Contact Dermatitis

For thousands of years, humans have used fragrances to change or affect their mood and enhance an “aura of beauty.”¹ Fragrance is a primary driver in consumer choice and purchasing decisions, especially when considering personal care products.² In addition to fragrance, consumers choose cleanser products based on compatibility with skin, cleansing properties, and sensory attributes such as viscosity and foaming.^3,4 However, fragrance sensitivity is among the most common causes of allergic contact dermatitis from cosmetics and personal care products,⁵ and estimates of the prevalence of fragrance sensitivity range from 1.8% to 4.2%.⁶

A panel of 26 fragrance ingredients that frequently induce contact dermatitis in sensitive individuals has been identified.⁷ Since 2003, regulatory authorities in the European Union require these compounds to be listed on the labels of consumer products to protect presensitized consumers.^7,8 However, manufacturers of cosmetics are not required to specify allergenic fragrance ingredients outside the European Union, and therefore it is difficult for consumers in the United States to avoid fragrance allergens.

Creation of a fragranced product for 
fragrance-sensitive individuals begins with careful selection of ingredients and extensive formulation testing and evaluation. This process usually is followed by testing in normal individuals to confirm that the fragranced product is well accepted and then evaluation is done in clinically confirmed fragrance-sensitive patients and those with a compromised skin barrier from atopic dermatitis, rosacea, or eczema.

Sensitive skin may be due to increased immune responsiveness, altered neurosensory input, and/or decreased skin barrier function, and presents a complex challenge for dermatologists.⁹ Subjective perceptions of sensitive skin include stinging, burning, pruritus, and tightness following product application. Clinically sensitive skin is defined by the presence of erythema, stratum corneum desquamation, papules, pustules, wheals, vesicles, bullae, and/or erosions.⁹ Although some of these symptoms may be observed immediately, others may be delayed by minutes, hours, or days following the use of an irritating product. Patients who present with subjective symptoms of sensitive skin may or may not show objective symptoms.

Gentle skin cleansing is particularly important for patients with compromised skin barrier integrity, such as those with acne, atopic dermatitis, eczema, or rosacea. Standard alkaline surfactants in skin cleansers help to remove dirt and oily soil and produce lather but can impair the skin barrier function and facilitate development of irritation.^10-13 The tolerability of a cleanser is influenced by its pH, the type and amount of surfactant ingredients, the presence of moisturizing agents, and the amount of residue left on the skin after washing.^11,12 Mild cleansers have been developed for patients with sensitive skin conditions and are expected to provide cleansing benefits without negatively affecting the hydration and viscoelastic properties of skin.¹¹ Mild cleansers interact minimally with skin proteins and lipids because they usually contain nonionic synthetic surfactant mixtures; they also have a pH value close to the slightly acidic pH of normal skin, contain moisturizing agents,^11,14,15 and usually produce less foam.^10,16 In patients with sensitive skin, mild and fragrance-free cleansers often are recommended.^17,18 Because fragrances often affect consumers’ perception of product performance¹⁹ and enhance the cleaning experience of the user, consumer compliance with clinical recommendations to use fragrance-free cleansers often is poor.

Low–molecular-weight, water-soluble, hydrophobically modified polymers (HMPs) have been used to create gentle foaming cleansers with reduced impact on the skin barrier.^12,16,20 In the presence of HMPs, surfactants assemble into larger, more stable polymer-surfactant structures that are less likely to penetrate the skin.¹⁶ Hydrophobically modified polymers can potentially reduce skin irritation by lowering the concentration of free micelles in solution. Additionally, both HMPs and HMP-surfactant complexes stabilize newly formed 
air-water interfaces, leading to thicker, denser, and longer-lasting foams.¹⁶ A gentle, fragrance-free, foaming liquid facial test cleanser with HMPs has been shown to be well tolerated in women with sensitive skin.²⁰

This report describes 2 studies of a new mild, 
HMP-containing, foaming facial cleanser with a 
fragrance that was free of common allergens and irritating essential oils in patients with sensitive skin. Study 1 was designed to evaluate the tolerance and acceptability of 2 variations of the HMP-containing cleanser—one fragrance free and the other with 
fragrance—in a small sample of healthy adults with clinically diagnosed fragrance-sensitive skin. Study 2 was a large, 2-center study of the tolerability and effectiveness of the fragranced HMP-containing cleanser compared with a benchmark dermatologist-recommended, gentle, fragrance-free, nonfoaming cleanser in women with clinically diagnosed sensitive skin.

Methods

Study 1 Design

The primary objective of this prospective, randomized, single-center, crossover study was to evaluate the tolerability of fragranced versus fragrance-free formulations of a mild, HMP-containing liquid facial cleanser in healthy male and female adults with Fitzpatrick skin types I to IV who were clinically diagnosed as having fragrance sensitivity. Fragrance sensitivity was defined as a history of positive reactions to a fragrance mixture of 8 components (fragrance mixture I) and/or a fragrance mixture of 14 fragrances (fragrance mixture II) that included balsam of Peru (Myroxylonpereirae), geraniol, jasmine oil, and oakmoss.⁵ All participants provided written informed consent prior to enrolling in the study, and both the study protocol and informed consent agreement were approved by an institutional review board.

Participants were instructed to wash their face twice daily, noting the time of cleansing and providing commentary about their cleansing experience in a diary. The liquid facial test cleansers contained the HMP potassium acrylates copolymer, glycerin, and a surfactant system primarily containing cocamidopropyl betaine and lauryl glucoside prepared without added fragrance (as previously described²⁰) or with a fragrance free of common allergens and irritating essential oils.

Half of the participants used the fragranced test cleanser and half used the fragrance-free test cleanser for a 3-week treatment period (weeks 1–3). Each treatment group subsequently switched to the other test cleanser for a second 3-week treatment period 
(weeks 4–6). Clinicians assessed global disease severity (an overall assessment of skin condition that was independent of other evaluation criteria), 
itching/burning, visible irritation, erythema, and desquamation at weekly time points throughout the study and graded each clinical tolerance attribute on a 5-point scale (0=none; 1=minimal; 2=mild; 3=moderate; 4=severe). Ordinal scores at baseline and at weeks 1 and 3 were used to calculate change from baseline.

A 7-item questionnaire also was administered to participants at each visit to assess skin condition, smoothness, softness, cleanliness, radiance, satisfaction with cleansing experience, and lathering. Each item was scored on a 5-point ordinal scale (0=none; 1=minimal; 2=good; 3=excellent; 4=superior). The scores for all parameters were statistically compared with baseline values using a paired t test with a significance level of P≤.05.

Study 2 Design

This prospective, 3-week, 
double-blind, randomized, comparative, 2-center study to evaluate the tolerability of the fragranced, HMP-containing test cleanser from study 1 versus a benchmark gentle, fragrance-free, nonfoaming cleanser in a large population of otherwise healthy females who had been clinically diagnosed with sensitive skin (not limited to fragrance sensitivity). The study sponsor provided blinded test materials, and neither the examiner nor the recorder knew which investigational product was administered to which participants. Additionally, personnel who dispensed the test cleansers to 
participants or supervised their use did not participate in the evaluation to minimize potential bias. All participants provided written informed consent prior to enrolling in the study, and the study protocol and informed consent agreement were approved by an institutional review board.

Participants included women aged 18 to 65 years with mild to moderate clinical symptoms of atopic dermatitis, eczema, acne, or rosacea within the 90 days prior to the study period. They were randomized into 
2 balanced treatment groups: group 1 received the mild, fragranced, HMP-containing liquid facial cleanser from study 1 and group 2 received a leading, dermatologist-recommended, gentle, fragrance-free, nonfoaming cleanser. Each treatment group used the test cleansers at least once daily for 3 weeks.

Clinicians evaluated facial skin for softness and smoothness, global disease severity (rated visually by the investigator as an overall assessment of skin condition that was independent of other evaluation criteria [as previously described²⁰]), itching, irritation, erythema, and desquamation at baseline and at weeks 1 and 3. The effectiveness of each product to remove facial dirt, cosmetics, and sebum also was assessed; clinical grading was performed as described for study 1 using the same grading scale as in study 1 and percentage change from baseline (improvement) was calculated.

The study also included a self-assessment of skin irritation in which participants responded yes or no to the following question: Have you experienced irritation using this product? Participants also completed a questionnaire in which they were asked to select the most appropriate answer—agree strongly, agree somewhat, neither, disagree somewhat, and disagree strongly— 
to the following statements: the cleanser leaves no residue; cleanses deep to remove dirt, oil, and makeup; the cleanser effectively removes makeup; the cleanser leaves my skin smooth; the cleanser leaves my skin soft; the cleanser rinses completely clean; cleanser does not over dry my skin; and my skin is completely clean.

The statistical analysis was performed using a 
nonparametric, 2-tailed, paired Mann-Whitney U test, and statistical significance was set at P≤.05.

Results

Study 1 Assessment

Eight female participants aged 22 to 60 years with clinically diagnosed fragrance sensitivity were enrolled in the study. After 3 weeks of use, clinician assessment showed that both the fragranced and fragrance-free test cleansers with HMPs improved several skin tolerance attributes, including global disease severity, irritation, and erythema (Figure 1). No notable differences in skin tolerance attributes were reported in the fragranced versus the fragrance-free formulations.

There were no reported differences in 
participant-reported cleanser effectiveness for the fragranced versus the fragrance-free cleanser either at baseline or weeks 1 or 3 (data not shown).

Study 2 Assessment

A total of 153 women aged 25 to 54 years with sensitive skin were enrolled in the study. Seventy-three participants were randomized to receive the fragranced test cleanser and 80 were randomized to receive the benchmark fragrance-free cleanser.

At week 3, there were no differences between the fragranced test cleanser and the benchmark cleanser in any of the clinician-assessed skin parameters 
(Figure 2). Of the parameters assessed, itching, irritation, and desquamation were the most improved from baseline in both treatment groups. Similar results were observed at week 1 (data not shown).

There were no apparent differences in subjective self-assessment of skin irritation between the test and benchmark cleansers at week 1 (15.7% vs 13.0%) or week 3 (24.3% vs 12.3%). When asked to respond to a series of 8 statements related to cleanser effectiveness, most participants either agreed strongly or agreed somewhat with the statements (Figure 3). There were no statistically significant differences between treatment groups, and responses to all statements indicated that participants were as satisfied with the test cleanser as they were with the benchmark cleanser.

