The role of preoperative Chlorhexidine as an antiseptic solution to reduce the risk of postoperative surgical site infection

C1369366-MET319

Word count: 3546

Contents:

Introduction: 3

Objective: 4

Methods: 4

Table 1: Search strategy 5

Critical appraisal of the literature: 5

Discussion: 17

Conclusion: 17

References: 18

Introduction:

Surgical Site Infection (SSI) is a common complication in surgical practice. The incidence depends on multiple factors including the type and location of surgical procedure ranging from 2%-4% in simple skin lesions (Rogues et al., 2007) to 36% in cases of reversal of stoma (Liang et al., 2013). Incidence of SSI can be kept low by simple measures such as rescheduling elective procedures in presence of infection; e.g.: Urinary Tract Infection, Respiratory Tract Infection which can seed Bacteria to surgical wounds (Ollivere et al., 2009). Prophylactic Antibiotics given prior to elective surgery remains debatable and of questionable value considering the risk of side effects, emergence of Multi-drug resistant Pathogens and Anaphylaxis, and therefore should be used according to guidelines like in patients with higher risk for developing SSI (Wright et al., 2008, Dixon et al., 2006). Also, procedures at certain body sites and those involving surgical reconstruction are better covered with prophylactic Antimicrobial agent (Rosengren and Dixon, 2010).

Use of antiseptic scrub has been shown to reduce the incidence of SSI. Studies suggest that Chlorhexidine is superior to Povidone Iodine solutions in reducing Bacterial Colonization and SSI in postoperative patients (Paocharoen et al., 2009, Mimoz, 2010 and, Lee et al., 2010). Also, the use of Chlorhexidine Gluconate shower or bath for cleansing the skin by patients prior to dermatologic surgical procedures reduces the risk for SSI (Edmiston et al., 2010), and is economic in prevention of SSI even with low patient compliance and cloth efficacy values (Bailey et al., 2011). Chlorhexidine is a cheap and easily available method of reducing SSI rates in surgical patients.

Objective:

The aim of this assignment is to evaluate the use of Chlorhexidine given preoperatively as an antiseptic solution in prepping skin before surgical incision to reduce the rate of postoperative surgical site infection. Chlorhexidine is an available and cheap product if proven effective in reducing morbidity from SSIs.

Methods:

A search of the literature has been conducted using the following terms in different combination “Preoperative”, “Antiseptic solution”, “Chlorhexidine” and “Surgical site infection”. A total of 84 relevant articles in the last 5 years in English language were retrieved from Embase, Medline, Ovid and web of knowledge. Clinical trials, reviews and systematic reviews related to humans were included for the final analysis. After going through the remaining 32 abstracts, the 5 most relevant with clear question and methodology outlined in the abstract were critically appraised due to length limitations of this paper (Table 1), this included 2 systematic reviews and 3 RCTs.

Critical Appraisal Skills Programme (CASP) tools will used as a critiquing tool for the purpose of this review, and guidelines published by Harbour and Miller (Harbour and Miller, 2001) will be used to evaluate the hierarchy of evidence.

Table 1: Search strategy

|1 |Search string |No. of articles |
|2 |Preoperative |473741 |
|3 |Chlorhexidine |23786 |
|4 |Surgical Site infection |5739 |
|5 |Preoperative AND Chlorhexidine AND Surgical site infection |145 |
|6 |Limit to English Language |143 |
|7 |Limit to Human |126 |
|8 |Limit to within 5 years |103 |
|9 |Remove duplicates |72 |

Critical appraisal of the literature:

Darouiche et al (Darouiche et al., 2010) conducted a prospective multicentre randomised controlled trial in 6 different hospitals comparing the use of Chlorhexidine-Alcohol scrub among adults undergoing clean-contaminated surgical procedures against the use of Povidone-Iodine scrub and paint. Their primary outcome was surgical site infection (SSI) within 30 days, with specific types of SSI as secondary outcomes. They addressed a clear and very specific issue in their study with well-constructed primary and secondary outcomes. Also the inclusion criteria were clear – Age above 18, clean-contaminated procedures. They excluded anyone with history of allergy to Chlorhexidine, Alcohol or Iodine, those with evidence of infection at or near the operative site and those who could not commit to 30 days of postoperative follow-up. All patients received a single prophylactic dose of antibiotics within 1 hour from surgery with no difference in type or dose of antibiotics across the groups.

