mellitus. A prospective, randomised study	Study not relevant to RQ Quasi randomised trial.
Chiu (2002)	Cefuroxime-impregnated cement in primary total knee arthroplasty: a prospective, randomized study of three hundred and forty knees	Study not relevant to RQ Quasi randomised trial.
Creanor (2012)	Effectiveness of a gentamicin impregnated collagen sponge on reducing sternal wound infections following cardiac surgery: a meta-analysis of randomised controlled trials	Systematic review did not contain new relevant papers
Culligan (2005)	A randomized trial that compared povidone iodine and chlorhexidine as antiseptics for vaginal hysterectomy	Study does not contain any of the outcomes of interest
de Bruin (2010)	Local application of gentamicin collagen implants in the prophylaxis of surgical site infections following gastrointestinal surgery: a review of clinical experience	Systematic review did not contain new relevant papers
de Bruin (2012)	Local application of gentamicin-containing collagen implant in the prophylaxis of surgical site infection following gastrointestinal surgery	Systematic review did not contain new relevant papers
Desmond (2003)	Topical vancomycin applied on closure of the sternotomy wound does not prevent high levels of systemic vancomycin	Study does not contain any of the outcomes of interest
Diefenbeck (2006)	Prophylaxis and treatment of implant-related infections by local application of antibiotics	Review article but not a systematic review
Donovan (2018)	Sternal application of vancomycin greatly reduces the incidence of sternal wound complications in patients undergoing cardiosurgical procedures	Conference abstract
Dunbar (2009)	Antibiotic bone cements: their use in routine primary total joint arthroplasty is justified	Conference abstract
Eklund (2007)	Prevention of sternal wound infections with locally administered gentamicin	Not a relevant study design. Summary of Eklund 2005.
Espehaug (1997)	Antibiotic prophylaxis in total hip arthroplasty. Review of 10,905 primary cemented total hip replacements reported to the Norwegian arthroplasty register, 1987 to 1995	Not a relevant study design Retrospective cohort study.
Evaniew (2015)	Intrawound vancomycin to prevent infections after spine surgery: a systematic review and meta-analysis.	Systematic review did not contain new relevant papers
Fleischman (2017)	Local Intra-wound Administration of Powdered Antibiotics in Orthopaedic Surgery	Review article but not a systematic review
Formanek (2014)	Gentamicin/collagen sponge use may reduce the risk of surgical site infections for patients undergoing cardiac operations: a meta-analysis	Systematic review did not contain new relevant papers
Friberg (2007)	Incidence, microbiological findings, and clinical presentation of sternal wound infections after cardiac surgery with and without local gentamicin prophylaxis	Study not relevant to RQ Study analysed the microbiological findings of sternal wound infections.
Friberg (2009)	Collagen-gentamicin implant for prevention of sternal wound infection; long-term follow-up of effectiveness	Not a relevant study design Historical cohort.
Fry (2016)	Topical Antimicrobials and the Open Surgical Wound	Review article but not a systematic review
Gaillard (1991)	Intra-operative antibiotic prophylaxis in neurosurgery. A prospective, randomized, controlled study on cefotiam	Study not relevant to RQ Antibiotic was administered intravenously.
Ghobrial (2015)	Complications from the use of intrawound vancomycin in lumbar spinal surgery: a systematic review	Systematic review did not match review protocol Review includes observational studies.
Gilmore (1977)	A study of the effect of povidone-iodine on wound healing	Study not relevant to RQ Animal study.
Godbole (2012)	Use of gentamicin-collagen sponges in closure of sternal wounds in cardiothoracic surgery to reduce wound infections	Systematic review did not contain new relevant papers
Godil (2013)	Comparative effectiveness and cost-benefit analysis of local application of vancomycin powder in posterior spinal fusion for spine trauma: clinical article	Not a relevant study design Retrospective review
Gomez (2016)	Does antibiotic-loaded cement decrease the risk of aseptic failure in primary hip arthroplasty? A systematic review	Study not reported in English
Gray (1983)	The role of prophylactic antibiotics in appendectomy using delayed primary closure	Study not relevant to RQ Antibiotics used intravenously.
Guzman (1999)	Effectiveness of collagen-gentamicin implant for treatment of “dirty” abdominal wounds	Comparator in study does not match that specified in protocol Intervention group received gentamicin sponge and comparator group received systemic gentamicin.
Hendriks (2004)	Backgrounds of antibiotic-loaded bone cement and prosthesis-related infection	Review article but not a systematic review
Hinarejos (2015)	Use of antibiotic-loaded cement in total knee arthroplasty	Review article but not a systematic review
Hu (2016)	Efficacy and safety of local gentamicin collagen implanting for preventing SSI following colorectal surgery: A systematic review and meta-analysis	Systematic review did not contain new relevant papers
Huiras (2012)	Local antimicrobial administration for prophylaxis of surgical site infections	Review article but not a systematic review
Hussain (2012)	Local application of gentamicin-containing collagen implant in the prophylaxis and treatment of surgical site infection following vascular surgery	Systematic review did not contain new relevant papers