Comment

Consumers value cleansing, fragrance, viscosity, and foaming attributes in skin care products very highly.^3,4,10 Fragrances are added to personal care products to positively affect consumers’ perception of product performance and to add emotional benefits by implying social or economic prestige to the use of a product.¹⁹ In one study, shampoo formulations that varied only in the added fragrance received different consumer evaluations for cleansing effectiveness and foaming.⁴

Although mild nonfoaming cleansers can be effective, adult consumers generally use cleansers that foam^10,16 and often judge the performance of a cleansing product based on its foaming properties.^3,10 Mild cleansers with HMPs maintain the ability to foam while also reducing the likelihood of skin irritation.¹⁶ One study showed that a mild, fragrance-free, foaming cleanser containing HMPs was as effective, well tolerated, and nonirritating in patients with sensitive skin as a benchmark nonfoaming gentle cleanser.²⁰

Results from study 1 presented here show that fragranced and fragrance-free formulations of a mild, HMP-containing cleanser are equally efficacious and well tolerated in a small sample of participants with clinically diagnosed fragrance sensitivity. Skin tolerance attributes improved with both cleansers over a 3-week period, particularly global disease severity, irritation, and erythema. These results suggest that a fragrance free of common allergens and irritating essential oils could be introduced into a mild foaming cleanser containing HMPs without causing adverse reactions, even in patients who are fragrance sensitive.

Although the populations of studies 1 and 2 both included female participants with sensitive skin, they were not identical. While study 1 assessed a limited number of participants with clinically diagnosed fragrance sensitivity, study 2 was larger and included a broader range of participants with clinically diagnosed skin sensitivity, which could include fragrance sensitivity. The well-chosen fragrance of the test cleanser containing HMPs was well tolerated; however, this does not imply that any other fragrances added to this cleanser formulation would be as well tolerated.

Conclusion

The current studies indicate that a gentle fragranced foaming cleanser with HMPs was well tolerated in a small population of participants with clinically diagnosed fragrance sensitivity. In a larger population of female participants with sensitive skin, the gentle fragranced foaming cleanser with HMPs was as effective as a leading dermatologist-recommended, 
fragrance-free, gentle, nonfoaming cleanser. The gentle, 
HMP-containing, foaming cleanser with a fragrance that does not contain common allergens and irritating essential oils offers a new cleansing option for adults with sensitive skin who may prefer to use a fragranced and foaming product.

Acknowledgments—The authors are grateful to the patients and clinicians who participated in these studies. Editorial and medical writing support was provided by Tove Anderson, PhD, and Alex Loeb, PhD, both from Evidence Scientific Solutions, Inc, Philadelphia, Pennsylvania, and was funded by Johnson & Johnson Consumer Inc.

For thousands of years, humans have used fragrances to change or affect their mood and enhance an “aura of beauty.”¹ Fragrance is a primary driver in consumer choice and purchasing decisions, especially when considering personal care products.² In addition to fragrance, consumers choose cleanser products based on compatibility with skin, cleansing properties, and sensory attributes such as viscosity and foaming.^3,4 However, fragrance sensitivity is among the most common causes of allergic contact dermatitis from cosmetics and personal care products,⁵ and estimates of the prevalence of fragrance sensitivity range from 1.8% to 4.2%.⁶

A panel of 26 fragrance ingredients that frequently induce contact dermatitis in sensitive individuals has been identified.⁷ Since 2003, regulatory authorities in the European Union require these compounds to be listed on the labels of consumer products to protect presensitized consumers.^7,8 However, manufacturers of cosmetics are not required to specify allergenic fragrance ingredients outside the European Union, and therefore it is difficult for consumers in the United States to avoid fragrance allergens.

Creation of a fragranced product for 
fragrance-sensitive individuals begins with careful selection of ingredients and extensive formulation testing and evaluation. This process usually is followed by testing in normal individuals to confirm that the fragranced product is well accepted and then evaluation is done in clinically confirmed fragrance-sensitive patients and those with a compromised skin barrier from atopic dermatitis, rosacea, or eczema.

Sensitive skin may be due to increased immune responsiveness, altered neurosensory input, and/or decreased skin barrier function, and presents a complex challenge for dermatologists.⁹ Subjective perceptions of sensitive skin include stinging, burning, pruritus, and tightness following product application. Clinically sensitive skin is defined by the presence of erythema, stratum corneum desquamation, papules, pustules, wheals, vesicles, bullae, and/or erosions.⁹ Although some of these symptoms may be observed immediately, others may be delayed by minutes, hours, or days following the use of an irritating product. Patients who present with subjective symptoms of sensitive skin may or may not show objective symptoms.

Gentle skin cleansing is particularly important for patients with compromised skin barrier integrity, such as those with acne, atopic dermatitis, eczema, or rosacea. Standard alkaline surfactants in skin cleansers help to remove dirt and oily soil and produce lather but can impair the skin barrier function and facilitate development of irritation.^10-13 The tolerability of a cleanser is influenced by its pH, the type and amount of surfactant ingredients, the presence of moisturizing agents, and the amount of residue left on the skin after washing.^11,12 Mild cleansers have been developed for patients with sensitive skin conditions and are expected to provide cleansing benefits without negatively affecting the hydration and viscoelastic properties of skin.¹¹ Mild cleansers interact minimally with skin proteins and lipids because they usually contain nonionic synthetic surfactant mixtures; they also have a pH value close to the slightly acidic pH of normal skin, contain moisturizing agents,^11,14,15 and usually produce less foam.^10,16 In patients with sensitive skin, mild and fragrance-free cleansers often are recommended.^17,18 Because fragrances often affect consumers’ perception of product performance¹⁹ and enhance the cleaning experience of the user, consumer compliance with clinical recommendations to use fragrance-free cleansers often is poor.

Low–molecular-weight, water-soluble, hydrophobically modified polymers (HMPs) have been used to create gentle foaming cleansers with reduced impact on the skin barrier.^12,16,20 In the presence of HMPs, surfactants assemble into larger, more stable polymer-surfactant structures that are less likely to penetrate the skin.¹⁶ Hydrophobically modified polymers can potentially reduce skin irritation by lowering the concentration of free micelles in solution. Additionally, both HMPs and HMP-surfactant complexes stabilize newly formed 
air-water interfaces, leading to thicker, denser, and longer-lasting foams.¹⁶ A gentle, fragrance-free, foaming liquid facial test cleanser with HMPs has been shown to be well tolerated in women with sensitive skin.²⁰

This report describes 2 studies of a new mild, 
HMP-containing, foaming facial cleanser with a 
fragrance that was free of common allergens and irritating essential oils in patients with sensitive skin. Study 1 was designed to evaluate the tolerance and acceptability of 2 variations of the HMP-containing cleanser—one fragrance free and the other with 
fragrance—in a small sample of healthy adults with clinically diagnosed fragrance-sensitive skin. Study 2 was a large, 2-center study of the tolerability and effectiveness of the fragranced HMP-containing cleanser compared with a benchmark dermatologist-recommended, gentle, fragrance-free, nonfoaming cleanser in women with clinically diagnosed sensitive skin.

Methods

Study 1 Design

The primary objective of this prospective, randomized, single-center, crossover study was to evaluate the tolerability of fragranced versus fragrance-free formulations of a mild, HMP-containing liquid facial cleanser in healthy male and female adults with Fitzpatrick skin types I to IV who were clinically diagnosed as having fragrance sensitivity. Fragrance sensitivity was defined as a history of positive reactions to a fragrance mixture of 8 components (fragrance mixture I) and/or a fragrance mixture of 14 fragrances (fragrance mixture II) that included balsam of Peru (Myroxylonpereirae), geraniol, jasmine oil, and oakmoss.⁵ All participants provided written informed consent prior to enrolling in the study, and both the study protocol and informed consent agreement were approved by an institutional review board.

Participants were instructed to wash their face twice daily, noting the time of cleansing and providing commentary about their cleansing experience in a diary. The liquid facial test cleansers contained the HMP potassium acrylates copolymer, glycerin, and a surfactant system primarily containing cocamidopropyl betaine and lauryl glucoside prepared without added fragrance (as previously described²⁰) or with a fragrance free of common allergens and irritating essential oils.

Half of the participants used the fragranced test cleanser and half used the fragrance-free test cleanser for a 3-week treatment period (weeks 1–3). Each treatment group subsequently switched to the other test cleanser for a second 3-week treatment period 
(weeks 4–6). Clinicians assessed global disease severity (an overall assessment of skin condition that was independent of other evaluation criteria), 
itching/burning, visible irritation, erythema, and desquamation at weekly time points throughout the study and graded each clinical tolerance attribute on a 5-point scale (0=none; 1=minimal; 2=mild; 3=moderate; 4=severe). Ordinal scores at baseline and at weeks 1 and 3 were used to calculate change from baseline.

A 7-item questionnaire also was administered to participants at each visit to assess skin condition, smoothness, softness, cleanliness, radiance, satisfaction with cleansing experience, and lathering. Each item was scored on a 5-point ordinal scale (0=none; 1=minimal; 2=good; 3=excellent; 4=superior). The scores for all parameters were statistically compared with baseline values using a paired t test with a significance level of P≤.05.

Study 2 Design

This prospective, 3-week, 
double-blind, randomized, comparative, 2-center study to evaluate the tolerability of the fragranced, HMP-containing test cleanser from study 1 versus a benchmark gentle, fragrance-free, nonfoaming cleanser in a large population of otherwise healthy females who had been clinically diagnosed with sensitive skin (not limited to fragrance sensitivity). The study sponsor provided blinded test materials, and neither the examiner nor the recorder knew which investigational product was administered to which participants. Additionally, personnel who dispensed the test cleansers to 
participants or supervised their use did not participate in the evaluation to minimize potential bias. All participants provided written informed consent prior to enrolling in the study, and the study protocol and informed consent agreement were approved by an institutional review board.

