This article discusses benzalkonium chloride, within the context of its historical and clinical significance in association with its use in antiseptics, cosmetics, detergents, and topical medications.
Allergic contact dermatitis (ACD) is a socially and economically significant condition. It is estimated to affect more than 72 million Americans each year.1 In addition to physical morbidity, ACD can have a significant impact on quality of life leading to missed workdays and lost income, inability to enjoy leisure activities, and loss of sleep. Often, numerous doctor visits and medications result in significant expenditures for the patient before the underlying cause is discovered. In 2004, the total direct cost (eg, prescription drugs, office visits, etc.) associated with treatment for contact dermatitis was $1.6 billion, a number that continues to increase.1
Patch testing is the gold standard for ACD diagnosis.2 Once the offending allergen is identified, avoidance is critical for sustained remission. ACD is divided into 2 phases: sensitization (afferent) and elicitation (efferent). Exogenous antigens come into contact with antigen-specific T cells through defects in the epidermis, and induce sensitization. Damage to the skin is thought to be primarily mediated by CD4+ type 1 (Th1) cells and CD8+ T cytotoxic (Tc1) cells through a combination of inflammatory cytokine and cell-mediated cytotoxicity.3 However, because ACD has a delayed-onset (time between sensitization or exposure and elicitation of the dermatitis), associations between the 2 may be difficult to make. Therefore, when ACD is suspected, a patient-centered educational approach focusing on pathophysiology, risk of recurrence, and avoidance strategies should be initiated to break the ACD cycle.
Experimental studies indicate that antigenic potency, in addition to the concentration of antigen, are important factors in determining whether exposure to an antigen will result in sensitization. For weak allergens, exposures can occur over many years before a reaction develops. Alternatively, sensitization with strong allergens can occur more rapidly. If the skin barrier is compromised from chemical irritation, even a single exposure of a weak allergen could induce primary sensitization. Common preservatives such as benzalkonium chloride (BAK) are known to irritate the skin at high concentrations. This dose-dependent effect causes disorganization and thickening of subcellular structures, which leads to activation of prostaglandin E2, IL-1α, IL-6, and cell death.3
Isaac and colleagues retrospective chart review of patients patch tested for suspected ACD (N=615) concluded that the irritant nature of BAK may predispose patients who have dermatitis or compromised skin barriers to develop sensitization to this chemical.4
Additional studies have also suggested that BAK may be associated with inducing ACD in particular subgroups of patients such as health care workers and cosmetic users, and again in patients with compromised skin barriers.4,5 On the contrary, Basketter and colleagues, who exclusively reviewed published literature regarding a number of substances with the potential for inducing skin sensitization suggested that BAK was an extremely rare allergen, and that many of the “supposed cases of ACD” may have been based on misinterpretation of an irritant patch test result, and that further investigation was indicated.6 This article highlights BAK, within the context of its historical and clinical significance in association with its use in cosmetics, topical medicine, detergents, and antiseptics.
Antibacterial Sanitation
Inspired by Louis Pasteur’s discovery that microorganisms cause infection, Joseph Lister pioneered the practice of antiseptic surgical methods and “modern surgery.” Lister discovered that applying carbolic acid (phenol) as an antiseptic to surgical equipment and wounds significantly decreased the incidence of infection transmission and gangrene.7 Similar advancements were made during the 19th century by Florence Nightingale, who recognized the statistical benefits of sanitation in field hospitals for reducing mortality rates during the Crimean War.
However, it should be noted that before Pasteur’s famous pasteurization experiment that proved the germ theory, the concept of antiseptic practices such as hand-washing was initially taken with offense and met with great resistance by the medical community. Dr Ignaz Semmelweis was a Hungarian physician who discovered that the use of hand disinfection with chlorinated lime solutions prior to performing labor and delivery could significantly reduce mortality associated with puerperal fever (the so-called childbed fever). As a chief resident, Dr Semmelweis was astonished by the difference in mortality rates between 2 clinics that used the exact same protocols. The first and second clinics mortality rates were 10% and 4%, respectively.8 The findings were alarming considering that the first clinic was staffed by attending teaching faculty with medical student participation, while midwives staffed the second clinic. He eventually arrived at the conclusion that it was the physicians and medical students who were the cause for the increased mortality for transferring deadly “contaminants” from cadavers, with which midwives from the other clinic did not come into contact. By instituting a policy for all providers to wash hands with a calcium chlorite hypochlorite solution, mortality rate dropped to near zero and essentially eliminated childbed fever. Despite promising results with startling reductions in morbidity, Dr Semmelweis remained challenged by the scientific community until the day he was sent to an asylum where he died shortly thereafter at the age of 47.
The increased fervor among the health care community to mitigate disease transmission in the early 20th century led to widespread development and use of antiseptics and routine hand-washing with soap and water. The concept of antiseptics eventually led to the development of a myriad of popular antimicrobial products used today containing alcohol, chlorhexidine, chlorine, hexachlorophene, iodine, chloroxylenol, triclosan, and quaternary ammonium compounds such as BAK.9 While it is well recognized that the hands are a primary source of disease transmission, health care associated transmission of infections continue to rank high among challenges in modern medicine.
Benzalkonium Chloride
BAK is a quaternary ammonium cation that has been used historically for multiple purposes including cleansers, detergents, and preservatives found in ophthalmic solutions, inhalers, and topical antiseptic creams.10 Alternative names for BAK are shown in Table 1. It is known to elicit irritant contact dermatitis at aqueous solution concentrations of 0.5% and above.11 With prolonged exposure or in the setting of compromised skin barriers, BAK has also been shown to predispose individuals to sensitization and potentially induce ACD.4,11,12
In 1994, the FDA began to set guidelines for the use of antiseptics that do not require rinsing and drying. BAK was specifically designated under class III (insufficient data to classify its safety and effectiveness profile).13,14 More than 2 decades later, the guidelines have not changed.15 While the FDA commonly states that soap and running water remains “one of the most important steps consumers can take to avoid getting sick and to prevent spreading infections,” antiseptic hand sanitizers, which often contain BAK, remain highly used in the health care industries due to their unparalleled convenience.5,11
Hand Sanitizers
The implementation of widespread hand hygiene within health care settings marks a landmark milestone for infection control, with inclinations bent upon developing the most potent and broad-spectrum antibacterial formulation while minimizing irritancy potential. The 3 major categories of hand sanitizers include ethanol alcohol, quaternary ammonium, and triclosan-based products.16 While the use of cleansers and chemicals is a leading cause of ACD, hand sanitizers play a pivotal role in infection control for those working in health care institutions and the food industry.
Randomized control trials of 95 health care providers demonstrated that while there are no significant antimicrobial advantages between ethanol alcohol and BAK-based sanitizers and soap hand-washing, hand sanitizers have been shown to prevent hand dermatitis flares in patients.17,18 For example, Crawford and colleagues (N=350) who sought to determine the prevalence of hand dermatitis among massage therapists found that hand-washing was ranked as a leading cause for skin aggravation according to participant self-reports.18 Alcohol and nonalcohol, BAK-containing antiseptic products were preferred over traditional hand-washing with soap for their convenience and lack of need for drying, thus saving time and, more importantly, avoiding any further unwanted potential contact with contaminated drying surfaces. Waterless alcohol-based hand sanitizers are generally formulated with a concentration of 60% to 80% ethanol, isopropanol, or n-propanol, and function to denature pathogenic proteins in fungi and both gram-positive and gram-negative bacteria.16 While alcohol-based antiseptics have no documented accounts of resistance, they generally have poor coverage against bacterial spores, protozoan oocysts, and select nonenveloped viruses.