Rigorous randomisation by a dedicated statistician was based on a 1:1 ratio stratified by hospital with use of computer generated randomisation numbers to assign patients to either preoperative scrubbing with 2% chlorhexidine gluconate and 70% isopropyl alcohol (ChloraPrep, Cardinal Health) or scrubbed and then painted with an aqueous solution of 10% povidone–iodine (Scrub Care Skin Prep Tray, Cardinal Health). Operating surgeons were blinded to the randomisation process and only found out inside the operating theatre. Both patients and site investigators who diagnosed surgical site infection based on Centre for Disease Control (CDC) criteria remained unaware of the group assignments to ensure double blindness of the study. The result was 2 groups with similar demographics with adequate blinding.

The authors based their power calculations on the average percentage for SSI in all six hospitals following clean-contaminated surgery (14%). To give 90% power to detect significant difference in outcome with p value of 0.05, they planned to enrol 430 patients. Out of 897 patients who were initially approached for inclusion, only 849 qualified for the intention-to-treat analysis. 409 received chlorhexidine–alcohol and 440 received povidone iodine, 36 of those were excluded; 25 had clean procedures rather than clean-contaminated, 4 dropped out and 7 died before the 30 days period. The remaining 813 patients (391 in the chlorhexidine–alcohol group and 422 in the povidone– iodine group) were included in the per-protocol analyses. The infection rate was significantly less in the chlorhexidine-alcohol group (9.5%) compared to the povidone-iodine group (16.1%) with a significant p value of 0.004. Similarly, chlorhexidine–alcohol was associated with significantly fewer superficial incisional infections (relative risk, 0.48; 95% CI, 0.28 to 0.84) and deep incisional infections (relative risk, 0.33; 95% CI, 0.11 to 1.01). However, there were no significant differences between the two study groups in the incidence of organ-space infection (relative risk, 0.97; 95% CI, 0.52 to 1.80) or sepsis from surgical- site infection (relative risk, 0.62; 95% CI, 0.30 to 1.29). Also there was significantly longer time to infection after surgery in the chlorhexidine–alcohol group than in the povidone–iodine group (P = 0.004 by the log-rank test).

The results show that chlorhexidine-alcohol based solutions are superior to povidone-iodine ones in preventing SSI. The outcome of this trial is applicable to all patients undergoing clean-contaminated surgical procedures. It is a rigorously conducted trial, however study was not powered to compare subcategories of patients. Also, the main authors in the study received grants from the supplier of the chlorhexidine-alcohol solution (Cardinal Health), however they also supplied the povidone-iodine product used in the second group of the study, so there does not seem to be a conflict of interest to reduce the objectivity of the study. The author would rate this study as grade 1+ (well conducted RCT with low risk of bias) according to harbour & miller guidelines (Harbour and Miller, 2001).

Swenson et al in 2009 (Swenson et al., 2009) conducted a prospective single centre randomised controlled trial in the University of Virginia Health System comparing three different skin preparations using a sequential design as the method for randomisation over three different time periods of 6 months for each period for all cases admitted under the care of the general surgeons in their hospital. They used a povidone-iodine scrub-paint combination (Betadine) with an isopropyl alcohol application between these steps in the first period. In period 2, all patients received a 2% chlorhexidine and 70% isopropyl alcohol (ChloraPrep). Period 3 used iodine povacrylex in isopropyl alcohol (DuraPrep). The follow-up period for SSIs was 30 days, with the primary outcome being the overall rate of SSIs for each 6 months period in an intention to treat manner.

They addressed a clear question which was evident in both title and abstract of the final publication, and had a robust design to answer that question by including all surgical patients in the study with very rigorous and clear methodology for intervention and outcome measures. Inclusion criteria were clearly outlined in the methodology. They included all adults at least 18 years old undergoing general surgical procedures between January 2006 and June 2007. Patients who did not receive the allocated skin preparation because of history of allergy, or for any other reasons, were also followed for same outcomes as the rest. Primary outcome measure was SSI conditioned on skin preparation assignment period. SSI was defined using established criteria from the Centres for Disease Control and Prevention/National Nosocomial Infections Surveillance system guideline for prevention of SSI (Mangram et al., 1999).