Participants included women aged 18 to 65 years with mild to moderate clinical symptoms of atopic dermatitis, eczema, acne, or rosacea within the 90 days prior to the study period. They were randomized into 
2 balanced treatment groups: group 1 received the mild, fragranced, HMP-containing liquid facial cleanser from study 1 and group 2 received a leading, dermatologist-recommended, gentle, fragrance-free, nonfoaming cleanser. Each treatment group used the test cleansers at least once daily for 3 weeks.

Clinicians evaluated facial skin for softness and smoothness, global disease severity (rated visually by the investigator as an overall assessment of skin condition that was independent of other evaluation criteria [as previously described²⁰]), itching, irritation, erythema, and desquamation at baseline and at weeks 1 and 3. The effectiveness of each product to remove facial dirt, cosmetics, and sebum also was assessed; clinical grading was performed as described for study 1 using the same grading scale as in study 1 and percentage change from baseline (improvement) was calculated.

The study also included a self-assessment of skin irritation in which participants responded yes or no to the following question: Have you experienced irritation using this product? Participants also completed a questionnaire in which they were asked to select the most appropriate answer—agree strongly, agree somewhat, neither, disagree somewhat, and disagree strongly— 
to the following statements: the cleanser leaves no residue; cleanses deep to remove dirt, oil, and makeup; the cleanser effectively removes makeup; the cleanser leaves my skin smooth; the cleanser leaves my skin soft; the cleanser rinses completely clean; cleanser does not over dry my skin; and my skin is completely clean.

The statistical analysis was performed using a 
nonparametric, 2-tailed, paired Mann-Whitney U test, and statistical significance was set at P≤.05.

Results

Study 1 Assessment

Eight female participants aged 22 to 60 years with clinically diagnosed fragrance sensitivity were enrolled in the study. After 3 weeks of use, clinician assessment showed that both the fragranced and fragrance-free test cleansers with HMPs improved several skin tolerance attributes, including global disease severity, irritation, and erythema (Figure 1). No notable differences in skin tolerance attributes were reported in the fragranced versus the fragrance-free formulations.

There were no reported differences in 
participant-reported cleanser effectiveness for the fragranced versus the fragrance-free cleanser either at baseline or weeks 1 or 3 (data not shown).

Study 2 Assessment

A total of 153 women aged 25 to 54 years with sensitive skin were enrolled in the study. Seventy-three participants were randomized to receive the fragranced test cleanser and 80 were randomized to receive the benchmark fragrance-free cleanser.

At week 3, there were no differences between the fragranced test cleanser and the benchmark cleanser in any of the clinician-assessed skin parameters 
(Figure 2). Of the parameters assessed, itching, irritation, and desquamation were the most improved from baseline in both treatment groups. Similar results were observed at week 1 (data not shown).

There were no apparent differences in subjective self-assessment of skin irritation between the test and benchmark cleansers at week 1 (15.7% vs 13.0%) or week 3 (24.3% vs 12.3%). When asked to respond to a series of 8 statements related to cleanser effectiveness, most participants either agreed strongly or agreed somewhat with the statements (Figure 3). There were no statistically significant differences between treatment groups, and responses to all statements indicated that participants were as satisfied with the test cleanser as they were with the benchmark cleanser.

Comment

Consumers value cleansing, fragrance, viscosity, and foaming attributes in skin care products very highly.^3,4,10 Fragrances are added to personal care products to positively affect consumers’ perception of product performance and to add emotional benefits by implying social or economic prestige to the use of a product.¹⁹ In one study, shampoo formulations that varied only in the added fragrance received different consumer evaluations for cleansing effectiveness and foaming.⁴

Although mild nonfoaming cleansers can be effective, adult consumers generally use cleansers that foam^10,16 and often judge the performance of a cleansing product based on its foaming properties.^3,10 Mild cleansers with HMPs maintain the ability to foam while also reducing the likelihood of skin irritation.¹⁶ One study showed that a mild, fragrance-free, foaming cleanser containing HMPs was as effective, well tolerated, and nonirritating in patients with sensitive skin as a benchmark nonfoaming gentle cleanser.²⁰

Results from study 1 presented here show that fragranced and fragrance-free formulations of a mild, HMP-containing cleanser are equally efficacious and well tolerated in a small sample of participants with clinically diagnosed fragrance sensitivity. Skin tolerance attributes improved with both cleansers over a 3-week period, particularly global disease severity, irritation, and erythema. These results suggest that a fragrance free of common allergens and irritating essential oils could be introduced into a mild foaming cleanser containing HMPs without causing adverse reactions, even in patients who are fragrance sensitive.

Although the populations of studies 1 and 2 both included female participants with sensitive skin, they were not identical. While study 1 assessed a limited number of participants with clinically diagnosed fragrance sensitivity, study 2 was larger and included a broader range of participants with clinically diagnosed skin sensitivity, which could include fragrance sensitivity. The well-chosen fragrance of the test cleanser containing HMPs was well tolerated; however, this does not imply that any other fragrances added to this cleanser formulation would be as well tolerated.

Conclusion

The current studies indicate that a gentle fragranced foaming cleanser with HMPs was well tolerated in a small population of participants with clinically diagnosed fragrance sensitivity. In a larger population of female participants with sensitive skin, the gentle fragranced foaming cleanser with HMPs was as effective as a leading dermatologist-recommended, 
fragrance-free, gentle, nonfoaming cleanser. The gentle, 
HMP-containing, foaming cleanser with a fragrance that does not contain common allergens and irritating essential oils offers a new cleansing option for adults with sensitive skin who may prefer to use a fragranced and foaming product.

Acknowledgments—The authors are grateful to the patients and clinicians who participated in these studies. Editorial and medical writing support was provided by Tove Anderson, PhD, and Alex Loeb, PhD, both from Evidence Scientific Solutions, Inc, Philadelphia, Pennsylvania, and was funded by Johnson & Johnson Consumer Inc.

For thousands of years, humans have used fragrances to change or affect their mood and enhance an “aura of beauty.”¹ Fragrance is a primary driver in consumer choice and purchasing decisions, especially when considering personal care products.² In addition to fragrance, consumers choose cleanser products based on compatibility with skin, cleansing properties, and sensory attributes such as viscosity and foaming.^3,4 However, fragrance sensitivity is among the most common causes of allergic contact dermatitis from cosmetics and personal care products,⁵ and estimates of the prevalence of fragrance sensitivity range from 1.8% to 4.2%.⁶

A panel of 26 fragrance ingredients that frequently induce contact dermatitis in sensitive individuals has been identified.⁷ Since 2003, regulatory authorities in the European Union require these compounds to be listed on the labels of consumer products to protect presensitized consumers.^7,8 However, manufacturers of cosmetics are not required to specify allergenic fragrance ingredients outside the European Union, and therefore it is difficult for consumers in the United States to avoid fragrance allergens.

Creation of a fragranced product for 
fragrance-sensitive individuals begins with careful selection of ingredients and extensive formulation testing and evaluation. This process usually is followed by testing in normal individuals to confirm that the fragranced product is well accepted and then evaluation is done in clinically confirmed fragrance-sensitive patients and those with a compromised skin barrier from atopic dermatitis, rosacea, or eczema.

Sensitive skin may be due to increased immune responsiveness, altered neurosensory input, and/or decreased skin barrier function, and presents a complex challenge for dermatologists.⁹ Subjective perceptions of sensitive skin include stinging, burning, pruritus, and tightness following product application. Clinically sensitive skin is defined by the presence of erythema, stratum corneum desquamation, papules, pustules, wheals, vesicles, bullae, and/or erosions.⁹ Although some of these symptoms may be observed immediately, others may be delayed by minutes, hours, or days following the use of an irritating product. Patients who present with subjective symptoms of sensitive skin may or may not show objective symptoms.

Gentle skin cleansing is particularly important for patients with compromised skin barrier integrity, such as those with acne, atopic dermatitis, eczema, or rosacea. Standard alkaline surfactants in skin cleansers help to remove dirt and oily soil and produce lather but can impair the skin barrier function and facilitate development of irritation.^10-13 The tolerability of a cleanser is influenced by its pH, the type and amount of surfactant ingredients, the presence of moisturizing agents, and the amount of residue left on the skin after washing.^11,12 Mild cleansers have been developed for patients with sensitive skin conditions and are expected to provide cleansing benefits without negatively affecting the hydration and viscoelastic properties of skin.¹¹ Mild cleansers interact minimally with skin proteins and lipids because they usually contain nonionic synthetic surfactant mixtures; they also have a pH value close to the slightly acidic pH of normal skin, contain moisturizing agents,^11,14,15 and usually produce less foam.^10,16 In patients with sensitive skin, mild and fragrance-free cleansers often are recommended.^17,18 Because fragrances often affect consumers’ perception of product performance¹⁹ and enhance the cleaning experience of the user, consumer compliance with clinical recommendations to use fragrance-free cleansers often is poor.

Low–molecular-weight, water-soluble, hydrophobically modified polymers (HMPs) have been used to create gentle foaming cleansers with reduced impact on the skin barrier.^12,16,20 In the presence of HMPs, surfactants assemble into larger, more stable polymer-surfactant structures that are less likely to penetrate the skin.¹⁶ Hydrophobically modified polymers can potentially reduce skin irritation by lowering the concentration of free micelles in solution. Additionally, both HMPs and HMP-surfactant complexes stabilize newly formed 
air-water interfaces, leading to thicker, denser, and longer-lasting foams.¹⁶ A gentle, fragrance-free, foaming liquid facial test cleanser with HMPs has been shown to be well tolerated in women with sensitive skin.²⁰

This report describes 2 studies of a new mild, 
HMP-containing, foaming facial cleanser with a 
fragrance that was free of common allergens and irritating essential oils in patients with sensitive skin. Study 1 was designed to evaluate the tolerance and acceptability of 2 variations of the HMP-containing cleanser—one fragrance free and the other with 
fragrance—in a small sample of healthy adults with clinically diagnosed fragrance-sensitive skin. Study 2 was a large, 2-center study of the tolerability and effectiveness of the fragranced HMP-containing cleanser compared with a benchmark dermatologist-recommended, gentle, fragrance-free, nonfoaming cleanser in women with clinically diagnosed sensitive skin.

