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Allergen Focus: Topical Antibiotics

Allergen Focus: Topical Antibiotics

Editor's Note: To see the tables included in this article, please download the PDF of the article posted above.

Allergen FocusAllergic Contact Dermatitis (ACD) is an important disease that affects 14.5 million Americans each year.1 The economic impact of this disease is high in terms of both patient morbidity and loss of income, school and work, not to mention significant expenditures for visits to health care providers and for medicaments.1 Once patch testing is performed and a culprit has been identified, education becomes the critical intervention to ensure adherence to an avoidance regimen. With allergen avoidance, remission of the dermatitis ensues. If patients are unable to comply with the avoidance regimen, they become at risk for recurrent or sustained dermatitis or progression to a systematized presentation.2,3 In fact, education of the patient often begins before the diagnostic patch test is ever placed. This ensures that the patient has an appropriate understanding of potential outcomes, including his or her central role in both disease and treatment.

At the initial consultation, patients are often taught about the pathophysiology of ACD: its delayed presentation; its relationship with the immune system (sensitization to a chemical and then elicitation of a dermatitis with re-exposure); and its occurrence at any point in time, even to something that the patient has been using regularly for a short period of time or intermittently for years. In certain cases, the topics of the other key players, such as irritant contact dermatitis (ICD) and contact urticaria, may be explained via history (not patch testing), which can point to these as the correct diagnosis for the patient. It is important to note that ICD, the most prevalent form of contact dermatitis, can, at times, precede, or be a concomitant diagnosis with, ACD.4,5 Unlike ACD, ICD is not immune mediated, but occurs secondary to contact with an irritating or abrasive substance. Contact urticaria (wheal and flare reaction), on the other hand, represents the least prevalent form of ICD. It is important to note that it is an immune-mediated phenomenon whose hallmark is an IgE and mast cell-mediated, immediate-type hypersensitivity reaction. We acknowledge this form of hypersensitivity due to the severity of the potential deleterious anaphylactic type reactions and direct the reader to key sources.6-8

In this section focus, we highlight ACD and explore top relevant allergens, regional-based dermatitis presentations, topic-based dermatitis presentations and clinical tips and pearls for diagnosis and treatment.
 
Background   

For many people, it is not difficult to recall a sporting event during childhood when a first-aid kit was brought to the rescue for a minor injury. Whether on the soccer field or in the doctor’s office, the knee-jerk reaction to small abrasions seems, generally, to include the use of some form of a topical antibacterial agent. The ubiquitous nature of these antibiotics in first-aid kits and over-the-counter products feeds these habits. The use of topical antibiotics in the emergency room and primary care settings seems to be pervasive. Not only do dermatologists prescribe more topical antibiotics than any other medical specialty, but we are also performing more than 25 million minor surgical procedures annually.9,10 As antibiotic resistance and complications like allergic contact dermatitis (ACD) continue to rise, we simply cannot afford to ignore this overuse any longer.

It is well documented that prolonged usage and an impaired skin barrier increase the risk of ACD to topical antibiotics.11 Several studies have shown an increased prevalence in those patients with chronic eczematous conditions, chronic otitis externa, anogenital dermatitis, chronic venous insufficiency and postoperative wounds.11 Furthermore, an impaired skin barrier is also present in those patients with diffuse actinic damage treated with topical agents like 5-fluorouracil and imiquimod, putting them at increased risk as well. Finally, there are certain occupations that place individuals at greater risk, including healthcare and pharmaceutical workers, veterinarians and farmers, who handle various antibiotics when feeding their livestock.11  

Despite the popular belief that intermittent use of an antibiotic on minor wounds does not increase rates of sensitization, this idea is currently under scrutiny. It is becoming increasingly recognized that young children, even those younger than 3 years of age, are being sensitized to various potential allergens, including antibiotics.12 According to an analysis performed by the North American Contact Dermatitis Group (NACDG), neomycin sulfate ranked fourth in terms of frequency of positive patch test reactions. Even more striking is that neomycin was the most frequent relevant positive reaction.13 Tertiary care patch test referral centers in the United States offer patch testing for pediatric patients with customized protocols when persistent dermatitis does not respond to standard therapies.14

