In 2002, surgical site infections (SSI) were noted by. Antimicrobial Formulation and Delivery in the Prevention of Surgical Site Infection

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1 SURGICAL INFECTIONS Volume 17, Number 3, 2016 ª Mary Ann Liebert, Inc. DOI: /sur Antimicrobial Formulation and Delivery in the Prevention of Surgical Site Infection Patrick B. O Neal 1,2 and Kamal M.F. Itani 1,2 Abstract Background: A number of adjunct antimicrobial measures have been studied in an attempt to reduce surgical site infection (SSI) rates. In addition to parenteral antibiotic prophylaxis, these measures include oral antibiotics in bowel preparation for colorectal surgery, antiseptic/antimicrobial irrigation, antimicrobial sutures, local antibiotics, skin incision antibacterial sealants, and antimicrobial dressings. It is the purpose of this review to study the evidence behind each of these measures and to evaluate relevant data for recommendations in each area. Methods: A systematic review of the literature through PubMed was performed. Results: Need for adequate dosing and re-dosing of intravenous peri-operative antibiotics, duration of antibiotic usage past wound closure, and the use of antibiotic bowel preparation in colorectal surgery are well defined in the published literature. However, data on local antimicrobial measures remain controversial. Conclusions: Proper dosing and re-dosing of prophylactic intravenous antibiotics should become standard practice. Continuation of intravenous antibiotic prophylaxis beyond wound closure is unnecessary in clean cases and remains controversial in clean-contaminated and complex cases. Oral antibiotic bowel preparation is an important adjunct to intravenous antibiotic prophylaxis in colorectal surgery. The use of topical antimicrobial and antiseptic agents such as antibacterial irrigations, local antimicrobial application, antimicrobial-coated sutures, antibacterial wound sealants, and antimicrobial impregnated dressings in the prevention of SSI is questionable. In 2002, surgical site infections (SSI) were noted by the U.S. Centers for Disease Control (CDC) to be the second most common cause of hospital-acquired infections (HAI). With an estimated incidence of nearly 300,000, this represents 22% of all HAI and complicates nearly 2% of monitored surgical procedures [1.. Surgical site infections substantially increase morbidity and mortality rates for patients undergoing surgery. Patients with SSI have been estimated to be 60% more likely to require intensive care, five times more likely to require readmission, and twice as likely to succumb to their disease process [2]. Additionally, the impact on overall healthcare costs is tremendous [2 6]. With such an impact, it is no surprise that the prevention of SSI has been a topic of extensive interest. The mainstay of SSI prevention remains peri-operative intravenous antibiotic prophylaxis. When administering peri-operative antibiotics, certain tenants of administration should be considered to optimize effectiveness. The Surgical Infection Prevention Program (SIP) started in 2004 and supplanted by the Surgical Care Improvement Project (SCIP) in 2006 have emphasized choice of antibiotic for the procedure performed, appropriate timing of intravenous administration, and timely discontinuation of prophylaxis. Appropriate dosing of the intravenous antibiotic and re-dosing during surgery were not addressed by SIP or SCIP. Adjunct antiseptic measures to intravenous antibiotic prophylaxis that would enhance the prevention of SSI have been evaluated. These measures include oral antibiotic bowel preparation in colorectal surgery, antiseptic/antimicrobial irrigation, antimicrobial sutures, local antibiotics, skin incision sealants, and antimicrobial dressings. Data on some of these measures are not definitive at this point and as such no unified guideline exists. It is the purpose of this review to address important considerations in intravenous antibiotic prophylaxis not specifically addressed by SCIP and to review the evidence behind adjunct antimicrobial measures. In our review, we only considered best evidence consisting of randomized trials, meta-analysis, and reviews of the topic. Parenteral Prophylactic Antimicrobial Agents In the sentinel publication by Mangram et al. [7] of The Hospital Infection Control Practices Advisory Committee, 1 Veterans Administration Boston Health Care System, West Roxbury, Massachusetts. 2 Department of Surgery, Boston University, Boston, Massachusetts. 275

2 276 O NEAL AND ITANI the goals for maximizing the benefits of peri-operative surgical antimicrobial prophylaxis were outlined as follows: 1) Use antimicrobial agents for all operations in which use of antimicrobial agents have been shown to reduce SSI rates based on evidence from clinical trials or for those operations after which incisional or organ/space SSI would represent a catastrophe. 2) Use an antimicrobial agent that is safe, inexpensive, and bactericidal with an in vitro spectrum that covers the most probable intra-operative contaminants for the operation. 3) Time the infusion of the initial dose of antimicrobial agent so that a bactericidal concentration of the drug is established in serum and tissues by the time the skin is incised. 4) Maintain therapeutic levels of the antimicrobial agent in both serum and tissues throughout the operation and until, at most, a few h after the incision is closed in the operating room. Although the first three points were addressed by SCIP, the last one was not and remains poorly addressed in practice. In order to obtain appropriate therapeutic levels, the proper dose of the intravenous prophylactic antibiotic should be administered. This becomes even more important with the growing epidemic of obesity. When determining an appropriate dose of peri-operative antibiotic for individuals weighing more than 30% over their ideal body weight, it is useful to calculate a more appropriate dosing weight. The dosing weight can be calculated as ideal body weight + (0.4 (total body weight ideal body weight)). In obese patients undergoing gastric surgery, blood and tissue levels of cefazolin were consistently below the minimal inhibitory concentration (MIC) for pathogens prone to causing SSI in patients who received one-gram versus twogram prophylaxis [8]. In 2004, Edmiston et al. evaluated the percentage of