They recorded patient demographic and past medical information as well as perioperative details, including procedure performed, wound classification, operative time, skin preparation solution used, estimated blood loss, and need for perioperative blood transfusion.

There was no blinding to either patients or participating surgeons in the study giving rise to a potential bias and reducing the reliability of the study. All patients were analysed in the groups they were assigned to at the beginning with intention to treat. Examining the patients demographic reported by the authors, they had mostly similar characteristics in the 3 different groups meaning that there is less risk of confounding factors based on patients’ demographics such as age, gender, race and past medical history. Also, they had similar distribution when assessing wound classification used by authors – clean, clean contaminated, contaminated and dirty. Minor variations were observed in the frequency of patients with a smoking history or preoperative sepsis and in sex. Mean operating room times were 13–14 minutes shorter in period 3, compared with the times in the other 2 periods (P = .002).

Power calculation was based on historical data from their hospital database. They estimated a baseline SSI rate of approximately 6.5%. A hypothetical reduction to 4.0% with α = 0.02 (adjusted for multiple comparisons) and β = 0.30 would require 1,060 patients per period, for a total of 3,180 patients. 3,209 operative cases meeting inclusion criteria were followed up (period 1, n p 987; period 2, n p 994; and period 3, n p 1,228).

The lowest SSI incidence (3.9%) was observed in period 3, compared with 6.4% in period 1 and 7.1% in period 2 (P = 0.002). Lower SSI rates overall were seen in the povidone-iodine preparation group (4.8%) and the iodine povacrylex in isopropyl alcohol group (4.8%), compared with the SSI rates in the 2% chlorhexidine and 70% isopropyl alcohol group (8.2%) (P < 0.05). Given that no significant differences were found between the povidone-iodine preparation group and the iodine povacrylex in isopropyl alcohol group, the patient preparation variable was dichotomized to iodophor-based preparations and the chlorhexidine-based preparation (2% chlorhexidine and 70% isopropyl alcohol). Lower infection rates were noted after the use of iodophor-based preparations for superficial SSI following clean procedures (infection in 4 [0.4%] of 930 patients for iodophor-based preparations and in 4 [1.8%] of 224 patients for 2% chlorhexidine and 70% isopropyl alcohol; P = 0.028) and for all SSI following dirty procedures (15 [7.5%] of 201 patients for iodophor-based preparations and 12 [15.6%] of 77 patients for 2% chlorhexidine and 70% isopropyl alcohol; P = 0.041) with odds ratio of 1.35 (0.97–1.87) with 95% confidence interval.

The findings in this study are relevant to all surgical patients. However, lack of blinding and presence of potential confounding factors in patients’ demographics impacts negatively on the trial.

The author would rate this study as grade [1-] (RCT with high risk of bias) according to harbour & miller guidelines (Harbour and Miller, 2001).

Cherian et al (Cherian et al., 2013) published a paper on “Oral Antibiotics Versus Topical Decolonization to prevent Surgical Site Infection after Mohs Micrographic Surgery” based on a prospective randomised controlled trial. The question asked by them was clearly outlined in the title and detailed in the abstract. They examined the rate of SSIs in patients undergoing Mohs microscopic surgery (MMS) with a proven positive nasal swab pre-procedure for S. aureus (Nasal Carriers). Patients were randomised to receive either pre- and postoperative dose of oral cephalexin, or topical decolonization with intranasal Mupirocin twice daily plus 4% chlorhexidine gluconate body wash daily for 5 consecutive days. Conducted over a 30-week period between November 2011 and June 2012. Patients were excluded if they were receiving antibiotics prior to the procedure, required antibiotics for endocarditis or prosthesis infection, lactating, pregnant or had their wounds reconstructed outside the facility. Patients were divided in swab positive (179 patients) group and swab negative (517 patients) group. Swab-positive patients were randomized to one of two preoperative interventions: 90 patients received topical mupirocin nasal ointment applied twice daily combined with once-daily head, neck, and body wash with 4% chlorhexidine gluconate solution for 5 consecutive days preoperatively and 89 patients were randomised to receive oral antibiotics, 87received oral cephalexin, one patient received clindamycin and another one erythromycin. An alternative antibiotic was administered in the case of betalactam sensitivity or drug resistance on the preoperative swab.

