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Topical antibiotic prophylaxis for surgical wound infections in clean and clean-contaminated surgery: a systematic review and meta-analysis

Abstract Background Topical antibiotics are widely prescribed as prophylaxis for surgical site infection (SSI). Despite giving high drug concentrations at local wound sites, their efficacy remains controversial. This study is a systematic review and meta-analysis designed to compare the efficacy and safety of topical antibiotics with non-antibiotic agents in preventing SSI. Methods Randomized controlled trials (RCTs) comparing topical antibiotics in patients with clean and clean-contaminated postsurgical wounds were included. Relevant trials published before 30 September 2020, were searched in the PubMed, Embase, and Cochrane databases, without language restrictions. The primary outcome was the incidence of SSIs, presented as the event rate. The secondary outcome was the incidence of contact dermatitis (safety outcome). Data were synthesized using the random-effects model, with the results expressed as risk ratio (RR) with 95 per cent confidence intervals (c.i.). Results Thirteen RCTs were included. The incidence of SSIs and contact dermatitis showed no significant difference between topical antibiotics and non-antibiotic agents (RR 0.89, 95 per cent c.i. 0.59 to 1.32 (P = 0.56, I2 = 48 per cent); and RR 2.79, 95 per cent c.i. 0.51 to 15.19 (P = 0.24, I2 = 0 per cent), respectively). In the subgroup analyses, a reduction in SSIs was also not observed in dermatological (RR 0.77, 95 per cent c.i. 0.39 to 1.55; P = 0.46, I2 = 65 per cent), ocular (RR 0.08, 95 per cent c.i. 0.00 to 1.52; P = 0.09), spinal (RR 1.34, 95 per cent c.i. 0.65 to 2.77; P = 0.43, I2 = 0 per cent), orthopaedic (RR 0.69, 95 per cent c.i. 0.37 to 1.29; P = 0.25, I2 = 0 per cent), or cardiothoracic surgeries (RR 1.60, 95 per cent c.i. 0.79 to 3.25; P = 0.19). Conclusion Given the current evidence, the routine application of topical antibiotics to surgical wounds did not reduce the incidence of SSI. Further trials are needed to assess their effectiveness in high-risk surgeries or in selected patient groups.


Introduction
Surgical site infection (SSI) is a common postoperative com plication and a substantial cause of morbidity, prolonged hospitalization, and death 1 . Of note, SSI was the most common healthcare-associated infection from 2015 to 2017, followed by catheter-associated urinary tract infection and central lineassociated bloodstream infection 2 . As such, SSI remains one of the most common preventable infections today 3 . Based on the concept that infection impairs the process of wound healing, prophylactic antibiotics play an essential role in wound management 4 .
Preoperatively, prophylactic antibiotics are primarily administered intravenously (i.v.). Extensive studies of the preoperative i.v. administration of antibiotic prophylaxis have shown it to be effective in reducing SSIs 5 . However, with the rise of Staphylococcus aureus-related healthcare infections 2 , the preoperative administration of intranasal mupirocin has also been suggested, owing to its role in the decolonization of methicillinresistant S. aureus (MRSA), thereby decreasing SSIs 6 .
The evidence for using topical antibiotics intraoperatively has been a matter of debate. A meta-analysis demonstrated that the use of topical antibiotic agents before wound closure could not be recommended 7 . According to recent guidelines, the irrigation of incisional wounds with antibiotic agents before closure should not be performed owing to the risk of multiple drug resistance 3,8,9 . However, the question over the intraoperative administration of vancomycin powder remains unsolved owing to the growing number of cases of MRSA infection in recent years 10 .
Postoperatively, topical antibiotics are an option with several advantages, including a high drug concentration at the application site, a low incidence of systemic side effects, and good patient compliance 11 . Nevertheless, there is still controversy over their use owing to possible detrimental effects, such as local allergic reactions, poor skin penetration, and the emergence of resistant organisms with antibiotic exposure 11 . The Centers for Disease Control and Prevention 2017 guideline for the prevention of SSI states that additional prophylactic antibiotics should not be administered after the closure of the surgical incision in clean and clean-contaminated procedures 3 . Furthermore, despite the low-quality evidence, it also recommended against the administration of antimicrobial agents into surgical incisions for the prevention of SSIs.
Although there is no robust evidence of whether topical antibiotic prophylaxis is beneficial in patients undergoing clean and clean-contaminated surgery, it remains common practice during postsurgical wound care. The aim of this systematic review and meta-analysis was to compare the efficacy and safety of topical antibiotics with non-antibiotic agents for the prevention of SSI.