Unlike alcohol-based antiseptics that irritate the skin, BAK-based sanitizers have a relatively lesser extent of hand skin irritation and lack of residual staining on clothing and wooden surfaces.19,20 BAK dries on average an estimated 10 to 15 seconds slower than alcohol-based hand sanitizers, which inadvertently allows for a more efficacious coverage (up to 4 hours of residual protection) and minimizes the number of reapplications needed.21 On the contrary, alcohol-based sanitizers offer no residual protection after drying. Therefore, some studies would argue that alcoholic-based sanitizers may actually be inferior to BAK sanitizers, which increases its antimicrobial activity upon multiple consecutive applications.20 Additionally, BAK sanitizers can be safely used around electrocautery devices prevalent in hospital settings whereas alcoholic-based sanitizers have flammability concerns. See Table 2 for examples of hand sanitizers with and without BAK.
Mechanism of Action
Quaternary ammonium compounds induce leakage of cytoplasmic contents by disrupting the membranes of bacterial, fungal, and enveloped viral membranes. Similar to alcohol-based sanitizers, BAK sanitizers are capable of eliciting fungistatic and bacteriostatic effects against gram-positive and some gram-negative bacteria, and also has a weak profile against non-enveloped viruses. Notably, certain species of Staphylococcus aureus are resistant to quaternary ammonium compounds, making BAK a poor candidate in areas where methicillin-resistant S aureus is prevalent (eg, hospitals).22 In addition to ACD, data suggest BAK has the capability to induce moderate genotoxic effects on human cells, histologic changes in skin, and biofilm formation.23-26
Article continues on page 2
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BAK and ACD
BAK has been used as an antiseptic for more than 50 years in products, but skin irritation and the possibility of subsequent contact sensitization have led to greater surveillance of the preservative. A large retrospective analysis (N=42,898) of all patients tested with 0.1% BAK between 1996 and 2006 weakly supported the notion that BAK, although rare, was indeed a contact allergen.27 BAK’s irritant effects are particularly amplified within health care settings where occupational exposure and use of hand sanitizers and antiseptics is common practice.5,28 Increasing rate of positive allergic patch testing results among patients who underwent patch testing with 0.1% BAK have supported the notion that BAK is an allergen of increasing importance.11
Preservatives, utilized for their ability to inhibit growth of microorganisms, and thereby providing a longer product shelf life, are common allergens in cosmetics, skin moisturizers, cleansers, and hair products.15,29 While BAK is commonly used as a preservative in personal care and cosmetic products, its allergen prevalence is notably low in comparison to other preservatives (eg, methylchloroisothiazolinone).30,31 Of note, a retrospective analysis (N=1215) aimed to identify relevant allergens among patients with, specifically, allergic eyelid dermatitis concluded that BAK was a prevalent allergen at a much higher frequency of 8.7%.32 More importantly, the study also highlighted that the current FDA-approved panels available within the United States do not include a significant number of the allergens responsible for causing eyelid ACD.32
Who Is Affected By BAK?
Generally those who frequently use personal hygiene products, cosmetics, contact lens solutions, and hand sanitizers containing BAK (Table 3) are at a relatively higher risk for developing ACD than the general population.5 This correlates with a recent survey study that revealed among 11,979 products listed including contact lens solution, emollients and toothpaste, 17% contained BAK.33 A particularly large scale patch testing study (N=2611) contrasting incidence, location, and diagnosis of skin diseases concluded that health care workers (N=165) experienced significantly more occupational-related ACD than non-healthcare workers (N=2446).34 In fact, further data stratification demonstrated that individuals who developed ACD also had significantly increased exposures to allergens such as BAK, which was also not available on the “standard allergen series” used in the patch testing study. Table 4 discusses questions to elicit from those who may be at risk for BAK dermatitis.
Testing for BAK Sensitivity
Skin patch testing has been the gold standard in testing for ACD since its introduction by the famous German dermatologist, Josef Jadassohn, in 1895.35 Efficacy of the patch test depends on the skill of the provider, the appropriate timing of the patch readings (eg, at least 1 delayed reading between 96-120 hours), and the breadth of the allergens tested. It has been reported that less than 1% of dermatologists use comprehensive patch testing.36 In patch-test quality-control metrics performed by the North American Contact Dermatitis Group (NACDG), BAK was identified as a “problematic” patch test preparation with a “high proportion of weak, irritant, and questionable reactions that may or may not be true reactions to allergens.”37 Thus, evaluators should be well versed in identifying irritant reactions and false positives without overreading the patch test results.38 It is also vital that practitioners evaluate the patient’s history thoroughly to clinically correlate the possibility of false-negative findings.38
Considering that BAK is a well-characterized skin irritant, patch test reactions should be judiciously evaluated to confirm that the skin reaction is indeed allergen rather than irritant induced, as strong irritants may masquerade as skin allergens.6 For patients who test positive, Ale and Maibacht recommended repeating the patch testing to rule out false-positive reactions and performing a “use test” that involves directly applying an aqueous BAK solution 5 times a day for 4 consecutive days to the patient’s medial upper arm to determine if the patient was truly allergic to BAK.39,40 Because BAK is not currently included on the commercially available patch test kit,41 International Standard Series42, or the NACDG screening series [last used in the 2001-2002 testing period, but deleted from the 2003-2004 series]43), testing could be performed as an additional supplemental substrate if using these screening series as a baseline screen. Notably, BAK is included in the evidenced-based American Contact Dermatitis Society (ACDS) 80 Core Series.43
Appropriate screening with patch testing is essential for the specific diagnosis and management of ACD.44 Considering that patch testing is used as a diagnostic screening test, the efficacy of the test relies on its sensitivity from a statistical standpoint. Patch test sensitivity can be increased through minimizing the false-negative results by including a broader spectrum of highly suspect allergens associated with inducing ACD.
Extended patch testing is often needed, and the evidence-based ACDS core series includes many of the same allergens available on common standard patch test series (European Standard Series, Extended International Series, British Contact Dermatitis Society Series, etc.), while notably expanding the screening to include allergens tested in descending order of prevalence rates including acrylates, bacitracin, benzophenone, multiple corticosteroids, sorbitan, and BAK.45
A 5-year retrospective allergen patch testing study (N=3854) conducted by the Mayo Clinic from 2001 to 2005 analyzed the types of allergens and reaction rates, including those tested by the “standard series” panel, and concluded that BAK had a significantly higher positive patch test rate than the previously reported rate observed in the 1998 to 2000 testing period.46 That said, currently, the Mayo standard series does not include BAK, as prevalence rates and clinical relevance did not support its inclusion.47
Identifying an individual’s positive patch test to an allergen is only part of the equation. Clinical relevance determination must be assigned and appropriate avoidance measures instituted. It is vital in clinical relevance determination to test the patients’ own products to increase the patch test efficacy.
To clinically differentiate whether positive skin reactions were elicited by irritation or allergen effects, repeated open application test (ROAT) can be performed by reapplying the particular substance near the flexor aspect of the forearm (cubital fossa) twice a day for 7 consecutive days.48 Table 5 lists testing indications. ROAT is particularly useful for patients who are suspected to be allergic to product-based allergens that are neither commercially available nor routinely tested for on standard series. Hannuksela and Salo’s study proved the efficacy of ROAT by demonstrating that in a group of 86 patients with questionable patch test results, only 44% of the patients were truly positive for ACD.48 ROAT is particularly useful to test cosmetic products for its ability to mimic real-life exposures and confirm positive patch testing outcomes. Adjunct ROAT performed alongside standard patch testing improves patch test efficacy and simultaneously educates the patient in product evaluation.
Pearls of Treatment
Personal care products, medications, and household cleaning supplies contribute to a large fraction of ACD cases worldwide.49 Unfortunately, BAK’s widespread use in coatings, chemical industry, water treatment, aquaculture, timber, paper, textile, aftershaves, cosmetics, deodorants, eye-care solutions, softeners, and much more, makes it a difficult allergen to consistently avoid in sensitized patients. When it comes to BAK, use of protective gear (eg, nitrile gloves) when working with cleaning supplies and minimizing exposure on damaged skin, will decrease the risk of sensitization.
As with each exposure, there is an increased risk of reaching a point where the immune system meets its metaphorical “threshold,” whereby any subsequent exposures can elicit a cutaneous response.50,51 Just as repeated contact over time leads to sensitization and an unwanted immune response, repeated avoidance of an allergen through appropriate avoidance strategies leads to remission.
