Preoperative skin antisepsis

When it comes to choosing a topical antiseptic for preoperative skin preparation that complies with SSI prevention guidelines, the options are limited. Current guidelines from the Centers for Disease Control and Prevention, Society for Healthcare Epidemiology of America, and Infectious Diseases Society of America call for an alcohol-containing preparation, based on alcohol’s highly bactericidal and rapid onset of action, along with an additive antiseptic that provides more persistent antisepsis.^1-2 In the US, the only commercially available preparations combining alcohol with an antiseptic for preoperative skin antisepsis include those with povidone iodine (PVI) or chlorhexidine gluconate (CHG). A study published in August 2019 by researchers from the University of Wisconsin and the University of Texas Southwestern, however, is poised to ‘expand the playing field’ and proponents of antiseptic stewardship are likely to think the timing could not be better.

The study, published in the journal Infection Control and Hospital Epidemiology, reports the results of two phase 2 trials assessing a novel topical skin antiseptic combining isopropyl alcohol with citrate, alkyl para-hydroxybenzoates, methylene blue (as a colorant), and purified water.³ In both trials, the novel formulation matched the efficacy of the widely-used 2% CHG/70% isopropyl alcohol formulation in achieving target post-application microbial reductions. Additionally, the formulation was effective even when suboptimal (shorter) application times were employed—a finding with practical implications for surgical practitioners given that compliance with application and dry-times have been reported to be as low as 24.6%.⁴

What makes this development noteworthy is the context of the current antiseptic landscape, particularly as it relates to CHG. CHG is a potent antiseptic with a broad spectrum of activity and a robust body of evidence supports its efficacy in reducing certain healthcare-associated infection risk.^5-8 CHG made its commercial debut in the 1950s in the UK and its use has grown exponentially ever since.⁹ Case in point: in 2013, a single regional hospital in Massachusetts reported 17 different applications of CHG, excluding the longstanding application of gingival and periodontal antisepsis.¹⁰ While none of the SSI guidelines preferentially recommend an additive antiseptic agent, market reports indicate 2% CHG/70% isopropyl alcohol products are among the most widely used topical skin preparations in the United States.¹¹ There is growing concern, however, surrounding the widespread use of CHG-containing products within the healthcare industry for two reasons:

1. reports of resistance/reduced susceptibility among clinical isolates in high-use settings, and
2. an up-tick in accounts of adverse events and allergic reactions. 

CHG resistance on the rise

Over the past eight to ten years, there has been increased detection of CHG resistance/reduced susceptibility within the acute care setting that appears to be associated with increased CHG exposure.^12-17 One of the first studies to demonstrate this came from a Taiwanese hospital in which CHG had been in use for hand hygiene for over 20 years.¹² The study, published in 2008, found that between 1990 and 2005, the percentage of MRSA isolates with reduced susceptibility to CHG rose from 1.7% to 46.7%.¹² Two years later, British researchers reported that use of CHG for MRSA decolonization in the ICU led to selection of a strain with CHG susceptibility three times lower than the other MRSA strains in the facility.¹³ Zhang et al reported that the prevalence of CHG-resistant genes in the skin commensal coagulase-negative staphylococci was significantly higher in nurses than in the general population (57% vs 14%, p<0.001), which they attributed to repeated exposure to CHG in the hospital environment.¹⁴

More recently, researchers from Johns Hopkins University studied CHG susceptibility in organisms causing central line-associated bloodstream infections (CLABSI) and found a 69% prevalence of reduced susceptibility.¹⁵ In units where CHG bathing was performed, organisms causing CLABSI were significantly more likely to have reduced susceptibility than in units without CHG bathing protocols (86% vs 64%, p=0.028).¹⁵ In a 2017 study, scientists identified a high prevalence of CHG-resistant genes (67% qac, 18% smr) in organisms recovered from the skin of patients with central venous catheters who wore CHG-impregnated dressings.¹⁶ The proportion of specimens with the qac resistance genes was significantly higher from patients who had worn the dressing for >72 hours compared with those with shorter exposure (p=0.04).¹⁶

Alarmingly, reports of cross resistance between CHG and certain antibiotics, including the last-resort antibiotic colistin, have also been published.^18-19 Taken together, these findings have led to a number of cautionary statements from experts in the field regarding judicious use of CHG and the need to champion “antiseptic stewardship.”^19-20

Adverse events/allergies

In 2017 the FDA issued a warning about allergic reactions with use of CHG based on a growing number of cases of CHG-induced anaphylaxis (FDA).²¹ Although the total number of cases is relatively small, it is widely acknowledged that they are on the rise—in fact, half of the reported anaphylaxis cases occurred since 2010 despite the fact that CHG has been available in the US since 1969.²¹