Inclusion and exclusion criteria
Surgical wounds were grouped into four classes, according to the National Academy of Sciences and the National Research Council: clean (I); clean-contaminated (II); contaminated (III); and infected/dirty (IV) (Table S1) 12 . The prophylaxis strategy was defined as the administration of topical antibiotics to wounds before the development of infection. Randomized controlled trials (RCTs) evaluating the outcome of using prophylactic topical antibiotics in patients undergoing surgery specifically classified as clean (I) or clean-contaminated (II) were included. Trials that contained other classes of wounds were included if the data from individual classes could be extracted. Additionally, trials were required to document their inclusion and exclusion criteria.
Different forms of topical antibiotics were included, such as ointment, cream, lotion, and powder. Trials that used antiseptic agents were also included. Studies of the use of irrigation solutions during surgery, the use of antibiotic dressings for wounds, and other delivery forms (e.g. collagen implants and antibioticimpregnated sponges) were excluded. Observational and duplicate studies were excluded from this study. In addition, trials regarding catheter infection, therapeutic and decolonization effects, and the use of polypropylene mesh were also excluded.

Search strategy and study selection
Relevant trials published up to 30 September 2020 were identified from the PubMed, Cochrane, and Embase databases. Unpublished trials were collected from the ClinicalTrials.gov registry (http://clinicaltrials.gov/). The following medical subject headings terms were used: surgical wound; surgical wound infection; wound healing; antibacterial agents; antibiotic prophylaxis; administration; topical; staphylococcal infections; topical antiinfective agent; local topical anti-infective agent; bacterial infection; postoperative complications; surgical wound dehiscence; dermatitis; and allergic contact ( Table S2). All retrieved abstracts, trials, and citations were reviewed. In addition, other trials were identified using the reference sections of relevant papers and through correspondence with subject experts. No language restrictions were imposed.

Methodological quality appraisal
Two reviewers (Y.M.H. and M.C.L.) independently assessed the methodological quality of each trial by using the risk of bias method, as recommended by the Cochrane Collaboration 13 .
Several domains were evaluated, including the adequacy of randomization, concealment of allocation, blinding of the patients and the outcome assessors, follow-up duration, the information provided to the patients regarding study withdrawals, whether an intention-to-treat (ITT) analysis was performed, and freedom from other biases.

Data and outcome extraction
Baseline and outcome data were independently extracted by two reviewers (Y.M.H. and M.C.L.). The trial design, population characteristics, inclusion and exclusion criteria, surgery type, patient source, regimen of drug administration, and postsurgical wound infection rates were extracted. Disagreements were resolved by a third reviewer (P.J.C.).
The primary outcome was the incidence of SSI, presented as the event rate. The secondary outcome was the incidence of contact dermatitis, which represents the safety outcome.