The Contact Allergen Management Program was developed by the ACDS with the mission to help patients with contact dermatitis effectively avoid allergens. This database contains full ingredients for more than 5000 commonly used products that is routinely updated by a dedicated team directed by Dr Andrew Scheman and Dave Seversen. While the advanced search function is catered toward health care providers familiar with the names of specific contact allergens, the streamlined mobile app is for patients to be able to narrow down exactly which products are safe for them to use. In fact, the companion mobile app allows patients to conveniently enter the name or brand of a specific product and determine if it contains any contraindicated allergens prior to purchase.52 Allergen identification is the key to avoidance.53 n
Mr Sung is with the school of medicine at the University of California, Riverside in Riverside, CA.
Dr Grigsby is with the internal medicine department at Loma Linda University in Loma Linda, CA.
Dr Lee is with Dermatology Skin and Surgery Center in Jackson, MI.
Dr Jacob, Section Editor of Allergen Focus, is a board-certified dermatologist and professor at Loma Linda University in Loma Linda, CA. She is founder and chief executive officer of the Dermatitis Academy public outreach education campaign.
Disclosure: The authors report no relevant financial relationships.
References
1. Bickers DR, Lim HW, Margolis D, et al; American Academy of Dermatology Association; Society for Investigative Dermatology. The burden of skin diseases: 2004 a joint project of the American Academy of Dermatology Association and the Society for Investigative Dermatology. J Am Acad Dermatol. 2006;55(3):490-500.
2. Weston WL, Weston JA, Kinoshita J, et al. Prevalence of positive epicutaneous tests among infants, children, and adolescents. Pediatrics. 1986;78(6):1070-1074.
3. Wolf R, Orion E, Matz H, Lipozencic J. Still elusive relationship between atopic dermatitis and allergic contact dermatitis. Acta Dermatovenerol Croat. 2003;11(4):247-250.
4. Isaac J, Scheinman PL. Benzalkonium chloride: an irritant and sensitizer [published online September 5, 2017]. Dermatitis. doi:10.1097/der.0000000000000316
5. Nettis E, Colanardi MC, Soccio AL, Ferrannini A, Tursi A. Occupational irritant and allergic contact dermatitis among healthcare workers. Contact Dermatitis. 2002;46(2):101-107.
6. Basketter DA, Marriott M, Gilmour NJ, White IR. Strong irritants masquerading as skin allergens: the case of benzalkonium chloride. Contact Dermatitis. 2004;50(4):213-217.
7. Saw NK, Hindmarsh JR. Acute irritant reaction to an antiseptic bath emollient. Postgrad Med J. 2005:81(952):131-32.
8. Noakes T, Borresen J, Hew-Butler T, Lambert M, Jordaan E. Semmelweis and the aetiology of puerperal sepsis 160 years on: an historical overview. Epidemiol Infect. 2008;136(1):1-9.
9. Larson E. A causal link between handwashing and risk of infection? Examination of the evidence. Infect Control Hosp Epidemiol. 1988;9(1):28-36.
10. Krob HA, Fleischer AB Jr, D’Agostino R Jr, Haverstock CL, Feldman S. Prevalence and relevance of contact dermatitis allergens: a meta-analysis of 15 years of published T.R.U.E. test data. J Am Acad Dermatol. 2004;51(3):349-353.
11. Wentworth AB, Yiannias JA, Davis MD, Killian JM. Benzalkonium chloride: a known irritant and novel allergen. Dermatitis. 2016;27(1):14-20.
12. Willis CM, Stephens JM, Wilkinson JD. Experimentally-induced irritant contact dermatitis. Determination of optimum irritant concentrations. Contact Dermatitis. 1988;18(1):20-24.
13. Visscher MO, Randall Wickett, R. Hand hygiene compliance and irritant dermatitis: a juxtaposition of healthcare issues. Int J Cosmet Sci. 2012;34(5):402-415.
14. Callahan A, Baron E, Fekedulegn D, et al. Winter season, frequent hand washing, and irritant patch test reactions to detergents are associated with hand dermatitis in health care workers. Dermatitis. 2013;24(4):170-175.
15. FDA requests additional information to address data gaps for consumer hand sanitizers [news release]. Silver Spring, MD: FDA; June 29, 2016. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm509097.htm. Accessed November 2, 2017.
16. Kampf G, Kramer A. Epidemiologic background of hand hygiene and evaluation of the most important agents for scrubs and rubs. Clin Microbiol Rev. 2004;17(4):863-893.
17. Therattil PJ, Yueh JH, Kordahi AM, Cherla DV, Lee ES, Granick MS. Randomized controlled trial of antiseptic hand hygiene methods in an outpatient surgery clinic. Wounds. 2015;27(12):347-353.
18. Crawford G, Katz KA, Ellis E, James WD. Use of aromatherapy products and increased risk of hand dermatitis in massage therapists. Arch Dermatol. 2004;140(8):991-996.
19. Chadwick S, Neskoski M, Spindler X, Lennard C, Roux C. Effect of hand sanitizer on the performance of fingermark detection techniques. Forensic Sci Int. 2017;273:153-160.
20. Dyer DL, Gerenraich KB, Wadhams PS. Testing a new alcohol-free hand sanitizer to combat infection. AORN J. 1998;68(2)239-241, 243-234, 247-251.
21. Smith K, Gemmell CG, Hunter IS. The association between biocide tolerance and the presence or absence of qac genes among hospital-acquired and community-acquired MRSA isolates. J Antimicrob Chemother. 2008;61(1):78-84.
22. Espigares E, Moreno Roldan E, Espigares M, et al. Phenotypic resistance to disinfectants and antibiotics in methicillin-resistant staphylococcus aureus strains isolated from pigs. Zoonoses Public Health. 2017;64(4):272-280.
23. Varani J, Perone P, Spahlinger DM, et al. Human skin in organ culture and human skin cells (keratinocytes and fibroblasts) in monolayer culture for assessment of chemically induced skin damage. Toxicol Pathol. 2007;35(5):693-701.
24. Ferk F, Misík M, Hoelzl C, et al. Benzalkonium chloride (BAC) and dimethyldioctadecyl-ammonium bromide (DDAB), two common quaternary ammonium compounds, cause genotoxic effects in mammalian and plant cells at environmentally relevant concentrations. Mutagenesis. 2007;22(6):363-370.
This article discusses benzalkonium chloride, within the context of its historical and clinical significance in association with its use in antiseptics, cosmetics, detergents, and topical medications.
Allergic contact dermatitis (ACD) is a socially and economically significant condition. It is estimated to affect more than 72 million Americans each year.1 In addition to physical morbidity, ACD can have a significant impact on quality of life leading to missed workdays and lost income, inability to enjoy leisure activities, and loss of sleep. Often, numerous doctor visits and medications result in significant expenditures for the patient before the underlying cause is discovered. In 2004, the total direct cost (eg, prescription drugs, office visits, etc.) associated with treatment for contact dermatitis was $1.6 billion, a number that continues to increase.1
Patch testing is the gold standard for ACD diagnosis.2 Once the offending allergen is identified, avoidance is critical for sustained remission. ACD is divided into 2 phases: sensitization (afferent) and elicitation (efferent). Exogenous antigens come into contact with antigen-specific T cells through defects in the epidermis, and induce sensitization. Damage to the skin is thought to be primarily mediated by CD4+ type 1 (Th1) cells and CD8+ T cytotoxic (Tc1) cells through a combination of inflammatory cytokine and cell-mediated cytotoxicity.3 However, because ACD has a delayed-onset (time between sensitization or exposure and elicitation of the dermatitis), associations between the 2 may be difficult to make. Therefore, when ACD is suspected, a patient-centered educational approach focusing on pathophysiology, risk of recurrence, and avoidance strategies should be initiated to break the ACD cycle.