patients with therapeutic levels of cefazolin in the serum and tissues including skin incision, subcutaneous fat, and omentum. Patients were given a two-gram dose just prior to incision and a second dose 3 h after incision. Patients were subdivided into groups with a body mass index (BMI) of A: 40 49, B: 50 59, and C: 60. Therapeutic serum concentrations were achieved in 73%, 68%, and 52% in groups A, B, and C, respectively. Therapeutic tissue concentrations were achieved in 48%, 29%, and 10% in groups A, B, and C. These data illustrate the possible inadequacies in peri-operative antibiotic dosing based on weight and the need for individualized adjustments in peri-operative prophylaxis tactic [9]. Weight-based dosing for commonly used intravenous prophylactic antibiotics is provided in Table 1. It is our opinion that re-dosing of intravenous prophylactic antibiotics based on the guidelines provided above is more important than the continuation of antibiotics after closure of the incision in the operating room. This opinion is based on evidence that demonstrates that antimicrobial prophylaxis after surgical incision closure is unnecessary [7,10 16]. In addition to the lack of benefit of providing an extended period of post-operative antibiotics, there is concern that prolonged use of antibiotics results in the emergence of resistant organisms as well as the development of Clostridium difficile. For this reason, the SCIP guidelines have recommended that peri-operative antibiotic prophylaxis should not be extended beyond 24 h. The one exception is with cardiothoracic surgery where an extended period of post-operative prophylaxis up to 48 h was accepted. When considering cardiac procedures, multiple studies have pointed to the possible benefit for antibiotic prophylaxis up to and past 24 h. In a study by Tamayo et al., 838 patients were randomized to a single dose of cefazolin versus 24-h administration. Patients receiving single-dose prophylaxis suffered an 8.3% rate of SSI, whereas patients receiving a full 24 h of post-operative coverage only developed SSI in 3.6% of the cases [17]. In 2012, Lador et al. published a meta-analysis of 59 trials showing a risk ratio of 1.83 of developing deep sternal wounds in patients who received single-dose prophylaxis versus prophylaxis of 48 h duration post-operatively [18]. Table 1. Suggested Initial Dose and Time to Redosing for Antimicrobial Drugs Commonly Utilized for Surgical Prophylaxis* Antimicrobial agent Standard dose a recommendation b Weight-based dose Recommended redosing interval, c h Cefazolin 1 2 g iv mg/kg (if <80 kg, use 1g; 2 5 if >80 kg, use 2g) Cefoxitin 1 2 g iv mg/kg 2 3 Cefotetan 1 2 g iv mg/kg 3 6 Ciprofloxacin 400 mg iv 400 mg 4 10 Clindamycin 900 mg iv If <10 kg, use at least 37.5 mg; 3 6 if >10 kg, use 3 6 mg/kg Erythromycin base 1 g po 19, 18, and 9 13 mg/kg NA 9 h before surgery Neomycin 1g po 19, 18, and 20 mg/kg NA 9 h before surgery Metronidazole g iv 15 mg/kg initial dose (adult); mg/kg on subsequent doses Vancomycin 1 g iv mg/kg (adult) 6 12 *Adapted from Bratzler and Houck [80]. a Dose may vary with renal function. b Data are primarily from published pediatric recommendations. c For procedures of long duration, antimicrobial agents should be readministered at intervals of one to two times the half-life of the drug. The intervals in the table were calculated for patients with normal renal function.

3 ANTIMICROBIAL AGENTS IN SSI PREVENTION 277 It is of note that proper dosing and re-dosing of prophylactic intravenous antimicrobial agents in these studies were not taken into consideration. In reviewing duration of post-operative antibiotic prophylaxis, it is not clear if duration of administration should change based on the type of case including clean versus clean-contaminated and complex cases. Clean cases Southwell-Keely et al. performed a meta-analysis reviewing 15 randomized controlled trials of patients undergoing hip fracture surgery comparing individuals who received perioperative antibiotics versus placebo and individuals who received single-dose prophylaxis versus multiple post-operative dose regimens. Their conclusion was that antibiotic prophylaxis substantially reduced the rate of wound infection and that one dose intravenous antibiotic prophylaxis seemed no different than multiple post-operative dose regimens [19]. This data is further supported by Glenny and Song, who performed a comparable review of 25 randomized controlled trials in patients undergoing total hip replacement. Antibiotic regimens in these trials lasted anywhere from single dose prophylaxis to a total of 14 d of post-operative prophylaxis. Again, the conclusion was that single-dose or short-term administration is as effective as long-term administration. This review further concluded that single-dose administration would lower overall cost and may reduce the risk of toxicity and the development of bacterial resistance [20]. Clean-contaminated cases Data for clean-contaminated cases is somewhat mixed. In a randomized, multi-center trial, Fujita et al. randomized 190 patients to a single-dose regimen of cefmetazole versus a three-dose regimen in 187 patients. This study revealed a 14% versus 4% incidence of incisional SSI but no difference in organ/space infection [21]. Conversely, in 2011, Suzuki et al. published a similar randomized, clinical trial comparing 179 patients who received a single dose of flomoxef versus 181 patients who received a dose of flomoxef twice daily through post-operative day three after surgery for colorectal cancer. They concluded that a single dose of intravenous antibiotic immediately before surgery is sufficient prophylaxis in elective colon cancer surgery [22]. Incidentally, patients in both studies received mechanical bowel preparation whereas antibiotic bowel preparation was only implemented in the Suzuki trial. Complex cases When considering complex cases, the use of multiple dose regimens does not appear to provide additional benefit over single-dose regimens. A review by McDonald et al. evaluated multiple studies in which patients undergoing major surgery received single-dose regimens versus multiple dose regimens. They concluded that there was no clear advantage of multiple dose regimens over single-dose regimens. Furthermore, subgroup analysis did not show any difference between single-dose regimens versus multiple dose regimens