Statistical analyses
Data were entered and analysed using Review Manager (version 5.4; The Cochrane Collaboration, Oxford, UK). The meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines 14 . Standard deviations were estimated from the provided confidence interval (c.i.) limits or standard error. Furthermore, dichotomous outcomes were analysed using risk ratios (RRs) as the summary statistics. The precision levels of the effect sizes are reported as 95 per cent confidence intervals. A pooled estimate of the RR and weighted mean difference was computed using the DerSimonian and Laird random-effects model 15 .
To evaluate the statistical heterogeneity and inconsistency of prophylaxis effects across the trials, the Cochrane Q tests and I 2 statistics were used. Statistical significance was set at P < 0.10 for the Cochrane Q tests. Statistical heterogeneity across the trials was assessed using I 2 statistics, which quantified the outcome variability across the trials. Heterogeneity was categorized as low (I 2 25 per cent), moderate (25 per cent < I 2 < 75 per cent) or high (I 2 75 per cent). Additionally, a sensitivity analysis was performed to strengthen the robustness of the results when I 2 > 50 per cent. A one-by-one exclusion method was applied for analysis, and subgroup analyses were performed to investigate the effect of the different types and phases of surgery (preoperative, intraoperative, and postoperative). Figure 1 shows the PRISMA flow diagram. The initial search strategy yielded 7157 studies, and after removing the duplicates and non-RCTs, 5057 studies were eligible for title and abstract screening. Seventy-two full-text articles were retrieved and, after further exclusions, 13 trials with complete data were included in the meta-analysis [16][17][18][19][20][21][22][23][24][25][26][27][28] .

Efficacy outcomes
Ten of the included trials [16][17][18][19][22][23][24][25][26]28 were pooled to compare the prophylactic effect of topical antibiotics to a placebo in clean post-surgical wounds. Figure 2 demonstrates the RR and incidence of SSI in both groups for each type of surgery. The total incidence of SSI was 100 of 2833 in the topical antibiotics group and 132 of 3502 in the non-antibiotic group. Compared with nonantibiotic agents, the use of topical antibiotics did not result in a statistically significant difference in SSI reduction in all populations (RR 0.89, 95 per cent c.i. 0.59 to 1.32; P ¼ 0.56, I 2 ¼ 48 per cent). The use of topical antibiotics in all types of surgery was not associated with a reduction in SSI, including dermatological surgery (four trials; RR 0.77, 95 per cent c.i. 0.39 to 1.55 (P ¼ 0.46, I 2 ¼ 65 per cent)), ocular surgery (one trial; RR 0.08, 95 per cent c.i. 0.00 to 1.52 (P ¼ 0.09)), spinal surgery (two trials; RR 1.34, 95 per cent c.i. 0.65 to 2.77 (P ¼ 0.43, I 2 ¼ 0 per cent)), orthopaedic surgery (two trials; RR 0.69, 95 per cent c.i. 0.37 to 1.29 (P ¼ 0.25, I 2 ¼ 0 per cent)), and cardiothoracic surgery (one trial; RR 1.60, 95 per cent c.i. 0.79 to 3.25 (P ¼ 0.19)).

Sensitivity analysis
The subgroup analyses of administration according to the different operative phases are presented in Fig. 4. In the preoperative phase, nasal mupirocin did not reduce SSI versus non-antibiotic agents (RR 1. 16 Records after exclusion of non-RCTs n = 5057 Full-text articles assessed for eligibility n = 72 Studies included in qualitative synthesis n = 13 Studies included in meta-analysis n = 13 In addition, a sensitivity analysis was performed using the one-by-one exclusion method (Table S6). After combining the RR values of the remaining trials, no significant impact was found by excluding any individual trial from the final results.
Furthermore, no individual trial was found to have a significant impact on the heterogeneity, based on I 2 .