CHG can elicit other allergic reactions, including mild contact dermatitis and delayed or immediate hypersensitivity reactions, and sensitization appears to play a role.^22-23 A review of CHG allergy found that the majority of patients who experienced a serious allergic reaction to CHG reported minor symptoms upon previous exposure to the antiseptic.²³ Just how prevalent these allergies are remains unclear—a review of adverse events with CHG published in the journal Dermatitis reported that studies of CHG allergen series patch testing yield positive results in anywhere from 0.5 to 13.1% of the studied population.¹⁰ Most experts agree, however, that cases are likely underreported and are likely to increase in frequency given the extensive use of CHG in a variety of healthcare products and applications ^10,22

The perioperative setting is no exception to this trend.^22-24 One Danish study found that 9.6% of perioperative anaphylaxis cases were attributable to CHG allergy.²⁵ A 2015 literature review of chlorhexidine-induced anaphylaxis in surgical patients published in the journal of the Royal Australasian College of Surgeons found that 39.71% of affected patients had to have their procedures canceled and 27.94% resulted in unplanned ICU admissions.²⁶ The authors conclude that “rationalization” of CHG-containing products is needed to avoid the morbidity and mortality associated with CHG-induced anaphylaxis.²⁶

Looking to alternatives

Preoperative skin antisepsis—or “skin prep”—is a well-established surgical site infection (SSI) prevention measure. Multiple studies have demonstrated that antisepsis with an alcohol-based agent reduces the concentration of bacteria residing on the skin at the surgical site and results in significantly fewer SSIs,^1,27-28 but the spectrum of alcohol-based agents available in the US is small. Formulations combining alcohol with PVI are currently the only alternative to CHG-alcohol products. Though CHG may have longer residual activity than PVI,²⁹ to date there is insufficient high-quality evidence to support the superiority of either formulation in preventing SSI.^1-2

The authors of the ICHE article argue that “continued diversification of [the] topical antiseptic armamentarium” is imperative to mitigating the upward trend in both CHG resistance and allergy.³ Champions of antiseptic stewardship similarly argue that the healthcare community must be cautious with such a valuable weapon in order to preserve its efficacy.²⁰ With as many as 48 million surgical procedures performed in the US each year³⁰ and the average American undergoing 9.2 surgical procedures in their lifetime, according to a study published by the Massachusetts Chapter of the American College of Surgeons,³¹ it may indeed be time to grow the ‘team’ of topical antiseptics used for preoperative skin prep in an effort to steward existing topical antiseptics.