Methods

Study 1 Design

The primary objective of this prospective, randomized, single-center, crossover study was to evaluate the tolerability of fragranced versus fragrance-free formulations of a mild, HMP-containing liquid facial cleanser in healthy male and female adults with Fitzpatrick skin types I to IV who were clinically diagnosed as having fragrance sensitivity. Fragrance sensitivity was defined as a history of positive reactions to a fragrance mixture of 8 components (fragrance mixture I) and/or a fragrance mixture of 14 fragrances (fragrance mixture II) that included balsam of Peru (Myroxylonpereirae), geraniol, jasmine oil, and oakmoss.⁵ All participants provided written informed consent prior to enrolling in the study, and both the study protocol and informed consent agreement were approved by an institutional review board.

Participants were instructed to wash their face twice daily, noting the time of cleansing and providing commentary about their cleansing experience in a diary. The liquid facial test cleansers contained the HMP potassium acrylates copolymer, glycerin, and a surfactant system primarily containing cocamidopropyl betaine and lauryl glucoside prepared without added fragrance (as previously described²⁰) or with a fragrance free of common allergens and irritating essential oils.

Half of the participants used the fragranced test cleanser and half used the fragrance-free test cleanser for a 3-week treatment period (weeks 1–3). Each treatment group subsequently switched to the other test cleanser for a second 3-week treatment period 
(weeks 4–6). Clinicians assessed global disease severity (an overall assessment of skin condition that was independent of other evaluation criteria), 
itching/burning, visible irritation, erythema, and desquamation at weekly time points throughout the study and graded each clinical tolerance attribute on a 5-point scale (0=none; 1=minimal; 2=mild; 3=moderate; 4=severe). Ordinal scores at baseline and at weeks 1 and 3 were used to calculate change from baseline.

A 7-item questionnaire also was administered to participants at each visit to assess skin condition, smoothness, softness, cleanliness, radiance, satisfaction with cleansing experience, and lathering. Each item was scored on a 5-point ordinal scale (0=none; 1=minimal; 2=good; 3=excellent; 4=superior). The scores for all parameters were statistically compared with baseline values using a paired t test with a significance level of P≤.05.

Study 2 Design

This prospective, 3-week, 
double-blind, randomized, comparative, 2-center study to evaluate the tolerability of the fragranced, HMP-containing test cleanser from study 1 versus a benchmark gentle, fragrance-free, nonfoaming cleanser in a large population of otherwise healthy females who had been clinically diagnosed with sensitive skin (not limited to fragrance sensitivity). The study sponsor provided blinded test materials, and neither the examiner nor the recorder knew which investigational product was administered to which participants. Additionally, personnel who dispensed the test cleansers to 
participants or supervised their use did not participate in the evaluation to minimize potential bias. All participants provided written informed consent prior to enrolling in the study, and the study protocol and informed consent agreement were approved by an institutional review board.

Participants included women aged 18 to 65 years with mild to moderate clinical symptoms of atopic dermatitis, eczema, acne, or rosacea within the 90 days prior to the study period. They were randomized into 
2 balanced treatment groups: group 1 received the mild, fragranced, HMP-containing liquid facial cleanser from study 1 and group 2 received a leading, dermatologist-recommended, gentle, fragrance-free, nonfoaming cleanser. Each treatment group used the test cleansers at least once daily for 3 weeks.

Clinicians evaluated facial skin for softness and smoothness, global disease severity (rated visually by the investigator as an overall assessment of skin condition that was independent of other evaluation criteria [as previously described²⁰]), itching, irritation, erythema, and desquamation at baseline and at weeks 1 and 3. The effectiveness of each product to remove facial dirt, cosmetics, and sebum also was assessed; clinical grading was performed as described for study 1 using the same grading scale as in study 1 and percentage change from baseline (improvement) was calculated.

The study also included a self-assessment of skin irritation in which participants responded yes or no to the following question: Have you experienced irritation using this product? Participants also completed a questionnaire in which they were asked to select the most appropriate answer—agree strongly, agree somewhat, neither, disagree somewhat, and disagree strongly— 
to the following statements: the cleanser leaves no residue; cleanses deep to remove dirt, oil, and makeup; the cleanser effectively removes makeup; the cleanser leaves my skin smooth; the cleanser leaves my skin soft; the cleanser rinses completely clean; cleanser does not over dry my skin; and my skin is completely clean.

The statistical analysis was performed using a 
nonparametric, 2-tailed, paired Mann-Whitney U test, and statistical significance was set at P≤.05.

Results

Study 1 Assessment

Eight female participants aged 22 to 60 years with clinically diagnosed fragrance sensitivity were enrolled in the study. After 3 weeks of use, clinician assessment showed that both the fragranced and fragrance-free test cleansers with HMPs improved several skin tolerance attributes, including global disease severity, irritation, and erythema (Figure 1). No notable differences in skin tolerance attributes were reported in the fragranced versus the fragrance-free formulations.

There were no reported differences in 
participant-reported cleanser effectiveness for the fragranced versus the fragrance-free cleanser either at baseline or weeks 1 or 3 (data not shown).

Study 2 Assessment

A total of 153 women aged 25 to 54 years with sensitive skin were enrolled in the study. Seventy-three participants were randomized to receive the fragranced test cleanser and 80 were randomized to receive the benchmark fragrance-free cleanser.

At week 3, there were no differences between the fragranced test cleanser and the benchmark cleanser in any of the clinician-assessed skin parameters 
(Figure 2). Of the parameters assessed, itching, irritation, and desquamation were the most improved from baseline in both treatment groups. Similar results were observed at week 1 (data not shown).

There were no apparent differences in subjective self-assessment of skin irritation between the test and benchmark cleansers at week 1 (15.7% vs 13.0%) or week 3 (24.3% vs 12.3%). When asked to respond to a series of 8 statements related to cleanser effectiveness, most participants either agreed strongly or agreed somewhat with the statements (Figure 3). There were no statistically significant differences between treatment groups, and responses to all statements indicated that participants were as satisfied with the test cleanser as they were with the benchmark cleanser.

Comment

Consumers value cleansing, fragrance, viscosity, and foaming attributes in skin care products very highly.^3,4,10 Fragrances are added to personal care products to positively affect consumers’ perception of product performance and to add emotional benefits by implying social or economic prestige to the use of a product.¹⁹ In one study, shampoo formulations that varied only in the added fragrance received different consumer evaluations for cleansing effectiveness and foaming.⁴

Although mild nonfoaming cleansers can be effective, adult consumers generally use cleansers that foam^10,16 and often judge the performance of a cleansing product based on its foaming properties.^3,10 Mild cleansers with HMPs maintain the ability to foam while also reducing the likelihood of skin irritation.¹⁶ One study showed that a mild, fragrance-free, foaming cleanser containing HMPs was as effective, well tolerated, and nonirritating in patients with sensitive skin as a benchmark nonfoaming gentle cleanser.²⁰

Results from study 1 presented here show that fragranced and fragrance-free formulations of a mild, HMP-containing cleanser are equally efficacious and well tolerated in a small sample of participants with clinically diagnosed fragrance sensitivity. Skin tolerance attributes improved with both cleansers over a 3-week period, particularly global disease severity, irritation, and erythema. These results suggest that a fragrance free of common allergens and irritating essential oils could be introduced into a mild foaming cleanser containing HMPs without causing adverse reactions, even in patients who are fragrance sensitive.

Although the populations of studies 1 and 2 both included female participants with sensitive skin, they were not identical. While study 1 assessed a limited number of participants with clinically diagnosed fragrance sensitivity, study 2 was larger and included a broader range of participants with clinically diagnosed skin sensitivity, which could include fragrance sensitivity. The well-chosen fragrance of the test cleanser containing HMPs was well tolerated; however, this does not imply that any other fragrances added to this cleanser formulation would be as well tolerated.

Conclusion

The current studies indicate that a gentle fragranced foaming cleanser with HMPs was well tolerated in a small population of participants with clinically diagnosed fragrance sensitivity. In a larger population of female participants with sensitive skin, the gentle fragranced foaming cleanser with HMPs was as effective as a leading dermatologist-recommended, 
fragrance-free, gentle, nonfoaming cleanser. The gentle, 
HMP-containing, foaming cleanser with a fragrance that does not contain common allergens and irritating essential oils offers a new cleansing option for adults with sensitive skin who may prefer to use a fragranced and foaming product.

Acknowledgments—The authors are grateful to the patients and clinicians who participated in these studies. Editorial and medical writing support was provided by Tove Anderson, PhD, and Alex Loeb, PhD, both from Evidence Scientific Solutions, Inc, Philadelphia, Pennsylvania, and was funded by Johnson & Johnson Consumer Inc.

The Diagnosis: Fixed Cutaneous Sporotrichosis

On further questioning at our dermatology clinic, the patient reported having landed face-first into rocks and gravel during the all-terrain vehicle accident. After his medical history was noted and a physical examination was completed, bacterial and fungal cultures of the wound were taken. The fungal culture was positive for Sporothrix schenckii. The patient was prescribed itraconazole 200 mg 3 times daily for 3 days, then 200 mg twice daily for an additional 4 weeks after the lesions completely resolved. An ophthalmologist was immediately consulted to rule out sinus and periorbital involvement. After computed tomography revealed possible preseptal cellulitis with frontal sinus involvement, the patient was admitted and intravenous amphotericin B was administered. Following consultations with infectious disease specialists and radiologists, amphotericin B was discontinued and the patient was discharged on itraconazole 200 mg twice daily with close monitoring. At 3-month follow-up, the sporotrichosis infection had completely cleared (Figure).

Deep fungal infections comprise 2 distinct groups: systemic and subcutaneous mycoses. Individuals with subcutaneous mycoses present with skin involvement as the primary feature. Sporotrichosis is the most common cause of this type of mycosis¹ and is caused by the dimorphic fungus S schenckii, an environmental saprophyte often residing in soil. Sporothrix schenckii exists as mold in a natural environment but exists as yeast in host tissue, thus causing ensuing infection.

Epidemiology

Sporotrichosis occurs worldwide but most frequently in temperate tropical and subtropical regions. The majority of cases are reported in Mexico and Central and South America¹; however, cases have been seen in the southern United States, Japan, and Australia.² In the United States, sporotrichosis is most commonly found in river valleys of the Midwest.