lasting less than 24 h or more than 24 h. Multiple different antibiotic selections were included in this review and did not alter the conclusions in subgroup analysis [23]. In a more recent study, Mohri et al. performed a multi-center, randomized trial in which patients undergoing gastric cancer surgery were randomized to single-dose versus multiple-dose regimens. Of the 243 patients in each arm of the study, there was no statistically significant difference in the rate of SSI [24]. Oral Antibiotic Bowel Preparation In 2011, Fry provided an excellent overview of the historical aspects and current status of oral antibiotics bowel preparation [25]. As a concept, it is accepted that oral antibiotics reduce the inoculums of bacteria contaminating the surgical site from the colon, and that systemic antibiotics provide a safety net of effective drug in the soft tissues to minimize the risk of infection. Like mechanical bowel preparation of the colon, oral antibiotic use has fallen out of favor and has been abandoned by many surgeons. In a recent study by Lewis [26], patients randomized to receive oral antibiotics had a 5% incidence of SSI compared with 17% in the control group, which received a placebo. In the same study, a meta-analysis of aggregated studies demonstrated a summary odds ratio of 0.47 (95% CI: ) in favor of using combined systemic antibiotics with the oral antibiotics bowel preparation. In another study, a propensity analysis of elective colon resection patients from a prospectively gathered state wide database in Michigan showed a 12% SSI rate for patients receiving only pre-operative systemic drugs, whereas systemic drugs plus the oral antibiotic bowel preparation resulted in 4.5% SSIs [27]. In the most recent study on this topic published from the Veterans Administration Hospital system, an adjusted analysis showed that oral antibiotics use resulted in a 67% decrease in SSI occurrence (OR = 0.33, 95% CI ). Oral antibiotics and mechanical bowel preparation resulted in a 57% decrease in SSI occurrence (OR = 0.43, 95% CI ). Hospitals with more oral antibiotic use had lower SSI rates [28]. Strong historical and more recent evidence suggest that the use of oral antibiotic bowel preparation is important in the prevention of SSI in colorectal surgery. Other Adjunct Antiseptic SSI Preventive Measures As data is not currently clear on the use of local antimicrobial agents in surgical incisions, there are no systematic recommendations on their usage. Adjunctive local antiseptic/ antimicrobial agents such as antiseptic irrigation, topical antibiotics, and impregnated dressings have historically and continue to be sporadically employed by surgeons. Table 2 summarizes the studies evaluating the efficacy of local antimicrobial preventive measures. Antiseptic irrigation It has long been the practice of many surgeons to irrigate surgical incisions prior to closure. Oftentimes, surgeons will try to enhance a simple saline irrigation by mixing saline with an antiseptic or antibiotic. Multiple non-antibiotic, antiseptic irrigation solutions have been studied but with varying success. Povidone-iodine rinses have often been used by surgeons to sterilize surgical incisions. Harihara et al. set out to determine if this rinse actually works when applied to the skin around surgical incisions. One hundred and seven patients undergoing

4 278 O NEAL AND ITANI Table 2. Benefit of Locally Applied Antimicrobial Agents in the Prevention of Surgical Site Infections First author/year Intervention Predicted benefit (yes/no) Antimicrobial irrigation Sindelar 1979 Povidone-iodine irrigation in wound Yes Rice 2000 Tetracycline sclerotherapy No Cheng 2005 Povidone-iodine irrigation in wound Yes, Deep infection only Chang 2006 Povidone-iodine irrigation in wound Yes, Deep infection only Harihara 2006 Povidone-iodine irrigation to skin No Mohd 2010 Dermacyn super-oxidized water irrigation Yes Tijerina 2010 Topical ionized irrigation Trend Takesue 2011 Electrolyzed sodium chloride irrigation Trend but results in impaired wound healing Local antibiotics Clean cases Musella 2001 Gentamicin-laced collagen Yes Eklund 2007 Gentamicin-laced collagen No Frieberg 2007 Gentamicin-laced collagen Yes Frieberg 2009 Gentamicin-laced collagen Yes Praveen 2009 Gentamicin irrigation No Bennett-Guerrero 2010 Gentamicin-laced collagen No Yetim 2010 Gentamicin-laced collagen Yes Bakhsheshian 2015 Vancomycin powder Yes Local antibiotics Clean-contaminated cases Gruessner 2001 Gentamicin-laced collagen Yes Charalambous 2003 Ampicillin irrigation Yes but No incremental effect over IV alone Haase 2005 Gentamicin-laced collagen No Neri 2008 Topical rifamycin Yes Bennett-Guerrero 2010 Gentamicin-laced collagen No, more SSI with the sponge De Bruin 2010 Gentamicin-laced collagen Yes Yetim 2010 Gentamicin-laced collagen Yes Ruiz-Tovar 2012 Gentamicin/Clindamycin abdominal irrigation Yes Antimicrobial coated sutures Rozelle 2008 Triclosan-coated suture (CSF shunt) Yes Deliaert 2009 Triclosan-coated suture (Breast) No, more dehiscence with triclosan Justinger 2009 Triclosan-coated suture (Laparotomy) Yes Mingmalairak 2009 Triclosan-coated suture (Appendix) No, more SSI with triclosan Galal 2011 Triclosan-coated suture ( Multiple sites) Yes Zhang 2011 Triclosan-coated suture (Breast) Trend Raš ic 2011 Triclosan-coated suture (Colon) Yes Williams 2011 Triclosan-coated suture (Breast) Trend Baracs 2011 Triclosan-coated suture (Colon) No Isik 2012 Triclosan-coated suture (Sternum/Leg) Trend Seim 2012 Triclosan-coated suture (Leg) No Turtianinen 2012 Triclosan-coated suture (Leg) No Thimour-Bergström 2013 Triclosan-coated suture (Leg) Yes Nakamura 2013 Triclosan-coated suture (Colon) Yes Justinger 2013 Triclosan-coated suture (Laparotomy) Yes Diener 2014 Triclosan-coated suture (Laparotomy) No Wound sealants Chambers 2010 Cyanoacrylate sealant Yes Iyer 2011 Cyanoacrylate sealant Yes Von Eckardstein 2011 Cyanoacrylate sealant Yes Lipp 2011 Cyanoacrylate sealant No Vierhout 2014 Cyanoacrylate sealant Trend Antimicrobial dressing Storm-Versloot 2010 Silver-impregnated dressing No Biffi 2012 Silver-impregnated dressing Trend