Experimental studies indicate that antigenic potency, in addition to the concentration of antigen, are important factors in determining whether exposure to an antigen will result in sensitization. For weak allergens, exposures can occur over many years before a reaction develops. Alternatively, sensitization with strong allergens can occur more rapidly. If the skin barrier is compromised from chemical irritation, even a single exposure of a weak allergen could induce primary sensitization. Common preservatives such as benzalkonium chloride (BAK) are known to irritate the skin at high concentrations. This dose-dependent effect causes disorganization and thickening of subcellular structures, which leads to activation of prostaglandin E2, IL-1α, IL-6, and cell death.3
Isaac and colleagues retrospective chart review of patients patch tested for suspected ACD (N=615) concluded that the irritant nature of BAK may predispose patients who have dermatitis or compromised skin barriers to develop sensitization to this chemical.4
Additional studies have also suggested that BAK may be associated with inducing ACD in particular subgroups of patients such as health care workers and cosmetic users, and again in patients with compromised skin barriers.4,5 On the contrary, Basketter and colleagues, who exclusively reviewed published literature regarding a number of substances with the potential for inducing skin sensitization suggested that BAK was an extremely rare allergen, and that many of the “supposed cases of ACD” may have been based on misinterpretation of an irritant patch test result, and that further investigation was indicated.6 This article highlights BAK, within the context of its historical and clinical significance in association with its use in cosmetics, topical medicine, detergents, and antiseptics.
Antibacterial Sanitation
Inspired by Louis Pasteur’s discovery that microorganisms cause infection, Joseph Lister pioneered the practice of antiseptic surgical methods and “modern surgery.” Lister discovered that applying carbolic acid (phenol) as an antiseptic to surgical equipment and wounds significantly decreased the incidence of infection transmission and gangrene.7 Similar advancements were made during the 19th century by Florence Nightingale, who recognized the statistical benefits of sanitation in field hospitals for reducing mortality rates during the Crimean War.
However, it should be noted that before Pasteur’s famous pasteurization experiment that proved the germ theory, the concept of antiseptic practices such as hand-washing was initially taken with offense and met with great resistance by the medical community. Dr Ignaz Semmelweis was a Hungarian physician who discovered that the use of hand disinfection with chlorinated lime solutions prior to performing labor and delivery could significantly reduce mortality associated with puerperal fever (the so-called childbed fever). As a chief resident, Dr Semmelweis was astonished by the difference in mortality rates between 2 clinics that used the exact same protocols. The first and second clinics mortality rates were 10% and 4%, respectively.8 The findings were alarming considering that the first clinic was staffed by attending teaching faculty with medical student participation, while midwives staffed the second clinic. He eventually arrived at the conclusion that it was the physicians and medical students who were the cause for the increased mortality for transferring deadly “contaminants” from cadavers, with which midwives from the other clinic did not come into contact. By instituting a policy for all providers to wash hands with a calcium chlorite hypochlorite solution, mortality rate dropped to near zero and essentially eliminated childbed fever. Despite promising results with startling reductions in morbidity, Dr Semmelweis remained challenged by the scientific community until the day he was sent to an asylum where he died shortly thereafter at the age of 47.
The increased fervor among the health care community to mitigate disease transmission in the early 20th century led to widespread development and use of antiseptics and routine hand-washing with soap and water. The concept of antiseptics eventually led to the development of a myriad of popular antimicrobial products used today containing alcohol, chlorhexidine, chlorine, hexachlorophene, iodine, chloroxylenol, triclosan, and quaternary ammonium compounds such as BAK.9 While it is well recognized that the hands are a primary source of disease transmission, health care associated transmission of infections continue to rank high among challenges in modern medicine.
Benzalkonium Chloride
BAK is a quaternary ammonium cation that has been used historically for multiple purposes including cleansers, detergents, and preservatives found in ophthalmic solutions, inhalers, and topical antiseptic creams.10 Alternative names for BAK are shown in Table 1. It is known to elicit irritant contact dermatitis at aqueous solution concentrations of 0.5% and above.11 With prolonged exposure or in the setting of compromised skin barriers, BAK has also been shown to predispose individuals to sensitization and potentially induce ACD.4,11,12
In 1994, the FDA began to set guidelines for the use of antiseptics that do not require rinsing and drying. BAK was specifically designated under class III (insufficient data to classify its safety and effectiveness profile).13,14 More than 2 decades later, the guidelines have not changed.15 While the FDA commonly states that soap and running water remains “one of the most important steps consumers can take to avoid getting sick and to prevent spreading infections,” antiseptic hand sanitizers, which often contain BAK, remain highly used in the health care industries due to their unparalleled convenience.5,11
Hand Sanitizers
The implementation of widespread hand hygiene within health care settings marks a landmark milestone for infection control, with inclinations bent upon developing the most potent and broad-spectrum antibacterial formulation while minimizing irritancy potential. The 3 major categories of hand sanitizers include ethanol alcohol, quaternary ammonium, and triclosan-based products.16 While the use of cleansers and chemicals is a leading cause of ACD, hand sanitizers play a pivotal role in infection control for those working in health care institutions and the food industry.
Randomized control trials of 95 health care providers demonstrated that while there are no significant antimicrobial advantages between ethanol alcohol and BAK-based sanitizers and soap hand-washing, hand sanitizers have been shown to prevent hand dermatitis flares in patients.17,18 For example, Crawford and colleagues (N=350) who sought to determine the prevalence of hand dermatitis among massage therapists found that hand-washing was ranked as a leading cause for skin aggravation according to participant self-reports.18 Alcohol and nonalcohol, BAK-containing antiseptic products were preferred over traditional hand-washing with soap for their convenience and lack of need for drying, thus saving time and, more importantly, avoiding any further unwanted potential contact with contaminated drying surfaces. Waterless alcohol-based hand sanitizers are generally formulated with a concentration of 60% to 80% ethanol, isopropanol, or n-propanol, and function to denature pathogenic proteins in fungi and both gram-positive and gram-negative bacteria.16 While alcohol-based antiseptics have no documented accounts of resistance, they generally have poor coverage against bacterial spores, protozoan oocysts, and select nonenveloped viruses.
Unlike alcohol-based antiseptics that irritate the skin, BAK-based sanitizers have a relatively lesser extent of hand skin irritation and lack of residual staining on clothing and wooden surfaces.19,20 BAK dries on average an estimated 10 to 15 seconds slower than alcohol-based hand sanitizers, which inadvertently allows for a more efficacious coverage (up to 4 hours of residual protection) and minimizes the number of reapplications needed.21 On the contrary, alcohol-based sanitizers offer no residual protection after drying. Therefore, some studies would argue that alcoholic-based sanitizers may actually be inferior to BAK sanitizers, which increases its antimicrobial activity upon multiple consecutive applications.20 Additionally, BAK sanitizers can be safely used around electrocautery devices prevalent in hospital settings whereas alcoholic-based sanitizers have flammability concerns. See Table 2 for examples of hand sanitizers with and without BAK.
Mechanism of Action
Quaternary ammonium compounds induce leakage of cytoplasmic contents by disrupting the membranes of bacterial, fungal, and enveloped viral membranes. Similar to alcohol-based sanitizers, BAK sanitizers are capable of eliciting fungistatic and bacteriostatic effects against gram-positive and some gram-negative bacteria, and also has a weak profile against non-enveloped viruses. Notably, certain species of Staphylococcus aureus are resistant to quaternary ammonium compounds, making BAK a poor candidate in areas where methicillin-resistant S aureus is prevalent (eg, hospitals).22 In addition to ACD, data suggest BAK has the capability to induce moderate genotoxic effects on human cells, histologic changes in skin, and biofilm formation.23-26
Article continues on page 2
{{pagebreak}}
BAK and ACD
BAK has been used as an antiseptic for more than 50 years in products, but skin irritation and the possibility of subsequent contact sensitization have led to greater surveillance of the preservative. A large retrospective analysis (N=42,898) of all patients tested with 0.1% BAK between 1996 and 2006 weakly supported the notion that BAK, although rare, was indeed a contact allergen.27 BAK’s irritant effects are particularly amplified within health care settings where occupational exposure and use of hand sanitizers and antiseptics is common practice.5,28 Increasing rate of positive allergic patch testing results among patients who underwent patch testing with 0.1% BAK have supported the notion that BAK is an allergen of increasing importance.11
Preservatives, utilized for their ability to inhibit growth of microorganisms, and thereby providing a longer product shelf life, are common allergens in cosmetics, skin moisturizers, cleansers, and hair products.15,29 While BAK is commonly used as a preservative in personal care and cosmetic products, its allergen prevalence is notably low in comparison to other preservatives (eg, methylchloroisothiazolinone).30,31 Of note, a retrospective analysis (N=1215) aimed to identify relevant allergens among patients with, specifically, allergic eyelid dermatitis concluded that BAK was a prevalent allergen at a much higher frequency of 8.7%.32 More importantly, the study also highlighted that the current FDA-approved panels available within the United States do not include a significant number of the allergens responsible for causing eyelid ACD.32
Who Is Affected By BAK?