Sporothrix schenckii is most commonly isolated in hay, sphagnum moss, thorny plants, and soil, but it also has been described in other manifold host environments. Unusual origins of inoculation include an old and rust-stained camping tent in Mexico,³ crawl space joists of a house in Indiana,⁴ and hay bales used as props in a haunted house in Oklahoma.⁵

The incidence of infection is primarily sporadic; however, outbreaks among individuals who share a common environment favorable for the growth of S schenckii are at risk. Those identified to be at risk include rose gardeners, berry pickers, those who work in tree nurseries, horticulturists, landscapers, and miners.

Pathogenesis

As a dimorphic fungus, infection occurs when a conidium in the mold phase is introduced into the skin, usually by traumatic skin injury, and is 
converted to the yeast form in vivo. Distribution of infection by this organism is most commonly 
localized to the cutaneous, subcutaneous, and lymphocutaneous regions in healthy hosts but can involve visceral and osteoarticular structures in immunocompromised hosts.^1,6 Pulmonary and disseminated forms are rare but can occur when 
S schenckii conidia are inhaled. Zoonotic transmission of the fungus also can occur with exposure to infected animals. Sporothrix schenckii has been reported to occur in cats, dogs, horses, donkeys, squirrels, armadillos, and dolphins.^7-11

Pathology

Sporothrix schenckii is typically not visualized on microscopic examination due to the small number of microorganisms present; however, cultures grow rapidly 
(3–5 days) on Sabouraud agar. The fungus most commonly develops as white or off-white compact colonies that progressively darken with age, transitioning to gray and then black.¹ Microscopically, the hyphae produce oval or pyriform conidia, which are assembled 
in a typical bouquetlike manner. Conversion of the organism to yeast on enriched medium such as brain-heart infusion agar or blood-cysteine-glucose agar confirms the diagnosis.

Acute lesions typically show a nonspecific mixed infiltrate, but established lesions may reveal granulomatous formation and neutrophilic microabscesses.^1,2 Asteroid bodies, which are cigar-shaped yeasts surrounded by eosinophilic coronae radiata, may be found. Organisms are sparsely distributed within the lesions, necessitating a thorough examination of the culture for identification.

Clinical Features

Sporotrichosis has 3 main classifications: lymphocutaneous, fixed cutaneous, and disseminated. Lymphocutaneous sporotrichosis is the most common form of the infection.² The disease presents with a small indurated papule occurring approximately 7 to 30 days after inoculation into the skin. The papule slowly enlarges, forms a nodule, and then frequently ulcerates. Over time, draining lymphatics become edematous and inflammatory, and a chain of secondary nodules begins to appear proximal to the initial lesion. The primary and secondary nodules may continue to ulcerate; alternately, they may heal or become chronic.

In fixed cutaneous sporotrichosis, the infection remains localized to one region and a granuloma may develop, which also may ulcerate. Satellite nodules may appear along the periphery of the lesion. Lymphatic spread is not observed in this form of 
the disease.

The disseminated form is a result of hematogenous spread from the primary inoculation site and typically occurs in an immunocompromised host. This form can present as pulmonary disease, sinusitis, and meningitis.¹

Differential Diagnosis

The differential diagnosis for sporotrichosis includes atypical mycobacteria, nocardiosis, blastomycosis, pyogenic bacteria, leishmaniasis, tularemia, 
and tuberculosis.

Treatment

Treatment of sporotrichosis is always required. A saturated solution of potassium iodide has classically been used; however, it is frequently associated with side effects and can be problematic to administer.¹² Given its low cost and traditional efficacy, it may still be used in some parts of the world.

Currently, the treatment of choice for fixed cutaneous and lymphocutaneous sporotrichosis is itraconazole 100 to 200 mg once daily for 3 to 6 months.¹ The recommended treatment of osteoarticular sporotrichosis is itraconazole, but prolonged therapy is required.

Heat therapy is an alternative treatment option, as certain strains of S schenckii do not grow at temperatures higher than 35°C. Hot compresses must be used for at least 1 hour a day for several months, which may affect patient compliance.

Immunocompromised patients often have disseminated infection and require lifelong suppressive therapy with itraconazole and may require initial treatment with amphotericin B.¹³

Conclusion

Subcutaneous sporotrichosis can develop in patients with a traumatic injury involving vegetation, soil, or animals. Although some patients may develop more invasive disease, most infections in immunocompetent patients will resolve after 3 to 6 months of itraconazole 100 to 200 mg once daily.¹

The Diagnosis: Fixed Cutaneous Sporotrichosis

On further questioning at our dermatology clinic, the patient reported having landed face-first into rocks and gravel during the all-terrain vehicle accident. After his medical history was noted and a physical examination was completed, bacterial and fungal cultures of the wound were taken. The fungal culture was positive for Sporothrix schenckii. The patient was prescribed itraconazole 200 mg 3 times daily for 3 days, then 200 mg twice daily for an additional 4 weeks after the lesions completely resolved. An ophthalmologist was immediately consulted to rule out sinus and periorbital involvement. After computed tomography revealed possible preseptal cellulitis with frontal sinus involvement, the patient was admitted and intravenous amphotericin B was administered. Following consultations with infectious disease specialists and radiologists, amphotericin B was discontinued and the patient was discharged on itraconazole 200 mg twice daily with close monitoring. At 3-month follow-up, the sporotrichosis infection had completely cleared (Figure).

Deep fungal infections comprise 2 distinct groups: systemic and subcutaneous mycoses. Individuals with subcutaneous mycoses present with skin involvement as the primary feature. Sporotrichosis is the most common cause of this type of mycosis¹ and is caused by the dimorphic fungus S schenckii, an environmental saprophyte often residing in soil. Sporothrix schenckii exists as mold in a natural environment but exists as yeast in host tissue, thus causing ensuing infection.

Epidemiology

Sporotrichosis occurs worldwide but most frequently in temperate tropical and subtropical regions. The majority of cases are reported in Mexico and Central and South America¹; however, cases have been seen in the southern United States, Japan, and Australia.² In the United States, sporotrichosis is most commonly found in river valleys of the Midwest.

Sporothrix schenckii is most commonly isolated in hay, sphagnum moss, thorny plants, and soil, but it also has been described in other manifold host environments. Unusual origins of inoculation include an old and rust-stained camping tent in Mexico,³ crawl space joists of a house in Indiana,⁴ and hay bales used as props in a haunted house in Oklahoma.⁵

The incidence of infection is primarily sporadic; however, outbreaks among individuals who share a common environment favorable for the growth of S schenckii are at risk. Those identified to be at risk include rose gardeners, berry pickers, those who work in tree nurseries, horticulturists, landscapers, and miners.

Pathogenesis

As a dimorphic fungus, infection occurs when a conidium in the mold phase is introduced into the skin, usually by traumatic skin injury, and is 
converted to the yeast form in vivo. Distribution of infection by this organism is most commonly 
localized to the cutaneous, subcutaneous, and lymphocutaneous regions in healthy hosts but can involve visceral and osteoarticular structures in immunocompromised hosts.^1,6 Pulmonary and disseminated forms are rare but can occur when 
S schenckii conidia are inhaled. Zoonotic transmission of the fungus also can occur with exposure to infected animals. Sporothrix schenckii has been reported to occur in cats, dogs, horses, donkeys, squirrels, armadillos, and dolphins.^7-11

Pathology

Sporothrix schenckii is typically not visualized on microscopic examination due to the small number of microorganisms present; however, cultures grow rapidly 
(3–5 days) on Sabouraud agar. The fungus most commonly develops as white or off-white compact colonies that progressively darken with age, transitioning to gray and then black.¹ Microscopically, the hyphae produce oval or pyriform conidia, which are assembled 
in a typical bouquetlike manner. Conversion of the organism to yeast on enriched medium such as brain-heart infusion agar or blood-cysteine-glucose agar confirms the diagnosis.

Acute lesions typically show a nonspecific mixed infiltrate, but established lesions may reveal granulomatous formation and neutrophilic microabscesses.^1,2 Asteroid bodies, which are cigar-shaped yeasts surrounded by eosinophilic coronae radiata, may be found. Organisms are sparsely distributed within the lesions, necessitating a thorough examination of the culture for identification.

Clinical Features

Sporotrichosis has 3 main classifications: lymphocutaneous, fixed cutaneous, and disseminated. Lymphocutaneous sporotrichosis is the most common form of the infection.² The disease presents with a small indurated papule occurring approximately 7 to 30 days after inoculation into the skin. The papule slowly enlarges, forms a nodule, and then frequently ulcerates. Over time, draining lymphatics become edematous and inflammatory, and a chain of secondary nodules begins to appear proximal to the initial lesion. The primary and secondary nodules may continue to ulcerate; alternately, they may heal or become chronic.

In fixed cutaneous sporotrichosis, the infection remains localized to one region and a granuloma may develop, which also may ulcerate. Satellite nodules may appear along the periphery of the lesion. Lymphatic spread is not observed in this form of 
the disease.

The disseminated form is a result of hematogenous spread from the primary inoculation site and typically occurs in an immunocompromised host. This form can present as pulmonary disease, sinusitis, and meningitis.¹

Differential Diagnosis

The differential diagnosis for sporotrichosis includes atypical mycobacteria, nocardiosis, blastomycosis, pyogenic bacteria, leishmaniasis, tularemia, 
and tuberculosis.

Treatment

Treatment of sporotrichosis is always required. A saturated solution of potassium iodide has classically been used; however, it is frequently associated with side effects and can be problematic to administer.¹² Given its low cost and traditional efficacy, it may still be used in some parts of the world.

Currently, the treatment of choice for fixed cutaneous and lymphocutaneous sporotrichosis is itraconazole 100 to 200 mg once daily for 3 to 6 months.¹ The recommended treatment of osteoarticular sporotrichosis is itraconazole, but prolonged therapy is required.

Heat therapy is an alternative treatment option, as certain strains of S schenckii do not grow at temperatures higher than 35°C. Hot compresses must be used for at least 1 hour a day for several months, which may affect patient compliance.