5 ANTIMICROBIAL AGENTS IN SSI PREVENTION 279 gastric or colorectal surgery were randomized to povidoneiodine peri-incisional rinses versus none. Cultures of the peri-incisional skin showed decontamination when treated with povidone-iodine. This, however, did not translate into a reduction of SSI in these surgical incisions [29]. In 1979, Sindelar and Mason randomized 500 patients undergoing all classes of general surgical procedures including clean, clean-contaminated, and contaminated cases to surgical incision irrigation with saline alone versus dilute betadine solution. In that study, there was a substantial decrease in surgical site infection for all types of surgery with an overall decrease in surgical site infection from 15.1% to 2.9% in betadine-treated patients [30]. Two studies from Taipei Veterans General Hospital echo the benefit of povidone-iodine irrigation in patients undergoing spinal surgery. In 2005, Cheng et al. randomized 414 patients to surgical incision irrigation with betadine versus saline. One superficial infection and six deep infections were noted in patients in the saline alone group. No patients treated with betadine developed infection. Although not substantial for superficial infection, treatment with betadine was substantial for reducing the rate of deep infection [31]. In 2006, Chang et al. randomized 244 patients undergoing spinal surgery to surgical incision irrigation with betadine versus saline alone. Again, a substantial decrease in deep surgical incision infections from 4.8% to 0% was noted when betadine irrigation was used [32]. A newer antiseptic agent, Dermacyn super-oxidized water, was compared with povidone-iodine by Mohd et al. as an antiseptic irrigation for median sternotomy surgical incisions. Eighty-eight patients were randomized to the Dermacyn irrigation and 90 patients were randomized to povidone-iodine irrigation. Sixteen percent of patients receiving povidone-iodine irrigation developed sternal infections whereas only 6% of patients receiving Dermacyn developed sternal infections [33]. In a study by Takesue et al., 291 patients undergoing colorectal surgery were randomized to surgical incision irrigation with electrolyzed sodium chloride creating a strongly acidic aqueous solution versus simple saline solution. Results showed a trend towards less surgical site infection; however, the acidic solution resulted in impaired surgical incision healing [34]. A 2010 paper by Tijerina et al. evaluated differences in surgical site infection rates by randomizing 529 patients with non-perforated appendicitis to either saline irrigation or topical ionized solution. Although the study did not reach statistical significance, Tijerina showed a trend to lower SSI incidence when topical ionized solution was employed over simple saline solution [35]. In 2000, Rice et al. evaluated topical tetracycline irrigation following mastectomy. In this prospective, randomized trial, tetracycline irrigation was not superior to simple irrigation with saline [36]. Local/topical antibiotics Local antibiotic irrigations have long been used by surgeons. Nonetheless, data regarding the use of these irrigation solutions and topical antibiotics are controversial. This is the case for irrigation of both clean and clean-contaminated surgical incisions. Clean cases In a comparison of intravenous versus local antibiotic prophylaxis for open herniorrhaphy, Praveen et al. randomized 202 patients to intravenous gentamicin or locally applied gentamicin alone. Their conclusion revealed no difference between the rates of SSI in either group, thus showing no increased benefit of local gentamicin administration [37]. Conversely, in a randomized, controlled trial, 595 patients undergoing herniorrhaphy with mesh were randomized to parenteral ceftriaxone alone versus parenteral ceftriaxone accompanied by a gentamicin-laced tampon placed adjacent to the mesh in the inguinal canal. By adding the local antibiotic, Musella et al. observed a decrease in SSI rate from 2% to 0.3%, p = 0.04 [38]. Multiple studies have evaluated the effectiveness of these gentamicin-laced sponges on sternal surgical incisions. In a large randomized-controlled trial, Bennett-Guerrero et al. randomized 1,502 cardiac surgery patients considered highrisk because of their comorbid diagnosis of diabetes mellitus or obesity. In addition to the standard parenteral antibiotic administered, the treatment group received gentamicin-laced collagen near the sternum. In this study population, there was no substantial difference in the rates of superficial or deep sternal surgical incision infection [39]. Similar findings were achieved in a study by Eklund et al. in which 272 patients undergoing CABG had gentamicinlaced collagen implants at the sternum versus 270 patients who did not receive antibiotic-laced implants. Although 4% of study group patients versus 5.9% control group patients developed SSI, this difference did not achieve statistical significance [40]. Yet another study evaluating gentamicin-impregnated collagen implants found a substantial impact when 1950 patients were randomized to antibiotic implants versus no implant at all. In this study by Friberg in Sweden, 9% of control group patients developed sternal surgical incision infections versus 4.3% of patients in the study group [41]. Friberg followed 2 y later with a second, prospective, twocenter trial in which 1331 patients were given gentamicin implants versus the control group from the previous study. Again, a statistically significant reduction of sternal surgical incision infections was observed with an overall infection rate of 3.7% in the gentamycin implant group [42]. Gentamicin-collagen has also been trialed in patients undergoing modified radical mastectomy. Although a small study in which 22 patients were randomly assigned to a control group versus 22 patients in the gentamicin-collagen group, Yetim et al. were successful in showing a statistically significant protective effect of gentamicin-collagen implants with four surgical incision infections in the control group and no infections in the study group [43]. Multiple studies in the spinal surgery literature have evaluated the effectiveness of vancomycin powder in reducing surgical site infection. A meta-analysis by Bakhsheshian et al. showed a statistically significant benefit with use of vancomycin powder in reducing the incidence of superficial and deep surgical site infections. Studies evaluating deep surgical site infection alone showed an odds ratio of developing infection of 0.23 with the use of vancomycin powder, whereas studies evaluating superficial and deep surgical site