Generally those who frequently use personal hygiene products, cosmetics, contact lens solutions, and hand sanitizers containing BAK (Table 3) are at a relatively higher risk for developing ACD than the general population.5 This correlates with a recent survey study that revealed among 11,979 products listed including contact lens solution, emollients and toothpaste, 17% contained BAK.33 A particularly large scale patch testing study (N=2611) contrasting incidence, location, and diagnosis of skin diseases concluded that health care workers (N=165) experienced significantly more occupational-related ACD than non-healthcare workers (N=2446).34 In fact, further data stratification demonstrated that individuals who developed ACD also had significantly increased exposures to allergens such as BAK, which was also not available on the “standard allergen series” used in the patch testing study. Table 4 discusses questions to elicit from those who may be at risk for BAK dermatitis.
Testing for BAK Sensitivity
Skin patch testing has been the gold standard in testing for ACD since its introduction by the famous German dermatologist, Josef Jadassohn, in 1895.35 Efficacy of the patch test depends on the skill of the provider, the appropriate timing of the patch readings (eg, at least 1 delayed reading between 96-120 hours), and the breadth of the allergens tested. It has been reported that less than 1% of dermatologists use comprehensive patch testing.36 In patch-test quality-control metrics performed by the North American Contact Dermatitis Group (NACDG), BAK was identified as a “problematic” patch test preparation with a “high proportion of weak, irritant, and questionable reactions that may or may not be true reactions to allergens.”37 Thus, evaluators should be well versed in identifying irritant reactions and false positives without overreading the patch test results.38 It is also vital that practitioners evaluate the patient’s history thoroughly to clinically correlate the possibility of false-negative findings.38
Considering that BAK is a well-characterized skin irritant, patch test reactions should be judiciously evaluated to confirm that the skin reaction is indeed allergen rather than irritant induced, as strong irritants may masquerade as skin allergens.6 For patients who test positive, Ale and Maibacht recommended repeating the patch testing to rule out false-positive reactions and performing a “use test” that involves directly applying an aqueous BAK solution 5 times a day for 4 consecutive days to the patient’s medial upper arm to determine if the patient was truly allergic to BAK.39,40 Because BAK is not currently included on the commercially available patch test kit,41 International Standard Series42, or the NACDG screening series [last used in the 2001-2002 testing period, but deleted from the 2003-2004 series]43), testing could be performed as an additional supplemental substrate if using these screening series as a baseline screen. Notably, BAK is included in the evidenced-based American Contact Dermatitis Society (ACDS) 80 Core Series.43
Appropriate screening with patch testing is essential for the specific diagnosis and management of ACD.44 Considering that patch testing is used as a diagnostic screening test, the efficacy of the test relies on its sensitivity from a statistical standpoint. Patch test sensitivity can be increased through minimizing the false-negative results by including a broader spectrum of highly suspect allergens associated with inducing ACD.
Extended patch testing is often needed, and the evidence-based ACDS core series includes many of the same allergens available on common standard patch test series (European Standard Series, Extended International Series, British Contact Dermatitis Society Series, etc.), while notably expanding the screening to include allergens tested in descending order of prevalence rates including acrylates, bacitracin, benzophenone, multiple corticosteroids, sorbitan, and BAK.45
A 5-year retrospective allergen patch testing study (N=3854) conducted by the Mayo Clinic from 2001 to 2005 analyzed the types of allergens and reaction rates, including those tested by the “standard series” panel, and concluded that BAK had a significantly higher positive patch test rate than the previously reported rate observed in the 1998 to 2000 testing period.46 That said, currently, the Mayo standard series does not include BAK, as prevalence rates and clinical relevance did not support its inclusion.47
Identifying an individual’s positive patch test to an allergen is only part of the equation. Clinical relevance determination must be assigned and appropriate avoidance measures instituted. It is vital in clinical relevance determination to test the patients’ own products to increase the patch test efficacy.
To clinically differentiate whether positive skin reactions were elicited by irritation or allergen effects, repeated open application test (ROAT) can be performed by reapplying the particular substance near the flexor aspect of the forearm (cubital fossa) twice a day for 7 consecutive days.48 Table 5 lists testing indications. ROAT is particularly useful for patients who are suspected to be allergic to product-based allergens that are neither commercially available nor routinely tested for on standard series. Hannuksela and Salo’s study proved the efficacy of ROAT by demonstrating that in a group of 86 patients with questionable patch test results, only 44% of the patients were truly positive for ACD.48 ROAT is particularly useful to test cosmetic products for its ability to mimic real-life exposures and confirm positive patch testing outcomes. Adjunct ROAT performed alongside standard patch testing improves patch test efficacy and simultaneously educates the patient in product evaluation.
Pearls of Treatment
Personal care products, medications, and household cleaning supplies contribute to a large fraction of ACD cases worldwide.49 Unfortunately, BAK’s widespread use in coatings, chemical industry, water treatment, aquaculture, timber, paper, textile, aftershaves, cosmetics, deodorants, eye-care solutions, softeners, and much more, makes it a difficult allergen to consistently avoid in sensitized patients. When it comes to BAK, use of protective gear (eg, nitrile gloves) when working with cleaning supplies and minimizing exposure on damaged skin, will decrease the risk of sensitization.
As with each exposure, there is an increased risk of reaching a point where the immune system meets its metaphorical “threshold,” whereby any subsequent exposures can elicit a cutaneous response.50,51 Just as repeated contact over time leads to sensitization and an unwanted immune response, repeated avoidance of an allergen through appropriate avoidance strategies leads to remission.
The Contact Allergen Management Program was developed by the ACDS with the mission to help patients with contact dermatitis effectively avoid allergens. This database contains full ingredients for more than 5000 commonly used products that is routinely updated by a dedicated team directed by Dr Andrew Scheman and Dave Seversen. While the advanced search function is catered toward health care providers familiar with the names of specific contact allergens, the streamlined mobile app is for patients to be able to narrow down exactly which products are safe for them to use. In fact, the companion mobile app allows patients to conveniently enter the name or brand of a specific product and determine if it contains any contraindicated allergens prior to purchase.52 Allergen identification is the key to avoidance.53 n
Mr Sung is with the school of medicine at the University of California, Riverside in Riverside, CA.
Dr Grigsby is with the internal medicine department at Loma Linda University in Loma Linda, CA.
Dr Lee is with Dermatology Skin and Surgery Center in Jackson, MI.
Dr Jacob, Section Editor of Allergen Focus, is a board-certified dermatologist and professor at Loma Linda University in Loma Linda, CA. She is founder and chief executive officer of the Dermatitis Academy public outreach education campaign.
Disclosure: The authors report no relevant financial relationships.
References
1. Bickers DR, Lim HW, Margolis D, et al; American Academy of Dermatology Association; Society for Investigative Dermatology. The burden of skin diseases: 2004 a joint project of the American Academy of Dermatology Association and the Society for Investigative Dermatology. J Am Acad Dermatol. 2006;55(3):490-500.