Prior to the 19th century, infected surgical and traumatic wounds often resulted in death due from sepsis. It was during the 1960s when combinations of neomycin, polymyxin, tetracycline and other antimicrobial agents were used in pressurized powder sprays; as a result, infection rates began to decline.9 Unfortunately, prophylactic and post-operative use of these topical antibiotics has remained steady, regardless of modern aseptic procedures like skin antiseptics and hand washing. In addition, an increase in the available topical formulations of antibiotics like erythromycin has resulted in a striking rise in resistant bacterial strains.10  

Certain body sites, like the distal extremities and groin, carry a high rate of infection, especially when subjected to reconstructive surgical procedures. Oral and/or topical prophylactic antibiotics in these instances may be used as the provider deems that the benefit of using either outweighs the risk of sensitization. It has been shown that a 48-hour prophylactic course of a topical antibiotic is all that is needed to provide this benefit.9 However, for the other millions of minor procedures performed, there simply is no scientific evidence supporting the routine use of topical antibiotics either pre- or post-procedure. Emerging studies that show no benefit of topical antibiotics following laser resurfacing are adding to this body of evidence.15,16

Most patients will fare best in terms of healing from a simple environment that is moist and closed.9 Multiple studies have documented the beneficial effects and equivalent healing of using a product like Aquaphor ointment and an occlusive dressing following minor dermatology procedures, such as biopsies and laser resurfacing.15,16 Not only can the development of ACD impede wound healing, but delayed wound healing can be the initial clinical presentation of ACD. In addition, several antibiotics have been shown to be cytotoxic to key players like fibroblasts and keratinocytes, further impeding wound healing.17

In the most recent NACDG data, neomycin and bacitracin have been included in the top 15 most frequently positive allergens, ranking fifth (10%) and sixth (9.2%), respectively.18 There have additionally been many topical antibiotics that have been implicated in cases of ACD (see Table 1). A few of these, like nitrofurazone, are no longer used in most of the Western hemisphere due to such a high rate of sensitization. In the United States, the most commonly used topical antibiotic products in dermatology offices are Polysporin (bacitracin and polymyxin B) and Neosporin (polymyxin B, bacitracin and neomycin).17 The latter is most often referred to by its generic name “triple antibiotic ointment.” The components of these two major products will be discussed in further detail, as well as a few other less common causes that should be considered in the work-up of a patient with suspected antibiotic ACD. Aside from common medicament formulations, other important routes of exposure for several of the antibiotics will be mentioned (see Table 2).11,19,20

Top Antibiotic Allergens   

Neomycin is an aminoglycoside antibiotic that is effective against Gram-negative and a few Gram-positive organisms. It acts by blocking the ribosomal 30s subunit and subsequent bacterial synthesis.11 Neomycin is the most commonly used topical antibiotic in the United States, in part because it is found in such a vast array of products. These include most triple antibiotic ointments and other over-the-counter salves, prescription eye and eardrops, deodorants, powders and even root canal fillings.21 It is also used as a genitourinary irrigant for patients with in-dwelling catheters.11

In addition, both neomycin and gentamicin have been implicated in cases of systemic contact dermatitis (SCD) after topical use.22 Although less common than bacitracin, neomycin has been implicated in life-threatening contact urticaria and anaphylaxis.23 There is a theoretical, albeit very low, risk of anaphylaxis in allergic individuals receiving neomycin-containing vaccines.20
According to the NACDG, between 7% and 13% of the patients whom they patch-tested have been allergic to neomycin since about 1990. Importantly, there may be cross-reactions within the aminoglycoside class, including streptomycin, tobramycin, paromomycin, gentamicin and butirosin. ACD to streptomycin has been reported in cattle breeders and nurses handling the medicine when taking care of patients with tuberculosis. Sensitization to both neomycin and gentamicin has been reported. The latter antibiotic is available as a cream and ointment, but is most often used in ophthalmic solutions. Tobramycin is an important potential allergen to keep in mind, since it is found in several different ophthalmic and otic preparations.11 Finally, sensitization to both neomycin and bacitracin has commonly been reported. This co-sensitivity is likely attributable to these antibiotics being found in the same preparations.11