Discussion
In the general population, topical antibiotics did not contribute to a reduction in SSIs, compared to non-antibiotics, during the perioperative period. There was also no benefit found in dermatological, spinal, orthopaedic, and cardiothoracic surgery. Regarding safety, the risk of contact dermatitis did not increase with the use of topical antibiotics in dermatological, cardiothoracic, or ocular surgery. A previous guideline 29 suggested that the use of topical antibiotics should be limited because of the unclear evidence and the potential adverse effects. Several meta-analyses have been performed to evaluate the effect of topical antibiotics. According to the meta-analysis conducted by Heal et al. 30 11 .
In contrast, the pooled results of this study showed that topical antibiotics tended to decrease the risk of an SSI, although these were not statistically significantly different. Compared to the previously mentioned meta-analyses, more recent RCTs were included in the current study, while quasi-randomized study designs were excluded to reduce the risk of selection bias.
In addition, to clarify the prophylactic effect of the topical antibiotics, the focus was only on clean and clean-contaminated wounds. In contrast, Heal et al. 30 included clean, clean-contaminated, and contaminated wounds. In addition, the current study assessed the three phases of surgery (preoperative, intraoperative, and postoperative), while previous studies mainly focused on wounds after primary wound closure. Furthermore, subgroup and sensitivity analyses were carried out to assess the heterogeneity and efficacy in specific conditions.
The rates of SSIs in the modern-day outpatient dermatological setting are low, typically ranging from 0.7-4.0 per cent 31 . However, the prescription of topical antibiotics by dermatologists remains ubiquitous. Statistics show that dermatologists in the USA alone wrote three to four million prescriptions of topical antibiotics in 2003 31 . Nevertheless, the current evidence supporting their use in patients undergoing clean dermatological surgery is conflicting. The current study did not support the use of topical antibiotics compared with placebo in the dermatological field (RR 0.77, 95 per cent c.i. 0.39 to 1.55). Another meta-analysis 31 had a similar finding, and also highlighted the advantages of petrolatum-based management, suggesting that the moist environment provided by the ointment may benefit wound healing, rather than the bactericidal actions of the antibiotic 32 .
In addition to wounds in patients with diabetes, wounds located in the groin or below the knees, basal cell carcinoma and  squamous cell carcinoma excisions, skin grafts, flaps on the nose or ears, and wedge resections of the ears or lip are associated with higher rates of SSI 31 . Even in wounds with a higher risk of developing an infection, petrolatum is equally efficacious in preventing postoperative wound infections as topical antibiotics, based on the study's results 31 . Furthermore, oral prophylactic antibiotics might be another option for patients at high risk of infection 31 .

Study or Subgroup Events
In intraocular surgery, topical antibiotics are regularly administered owing to the restricted effect of systemic antibiotics caused by the blood-ocular barriers, such as the blood-aqueous barrier and the blood-retinal barrier 33 . Hence, intracameral or subconjunctival administration of topical antibiotics for surgical prophylaxis has been advocated to achieve adequate tissue drug concentration. However, a recent review on infection prophylaxis for periorbital Mohs surgery and reconstruction contradicted the recommendation of antibiotic ointment use 34 . Although the rate of SSI in oculoplastic surgery is low, typically between 0.04 and 1.7 per cent 26,35 , the related complications of SSI can be devastating, possibly even vision-threatening. The included RCT of periocular surgery demonstrated that postoperative SSI was more common in the non-antibiotic group (5 versus 0 in the antibiotics group), although this did not reach statistical significance 26 . There is an overall trend toward increased prescription of topical antibiotics during intraorbital or oculofacial surgery by ophthalmologists.
For spinal surgery, the rate of SSI is approximately 0.7-10 per cent, despite appropriate antibiotic prophylaxis; this can cause severe complications, such as spinal instability and neurological deficit 36 . SSIs are often caused by common skin flora, mainly staphylococci. In addition, there have been growing cases of MRSA infection in recent years 10 . Therefore, vancomycin has been postulated to decrease the rates of SSI. Intravenous vancomycin was initially espoused by investigators but was later proven to be of no benefit in postoperative wound infection, compared to intravenous cephalosporins 37 . However, the intraoperative administration of vancomycin powder has gradually gained attention from researchers because of its high concentration levels at the site of operative wounds without causing any systemic side effects 24 .
According to a recent guideline, for patients undergoing complicated spinal surgery, especially those with comorbidities, alternative prophylactic regimens such as intrawound vancomycin could be considered 36 . A meta-analysis, which pooled two RCTs and 19 retrospective cohort studies, found that vancomycin powder reduced SSI caused by Gram-positive bacilli and polymicrobial infections 38 . The current study only included two RCTs on spinal surgery 24,25 , and pooled analysis failed to show any difference in the reduction of SSI rates versus placebo. The difference in results, compared to the previous meta-analysis 38 , might be due to the potential confounding factors inherent to cohort studies.
Staphylococcus aureus is a leading cause of postoperative wound infections, and studies regarding orthopaedic and cardiothoracic surgery have explicitly shown that nasal colonization by S. aureus is a notable risk factor in the development of an SSI 6,12,39,40 . Of note, nasal decolonization has been shown to decrease the risk of S. aureus-related healthcare-associated infections in patients with known nasal carriage of S. aureus 22,28 . The evidence is particularly robust for patients undergoing cardiothoracic and orthopaedic surgery. Considering the high risk of SSI in cardiac surgery, reportedly up to 33 per cent 41 , and the possible need for implant removal if SSI occurs in orthopaedic procedures 22 , the preoperative intranasal application of mupirocin 2 per cent ointment for known S. aureus carriers is beneficial in decolonization and is highly supported by current evidence 6,9,42,43 .
A meta-analysis conducted by the WHO Guidelines Development Group concluded that nasal decolonization using mupirocin ointment, with or without the combination of chlorhexidine gluconate soap body wash preoperatively, had a significant benefit in reducing the incidence of S. aureus SSI in patients with known S. aureus carriage compared with placebo or no treatment (odds ratio 0.46, 95 per cent c.i. 031 to 069) 6 .