Ibrahim (2002)	Comparison of local povidone-iodine antisepsis with parenteral antibacterial prophylaxis for prevention of infective complications of TURP: a prospective randomized controlled study	Comparator in study does not match that specified in protocol Intervention compared to saline solution and intravenous antibiotics.
Jiranek (2006)	Antibiotic-loaded bone cement for infection prophylaxis in total joint replacement	Review article but not a systematic review
Josefsson (1981)	Systemic antibiotics and gentamicincontaining bone cement in the prophylaxis of postoperative infections in total hip arthroplasty	Comparator in study does not match that specified in protocol Systemic antibiotics used as comparator.
Josefsson (1990)	Prophylaxis with systemic antibiotics versus gentamicin bone cement in total hip arthroplasty. A five-year survey of 1688 hips	Comparator in study does not match that specified in protocol Systemic antibiotics used as comparator.
Joseph (2003)	Use of antibiotic-impregnated cement in total joint arthroplasty	Review article but not a systematic review
Kang (2015)	Intrasite vancomycin powder for the prevention of surgical site infection in spine surgery: a systematic literature review	Systematic review did not contain new relevant papers
Kanj (2013)	Vancomycin prophylaxis of surgical site infection in clean orthopaedic surgery	Systematic review did not contain new relevant papers
Katarincic (2018)	Local Modalities for Preventing Surgical Site Infections: An Evidence-based Review	Review article but not a systematic review
Khan (2014)	A meta-analysis of spinal surgical site infection and vancomycin powder	Systematic review did not contain new relevant papers
Kleppel (2017)	Antibiotic bone cement’s effect on infection rates in primary and revision total knee arthroplasties	Systematic review did not match review protocol Included studies in which antibiotic bone cement was compared to intravenous antibiotics alone.
Knaepler (2012)	Local application of gentamicin-containing collagen implant in the prophylaxis and treatment of surgical site infection in orthopaedic surgery	Systematic review did not contain new relevant papers
Kochanski (2017)	The effect of vancomycin powder on surgical site infections in deep brain stimulation surgery	Conference abstract
Konstantelias (2016)	Gentamicin-Collagen Sponges for the Prevention of Surgical Site Infections: A Meta-Analysis of Randomized Controlled Trials	Systematic review cross referenced to identify relevant studies.
Kowalewski (2015)	Gentamicin-collagen sponge reduces the risk of sternal wound infections after heart surgery: Meta-analysis	Systematic review did not contain new relevant papers
Leyh (1999)	Adjuvant treatment of deep sternal wound infection with collagenous gentamycin	Study does not contain any of the outcomes of interest
Lopez (2015)	Should we add vancomycin antibiotic powder to prevent post-operative infection in spine surgery? - First update	Systematic review did not contain new relevant papers
Mallela (2017)	Topical Vancomycin Reduces Surgical-Site Infections After Craniotomy: A Prospective, Controlled Study	Study not relevant to RQ Prospective cohort study.
Martinez-Moreno (2017)	Antibiotic-loaded Bone Cement as Prophylaxis in Total Joint Replacement	Systematic review did not match review protocol
Mavros (2012)	Gentamicin collagen sponges for the prevention of sternal wound infection: a meta-analysis of randomized controlled trials	Systematic review did not contain new relevant papers
Mavros (2013)	Antimicrobials as an adjunct to pilonidal disease surgery: a systematic review of the literature	Systematic review did not match review protocol Review examined pre-operative and postoperative antibiotic prophylaxis.
Mishra (2014)	Role of topical application of gentamicin containing collagen implants in cardiac surgery	Review article but not a systematic review
Morawiec (2012)	Local antibiotic therapy in rectal cancer surgery	Study not relevant to RQ Prospective observational study.
Murphy (2017)	A review of the application of vancomycin powder to posterior spinal fusion wounds with a focus on side effects and infection. A prospective study	Not a relevant study design Prospective cohort study.
Naunton (1980)	Prophylactic povidone iodine in minor wounds	Does not contain a population of interest
Nelson (1993)	A comparison of gentamicin-impregnated polymethylmethacrylate bead implantation to conventional parenteral antibiotic therapy in infected total hip and knee arthroplasty	Does not contain a population of interest
Nguyen (2016)	Local administration of gentamicin collagen sponge in surgical excision of sacrococcygeal pilonidal sinus disease: a systematic review and meta-analysis of the literature	Systematic review did not contain new relevant papers
O’Toole (2017)	Local Antibiotic Therapy to Reduce Infection After Operative Treatment of Fractures at High Risk of Infection: A Multicenter, Randomized, Controlled Trial (VANCO Study)	Not a relevant study design Study protocol.
Parvizi (2008)	Efficacy of antibiotic-impregnated cement in total hip replacement	Systematic review did not contain new relevant papers
Periti (1998)	Antimicrobial prophylaxis in orthopaedic surgery: The role of teicoplanin	Review article but not a systematic review
Pitt (1980)	Prophylactic antibiotics in vascular surgery. Topical, systemic, or both?	Comparator in study does not match that specified in protocol Saline used as a comparator.
Raja (2012)	Local application of gentamicin-containing collagen implant in the prophylaxis and treatment of surgical site infection following cardiac surgery	Systematic review did not contain new relevant papers