6 280 O NEAL AND ITANI infection showed an odds ratio of 0.43 with the use of vancomycin powder [44]. Various prosthetics including meshes, orthopedic prostheses, and cement impregnated with different antimicrobial agents are available. Small studies with these products have shown mixed results. Details regarding these products are beyond the scope of this review. Clean-contaminated cases Charalambous et al. performed a meta-analysis published in 2003 summarizing randomized controlled trials in which ampicillin was used in the irrigation solution in cleancontaminated cases such as appendectomy and colorectal surgery. It was determined that topical antibiotic did reduce SSI rates with an odds ratio (OR) of 0.084, p < when compared with patients who received no antibiotic prophylaxis at all. This meta-analysis did not, however, show a statistically significant improvement in SSI when ampicillinimpregnated irrigation was used in conjunction with parenteral antibiotics versus parenteral antibiotics alone (OR 0.927, p = 0.90). Hence, it was concluded that topical ampicillin improved rates of SSI, but there was no incremental benefit when used adjunctively with systemic antibiotics [45]. Umbilical port site infections are not uncommon occurrences. Neri et al. randomized 48 patients to a rigorous regimen of pre-, peri-, and post-operative local rifamycin application to umbilical port sites in patients undergoing laparoscopic cholecystectomy for cholecystitis. They found that patients treated with this local antibiotic had a lower incidence of port site infection compared with patients who did not receive this local antibiotic [46]. Gentamicin-collagen sponges have been studied for cleancontaminated cases by a number of groups. Bennett-Guerrero et al., in 2010, randomized 602 patients undergoing colorectal surgery to parenteral antibiotics alone versus local antibiotics supplemented with a gentamicin-rich collagen sponge that was implanted above the abdominal fascia prior to surgical incision closure. Surprisingly, this antibioticimpregnated sponge increased the rate of SSI from 20% in patients not given the sponge to 30% in patients who did receive the sponge. Additionally, it was noted that patients who received the sponge were nearly twice as likely to be rehospitalized for surgical incision infections [47]. Although Bennett-Guerrero et al. showed increase in SSI with the use of gentamicin-collagen sponge for primary colorectal incisions, Gruessner et al. showed the opposite when used in the perineal incisions of abdominoperineal (APR) resections for rectal cancer. When applied to the perineal surgical incisions in patients undergoing APR, this group not only documented lower bacterial loads in the drainage of these surgical incisions, they also found that patients who received the gentamicin-impregnated collagen had a 6% incidence of surgical incision infection versus 21% in control patients [48]. Loop-ileostomy sites have been particularly problematic with frequent development of surgical site infection. This has resulted in a wide range of closure techniques including primary closure, delayed-primary closure, and closure by secondary intention. The Haase group has attempted reduction of SSI in these surgical incisions with similar gentamicin implants. With standardized peri-operative management and closure techniques, 40 patients were closed with gentamicinimpregnated implants, whereas 40 patients received the same collagen implants with no antibiotic. Identical rates of infection were observed in both groups [49]. Other groups have studied gentamicin-impregnated collagen. Yetim et al., for example, have trialed these collagen sponges in patients undergoing pilonidal cyst excision. In an unusual comparison, this group randomized patients to 7 d of oral antibiotics versus implantation of the gentamicinimpregnated collagen at the presacral fascia. Interestingly, the group observed four times as many infections in the oral antibiotic group compared with the locally treated group. This study did not mention whether the patients received pre-operative parenteral antibiotic administration [50]. De Bruin and colleagues summarize nine papers in a metaanalysis collectively evaluating these gentamicin-impregnated collagen implants in high-risk gastrointestinal procedures. In this study totaling 483 patients, De Bruin et al. conclude that the implants reduce the risk of SSI by as much as 70% in the colorectal surgery population and may reduce the length of hospital stay by as much as 40% [51]. More recently, Ruiz-Tovar et al. randomized patients undergoing elective surgery for colorectal neoplasms to intraperitoneal irrigation with saline alone versus saline with gentamicin and clindamycin. This study found that the incidence of both surgical site infection and intra-abdominal infection were substantially reduced in the antimicrobial irrigation group. Incidence of surgical incision infection dropped from 14% to 4%, whereas incidence of intraabdominal infection dropped from 6% to 0% [52]. Antimicrobial sutures In addition to placing antimicrobial solutions and antibiotic formulations into surgical incisions, there has been recent enthusiasm with the development of antimicrobial coated sutures as a possible adjunct in reducing the rate of SSI. Unfortunately, the use of antimicrobial sutures in clinical trials has shown variable efficacy making a recommendation on their use difficult. Braided polyglactin 910 coated with the antimicrobial triclosan (Vicryl Plus Ethicon, Johnson & Johnson Company, Somerville, NJ) is the suture material most frequently studied. Triclosan is a broad-spectrum antiseptic effective at inhibiting the growth of Staphylococcus aureus, Staphylococcus epidermidis, and methicillin-resistant Staphylococcus aureus (MRSA) [53]. It seems to act by inhibiting enzymes involved in bacteria s fatty acid synthesis [54]. Triclosan has long been used in over-the-counter health care products and is not considered to be toxic. Furthermore, the tissue reaction, healing response, and absorption profile of Vicryl have not been affected by the addition of triclosan [55]. Deliaert et al. have postulated that one potential cofactor in the development of SSI is the actual use of suture material. This group sought to evaluate the efficacy of triclosan-coated sutures in reducing the incidence of SSI. In a study including 26 patients undergoing breast reduction surgery, one breast was randomized to standard suture material, whereas the opposite breast was closed using triclosan-coated sutures. Sixteen treatment breasts developed dehiscence but only