2. Weston WL, Weston JA, Kinoshita J, et al. Prevalence of positive epicutaneous tests among infants, children, and adolescents. Pediatrics. 1986;78(6):1070-1074.
3. Wolf R, Orion E, Matz H, Lipozencic J. Still elusive relationship between atopic dermatitis and allergic contact dermatitis. Acta Dermatovenerol Croat. 2003;11(4):247-250.
4. Isaac J, Scheinman PL. Benzalkonium chloride: an irritant and sensitizer [published online September 5, 2017]. Dermatitis. doi:10.1097/der.0000000000000316
5. Nettis E, Colanardi MC, Soccio AL, Ferrannini A, Tursi A. Occupational irritant and allergic contact dermatitis among healthcare workers. Contact Dermatitis. 2002;46(2):101-107.
6. Basketter DA, Marriott M, Gilmour NJ, White IR. Strong irritants masquerading as skin allergens: the case of benzalkonium chloride. Contact Dermatitis. 2004;50(4):213-217.
7. Saw NK, Hindmarsh JR. Acute irritant reaction to an antiseptic bath emollient. Postgrad Med J. 2005:81(952):131-32.
8. Noakes T, Borresen J, Hew-Butler T, Lambert M, Jordaan E. Semmelweis and the aetiology of puerperal sepsis 160 years on: an historical overview. Epidemiol Infect. 2008;136(1):1-9.
9. Larson E. A causal link between handwashing and risk of infection? Examination of the evidence. Infect Control Hosp Epidemiol. 1988;9(1):28-36.
10. Krob HA, Fleischer AB Jr, D’Agostino R Jr, Haverstock CL, Feldman S. Prevalence and relevance of contact dermatitis allergens: a meta-analysis of 15 years of published T.R.U.E. test data. J Am Acad Dermatol. 2004;51(3):349-353.
11. Wentworth AB, Yiannias JA, Davis MD, Killian JM. Benzalkonium chloride: a known irritant and novel allergen. Dermatitis. 2016;27(1):14-20.
12. Willis CM, Stephens JM, Wilkinson JD. Experimentally-induced irritant contact dermatitis. Determination of optimum irritant concentrations. Contact Dermatitis. 1988;18(1):20-24.
13. Visscher MO, Randall Wickett, R. Hand hygiene compliance and irritant dermatitis: a juxtaposition of healthcare issues. Int J Cosmet Sci. 2012;34(5):402-415.
14. Callahan A, Baron E, Fekedulegn D, et al. Winter season, frequent hand washing, and irritant patch test reactions to detergents are associated with hand dermatitis in health care workers. Dermatitis. 2013;24(4):170-175.
15. FDA requests additional information to address data gaps for consumer hand sanitizers [news release]. Silver Spring, MD: FDA; June 29, 2016. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm509097.htm. Accessed November 2, 2017.
16. Kampf G, Kramer A. Epidemiologic background of hand hygiene and evaluation of the most important agents for scrubs and rubs. Clin Microbiol Rev. 2004;17(4):863-893.
17. Therattil PJ, Yueh JH, Kordahi AM, Cherla DV, Lee ES, Granick MS. Randomized controlled trial of antiseptic hand hygiene methods in an outpatient surgery clinic. Wounds. 2015;27(12):347-353.
18. Crawford G, Katz KA, Ellis E, James WD. Use of aromatherapy products and increased risk of hand dermatitis in massage therapists. Arch Dermatol. 2004;140(8):991-996.
19. Chadwick S, Neskoski M, Spindler X, Lennard C, Roux C. Effect of hand sanitizer on the performance of fingermark detection techniques. Forensic Sci Int. 2017;273:153-160.
20. Dyer DL, Gerenraich KB, Wadhams PS. Testing a new alcohol-free hand sanitizer to combat infection. AORN J. 1998;68(2)239-241, 243-234, 247-251.
21. Smith K, Gemmell CG, Hunter IS. The association between biocide tolerance and the presence or absence of qac genes among hospital-acquired and community-acquired MRSA isolates. J Antimicrob Chemother. 2008;61(1):78-84.
22. Espigares E, Moreno Roldan E, Espigares M, et al. Phenotypic resistance to disinfectants and antibiotics in methicillin-resistant staphylococcus aureus strains isolated from pigs. Zoonoses Public Health. 2017;64(4):272-280.
23. Varani J, Perone P, Spahlinger DM, et al. Human skin in organ culture and human skin cells (keratinocytes and fibroblasts) in monolayer culture for assessment of chemically induced skin damage. Toxicol Pathol. 2007;35(5):693-701.
24. Ferk F, Misík M, Hoelzl C, et al. Benzalkonium chloride (BAC) and dimethyldioctadecyl-ammonium bromide (DDAB), two common quaternary ammonium compounds, cause genotoxic effects in mammalian and plant cells at environmentally relevant concentrations. Mutagenesis. 2007;22(6):363-370.
This article discusses benzalkonium chloride, within the context of its historical and clinical significance in association with its use in antiseptics, cosmetics, detergents, and topical medications.
Allergic contact dermatitis (ACD) is a socially and economically significant condition. It is estimated to affect more than 72 million Americans each year.1 In addition to physical morbidity, ACD can have a significant impact on quality of life leading to missed workdays and lost income, inability to enjoy leisure activities, and loss of sleep. Often, numerous doctor visits and medications result in significant expenditures for the patient before the underlying cause is discovered. In 2004, the total direct cost (eg, prescription drugs, office visits, etc.) associated with treatment for contact dermatitis was $1.6 billion, a number that continues to increase.1
Patch testing is the gold standard for ACD diagnosis.2 Once the offending allergen is identified, avoidance is critical for sustained remission. ACD is divided into 2 phases: sensitization (afferent) and elicitation (efferent). Exogenous antigens come into contact with antigen-specific T cells through defects in the epidermis, and induce sensitization. Damage to the skin is thought to be primarily mediated by CD4+ type 1 (Th1) cells and CD8+ T cytotoxic (Tc1) cells through a combination of inflammatory cytokine and cell-mediated cytotoxicity.3 However, because ACD has a delayed-onset (time between sensitization or exposure and elicitation of the dermatitis), associations between the 2 may be difficult to make. Therefore, when ACD is suspected, a patient-centered educational approach focusing on pathophysiology, risk of recurrence, and avoidance strategies should be initiated to break the ACD cycle.
Experimental studies indicate that antigenic potency, in addition to the concentration of antigen, are important factors in determining whether exposure to an antigen will result in sensitization. For weak allergens, exposures can occur over many years before a reaction develops. Alternatively, sensitization with strong allergens can occur more rapidly. If the skin barrier is compromised from chemical irritation, even a single exposure of a weak allergen could induce primary sensitization. Common preservatives such as benzalkonium chloride (BAK) are known to irritate the skin at high concentrations. This dose-dependent effect causes disorganization and thickening of subcellular structures, which leads to activation of prostaglandin E2, IL-1α, IL-6, and cell death.3
Isaac and colleagues retrospective chart review of patients patch tested for suspected ACD (N=615) concluded that the irritant nature of BAK may predispose patients who have dermatitis or compromised skin barriers to develop sensitization to this chemical.4
Additional studies have also suggested that BAK may be associated with inducing ACD in particular subgroups of patients such as health care workers and cosmetic users, and again in patients with compromised skin barriers.4,5 On the contrary, Basketter and colleagues, who exclusively reviewed published literature regarding a number of substances with the potential for inducing skin sensitization suggested that BAK was an extremely rare allergen, and that many of the “supposed cases of ACD” may have been based on misinterpretation of an irritant patch test result, and that further investigation was indicated.6 This article highlights BAK, within the context of its historical and clinical significance in association with its use in cosmetics, topical medicine, detergents, and antiseptics.