Randelli (2010)	Prophylactic use of antibiotic-loaded bone cement in primary total knee replacement	Review article but not a systematic review
Rapetto (2016)	Gentamicin-Impregnated Collagen Sponge: Effectiveness in Preventing Sternal Wound Infection in High-Risk Cardiac Surgery	Review article but not a systematic review
Rice (2000)	Intraoperative topical tetracycline sclerotherapy following mastectomy: a prospective, randomized trial	Comparator in study does not match that specified in protocol Saline used as a comparator.
Rodrigo-Perez (2016)	Use of cement with antibiotics as prophylaxis in hip replacement surgery: A literature review	Study not reported in English
Rosen (1991)	Local gentamicin application for perineal wound healing following abdominoperineal rectum excision	Study does not contain any of the outcomes of interest
Schiavone (2016)	Antibiotic-loaded bone cement reduces risk of infections in primary total knee arthroplasty? A systematic review	Systematic review did not contain new relevant papers
Schimmer (2017)	Prevention of surgical site sternal infections in cardiac surgery: a two-centre prospective randomized controlled study	Comparator in study does not match that specified in protocol Cyanoacrylate-based microbial skin sealant used as comparator.
Schultz (1983)	Septic complications after appendicectomy for perforated appendicitis. A controlled clinical trial metronidazole and topical ampicillin	Comparator in study does not match that specified in protocol Study compared systemic metronidazole plus topic ampicillin to topical ampicillin alone.
Senthi (2011)	Infection in total hip replacement: Meta-analysis	Study not relevant to RQ Study examined management of deep infection.
Shapiro (1986)	Randomized clinical trial of intra-operative antimicrobial prophylaxis of infection after neurosurgical procedures	Study not relevant to RQ Intervention administered intravenously.
Simons (2001)	The role of topical antibiotic prophylaxis in patients undergoing contaminated head and neck surgery with flap reconstruction	Study not relevant to RQ Study looked at intraoperative and postoperative use of intervention.
Stewart (2006)	Prevention of infection in arterial reconstruction	Systematic review did not match review protocol Systematic review examined all pre-operative interventions.
Stewart (2007)	Prevention of infection in peripheral arterial reconstruction: a systematic review and meta-analysis	Systematic review did not match review protocol Systematic review examined all pre-operative interventions.
Van Hal (2017)	Vancomycin Powder Regimen for Prevention of Surgical Site Infection in Complex Spine Surgeries	Not a relevant study design Before and after study.
Vander (1989)	Reduction of sternal infection by application of topical vancomycin	Not a relevant study design Quasi randomised trial.
Vogel (1992)	Treatment of pilonidal sinus with excision and primary suture using a local, resorbable antibiotic carrier. Results of a prospective randomized study	Study not reported in English
Voigt (2016)	Antibiotics and antiseptics for preventing infection in people receiving revision total hip and knee prostheses: A systematic review of randomized controlled trials	Systematic review did not match review protocol
Wang (2013)	A systematic review and meta-analysis of antibiotic-impregnated bone cement use in primary total hip or knee arthroplasty	Systematic review did not contain new relevant papers
Wang (2015)	Antibiotic bone cement cannot reduce deep infection after primary total knee arthroplasty	Not a relevant study design Retrospective cohort study.
Woodard (2017)	Topical antibiotics for preventing surgical site infection in wounds healing by primary intention (Review)	Not a relevant study design Commentary.
Xie (2017)	Effect of Intra-wound Vancomycin for Spinal Surgery: A Systematic Review and Meta-analysis	Systematic review did not match review protocol Review included retrospective cohort studies and prospective case study.
Xiong (2014)	Topical intrawound application of vancomycin powder in addition to intravenous administration of antibiotics: A meta-analysis on the deep infection after spinal surgeries	Systematic review did not contain new relevant papers
Yao (2018)	Prophylaxis of surgical site infection in adult spine surgery: A systematic review	Systematic review examined a number of different strategies for prophylaxis of SSI.
Yetim (2010)	Effect of gentamicin-absorbed collagen in wound healing in pilonidal sinus surgery: a prospective randomized study	Comparator in study does not match that specified in protocol Patients were randomised to receive gentamicin sponge or no sponge and postoperative antibiotics.
Yi (2014)	No decreased infection rate when using antibiotic-impregnated cement in primary total joint arthroplasty	Systematic review did not contain new relevant papers
Zhang (2013)	Extended antimicrobial prophylaxis after gastric cancer surgery: a systematic review and meta-analysis	Systematic review did not match review protocol Study examined antibiotic prophylaxis before and after surgery.
Zheng (2014)	Control strategies to prevent total hip replacement-related infections: a systematic review and mixed treatment comparison	Systematic review did not match review protocol Study examined mixed treatments (antibiotic-impregnated cement, antibiotic prophylaxis and laminar flow).
Zhou (2015)	Lack of efficacy of prophylactic application of antibiotic-loaded bone cement for prevention of infection in primary total knee arthroplasty: results of a meta-analysis	Systematic review did not contain new relevant papers