References:
1. Berrios-Torres SI, Umscheid CA, Bratzler DW, et al. Centers for Disease Control and Prevention guideline for the prevention of surgical site infection, 2017. JAMA Surg 2017; 152: 784-91.
2. Anderson DJ, Podgorny K, Berrios-Torres SI, et al. Strategies to prevent surgical site infections in acute care hospitals: 2014 update. Infect Control Hosp Epidemiol 2014; 35 suppl2: S66-S88.
3. Crnich CJ, Pop-Vicas AE, Hedberg TG, et al. Efficacy and safety of a novel antimicrobial preoperative skin preparation. Infect Control Hosp Epidemiol 2019; article in press. doi:10.1017/ice.2019.200.
4. El-Othmani MM, Mahmood BM, Pearson L, et al. Assessment of standardization in surgical site preparation: does a compliance culture exist? Int Surg J 2016; 3:1-10.
5. Edmiston CE, Bruden B, Rucinski MC, et al. Reducing the risk of surgical site infections: does chlorhexidine gluconate provide a risk reduction benefit? Am J Infect Control 2013; 41 suppl5: S49-S55.
6. Zhang TT, Tang SS, Fu LJ. The effectiveness of different concentrations of chlorhexidine for prevention of ventilator-associated pneumonia: a meta-analysis. J Clin Nurs 2014; 23:1461-1475.
7. O’Grady NP, Alexander M, Burns LA, et al. Guidelines for the prevention of intravascular catheter-related infections. Am J Infect Control 2011; 39 suppl 1: S1-S34.
8. Mimoz O, Lucet JC, Kerforne T, et al. Skin antisepsis with chlorhexidine-alcohol versus povidone iodine-alcohol, with and without skin scrubbing, for prevention of intravascular-catheter-related infection (CLEAN): an open-label, multicenter, randomized, controlled, two-by-two factorial trial. Lancet 2015; 386:2069-77.
9.  ChlorhexidineFacts.com About chlorhexidine: history of chlorhexidine. Available from: https://chlorhexidinefacts.com/history-of-chlorhexidine.html. Accessed 11 June 2019.
10. Silvestri DL, McEnery-Stonelake M. Chlorhexidine: uses and adverse reactions. Dermatitis 2013; 24(3): 112-18.
11. Adapted from GHX Database; Global Healthcare Exchange Market Intelligence Medical/Surgical Product Schema 2017.
12.  Wang JT, Sheng WH, Wang JL, et al. Longitudinal analysis of chlorhexidine susceptibilities of nosocomial methicillin-resistant Staphylococcus aureus isolates at a teaching hospital in Taiwan, J Antimicrob Chemother 2008; 62(3): 514-17.
13. Batra R, Cooper BS, Whitely C, et al. Efficacy and limitation of a chlorhexidine-based decolonization strategy in preventing transmission of methicillin-resistant Staphylococcus aureus in an intensive care unit. Clin Infect Dis 2010; 50(2): 210-7.
14. Zhang M, O’Donoghue MM, Hiramatsu K, et al. Prevalence of antiseptic-resistance genes in Staphylococcus aureus and coagulase-negative staphylococci colonizing nurses and the general population in Hong Kong. J Hosp Infect 2011; 78(2): 113-7.
15. Suwantarat N, Carroll KC, Tekle T, et al. High prevalence of reduced chlorhexidine susceptibility in organisms causing central line-associated bloodstream infections. Infect Control Hosp Epidemiol 2014; 35(9): 1183-186.
16. Choudhury MA, Sidjabat HE, Rathnayake IU, et al. Culture-independent detection of chlorhexidine resistance genes qacA/B and smr in bacterial DNA recovered from body sites treated with chlorhexidine-containing dressings. J Med Microbiol 2017; 66: 447-453.
17. Addetia A, Greninger AL, Adler A, et al. A novel, widespread qacA allele results in reduced chlorhexidine susceptibility in staphylococcus epidermis. Antimicrob Agents Chemother 2019; 63(6): e02607-18.
18. Wand ME, Bock LJ, Bonney LC, et al. Mechanisms of increased resistance to chlorhexidine and cross-resistance to colistin following exposure of Klebsiella pneumoniae clinical isolates to chlorhexidine. Antimicrob Agents Chemother 2016; 61: e01162-16.
19. Horner C, Mawer D, Wilcox M. Reduced susceptibility to chlorhexidine in staphylococci” is it increasing and does it matter? J Antimicrob Chemother 2012; 67(11): 2547-559.
20. Kampf G. Acquired resistance to chlorhexidine—is it time to establish an “antiseptic stewardship” initiative? J Hosp Infect 2016; 94:213-27.
21. U.S. Food and Drug Administration. FDA drug safety communication: FDA warns about rare but serious allergic reactions with the skin antiseptic chlorhexidine gluconate. 2017. Available from: https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-about-rare-serious-allergic-reactions-skin-antiseptic. Accessed 6 June 2019.
22. Moka E, Argyra E, Siafaka I, et al. Chlorhexidine: hypersensitivity and anaphylactic reactions in the perioperative setting. J Anaesthesiol Clin Pharmacol 2015; 31:145-48.
23. Abdallah C. Perioperative chlorhexidine allergy: is it serious? J Anaesthesiol Clin Pharmacol 2015; 31(2): 152-154.
24. Krishna MT, York M, Chin T, et al. Multi-centre retrospective analysis of anaphylaxis during general anaesthesia in the United Kingdom: aetiology and diagnostic performance of acute serum tryptase. Clin Exp Immunol 2014; 178:399-404.
25. Opstrup MS, Malling HJ, Kroigarrd M, et al. Standardized testing with chlorhexidine in perioperative allergy--a large single-centre evaluation. Allergy. 2014;69(100):1390.
26. Sharp G, Green S, Rose M. Chlorhexidine-induced anaphylaxis in surgical patients: a review of the literature. ANZ J Surg 2016; 86(4): 237-43.
27. Tuuli MG, Liu J, Stout MJ, et al. A randomized trial comparing skin antiseptic agents at cesarean delivery. New Eng J Med 2016; 374: 647-55.
28. Darouiche RO, Wall MJ, Itani KMF, et al. Chlorhexidine-alcohol versus povidone-iodine for surgical-site antisepsis. New Eng J Med 2010; 362: 18-26.
29. Maiwald M, Chan ESY. The forgotten role of alcohol: a systematic review and meta-analysis of the clinical efficacy and perceived role of chlorhexidine in skin antisepsis. PLoS One 2012; 7(9): e44277.
30. Stanford Healthcare. General Surgery: surgery statistics. Available from: https://stanfordhealthcare.org/medical-clinics/surgery-clinic/patient-resources/surgery-statistics.html. Accessed 25 September 2019.
31. American College of Surgeons, Massachusetts Chapter. How many surgical procedures will Americans experience in an average lifetime? Evidence from three states. Available from: https://mcacs.org/abstracts/2008/P15.cgi. Accessed 25 September 2019.