The primary endpoint was rate of SSI within 7 days of MMS. Wound infection was defined as culture confirmation of a clinically suspected infection. Clinical indicators of infection were the presence of one or more of purulent discharge from the wound, pain, localized swelling, redness, or heat. Intention to treat analysis was used. Five patients assigned to the topical group did not complete the preoperative decolonization, and one patient in the oral antibiotic group received a course of postoperative antibiotics. There were no significant differences between the groups in terms of demographic characteristics or comorbidities, anatomic site, tumour size, mean number of Mohs stages, or nature of reconstruction conducted. The infection rate was 9% in the S. aureus carrier group and 6% in the non-carrier group. Eight of the patients receiving oral antibiotic prophylaxis

(9%) developed infection. In contrast, no patient who received topical decolonization developed SSI. Using intention-to-treat analysis, this difference was statistically significant [p = .003].

The trial had a robust design and clear inclusion and exclusion criteria. However, no power calculation or blinding were carried out. Also, it is not clear if the 2 patients who did not receive cephalexin developed SSI or not. The trial is of particular relevance to dermatologists, however the implications on procedures for different types of skin lesions are relevant to all general surgeons and general practitioners who perform those procedures. The author would rate this study as grade [1-] (RCT with high risk of bias) according to harbour & miller guidelines (Harbour and Miller, 2001).

Lee et al (Lee et al., 2010) performed a systematic review and cost analysis comparing use of chlorhexidine with use of iodine for preoperative skin antisepsis to prevent SSI. The review addressed a clear question and had a rigorous and reproducible search strategy. They searched the Agency for Healthcare Research and Quality website, the Cochrane Library, Medline, and EMBASE. Included studies were systematic reviews, meta-analyses, or RCTs comparing preoperative skin antisepsis with chlorhexidine and with iodine and assessing for the outcomes of SSI – primary outcome - or positive skin culture result after application – secondary outcome. They only included papers published in English. Also, unpublished studies were not included. Papers included had clear data about at least one outcome measure. Reference lists for included RCTs were screened for additional relevant articles. They assessed bias visually by funnel plots, and heterogenicity by I2 test (I2 test ≥ 50% was considered to indicate significant heterogeneity) and the P value of the X2 test for heterogeneity (P ≤.10 was considered to indicate significant heterogeneity). The quality of each included RCT was graded using a 9-point scale combining elements from the Jadad and the Chalmers scales evaluating 3 aspects of the included studies: randomisation, blinding and patient attrition (Jadad et al., 1996, Chalmers et al., 1981). Quality of evidence of each study was assessed using criteria proposed by the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group (Guyatt et al., 2008).

From 1508 articles identified by primary search, 9 RCTs were included for final analysis. 5 trials reported on only one type of surgery, 4 on a mix of surgical patients. Chlorhexidine and povidone-iodine concentrations varied in the included studies. 4 trials reported only on SSI, 2 trials only on positive skin culture, and 3 trials on both outcomes. Meta-analysis of 7 studies that evaluated the outcome of SSI reported that use of chlorhexidine significantly decreased the risk for SSI, compared with use of iodine (adjusted RR, 0.64 [95% CI, 0.51–0.80]). No significant study heterogeneity was found (I2 test, 0%; X2 test, P = 0.70). Meta-analysis of 4 studies found that use of chlorhexidine significantly decreased the risk for a positive skin culture result after application, compared with iodine (adjusted RR, 0.44 [95% CI, 0.35–0.56]) (Figure 4). No significant study heterogeneity was found (I2 test, 0%; X2 test, P = 0.78).

The results were precise with clear CI and RR mentioned in meta-analysis. This was a rigorous systematic review with a robust design and methodology. The author would rate this study as grade 1+ (well conducted meta­analysis with low risk of bias) according to harbour & miller guidelines (Harbour and Miller, 2001).