7 ANTIMICROBIAL AGENTS IN SSI PREVENTION 281 seven dehiscences were observed in control breasts. Thus, this study questioned the safety of triclosan-coated suture material [56]. Another study evaluating triclosan-coated suture, this time in patients undergoing appendectomy, randomized 100 patients to closure with standard Vicryl suture versus Vicryl Plus. The result was somewhat puzzling; not only was there no statistical significance in the reduction of SSI with Vicryl Plus, but there was actually a trend toward more SSI, 8% versus 10%, in the patients treated with coated suture [57]. Conversely, Rozzelle et al., a neurosurgery group in New York, evaluated Vicryl Plus in a prospective, double-blinded, randomized controlled trial assigning patients undergoing CSF shunt implantation to closure with either Vicryl or Vicryl Plus. Indeed, they revealed a much better SSI rate in the study group versus the control group, 4.3% versus 21%. Additionally, this study did not reveal any suture related adverse events [58]. In a Chinese study, Zhang et al. sought to evaluate the cosmetic results of Vicryl Plus in patients undergoing mastectomy. Comparison was made to Chinese silk. The Vicryl Plus suture resulted in much better cosmetic outcomes than Chinese silk. This study also showed a trend toward less SSI when Vicryl plus was used. This, however, may not be the best comparison as the control suture was not nonantimicrobial-coated Vicryl [59]. In 2009, Justinger et al. published a much larger study evaluating Vicryl Plus effectiveness in reducing rates of SSI in patients undergoing midline laparotomy to a historical cohort of patients undergoing closure with standard looped PDS suture. A much more varied study population was included. Operations ran the spectrum of clean, clean-contaminated, contaminated, non-emergent, and emergency operations. There were no statistical differences between the types of operations performed between the control and study groups. Patients with midline surgical incisions closed with the antibacterial-coated suture developed SSI in only about half the frequency as patient surgical incisions closed with standard PDS, 4.9% versus 10.8%, respectively [60]. Later in 2013, Justinger further honed his work by prospectively studying the specialized suture against a control group within the context of a more rigorously defined clinical pathway for abdominal wall closures in general and vascular surgery. Again, he showed a substantial reduction in SSI incidence from 11.3% to 6.4% [61]. Conversely, in the 2014 multi-center PROUD trial out of Germany, Diener et al. failed to show similar substantial results [62]. In a randomized trial, Galal et al. have broadened the use of Vicryl Plus in their study to include an extensively varied array of operations with multiple different incision configurations in clean, clean-contaminated, and contaminated surgical incisions. In this study, a direct comparison was made between Vicryl Plus used in the study group of 230 patients with standard Vicryl suture used in the control group of 220 patients. Again, the reduction in SSI rates was approximately half in the study group compared with the control group, 7% versus 15%, respectively. The Galal group further highlighted the impact of SSI on patient care by documenting a mean 3.7-d extension in hospital stay for their patients who developed SSI [63]. In 2011, Rasic et al., a Croatian group, evaluated the effectiveness of Triclosan-coated suture for closure of the abdominal wall in colorectal cancer cases. Ninety-one patients underwent closure with Triclosan-coated suture versus a control group of 93. Indeed, closures utilizing TriclosansutureshowedareductioninSSIfrom13.2%to 4.3% [64]. Conversely in the colorectal literature, Baracs et al. showed equivalent SSI rates of 12.2% when comparing midline closures using the two different sutures [65]. Later, in 2013, Nakamura et al. of Japan randomized 410 patients undergoing elective colorectal surgery to abdominal wall closures with Triclosan suture versus control and revealed a substantial reduction in SSI rates by more than half [66]. That same year, Williams et al. compared 150 patients undergoing breast surgery. Of 75 patients closed with Triclosan suture, 15.2% developed SSI, whereas of the 75 patients closed with standard suture, 22.9% developed SSI. Although not substantial, this trend showing benefit of the coated suture was suspected to fail statistical significance because of the power of the study [67]. Multiple studies in the cardiovascular literature have evaluated the effectiveness of Triclosan-coated suture. Again, these studies have achieved varying results. Isik et al. randomized both sternal surgical incision closures and lower extremity harvest site closures. Overall, the incidence off SSI dropped from 5.6% to 5.3% when Triclosan-treated suture was employed. Although a trend toward fewer SSIs was observed in both sternal surgical incisions and lower extremity incision sites, neither arm reached statistical significance [68]. Seim et al. evaluated lower extremity surgical incisions alone in patients undergoing coronary bypass surgery. Not only did they not show lower rates of SSI in the Triclosan treated group, they may have even observed a slight trend to more SSI with the Triclosan suture closed surgical incisions [54]. On the other side of the spectrum, Thimour- Bergstrom et al. revealed promising data in the lower extremity harvest site incisions of cardiac surgery patients. In this study, SSI was defined in three ways: 1) By CDC definition, 2) Culture proved, 3) Surgical incisions treated with antibiotics. In all three categories, substantially lower SSI rates were observed when the leg incisions were closed using the Triclosan sutures [69]. Finally, Turtianien et al. randomized lower extremity surgical incision closures in patients undergoing lower extremity revascularization procedures. In this study, the Triclosan group showed more SSI (22.3%) versus the control group (21.9%) [70]. Antimicrobial sealants Cyanoacrylate is a generic term referring to a class of compounds that readily polymerize to create sealants. The first cyanoacrylates were discovered in 1942 when searching for a compound that would form a solid adhesive for weapon development. Noted as a wondrous compound that stuck to everything it came into contact with, it quickly fell out of favor. With time, however, uses for these compounds were reexplored [71]. Perhaps the most well-known, household cyanoacrylate, ethyl-2-cyanoacrylate, is more commonly known as SuperGlue. In 1998, the Food and Drug Administration approved another cyanoacrylate, 2-octyl-cyanoacrylate, for use as a surgical incision sealant. More commonly known by trade names such as Dermabond (Ethicon, Somerville, NJ), this compound readily polymerizes when exposed to skin, blood, or moisture creating a barrier to the migration of