Immunocompromised patients often have disseminated infection and require lifelong suppressive therapy with itraconazole and may require initial treatment with amphotericin B.¹³

Conclusion

Subcutaneous sporotrichosis can develop in patients with a traumatic injury involving vegetation, soil, or animals. Although some patients may develop more invasive disease, most infections in immunocompetent patients will resolve after 3 to 6 months of itraconazole 100 to 200 mg once daily.¹

The Diagnosis: Fixed Cutaneous Sporotrichosis

On further questioning at our dermatology clinic, the patient reported having landed face-first into rocks and gravel during the all-terrain vehicle accident. After his medical history was noted and a physical examination was completed, bacterial and fungal cultures of the wound were taken. The fungal culture was positive for Sporothrix schenckii. The patient was prescribed itraconazole 200 mg 3 times daily for 3 days, then 200 mg twice daily for an additional 4 weeks after the lesions completely resolved. An ophthalmologist was immediately consulted to rule out sinus and periorbital involvement. After computed tomography revealed possible preseptal cellulitis with frontal sinus involvement, the patient was admitted and intravenous amphotericin B was administered. Following consultations with infectious disease specialists and radiologists, amphotericin B was discontinued and the patient was discharged on itraconazole 200 mg twice daily with close monitoring. At 3-month follow-up, the sporotrichosis infection had completely cleared (Figure).

Deep fungal infections comprise 2 distinct groups: systemic and subcutaneous mycoses. Individuals with subcutaneous mycoses present with skin involvement as the primary feature. Sporotrichosis is the most common cause of this type of mycosis¹ and is caused by the dimorphic fungus S schenckii, an environmental saprophyte often residing in soil. Sporothrix schenckii exists as mold in a natural environment but exists as yeast in host tissue, thus causing ensuing infection.

Epidemiology

Sporotrichosis occurs worldwide but most frequently in temperate tropical and subtropical regions. The majority of cases are reported in Mexico and Central and South America¹; however, cases have been seen in the southern United States, Japan, and Australia.² In the United States, sporotrichosis is most commonly found in river valleys of the Midwest.

Sporothrix schenckii is most commonly isolated in hay, sphagnum moss, thorny plants, and soil, but it also has been described in other manifold host environments. Unusual origins of inoculation include an old and rust-stained camping tent in Mexico,³ crawl space joists of a house in Indiana,⁴ and hay bales used as props in a haunted house in Oklahoma.⁵

The incidence of infection is primarily sporadic; however, outbreaks among individuals who share a common environment favorable for the growth of S schenckii are at risk. Those identified to be at risk include rose gardeners, berry pickers, those who work in tree nurseries, horticulturists, landscapers, and miners.

Pathogenesis

As a dimorphic fungus, infection occurs when a conidium in the mold phase is introduced into the skin, usually by traumatic skin injury, and is 
converted to the yeast form in vivo. Distribution of infection by this organism is most commonly 
localized to the cutaneous, subcutaneous, and lymphocutaneous regions in healthy hosts but can involve visceral and osteoarticular structures in immunocompromised hosts.^1,6 Pulmonary and disseminated forms are rare but can occur when 
S schenckii conidia are inhaled. Zoonotic transmission of the fungus also can occur with exposure to infected animals. Sporothrix schenckii has been reported to occur in cats, dogs, horses, donkeys, squirrels, armadillos, and dolphins.^7-11

Pathology

Sporothrix schenckii is typically not visualized on microscopic examination due to the small number of microorganisms present; however, cultures grow rapidly 
(3–5 days) on Sabouraud agar. The fungus most commonly develops as white or off-white compact colonies that progressively darken with age, transitioning to gray and then black.¹ Microscopically, the hyphae produce oval or pyriform conidia, which are assembled 
in a typical bouquetlike manner. Conversion of the organism to yeast on enriched medium such as brain-heart infusion agar or blood-cysteine-glucose agar confirms the diagnosis.

Acute lesions typically show a nonspecific mixed infiltrate, but established lesions may reveal granulomatous formation and neutrophilic microabscesses.^1,2 Asteroid bodies, which are cigar-shaped yeasts surrounded by eosinophilic coronae radiata, may be found. Organisms are sparsely distributed within the lesions, necessitating a thorough examination of the culture for identification.

Clinical Features

Sporotrichosis has 3 main classifications: lymphocutaneous, fixed cutaneous, and disseminated. Lymphocutaneous sporotrichosis is the most common form of the infection.² The disease presents with a small indurated papule occurring approximately 7 to 30 days after inoculation into the skin. The papule slowly enlarges, forms a nodule, and then frequently ulcerates. Over time, draining lymphatics become edematous and inflammatory, and a chain of secondary nodules begins to appear proximal to the initial lesion. The primary and secondary nodules may continue to ulcerate; alternately, they may heal or become chronic.

In fixed cutaneous sporotrichosis, the infection remains localized to one region and a granuloma may develop, which also may ulcerate. Satellite nodules may appear along the periphery of the lesion. Lymphatic spread is not observed in this form of 
the disease.

The disseminated form is a result of hematogenous spread from the primary inoculation site and typically occurs in an immunocompromised host. This form can present as pulmonary disease, sinusitis, and meningitis.¹

Differential Diagnosis

The differential diagnosis for sporotrichosis includes atypical mycobacteria, nocardiosis, blastomycosis, pyogenic bacteria, leishmaniasis, tularemia, 
and tuberculosis.

Treatment

Treatment of sporotrichosis is always required. A saturated solution of potassium iodide has classically been used; however, it is frequently associated with side effects and can be problematic to administer.¹² Given its low cost and traditional efficacy, it may still be used in some parts of the world.

Currently, the treatment of choice for fixed cutaneous and lymphocutaneous sporotrichosis is itraconazole 100 to 200 mg once daily for 3 to 6 months.¹ The recommended treatment of osteoarticular sporotrichosis is itraconazole, but prolonged therapy is required.

Heat therapy is an alternative treatment option, as certain strains of S schenckii do not grow at temperatures higher than 35°C. Hot compresses must be used for at least 1 hour a day for several months, which may affect patient compliance.

Immunocompromised patients often have disseminated infection and require lifelong suppressive therapy with itraconazole and may require initial treatment with amphotericin B.¹³

Conclusion

Subcutaneous sporotrichosis can develop in patients with a traumatic injury involving vegetation, soil, or animals. Although some patients may develop more invasive disease, most infections in immunocompetent patients will resolve after 3 to 6 months of itraconazole 100 to 200 mg once daily.¹

Case Report

An 18-year-old Iranian man presented to the dermatology clinic with hair loss of 1 night’s duration. He denied pruritus, pain, discharge, or flaking. The patient had no notable personal, family, or surgical history and was not currently taking any medications. He denied recent travel. The patient reported that he found hair on his pillow upon waking up in the morning prior to coming to the clinic. On physical examination, 2 ants 
(Figure 1) were found on the scalp and alopecia with a vertical linear distribution was noted (Figure 2). Hairs of various lengths were found on the scalp within the distribution of the alopecia. No excoriations, crusting, seborrhea, or other areas of hair loss were detected. Wood lamp examination was negative. Based on these findings, which were concordant with similar findings from prior reports,^1-4 a diagnosis of ant-induced alopecia was made. Hair regrowth was noted within 1 week with full appearance of normal-length hair within 2.5 weeks.

Comment

Ant-induced alopecia is a form of localized hair loss caused by the Pheidole genus, the second largest genus of ants in the world.⁵ These ants can be found worldwide, but most cases of ant-induced alopecia have been from Iran, with at least 1 reported case from Turkey.^1-4,6 An early case series of ant-induced alopecia was reported in 1999,⁶ but the causative species was not described at that time.

The majority of reported cases of ant-induced alopecia are attributed to the barber ant (Pheidole pallidula). This type of alopecia is caused by worker ants within the species hierarchy.^1,4,6 The P pallidula worker ants are dimorphic and are classified as major and minor workers.⁷ Major workers have body lengths ranging up to 6 mm, whereas minor workers have body lengths ranging up to 4 mm. Major workers have larger heads and mandibles than minor workers and also have up to 2 pairs of denticles on the cranium.⁵ The minor workers are foragers and mainly collect food, whereas the major workers defend the nest and store food.⁸ These ants have widespread habitats with the ability to live in indoor and outdoor environments.

The presentation of hair loss caused by these ants is acute. Hair loss usually is confined to one specific area. Some patients may report pruritus or may present with erythematous lesions from ant stings or manual scratching.⁵ None of these signs or symptoms were seen in our patient. Some investigators have suggested that the barber ant is attracted to the hair of individuals with seborrheic dermatitis,¹ but our patient had no medical history of seborrheic dermatitis. Most likely, ants are attracted to excess sebum on the scalp in select individuals in their search for food and cause localized hair destruction.

Localized hair loss, as depicted in our case, should warrant a thorough evaluation for alopecia areata, trichotillomania, and tinea capitis.⁹ Alopecia areata should be considered in individuals with multiple focal patches of hair loss that have a positive hair pull test from peripheral sites of active lesions. Tinea capitis usually has localized sites of hair loss with underlying scaling, crusting, pruritus, erythema, and discharge from lesions, with positive potassium hydroxide preparations or fungal cultures. Trichotillomania typically presents with a spared peripheral fringe of hair. Remaining hairs may be thick and hyperpigmented as a response to repeated pulling, and biopsy often demonstrates fracture or degeneration of the hair shaft. A psychiatric evaluation may be warranted in cases of trichotillomania. Other cases of arthropod-induced hair loss include tick bite alopecia^10,11 and hair loss induced by numerous honeybee stings,¹² and these diagnoses should be suspected in patients with a history of ants on their pillow or in those from endemic areas.

No specific treatment is indicated in cases of 
ant-induced alopecia because hair usually regrows to its normal length without intervention.

Case Report

An 18-year-old Iranian man presented to the dermatology clinic with hair loss of 1 night’s duration. He denied pruritus, pain, discharge, or flaking. The patient had no notable personal, family, or surgical history and was not currently taking any medications. He denied recent travel. The patient reported that he found hair on his pillow upon waking up in the morning prior to coming to the clinic. On physical examination, 2 ants 
(Figure 1) were found on the scalp and alopecia with a vertical linear distribution was noted (Figure 2). Hairs of various lengths were found on the scalp within the distribution of the alopecia. No excoriations, crusting, seborrhea, or other areas of hair loss were detected. Wood lamp examination was negative. Based on these findings, which were concordant with similar findings from prior reports,^1-4 a diagnosis of ant-induced alopecia was made. Hair regrowth was noted within 1 week with full appearance of normal-length hair within 2.5 weeks.