Another systematic review and met-analysis by Noorani et al evaluated preoperative antisepsis with chlorhexidine versus povidone–iodine in clean-contaminated surgery (Noorani et al., 2010). The review addressed a clear question. The systematic review was conducted in accordance with PRISMA guidelines (Moher et al., 2009). Both MedLine and EmBase were searched for relevant articles. They also searched proceedings from major conferences for relevant abstracts. Reference lists from included papers were searched for additional eligible articles. Antiseptic manufacturer websites were searched for relevant publications or presentations. Studies included were clinical trials, conducted in patients aged 18 years or older, and at least one clinical endpoint reported by trial authors. Trial quality was evaluated using the Jadad score (Jadad et al., 1996). The primary outcome measure was SSI, and secondary outcome measure was intra-abdominal infection. Pooled odds ratios (ORs) with 95 per cent confidence intervals were calculated using the random-effects model of DerSimonian and Laird. Heterogeneity was assessed using Cochran’s Q test. In this test, P < 0·050 indicated significant heterogeneity between the pooled studies. Bias was assessed visually by a funnel plot, and also by means of Egger test, with significance set at 10%. Of 21 potentially relevant studies, 6 were included in the final analysis, one study had sequential implemental design rather than randomisation.

All six studies reported postoperative SSI rates. SSI occurred in 145 (5·7 per cent) of 2529 patients who had chlorhexidine and 198 (7·9 per cent) of 2502 who had povidone–iodine antisepsis. This yielded a pooled OR of 0·68 (0·50 to 0·94; P = 0·019) (Fig. 2). There was no evidence of heterogeneity (Cochran’s Q 8·21, 5 d.f, P = 0·144) or bias (Egger test −0·35, P = 0·789). The analysis was repeated after excluding the sequential study; SSI occurred in 93 (6·1 per cent of 1535 patients treated with chlorhexidine compared with

149 (9·8 per cent) of 1515 who had povidone–iodine. This sensitivity analysis yielded a pooled OR of 0·58 (0·44 to 0·75; P < 0·001). There was no evidence of heterogeneity (Cochran’s Q 2·34, 4 d.f., P = 0·672) or bias (Egger test 0·14; P = 0·868). Intra-abdominal sepsis was reported in 3 trials. Overall, intra-abdominal infections occurred in 38 (2·1 per cent) of 1803 chlorhexidine-treated patients versus 39 (2·2 per cent) of 1812 who had povidone–iodine. The pooled OR for intra-abdominal infection was 0·98 (0·53 to 1·86; P = 0·971). There was no evidence of heterogeneity (Cochran’sQ3·05, 2 d.f., P = 0·217). There were insufficient studies to undertake an Egger test.

This was a rigoursly designed systematic review with proper statistical tools used for the meta-analysis part – although risk ratio would have been better than odds ratio. It is relevant to all surgical patients. The author would rate this study as grade 1+ (well conducted meta­analysis with low risk of bias) according to harbour & miller guidelines (Harbour and Miller, 2001).

Discussion:

The use of Chlorhexidine based solutions as an alternative to the more traditional Povidone-Iodine based solutions in skin preparation prior to a wide range of surgical procedures seems to be a valid method of reducing SSI. Even though the studies included -with the exception of Darouiche et al (Darouiche et al., 2010)– lacked proper blinding, and the one study used a sequential implemental design (Swenson et al., 2009), the main clinical outcome in question which is rate of SSI following surgical procedures was properly assessed according to available and accepted guidelines. The 2 systematic reviews with their meta-analyses both showed results favouring Chlorhexidine based solutions. Different solutions concentration, and different application techniques should be taken into consideration however when evaluating the evidence from the meta-analyses.

Conclusion:

Current evidence suggest superiority of Chlorhexidine based solution when used to prep the skin preoperatively in terms of reducing the rate of SSI. Chlorhexidine solutions are cheap, available and have acceptable level of safety with severe allergic reactions reported as an extremely rare complication. It has been widely accepted before placement of central catheters for some time. Until more double blinded studies are well conducted systematic reviews show otherwise, Chlorhexidine based solutions should be considered superior to Povidone-Iodine solutions.

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