Study	Full title	Primary reason for exclusion
Bradley 1999	Bradley M, Cullum N, Nelson EA, et al. (1999). Systematic review of wound care management: (2) dressings and topical agents used in the healing of chronic wounds. Health Technol Assess, 3 (17).	Review article, no additional CUAs
Etchells 2012	Etchells E, Koo M, Daneman N, et al. (2012). Comparative economic analyses of patient safety improvement strategies in acute care: a systematic review. BMJ Qual Saf, 21: 448–56.	Review article, no additional CUAs
Gillespie 2017	Gillespie BM, Chaboyer W, Erichsen-Andersson A, et al. (2017). Economic case for intraoperative interventions to prevent surgical-site infection. Br J Surg, 104: e55–64.	Review article, no additional CUAs
Hatch 2017	Hatch MD, Daniels SD, Glerum KM, Higgins LD (2017). The cost effectiveness of vancomycin for preventing infections after shoulder arthroplasty: a break-even analysis. J Shoulder Elbow Surg, 26 (3): 472–7.	Not a full economic evaluation
Hernandez-Vaquero 2013	Hernández-Vaquero D, Fernández-Fairen M, Torres A, et al. (2017). Treatment of periprosthetic infections: an economic analysis. Scientific World Journal, 11.	Review article, no additional CUAs
Mallela 2017	Mallela AN, Abdullah KG, Brandon C, et al. (2017). Topical vancomycin reduces surgical-site infections after craniotomy: a prospective, controlled study. Neurosurgery, ePub ahead of print.	Based on non-randomised evidence
Merollini 2013	Merollini KMD, Crawford RW, Whitehouse SL, Graves N. (2013). Surgical site infection prevention following total hip arthroplasty in Australia: a cost-effectiveness analysis. Am J Inf Control, 41: 803–9.	Same model as included study (Graves et al., 2016), adapted to non-UK setting.
Pan & Dendukuri 2010	Pan I & Dendukuri N (2010). Efficacy and costeffectiveness of a gentamicin-loaded collagen sponge as an adjuvant antibiotic prophylaxis for colorectal surgery. Technology Assessment Unit Report 41.	Insufficient information provided
Schwebel 2012	Schwebel C, Lucet J-C, Vesin A, et al. (2012). Economic evaluation of chlorhexidine-impregnated sponges for preventing catherer-related infections in critically ill adults in the Dressing Study. Crit Care Med, 40 (1): 11–7.	Intervention (post-operative)
Trentinaglia 2018	Trentinaglia MT, van der Straeten C, Morelli I, et al. (2018). Economic evaluation of antibacterial coatings on healthcare costs in first year following total joint arthroplasty. J Arthroplasty, Epub ahead of print.	Not a full economic evaluation