Polymyxin B is a polypeptide antibiotic produced by a similar strain of the Bacillus bacteria that produces bacitracin. As a result, there is potential cross-reactivity between polymyxin and bacitracin.24 Polymyxin is only effective against Gram-negative organisms including Pseudomonas aeruginosa. It acts by binding the bacterial cell membrane and disrupting osmosis. Polymyxin is thought to be a much weaker sensitizer than other topical antibiotics, but needs to be remembered in certain situations like patients with chronic leg ulcers.11  

Bacitracin is a polypeptide antibiotic that was derived from Bacillus subtilis and has been used since the 1950s. It is effective against gram-positive organisms by inhibiting bacterial cell wall synthesis. The use of bacitracin has been limited to topical preparations, since systemic exposure may cause nephrotoxicity.11 Current topical preparations include ophthalmic solutions and various medicated ointments, either singly or combined with other antibiotics, topical steroids and other chemicals.25 Furthermore, it is often prepared with zinc, because the addition of this metal is purported to make it less sensitizing.11

Initially only thought to be a causative allergen in patients with sensitivity to neomycin, bacitracin’s distinctive significance has become increasingly recognized. It ranked seventh among the most commonly prescribed medicines for injuries in United States emergency departments in 1992.24 Per the 1985-2002 data from the NACDG, bacitracin allergy in North America has drastically increased in the past 15 years. Among 6,000 patients thought to have ACD, prevalence of sensitization to this antibiotic was up to 15%. It was made the Contact Allergen of the Year in 2003 to educate people on its rising importance. Notably, these statistics may underrepresent bacitracin’s capabilities for a few key reasons. It is one of several allergens that have delayed reactions, whereby positive reactions are often not detected until 96-hour readings.11,25 This characteristic may make bacitracin allergy a challenge to identify.
Bacitracin is the most likely topical antibiotic to be linked to a type I hypersensitivity, IgE-mediated reaction.11 More than 26 cases of the latter have been described, including patients with stasis dermatitis, burn wounds, recent tattoos, atopic dermatitis and intra-operative exposures. However, the most distressing documented cases have been in those otherwise healthy individuals developing anaphylaxis after using bacitracin on minor abrasions.25-27
 
Less Common Causes of Antibiotic ACD    

Penicillin is a beta-lactam antibiotic that acts by inhibiting bacterial cell wall synthesis. Due to its high rate of contact sensitivity, topical use of penicillin is rare and there are a limited number of case reports of ACD. Most reported cases have involved occupational exposures, mainly in farmers and healthcare and pharmaceutical workers. There are additionally scarce cases in the literature of ACD to semisynthetic penicillins and cephalosporins. These latter two classes of antibiotics are believed to have very little cross-reactivity with penicillin.11

Despite the heavy usage of topical formulations of erythromycin, benzoyl peroxide and clindamycin in treating acne, developing sensitivity and ACD to these antibiotics is actually quite uncommon. Erythromycin is a member of the macrolide class and works against most Gram-positive organisms by inhibiting the ribosomal 50s subunit. Aside from acne, it is commonly found in ophthalmic preparations.11 Topical use of erythromycin has been implicated in cases of SCD.22 Of interest, cross-reactivity between erythromycin and azithromycin has been documented. The latter has mainly been implicated in occupational airborne contact dermatitis. However, there has been one report of ACD developing in a woman using azithromycin-containing drops after eye surgery.28  

Benzoyl peroxide is best known for its use in treating acne and other superficial skin infections. However, it is also used at various points in the production of resins, plastics and elastosmers. Although more commonly causing an irritant reaction, there have been a handful of ACD reports in both recreational and occupational settings. Just a few examples of exposures causing the latter have included podiatrists pumicing insoles and electricians working with plastics in insulation.11