Comment

Ant-induced alopecia is a form of localized hair loss caused by the Pheidole genus, the second largest genus of ants in the world.⁵ These ants can be found worldwide, but most cases of ant-induced alopecia have been from Iran, with at least 1 reported case from Turkey.^1-4,6 An early case series of ant-induced alopecia was reported in 1999,⁶ but the causative species was not described at that time.

The majority of reported cases of ant-induced alopecia are attributed to the barber ant (Pheidole pallidula). This type of alopecia is caused by worker ants within the species hierarchy.^1,4,6 The P pallidula worker ants are dimorphic and are classified as major and minor workers.⁷ Major workers have body lengths ranging up to 6 mm, whereas minor workers have body lengths ranging up to 4 mm. Major workers have larger heads and mandibles than minor workers and also have up to 2 pairs of denticles on the cranium.⁵ The minor workers are foragers and mainly collect food, whereas the major workers defend the nest and store food.⁸ These ants have widespread habitats with the ability to live in indoor and outdoor environments.

The presentation of hair loss caused by these ants is acute. Hair loss usually is confined to one specific area. Some patients may report pruritus or may present with erythematous lesions from ant stings or manual scratching.⁵ None of these signs or symptoms were seen in our patient. Some investigators have suggested that the barber ant is attracted to the hair of individuals with seborrheic dermatitis,¹ but our patient had no medical history of seborrheic dermatitis. Most likely, ants are attracted to excess sebum on the scalp in select individuals in their search for food and cause localized hair destruction.

Localized hair loss, as depicted in our case, should warrant a thorough evaluation for alopecia areata, trichotillomania, and tinea capitis.⁹ Alopecia areata should be considered in individuals with multiple focal patches of hair loss that have a positive hair pull test from peripheral sites of active lesions. Tinea capitis usually has localized sites of hair loss with underlying scaling, crusting, pruritus, erythema, and discharge from lesions, with positive potassium hydroxide preparations or fungal cultures. Trichotillomania typically presents with a spared peripheral fringe of hair. Remaining hairs may be thick and hyperpigmented as a response to repeated pulling, and biopsy often demonstrates fracture or degeneration of the hair shaft. A psychiatric evaluation may be warranted in cases of trichotillomania. Other cases of arthropod-induced hair loss include tick bite alopecia^10,11 and hair loss induced by numerous honeybee stings,¹² and these diagnoses should be suspected in patients with a history of ants on their pillow or in those from endemic areas.

No specific treatment is indicated in cases of 
ant-induced alopecia because hair usually regrows to its normal length without intervention.

Case Report

An 18-year-old Iranian man presented to the dermatology clinic with hair loss of 1 night’s duration. He denied pruritus, pain, discharge, or flaking. The patient had no notable personal, family, or surgical history and was not currently taking any medications. He denied recent travel. The patient reported that he found hair on his pillow upon waking up in the morning prior to coming to the clinic. On physical examination, 2 ants 
(Figure 1) were found on the scalp and alopecia with a vertical linear distribution was noted (Figure 2). Hairs of various lengths were found on the scalp within the distribution of the alopecia. No excoriations, crusting, seborrhea, or other areas of hair loss were detected. Wood lamp examination was negative. Based on these findings, which were concordant with similar findings from prior reports,^1-4 a diagnosis of ant-induced alopecia was made. Hair regrowth was noted within 1 week with full appearance of normal-length hair within 2.5 weeks.

Comment

Ant-induced alopecia is a form of localized hair loss caused by the Pheidole genus, the second largest genus of ants in the world.⁵ These ants can be found worldwide, but most cases of ant-induced alopecia have been from Iran, with at least 1 reported case from Turkey.^1-4,6 An early case series of ant-induced alopecia was reported in 1999,⁶ but the causative species was not described at that time.

The majority of reported cases of ant-induced alopecia are attributed to the barber ant (Pheidole pallidula). This type of alopecia is caused by worker ants within the species hierarchy.^1,4,6 The P pallidula worker ants are dimorphic and are classified as major and minor workers.⁷ Major workers have body lengths ranging up to 6 mm, whereas minor workers have body lengths ranging up to 4 mm. Major workers have larger heads and mandibles than minor workers and also have up to 2 pairs of denticles on the cranium.⁵ The minor workers are foragers and mainly collect food, whereas the major workers defend the nest and store food.⁸ These ants have widespread habitats with the ability to live in indoor and outdoor environments.

The presentation of hair loss caused by these ants is acute. Hair loss usually is confined to one specific area. Some patients may report pruritus or may present with erythematous lesions from ant stings or manual scratching.⁵ None of these signs or symptoms were seen in our patient. Some investigators have suggested that the barber ant is attracted to the hair of individuals with seborrheic dermatitis,¹ but our patient had no medical history of seborrheic dermatitis. Most likely, ants are attracted to excess sebum on the scalp in select individuals in their search for food and cause localized hair destruction.

Localized hair loss, as depicted in our case, should warrant a thorough evaluation for alopecia areata, trichotillomania, and tinea capitis.⁹ Alopecia areata should be considered in individuals with multiple focal patches of hair loss that have a positive hair pull test from peripheral sites of active lesions. Tinea capitis usually has localized sites of hair loss with underlying scaling, crusting, pruritus, erythema, and discharge from lesions, with positive potassium hydroxide preparations or fungal cultures. Trichotillomania typically presents with a spared peripheral fringe of hair. Remaining hairs may be thick and hyperpigmented as a response to repeated pulling, and biopsy often demonstrates fracture or degeneration of the hair shaft. A psychiatric evaluation may be warranted in cases of trichotillomania. Other cases of arthropod-induced hair loss include tick bite alopecia^10,11 and hair loss induced by numerous honeybee stings,¹² and these diagnoses should be suspected in patients with a history of ants on their pillow or in those from endemic areas.

No specific treatment is indicated in cases of 
ant-induced alopecia because hair usually regrows to its normal length without intervention.

To the Editor:

Staphylococcal scalded skin syndrome (SSSS) is a superficial blistering disorder mediated by Staphylococcus aureus exfoliative toxins (ETs).¹ It is rare in adults, but when diagnosed, it is often associated with renal failure, immunodeficiency, or overwhelming staphylococcal infection.² We present a unique case of a pregnant woman with chronic atopic dermatitis (AD) who developed SSSS.

A 21-year-old gravida 3, para 2, aborta 0pregnant woman (29 weeks’ gestation) with a history of chronic AD who was hospitalized with facial edema, purulent ocular discharge, and substantial worsening of AD presented for a dermatology consultation. Her AD was previously managed with topical steroids but had been complicated by multiple methicillin-resistant Staphylococcus aureus (MRSA) infections. On physical examination, she had substantial periorbital edema with purulent discharge from both eyes (Figure 1A), perioral crust with radial fissures (Figure 2A), and mild generalized facial swelling and desquamation (Figure 3). However, the oral cavity was not involved. She had diffuse desquamation in addition to chronic lichenified plaques of the arms, legs, and trunk and SSSS was clinically diagnosed. Cultures of conjunctival discharge were positive for MRSA. The patient was treated with intravenous vancomycin and had a full recovery (Figures 1B and 2B). She delivered a healthy newborn with Apgar scores of 9 and 9 at 1 and 5 minutes, respectively, at 36 weeks and 6 days’ gestation by cesarean delivery; however, her postoperative care was complicated by preeclampsia, which was treated with magnesium sulfate. The newborn showed no evidence of infection or blistering at birth or during the hospital stay.

Figure 1. Periorbital edema with purulent ocular discharge before (A) and after (B) treatment.			Figure 2. Perioral desquamation and radial fissuring before (A) and after (B) treatment.

Staphylococcal scalded skin syndrome is a superficial blistering disorder that ranges in severity from localized blisters to generalized exfoliation.¹ Exfoliative toxin is the major virulence factor responsible for SSSS. Exfoliative toxin is a serine protease that targets desmoglein 1, resulting in intraepidermal separation of keratinocytes.³ Two serologically distinct exfoliative toxins—ETA and ETB—have been associated with human disease.⁴ Although ETA is encoded on a phage genome, ETB is encoded on a large plasmid.³ Initially it was thought that only strains of S aureus carrying lytic group II phages were responsible for ET production; however, it is now accepted that all phage groups are capable of producing ET and causing SSSS.¹

Staphylococcal scalded skin syndrome is most common in infants and children and rare in adults. Although it has been occasionally described in otherwise healthy adults,⁵ it is most often diagnosed in patients with renal failure (decreased toxin excretion), immunodeficiency (lack of antibodies against toxins), and overwhelming staphylococcal infection (excessive toxin).² Mortality in treated children is low, but it can reach almost 60% in adults¹; therefore, defining risk factors that may aid in early diagnosis are exceedingly important.

We believe that both our patient’s history of 
AD and her pregnancy contributed to the development of SSSS. The patient had a history of multiple MRSA infections prior to this hospitalization, suggesting MRSA colonization, which is a common complication of AD with more than 75% of 
AD patients colonized with S aureus.⁶ Additionally, 
S aureus superantigen stimulation can result in the loss of regulatory T cells’ natural immunosuppression. Regulatory T cells are remarkably increased in patients with AD; therefore, the inflammatory response to S aureus is likely amplified in an atopic patient, as there is more native immunosuppressive capacity to be affected.⁴ Furthermore, we believe that pregnancy and its associated immunomodulation is a risk for SSSS. Immune changes in pregnancy are still not well understood; however, it is known that there are alterations to allow symbiosis between the mother and fetus. Anti-ET IgG antibodies are thought to play an important role in protecting against SSSS. Historically, studies on serum immunoglobulin levels during pregnancy have had conflicting findings. They have shown that IgG is either unchanged or decreased, while IgA, IgE, and IgM can be increased, decreased, or unchanged.⁷ In a study of immunoglobulins in pregnancy, Bahna et al⁷ showed that IgE is unchanged over the course of pregnancy, but their analysis did not address IgG levels. If IgG levels in fact decrease during pregnancy, the mother could be at risk for SSSS due to her inability to neutralize toxins. Even if total IgG levels remain unchanged, it is possible that specific antitoxin antibodies are decreased. Additionally, there is a documented suppression and alteration in T-cell response to prevent fetal rejection during pregnancy.⁸ Adult SSSS has been documented several times in human immunodeficiency virus–positive patients, suggesting there may be some association between T-cell suppression and SSSS susceptibility.⁹ Interestingly, pregnancy, similar to AD, results in an increase in immunosuppressive T cells,¹⁰ which, if deactivated by superantigens, could potentially contribute to an increased inflammatory response. All of these immune system alterations likely leave the mother vulnerable to toxin-mediated events such as SSSS.