8 282 O NEAL AND ITANI bacteria into surgical incisions. Additionally, cytotoxic compounds released by this polymerization reaction exhibit bactericidal properties [72]. A number of studies have tried to ascertain if cyanoacrylates can effectively reduce the rate of SSI. Again, results have been mixed and study subject numbers small making it difficult to make a recommendation supporting the widespread use of this compound for the purpose of reducing SSI, particularly in light of its expense. In 2010, Chambers et al. performed a best evidence review evaluating the use of cyanoacrylate glue on sternal surgical incision infections. In this review, a substantial benefit reducing both superficial and deep surgical incision infections in cardiac surgery was observed when cyanoacrylate was applied post-operatively (4.9% versus 2.1%) or even preoperatively (10.8% versus 2.7% or 7.8% versus 1.1% depending on the study) [73]. Enthusiasm for applying these antimicrobial sealants immediately prior to incision has been particularly observed in the cardiothoracic literature. In 2011, Iyer et al. published a study evaluating patients undergoing cardiac bypass in which saphenous vein harvesting was performed bilaterally. In each patient, one leg was pre-treated with sealant whereas the contralateral leg was not pre-treated. Treated legs developed a 2% incidence of infection, whereas untreated legs became infected in 25% of patients. The study was terminated after 47 patients were enrolled [74]. A larger, randomized trial by von Eckardstein et al. comparing patients who underwent cardiac surgery, allocated 146 patients to pretreatment with cyanoacrylate sealant to sternal and graft harvest sites and 147 patients to no treatment. In this study, there was a 35% relative risk reduction in the rate of SSI in pretreated patients. Furthermore, in subgroup analysis, this study showed an 83% relative risk reduction in obese patients who received pre-treatment [75]. In 2010, Lipp et al. performed a systematic review submitted to the Cochran Database including all randomized trials evaluating the use of cyanoacrylate sealants as a pretreatment of skin incisions. Sufficient evidence supporting the use of such sealants was not found and studies noted to be lacking in rigor and quality [76]. In 2014, Vierhout et al. randomized 47 patients undergoing lower extremity revascularization surgery to closure with cyanoacrylate. Although there was a trend to less SSI (4% vs 9%), this study failed to reach statistical significance.[77] Impregnated dressings The 1999 Guideline for Prevention of Surgical Site Infection is clear in its recommendations for management of post-operative surgical incision dressings stating that surgical incisions should be protected with a sterile occlusive dressing for 24 to 48 h post-operatively [7]. Furthermore, when a dressing must be changed, sterile technique should be employed. Beyond simple sterile dressings, there has been question raised as to the benefit of enhancing dressings with antibacterial agents. In particular, a number of studies have attempted to show improved surgical incision healing and decreased SSI in surgical incisions treated with silver impregnated surgical incision dressings. It has long been believed that silver containing compounds have antibacterial properties. In 2011, the Cochrane Database released a review of sixteen randomized trials employing silver impregnated dressings. Unfortunately, it was noted that these trials were too small and of poor quality. It was concluded that there is no evidence that one type of dressing is better than another. In addition, one study even showed slowed surgical incision healing in patients treated with impregnated dressings [78]. In 2012, Biffi et al. again evaluated the use of silverimpregnated dressings in patients undergoing surgery for colorectal cancer. Fifty-eight patients surgical incisions were covered with silver-impregnated dressings and 54 patients surgical incisions were covered with standard dry sterile dressings. After a follow-up of 30 d, a trend to fewer surgical site infections were noted in the silver dressing group (15.5% vs 20.4%), but this was not statistically significant [79]. Conclusion Peri-operative intravenous antibiotics are important in the reduction of surgical site infection. In addition to the SCIP measures, proper dosing and re-dosing should become an established practice in every patient receiving intravenous prophylactic antibiotics. Continuation of intravenous antibiotic prophylaxis beyond surgical incision closure is unnecessary in clean cases and remains controversial in clean-contaminated and complex cases. Oral antibiotic bowel preparation is an important adjunct to intravenous antibiotic prophylaxis in colorectal surgery. On the other hand, evidence remains vague regarding topical antimicrobial and antiseptic agents such as antibacterial irrigations, local antibiotic application, antimicrobialcoated sutures, antibacterial surgical incision sealants, and antimicrobial impregnated dressings. Further rigorous testing is required before a directed recommendation can be made for universal implementation of such measures. Author Disclosure Statement Dr. O Neal does not have any conflicts to disclose. Dr. Itani s institution received support for research from Sanofi and Merck. References 1. Klevens RM, Edwards JR, Richards CL Jr, et al. Estimating health care-associated infections and deaths in U.S. hospitals, Public Health Rep 2007;122: Kirkland KB, Briggs JP, Trivette SL, et al. The impact of surgical site infections in the 1990s: Attributable mortality, excess length of hospitalization, and extra costs. Infect Control Hosp Epidemiol 1999;20: Burke JP. Infection control a problem for patient safety. N Engl J Med 2003;348: Martone WJ, Jarvis WR, Culver DH, Haley RW. Incidence and nature of endemic and epidemic nosocomial infections. In: Bennett JV, Brachman PS, (eds): Hospital infections. 3rd ed. New York: Little, Brown Medical Division, 1992: Hollenbeak CS, Murphy D, Dunagan WC, Fraser VJ. Nonrandom selection and the attributable cost of surgicalsite infections. Infect Control Hosp Epidemiol 2002;23:

9 ANTIMICROBIAL AGENTS IN SSI PREVENTION Perencevich EN, Sands KE, Cosgrove SE, et al. Health and economic impact of surgical site infections diagnosed after hospital discharge. Emerg Infect Dis 2003;9: Mangram AJ, Horan TC, Pearson ML, et al. Guideline for prevention of surgical site infection, Infect Control Hosp Epidemiol 1999;20(4): Forse RA, Karam B, MacLean LD, Christou NV. Antibiotic prophylaxis for surgery in morbidly obese patients. Surgery 1989;106: Edmiston C, Krepel C, Kelly H, Larson J, et al. Perioperative antibiotic prophylaxis in the gastric bypass patient: Do we achieve therapeutic levels? Surgery. 2004;136(4): Page CP, Bohnen JM, Fletcher JR, et al. Antimicrobial prophylaxis for surgical wounds. Guidelines for clinical care. Arch Surg 1993;128: Dellinger EP, Gross PA, Barrett TL, et al. Quality standard for antimicrobial prophylaxis in surgical procedures. Infectious Diseases Society of America. Clin Infect Dis 1994; 18: American Society of Health-System Pharmacists. ASHP therapeutic guidelines on antimicrobial prophylaxis in surgery. Am J Health Syst Pharm 1999;56: Antimicrobial prophylaxis in surgery. Med Lett Drugs Ther 2001;43: Meijer WS, Schmitz PI, Jeekel J. Meta-analysis of randomized, controlled clinical trials of antibiotic prophylaxis in biliary tract surgery. Br J Surg 1990;77: Kreter B, Woods M. Antibiotic prophylaxis for cardiothoracic operations: Meta-analysis of thirty years of clinical trials. J Thorac Cardiovasc Surg 1992;104: McDonald M, Grabsch E, Marshall C, Forbes A. Singleversus multiple-dose antimicrobial prophylaxis for major surgery: A systematic review. Aust N Z J Surg 1998;68: Tamayo E, Gualis J, Florez S, et al. Comparative study of single-dose and 24-hour multiple-dose antibiotic prophylaxis for cardiac surgery. J Thorac Cardiovasc Surg 2008; 136: Lador A, Nasir H, Mansur N, et al. Antibiotic prophylaxis in cardiac surgery: Systematic review and meta-analysis. J Antimicrob Chemother. 2012;67: Southwell-Keely JP, Russo RR, March L, et al. Antibiotic prophylaxis in hip fracture surgery: A metaanalysis. Clin Orthop Relat Res. 2004;Feb: Glenny AM, Song F. Antimicrobial prophylaxis in total hip replacement: A systematic review. Health Technol Assess. 1999;3: Fujita S, Saito N, Yamada T, et al. Randomized, multicenter trial of antibiotic prophylaxis in elective colorectal surgery: Single dose vs 3 doses of a second-generation cephalosporin without metronidazole and oral antibiotics. Arch Surg. 2007;142: Suzuki T, Sadahiro S, Maeda Y, et al. Optimal duration of prophylactic antibiotic administration for elective colon cancer surgery: A randomized, clinical trial. Surgery 2011; 149: McDonald M, Grabsch E, Marshall C, Forbes A. Singleversus multiple-dose antimicrobial prophylaxis for major surgery: A systematic review. Aust N Z J Surg 1998;68: Mohri Y, Tonouchi H, Kobayashi M, et al. Randomized clinical trial of single- versus multiple-dose antimicrobial prophylaxis in gastric cancer surgery. Br J Surg 2007;94: Fry DE. Colon preparation and surgical site infection. Am J Surg. 2011;202: Lewis RT. Oral versus systemic antibiotic prophylaxis in elective colon surgery: A randomized study and metaanalysis send a message from the 1990s. Can J Surg 2002; 45: Englesbe MI, Brooks L, Kubus J, et al. A statewide assessment of surgical site infection following colectomy: The role of oral antibiotics. Ann Surg 2010;252: Cannon JA, Altom LK, Deierhoi RJ, et al. Preoperative oral antibiotics reduce surgical site infection following elective colorectal resections. Dis Colon Rectum 2012;55: Harihara Y, Konishi T, Kobayashi H, et al. Effects of applying povidone-iodine just before skin closure. Dermatology 2006;212: Sindelar WF, Mason GR. Irrigation of subcutaneous tissue with povidone-iodine solution for prevention of surgical wound infections. Surg Gynecol Obstet 1979;148: Cheng MT, Chang MC, Wang ST, et al. Efficacy of dilute betadine solution irrigation in the prevention of postoperative infection of spinal surgery. Spine 2005;30: Chang FY, Chang MC, Wang ST, et al. Can povidoneiodine solution be used safely in a spinal surgery? Eur Spine J 2006;15: Mohd AR, Ghani MK, Awang RR, et al. Dermacyn irrigation in reducing infection of a median sternotomy wound. Heart Surg Forum 2010;13:E228 E Takesue Y, Takahashi Y, Ichiki K, et al. Application of an electrolyzed strongly acidic aqueous solution before wound closure in colorectal surgery. Dis Colon Rectum 2011;54: Tijerina J, Velasco-Rodriguez R, Vasquez C, et al. Effectiveness of a systemic antibiotic followed by topical ionized solution as surgical site infection prophylaxis. J Int Med Res 2010;38: Rice DC, Morris SM, Sarr MG, et al. Intraoperative topical tetracycline sclerotherapy following mastectomy: A prospective, randomized trial. J Surg Oncol 2000;73: Praveen S, Rohaizak M. Local antibiotics are equivalent to intravenous antibiotics in the prevention of superficial wound infection in inguinal hernioplasty. Asian J Surg 2009;32: Musella M, Guido A, Musella S. Collagen tampons as aminoglycoside carriers to reduce postoperative infection rate in prosthetic repair of groin hernias. Eur J Surg 2001;167: Bennett-Guerrero E, Ferguson TB Jr, Lin M, et al. Effect of an implantable gentamicin-collagen sponge on sternal wound infections following cardiac surgery: A randomized trial. JAMA 2010;304: Eklund AM. Prevention of sternal wound infections with locally administered gentamicin. APMIS 2007;115: Friberg O. Local collagen-gentamicin for prevention of sternal wound infections: the LOGIP trial. APMIS 2007; 115: Friberg O, Dahlin LG, Kallman J, et al. Collagengentamicin implant for prevention of sternal wound infection; long-term follow-up of effectiveness. Interact Cardiovasc Thorac Surg 2009;9: Yetim I, Ozkan OV, Dervisoglu A, et al. Effect of local gentamicin application on healing and wound infection in