There are two more commonly used topical antibiotics that are important to mention. Mupirocin is effective against aerobic Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus. It acts by specifically and reversibly binding to bacterial isoleucyl t-RNA synthetase. ACD to this agent was first reported in 1995 in a patient with venous leg insufficiency and ulceration. A subsequent case of ACD occurred in a patient after undergoing surgery to remove a basal cell skin cancer. There have been reports of antibiotic resistance with mupirocin and, to date, an absence of documented cross-reactivity with other antibiotics.11,16

The low incidence of ACD to topical metronidazole is impressive when one considers how often this antibiotic is used. Metronidazole is a synthetic nitroimidazole-derivative that has both antibacterial and antiprotozoal properties. It is therefore frequently used to treat rosacea, perioral dermatitis and other infections like bacterial vaginosis.11 There have been only a handful of case reports of ACD and most of these have occurred when a person had a previous history of occupational exposure (ie, a gastrointestinal nurse handling metronidazole in both tablet and intravenous formulations).29 Additionally, it is important to be aware that this antibiotic may cross-react with imidazole antifungal agents like econazole, clotrimazole and miconazole.11

Practical Aspects of Patch Testing

It is always important to keep in mind that patch test reactions to both neomycin and bacitracin may be slow to appear. A peak positive reaction for these antibiotics may occur at 96 hours after patch placement and may sometimes be even more delayed.11,20 Additionally, one must consider other potential allergens in the work-up of a patient with suspected ACD to a topical antibiotic. The dermatologist’s primary role is to take a thorough history and ascertain all of the products a patient is using. It is important to recognize that many antibiotic formulations contain “inactive” ingredients like preservatives and other vehicle components. One example is a mupirocin ointment containing polyethylene glycol, which is a known possible contact sensitizer.11 Although it does not occur frequently, some surgical practices are now mixing antibiotics into anesthetic solutions prior to Mohs and other surgical procedures.30 This would clearly be a rare exposure causing antibiotic ACD, but, importantly, there have also been rare cases of ACD due to lidocaine and other amide anesthetics.31 This highlights the fact that all possible exposures and contacts must be considered.

Pearls of Treatment: Every Dose Counts    

As alluded to in this preface, one may be exposed, and subsequently sensitized to, a contact allergen such as fragrance for days to years before demonstrating the clinical picture of ACD. With each exposure, there is an increasing risk of reaching a point at which the immune system meets its metaphorical “threshold” and subsequent exposures at this point can lead to elicitation of a cutaneous response, such as cheilitis.32 Just as repeated contact over time led to this immune response, repeated avoidance of the majority of exposures over time will be required to induce remission.  

Avoidance of specific allergens in personal care products can prove to be a tedious task; however, there are programs available to aid in this endeavor. Both the Contact Allergen Management Program (CAMP), a service offered through the American Contact Dermatitis Society (ACDS),33 and the Contact Allergen Replacement Database (CARD), developed by Mayo Clinic,34 allow for a provider to enter a patient’s known contact allergens and produce a “shopping list” of products void of those particular chemicals. The programs also have the ability to exclude cross-reactors.

Some sources, however, require avoidance creativity and finding alternatives. In cheilitis patients, ingestible sources such as chewing gum, cough drops and liqueurs in menthol-allergic patients, margarine in gallate-allergic patients and peanut butter in nickel-allergic patients,35 should be given consideration. Educating patients to increase their awareness of sources of allergens and having the patient inform their health and dental professionals of their contact allergens is also important.

Dr. Mowad is an associate professor of clinical dermatology at Geisinger Medical Center in Danville, PA.

Dr. Findley is a senior dermatology resident at Geisinger Medical Center in Danville, PA.

Disclosure: The authors have no conflicts of interest or financial disclosures to report.

Dr. Jacob, the Section Editor of Allergen Focus, is Associate Clinical Professor of Medicine and Pediatrics WOS (Dermatology) at the University of California, San Diego.

Disclosure: Dr. Jacob is the principal investigator for Smartchoice USA PREA-2 trial.

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