Antibacterial Sanitation
Inspired by Louis Pasteur’s discovery that microorganisms cause infection, Joseph Lister pioneered the practice of antiseptic surgical methods and “modern surgery.” Lister discovered that applying carbolic acid (phenol) as an antiseptic to surgical equipment and wounds significantly decreased the incidence of infection transmission and gangrene.7 Similar advancements were made during the 19th century by Florence Nightingale, who recognized the statistical benefits of sanitation in field hospitals for reducing mortality rates during the Crimean War.
However, it should be noted that before Pasteur’s famous pasteurization experiment that proved the germ theory, the concept of antiseptic practices such as hand-washing was initially taken with offense and met with great resistance by the medical community. Dr Ignaz Semmelweis was a Hungarian physician who discovered that the use of hand disinfection with chlorinated lime solutions prior to performing labor and delivery could significantly reduce mortality associated with puerperal fever (the so-called childbed fever). As a chief resident, Dr Semmelweis was astonished by the difference in mortality rates between 2 clinics that used the exact same protocols. The first and second clinics mortality rates were 10% and 4%, respectively.8 The findings were alarming considering that the first clinic was staffed by attending teaching faculty with medical student participation, while midwives staffed the second clinic. He eventually arrived at the conclusion that it was the physicians and medical students who were the cause for the increased mortality for transferring deadly “contaminants” from cadavers, with which midwives from the other clinic did not come into contact. By instituting a policy for all providers to wash hands with a calcium chlorite hypochlorite solution, mortality rate dropped to near zero and essentially eliminated childbed fever. Despite promising results with startling reductions in morbidity, Dr Semmelweis remained challenged by the scientific community until the day he was sent to an asylum where he died shortly thereafter at the age of 47.
The increased fervor among the health care community to mitigate disease transmission in the early 20th century led to widespread development and use of antiseptics and routine hand-washing with soap and water. The concept of antiseptics eventually led to the development of a myriad of popular antimicrobial products used today containing alcohol, chlorhexidine, chlorine, hexachlorophene, iodine, chloroxylenol, triclosan, and quaternary ammonium compounds such as BAK.9 While it is well recognized that the hands are a primary source of disease transmission, health care associated transmission of infections continue to rank high among challenges in modern medicine.
Benzalkonium Chloride
BAK is a quaternary ammonium cation that has been used historically for multiple purposes including cleansers, detergents, and preservatives found in ophthalmic solutions, inhalers, and topical antiseptic creams.10 Alternative names for BAK are shown in Table 1. It is known to elicit irritant contact dermatitis at aqueous solution concentrations of 0.5% and above.11 With prolonged exposure or in the setting of compromised skin barriers, BAK has also been shown to predispose individuals to sensitization and potentially induce ACD.4,11,12
In 1994, the FDA began to set guidelines for the use of antiseptics that do not require rinsing and drying. BAK was specifically designated under class III (insufficient data to classify its safety and effectiveness profile).13,14 More than 2 decades later, the guidelines have not changed.15 While the FDA commonly states that soap and running water remains “one of the most important steps consumers can take to avoid getting sick and to prevent spreading infections,” antiseptic hand sanitizers, which often contain BAK, remain highly used in the health care industries due to their unparalleled convenience.5,11
Hand Sanitizers
The implementation of widespread hand hygiene within health care settings marks a landmark milestone for infection control, with inclinations bent upon developing the most potent and broad-spectrum antibacterial formulation while minimizing irritancy potential. The 3 major categories of hand sanitizers include ethanol alcohol, quaternary ammonium, and triclosan-based products.16 While the use of cleansers and chemicals is a leading cause of ACD, hand sanitizers play a pivotal role in infection control for those working in health care institutions and the food industry.
Randomized control trials of 95 health care providers demonstrated that while there are no significant antimicrobial advantages between ethanol alcohol and BAK-based sanitizers and soap hand-washing, hand sanitizers have been shown to prevent hand dermatitis flares in patients.17,18 For example, Crawford and colleagues (N=350) who sought to determine the prevalence of hand dermatitis among massage therapists found that hand-washing was ranked as a leading cause for skin aggravation according to participant self-reports.18 Alcohol and nonalcohol, BAK-containing antiseptic products were preferred over traditional hand-washing with soap for their convenience and lack of need for drying, thus saving time and, more importantly, avoiding any further unwanted potential contact with contaminated drying surfaces. Waterless alcohol-based hand sanitizers are generally formulated with a concentration of 60% to 80% ethanol, isopropanol, or n-propanol, and function to denature pathogenic proteins in fungi and both gram-positive and gram-negative bacteria.16 While alcohol-based antiseptics have no documented accounts of resistance, they generally have poor coverage against bacterial spores, protozoan oocysts, and select nonenveloped viruses.
Unlike alcohol-based antiseptics that irritate the skin, BAK-based sanitizers have a relatively lesser extent of hand skin irritation and lack of residual staining on clothing and wooden surfaces.19,20 BAK dries on average an estimated 10 to 15 seconds slower than alcohol-based hand sanitizers, which inadvertently allows for a more efficacious coverage (up to 4 hours of residual protection) and minimizes the number of reapplications needed.21 On the contrary, alcohol-based sanitizers offer no residual protection after drying. Therefore, some studies would argue that alcoholic-based sanitizers may actually be inferior to BAK sanitizers, which increases its antimicrobial activity upon multiple consecutive applications.20 Additionally, BAK sanitizers can be safely used around electrocautery devices prevalent in hospital settings whereas alcoholic-based sanitizers have flammability concerns. See Table 2 for examples of hand sanitizers with and without BAK.
Mechanism of Action
Quaternary ammonium compounds induce leakage of cytoplasmic contents by disrupting the membranes of bacterial, fungal, and enveloped viral membranes. Similar to alcohol-based sanitizers, BAK sanitizers are capable of eliciting fungistatic and bacteriostatic effects against gram-positive and some gram-negative bacteria, and also has a weak profile against non-enveloped viruses. Notably, certain species of Staphylococcus aureus are resistant to quaternary ammonium compounds, making BAK a poor candidate in areas where methicillin-resistant S aureus is prevalent (eg, hospitals).22 In addition to ACD, data suggest BAK has the capability to induce moderate genotoxic effects on human cells, histologic changes in skin, and biofilm formation.23-26
Article continues on page 2
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BAK and ACD
BAK has been used as an antiseptic for more than 50 years in products, but skin irritation and the possibility of subsequent contact sensitization have led to greater surveillance of the preservative. A large retrospective analysis (N=42,898) of all patients tested with 0.1% BAK between 1996 and 2006 weakly supported the notion that BAK, although rare, was indeed a contact allergen.27 BAK’s irritant effects are particularly amplified within health care settings where occupational exposure and use of hand sanitizers and antiseptics is common practice.5,28 Increasing rate of positive allergic patch testing results among patients who underwent patch testing with 0.1% BAK have supported the notion that BAK is an allergen of increasing importance.11
Preservatives, utilized for their ability to inhibit growth of microorganisms, and thereby providing a longer product shelf life, are common allergens in cosmetics, skin moisturizers, cleansers, and hair products.15,29 While BAK is commonly used as a preservative in personal care and cosmetic products, its allergen prevalence is notably low in comparison to other preservatives (eg, methylchloroisothiazolinone).30,31 Of note, a retrospective analysis (N=1215) aimed to identify relevant allergens among patients with, specifically, allergic eyelid dermatitis concluded that BAK was a prevalent allergen at a much higher frequency of 8.7%.32 More importantly, the study also highlighted that the current FDA-approved panels available within the United States do not include a significant number of the allergens responsible for causing eyelid ACD.32
Who Is Affected By BAK?
Generally those who frequently use personal hygiene products, cosmetics, contact lens solutions, and hand sanitizers containing BAK (Table 3) are at a relatively higher risk for developing ACD than the general population.5 This correlates with a recent survey study that revealed among 11,979 products listed including contact lens solution, emollients and toothpaste, 17% contained BAK.33 A particularly large scale patch testing study (N=2611) contrasting incidence, location, and diagnosis of skin diseases concluded that health care workers (N=165) experienced significantly more occupational-related ACD than non-healthcare workers (N=2446).34 In fact, further data stratification demonstrated that individuals who developed ACD also had significantly increased exposures to allergens such as BAK, which was also not available on the “standard allergen series” used in the patch testing study. Table 4 discusses questions to elicit from those who may be at risk for BAK dermatitis.