PICO	Population: People of any age undergoing any surgery, including minimally invasive surgery (arthroscopic, thoracoscopic and laparoscopic surgery) Interventions: Different antibiotics and antiseptics applied to the operative field (including antibiotic impregnated implants and antibiotic loaded bone cement) Comparator: Placebo No treatment Interventions compared to each other Outcomes: Surgical site infection (superficial, deep and organ/space SSI), including SSIs up to 30 days and 1 year, defined using appropriate criteria such as CDC SSI criteria. Mortality post-surgery Length of hospital stay Postoperative antibiotic use. Infectious complications such as septicaemia or septic shock Adverse events: Antimicrobial resistance Organ toxicity Anaphylaxis Resource implication
Current evidence base	Overall, 30 studies identified, 10 of which were conducted before the 1990s.
Study design	Randomised controlled trial
Other comments	These studies should take into account different surgery procedures and should be conducted within the UK with an adequate sample size.

Evidence review for application of intraoperative topical antiseptics and antibiotics before wound closure

Effectiveness of intraoperative topical antiseptics and antibiotics before wound closure in the prevention of surgical site infection

Review question

Introduction

Table 1

Methods and process

Clinical evidence

Included studies

Excluded studies

Summary of clinical studies included in the evidence review

Table 2

Quality assessment of clinical studies included in the evidence review

Economic evidence

Included studies

Graves et al. (2016)

Cummins et al. (2009)

Excluded studies

Economic model

Summary of studies included in the economic evidence review

Evidence statements

Clinical evidence

Erythromycin and colistin loaded bone cement

Outcomes at 1 year after surgery

Vancomycin powder

Outcomes at 3 months after surgery

Ampicillin powder

Outcomes at 3 weeks after surgery

Topical cefotaxime

Outcomes at 1 month after surgery

Topical cephaloridine

Outcomes at 1 month after surgery

Topical povidone iodine spray

Outcomes at 2 weeks after surgery

Outcomes at 1 month after surgery

Povidone iodine solution

Outcomes during postoperative period

2.5% Iodine in 70% ethanol

Outcomes at 2 weeks after surgery

Gentamicin collagen sponge

Outcomes at 1 week after surgery

Outcomes at 2 weeks after surgery

Outcomes at 1 month after surgery

Outcomes at 2 months after surgery

Outcomes at 3 months after surgery

Outcomes at 6 months after surgery

Outcomes during postoperative phase

Economic evidence

Antibiotic-impregnated bone cement

The committee’s discussion of the evidence

Interpreting the evidence

The outcomes that matter most

The quality of the evidence

Benefits and harms

Cost effectiveness and resource use

Other factors the committee took into account

Appendices

Appendix A. Review protocols

Review protocol for application of intraoperative antiseptics and antibiotics before wound closure

Appendix B. Methods

Priority screening

Quality assessment

Using systematic reviews as a source of data

Evidence of effectiveness of interventions

Quality assessment

Methods for combining intervention evidence

Minimal clinically important differences (MIDs)

GRADE for pairwise meta-analyses of interventional evidence

Publication bias

Evidence statements

Health economics

Appendix C. Literature search strategies

Table

Economic evaluations and quality of life data

Table

Economic evaluations

Quality of Life

Appendix D. Clinical evidence study selection

Appendix E. Clinical evidence tables

E.1. Andersson 2010

E.2. Bennett-Guerrero 2010a