Study or Subgroup Events
In the current meta-analysis, trials evaluating the efficacy of preoperative nasal mupirocin administration were also included. The two included RCTs demonstrated that prophylactic intranasal mupirocin did not decrease the overall SSI or S. aureus-related infection rate 22,28 . Therefore, there is no clear evidence that routine nasal decolonization with mupirocin in all patients resulted in a reduction of SSIs versus placebo. The different results obtained by this study and the published evidence may lie in the enrolled patient groups (whether there was nasal carriage of S. aureus or not). The current study included patients who underwent surgery and were noticeably distinct from the WHO study groups, which consisted mainly of S. aureus carriers.
The strengths of the current study are that only RCTs were included in the meta-analysis to minimize selection bias and confounding factors. Further, more trials were included and provided additional results from the different types and different phases of surgery were provided. Furthermore, the sensitivity analysis strengthened the robustness of the primary outcome. Nevertheless, there are several limitations. Firstly, heterogeneity could not be avoided because the study design, perioperative management related to SSI, definition of outcomes, and enrolled patients varied among the trials. Although a subgroup and sensitivity analysis was performed, moderate heterogeneity still existed. Secondly, not all surgical wounds were included and therefore the results are not applicable to other patient groups. Finally, the number of trials in each subgroup was still insufficient, and patients at a high risk of infection were not discussed separately. Further RCTs are required to resolve these clinical problems.
Overall, this study does not support the routine use of topical antibiotics to prevent SSIs in patients undergoing clean surgeries, especially dermatological procedures. However, there is a potential benefit during ocular surgery because of the devastating outcomes of SSIs in these scenarios. In other types of surgery, the number of enrolled trials was limited and thus no conclusions concerning clean-contaminated surgical wounds can be made.

Supplementary material
Supplementary material is available at BJS Open online.

Funding
None.

Acknowledgements
PCJ and YMH contributed equally to this study, including the conception or design of the work and drafting of the manuscript. MCL and HST contributed to the acquisition, analysis, and interpretation of the data for this study. All authors critically revised the manuscript, gave final approval, agreed to be accountable for all aspects of work, and ensured its integrity and accuracy. Po-Jung Chen and Yi-Ming Hua had an equal contribution to the present study.
Disclosure. The authors declare no conflicts of interest.