Testing for BAK Sensitivity
Skin patch testing has been the gold standard in testing for ACD since its introduction by the famous German dermatologist, Josef Jadassohn, in 1895.35 Efficacy of the patch test depends on the skill of the provider, the appropriate timing of the patch readings (eg, at least 1 delayed reading between 96-120 hours), and the breadth of the allergens tested. It has been reported that less than 1% of dermatologists use comprehensive patch testing.36 In patch-test quality-control metrics performed by the North American Contact Dermatitis Group (NACDG), BAK was identified as a “problematic” patch test preparation with a “high proportion of weak, irritant, and questionable reactions that may or may not be true reactions to allergens.”37 Thus, evaluators should be well versed in identifying irritant reactions and false positives without overreading the patch test results.38 It is also vital that practitioners evaluate the patient’s history thoroughly to clinically correlate the possibility of false-negative findings.38
Considering that BAK is a well-characterized skin irritant, patch test reactions should be judiciously evaluated to confirm that the skin reaction is indeed allergen rather than irritant induced, as strong irritants may masquerade as skin allergens.6 For patients who test positive, Ale and Maibacht recommended repeating the patch testing to rule out false-positive reactions and performing a “use test” that involves directly applying an aqueous BAK solution 5 times a day for 4 consecutive days to the patient’s medial upper arm to determine if the patient was truly allergic to BAK.39,40 Because BAK is not currently included on the commercially available patch test kit,41 International Standard Series42, or the NACDG screening series [last used in the 2001-2002 testing period, but deleted from the 2003-2004 series]43), testing could be performed as an additional supplemental substrate if using these screening series as a baseline screen. Notably, BAK is included in the evidenced-based American Contact Dermatitis Society (ACDS) 80 Core Series.43
Appropriate screening with patch testing is essential for the specific diagnosis and management of ACD.44 Considering that patch testing is used as a diagnostic screening test, the efficacy of the test relies on its sensitivity from a statistical standpoint. Patch test sensitivity can be increased through minimizing the false-negative results by including a broader spectrum of highly suspect allergens associated with inducing ACD.
Extended patch testing is often needed, and the evidence-based ACDS core series includes many of the same allergens available on common standard patch test series (European Standard Series, Extended International Series, British Contact Dermatitis Society Series, etc.), while notably expanding the screening to include allergens tested in descending order of prevalence rates including acrylates, bacitracin, benzophenone, multiple corticosteroids, sorbitan, and BAK.45
A 5-year retrospective allergen patch testing study (N=3854) conducted by the Mayo Clinic from 2001 to 2005 analyzed the types of allergens and reaction rates, including those tested by the “standard series” panel, and concluded that BAK had a significantly higher positive patch test rate than the previously reported rate observed in the 1998 to 2000 testing period.46 That said, currently, the Mayo standard series does not include BAK, as prevalence rates and clinical relevance did not support its inclusion.47
Identifying an individual’s positive patch test to an allergen is only part of the equation. Clinical relevance determination must be assigned and appropriate avoidance measures instituted. It is vital in clinical relevance determination to test the patients’ own products to increase the patch test efficacy.
To clinically differentiate whether positive skin reactions were elicited by irritation or allergen effects, repeated open application test (ROAT) can be performed by reapplying the particular substance near the flexor aspect of the forearm (cubital fossa) twice a day for 7 consecutive days.48 Table 5 lists testing indications. ROAT is particularly useful for patients who are suspected to be allergic to product-based allergens that are neither commercially available nor routinely tested for on standard series. Hannuksela and Salo’s study proved the efficacy of ROAT by demonstrating that in a group of 86 patients with questionable patch test results, only 44% of the patients were truly positive for ACD.48 ROAT is particularly useful to test cosmetic products for its ability to mimic real-life exposures and confirm positive patch testing outcomes. Adjunct ROAT performed alongside standard patch testing improves patch test efficacy and simultaneously educates the patient in product evaluation.
Pearls of Treatment
Personal care products, medications, and household cleaning supplies contribute to a large fraction of ACD cases worldwide.49 Unfortunately, BAK’s widespread use in coatings, chemical industry, water treatment, aquaculture, timber, paper, textile, aftershaves, cosmetics, deodorants, eye-care solutions, softeners, and much more, makes it a difficult allergen to consistently avoid in sensitized patients. When it comes to BAK, use of protective gear (eg, nitrile gloves) when working with cleaning supplies and minimizing exposure on damaged skin, will decrease the risk of sensitization.
As with each exposure, there is an increased risk of reaching a point where the immune system meets its metaphorical “threshold,” whereby any subsequent exposures can elicit a cutaneous response.50,51 Just as repeated contact over time leads to sensitization and an unwanted immune response, repeated avoidance of an allergen through appropriate avoidance strategies leads to remission.
The Contact Allergen Management Program was developed by the ACDS with the mission to help patients with contact dermatitis effectively avoid allergens. This database contains full ingredients for more than 5000 commonly used products that is routinely updated by a dedicated team directed by Dr Andrew Scheman and Dave Seversen. While the advanced search function is catered toward health care providers familiar with the names of specific contact allergens, the streamlined mobile app is for patients to be able to narrow down exactly which products are safe for them to use. In fact, the companion mobile app allows patients to conveniently enter the name or brand of a specific product and determine if it contains any contraindicated allergens prior to purchase.52 Allergen identification is the key to avoidance.53 n
Mr Sung is with the school of medicine at the University of California, Riverside in Riverside, CA.
Dr Grigsby is with the internal medicine department at Loma Linda University in Loma Linda, CA.
Dr Lee is with Dermatology Skin and Surgery Center in Jackson, MI.
Dr Jacob, Section Editor of Allergen Focus, is a board-certified dermatologist and professor at Loma Linda University in Loma Linda, CA. She is founder and chief executive officer of the Dermatitis Academy public outreach education campaign.
Disclosure: The authors report no relevant financial relationships.
References
1. Bickers DR, Lim HW, Margolis D, et al; American Academy of Dermatology Association; Society for Investigative Dermatology. The burden of skin diseases: 2004 a joint project of the American Academy of Dermatology Association and the Society for Investigative Dermatology. J Am Acad Dermatol. 2006;55(3):490-500.
2. Weston WL, Weston JA, Kinoshita J, et al. Prevalence of positive epicutaneous tests among infants, children, and adolescents. Pediatrics. 1986;78(6):1070-1074.
3. Wolf R, Orion E, Matz H, Lipozencic J. Still elusive relationship between atopic dermatitis and allergic contact dermatitis. Acta Dermatovenerol Croat. 2003;11(4):247-250.
4. Isaac J, Scheinman PL. Benzalkonium chloride: an irritant and sensitizer [published online September 5, 2017]. Dermatitis. doi:10.1097/der.0000000000000316
5. Nettis E, Colanardi MC, Soccio AL, Ferrannini A, Tursi A. Occupational irritant and allergic contact dermatitis among healthcare workers. Contact Dermatitis. 2002;46(2):101-107.
6. Basketter DA, Marriott M, Gilmour NJ, White IR. Strong irritants masquerading as skin allergens: the case of benzalkonium chloride. Contact Dermatitis. 2004;50(4):213-217.
7. Saw NK, Hindmarsh JR. Acute irritant reaction to an antiseptic bath emollient. Postgrad Med J. 2005:81(952):131-32.
8. Noakes T, Borresen J, Hew-Butler T, Lambert M, Jordaan E. Semmelweis and the aetiology of puerperal sepsis 160 years on: an historical overview. Epidemiol Infect. 2008;136(1):1-9.
9. Larson E. A causal link between handwashing and risk of infection? Examination of the evidence. Infect Control Hosp Epidemiol. 1988;9(1):28-36.
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