We believe this case highlights the importance of considering SSSS in both atopic and pregnant patients with desquamating eruptions. In the case of pregnant patients, it is important to consider the risks and benefits of any medical treatments for both the mother and infant. Vancomycin is a pregnancy category B drug and was chosen for its known effectiveness and safety in pregnancy. One study compared 10 babies with mothers who were treated with vancomycin during the second and third trimesters for MRSA to 20 babies with mothers who did not receive vancomycin and did not find an increased risk for sensorineural hearing loss or nephrotoxicity.¹¹ There is no known increased risk for preeclampsia with vancomycin, but some studies have suggested that maternal infection independently increases the risk for preeclampsia.¹² Other treatment options were not as safe as vancomycin in this case: doxycycline is contraindicated (pregnancy category D) due to the potential for staining of deciduous teeth and skeletal growth impairment, trimethoprim-sulfamethoxazole is a pregnancy category D drug during the third trimester due to the risk of kernicterus, and linezolid is a pregnancy category C drug.¹³

To the Editor:

Staphylococcal scalded skin syndrome (SSSS) is a superficial blistering disorder mediated by Staphylococcus aureus exfoliative toxins (ETs).¹ It is rare in adults, but when diagnosed, it is often associated with renal failure, immunodeficiency, or overwhelming staphylococcal infection.² We present a unique case of a pregnant woman with chronic atopic dermatitis (AD) who developed SSSS.

A 21-year-old gravida 3, para 2, aborta 0pregnant woman (29 weeks’ gestation) with a history of chronic AD who was hospitalized with facial edema, purulent ocular discharge, and substantial worsening of AD presented for a dermatology consultation. Her AD was previously managed with topical steroids but had been complicated by multiple methicillin-resistant Staphylococcus aureus (MRSA) infections. On physical examination, she had substantial periorbital edema with purulent discharge from both eyes (Figure 1A), perioral crust with radial fissures (Figure 2A), and mild generalized facial swelling and desquamation (Figure 3). However, the oral cavity was not involved. She had diffuse desquamation in addition to chronic lichenified plaques of the arms, legs, and trunk and SSSS was clinically diagnosed. Cultures of conjunctival discharge were positive for MRSA. The patient was treated with intravenous vancomycin and had a full recovery (Figures 1B and 2B). She delivered a healthy newborn with Apgar scores of 9 and 9 at 1 and 5 minutes, respectively, at 36 weeks and 6 days’ gestation by cesarean delivery; however, her postoperative care was complicated by preeclampsia, which was treated with magnesium sulfate. The newborn showed no evidence of infection or blistering at birth or during the hospital stay.

Figure 1. Periorbital edema with purulent ocular discharge before (A) and after (B) treatment.			Figure 2. Perioral desquamation and radial fissuring before (A) and after (B) treatment.

Staphylococcal scalded skin syndrome is a superficial blistering disorder that ranges in severity from localized blisters to generalized exfoliation.¹ Exfoliative toxin is the major virulence factor responsible for SSSS. Exfoliative toxin is a serine protease that targets desmoglein 1, resulting in intraepidermal separation of keratinocytes.³ Two serologically distinct exfoliative toxins—ETA and ETB—have been associated with human disease.⁴ Although ETA is encoded on a phage genome, ETB is encoded on a large plasmid.³ Initially it was thought that only strains of S aureus carrying lytic group II phages were responsible for ET production; however, it is now accepted that all phage groups are capable of producing ET and causing SSSS.¹

Staphylococcal scalded skin syndrome is most common in infants and children and rare in adults. Although it has been occasionally described in otherwise healthy adults,⁵ it is most often diagnosed in patients with renal failure (decreased toxin excretion), immunodeficiency (lack of antibodies against toxins), and overwhelming staphylococcal infection (excessive toxin).² Mortality in treated children is low, but it can reach almost 60% in adults¹; therefore, defining risk factors that may aid in early diagnosis are exceedingly important.

We believe that both our patient’s history of 
AD and her pregnancy contributed to the development of SSSS. The patient had a history of multiple MRSA infections prior to this hospitalization, suggesting MRSA colonization, which is a common complication of AD with more than 75% of 
AD patients colonized with S aureus.⁶ Additionally, 
S aureus superantigen stimulation can result in the loss of regulatory T cells’ natural immunosuppression. Regulatory T cells are remarkably increased in patients with AD; therefore, the inflammatory response to S aureus is likely amplified in an atopic patient, as there is more native immunosuppressive capacity to be affected.⁴ Furthermore, we believe that pregnancy and its associated immunomodulation is a risk for SSSS. Immune changes in pregnancy are still not well understood; however, it is known that there are alterations to allow symbiosis between the mother and fetus. Anti-ET IgG antibodies are thought to play an important role in protecting against SSSS. Historically, studies on serum immunoglobulin levels during pregnancy have had conflicting findings. They have shown that IgG is either unchanged or decreased, while IgA, IgE, and IgM can be increased, decreased, or unchanged.⁷ In a study of immunoglobulins in pregnancy, Bahna et al⁷ showed that IgE is unchanged over the course of pregnancy, but their analysis did not address IgG levels. If IgG levels in fact decrease during pregnancy, the mother could be at risk for SSSS due to her inability to neutralize toxins. Even if total IgG levels remain unchanged, it is possible that specific antitoxin antibodies are decreased. Additionally, there is a documented suppression and alteration in T-cell response to prevent fetal rejection during pregnancy.⁸ Adult SSSS has been documented several times in human immunodeficiency virus–positive patients, suggesting there may be some association between T-cell suppression and SSSS susceptibility.⁹ Interestingly, pregnancy, similar to AD, results in an increase in immunosuppressive T cells,¹⁰ which, if deactivated by superantigens, could potentially contribute to an increased inflammatory response. All of these immune system alterations likely leave the mother vulnerable to toxin-mediated events such as SSSS.

We believe this case highlights the importance of considering SSSS in both atopic and pregnant patients with desquamating eruptions. In the case of pregnant patients, it is important to consider the risks and benefits of any medical treatments for both the mother and infant. Vancomycin is a pregnancy category B drug and was chosen for its known effectiveness and safety in pregnancy. One study compared 10 babies with mothers who were treated with vancomycin during the second and third trimesters for MRSA to 20 babies with mothers who did not receive vancomycin and did not find an increased risk for sensorineural hearing loss or nephrotoxicity.¹¹ There is no known increased risk for preeclampsia with vancomycin, but some studies have suggested that maternal infection independently increases the risk for preeclampsia.¹² Other treatment options were not as safe as vancomycin in this case: doxycycline is contraindicated (pregnancy category D) due to the potential for staining of deciduous teeth and skeletal growth impairment, trimethoprim-sulfamethoxazole is a pregnancy category D drug during the third trimester due to the risk of kernicterus, and linezolid is a pregnancy category C drug.¹³

To the Editor:

Staphylococcal scalded skin syndrome (SSSS) is a superficial blistering disorder mediated by Staphylococcus aureus exfoliative toxins (ETs).¹ It is rare in adults, but when diagnosed, it is often associated with renal failure, immunodeficiency, or overwhelming staphylococcal infection.² We present a unique case of a pregnant woman with chronic atopic dermatitis (AD) who developed SSSS.

A 21-year-old gravida 3, para 2, aborta 0pregnant woman (29 weeks’ gestation) with a history of chronic AD who was hospitalized with facial edema, purulent ocular discharge, and substantial worsening of AD presented for a dermatology consultation. Her AD was previously managed with topical steroids but had been complicated by multiple methicillin-resistant Staphylococcus aureus (MRSA) infections. On physical examination, she had substantial periorbital edema with purulent discharge from both eyes (Figure 1A), perioral crust with radial fissures (Figure 2A), and mild generalized facial swelling and desquamation (Figure 3). However, the oral cavity was not involved. She had diffuse desquamation in addition to chronic lichenified plaques of the arms, legs, and trunk and SSSS was clinically diagnosed. Cultures of conjunctival discharge were positive for MRSA. The patient was treated with intravenous vancomycin and had a full recovery (Figures 1B and 2B). She delivered a healthy newborn with Apgar scores of 9 and 9 at 1 and 5 minutes, respectively, at 36 weeks and 6 days’ gestation by cesarean delivery; however, her postoperative care was complicated by preeclampsia, which was treated with magnesium sulfate. The newborn showed no evidence of infection or blistering at birth or during the hospital stay.

Figure 1. Periorbital edema with purulent ocular discharge before (A) and after (B) treatment.			Figure 2. Perioral desquamation and radial fissuring before (A) and after (B) treatment.

Staphylococcal scalded skin syndrome is a superficial blistering disorder that ranges in severity from localized blisters to generalized exfoliation.¹ Exfoliative toxin is the major virulence factor responsible for SSSS. Exfoliative toxin is a serine protease that targets desmoglein 1, resulting in intraepidermal separation of keratinocytes.³ Two serologically distinct exfoliative toxins—ETA and ETB—have been associated with human disease.⁴ Although ETA is encoded on a phage genome, ETB is encoded on a large plasmid.³ Initially it was thought that only strains of S aureus carrying lytic group II phages were responsible for ET production; however, it is now accepted that all phage groups are capable of producing ET and causing SSSS.¹

Staphylococcal scalded skin syndrome is most common in infants and children and rare in adults. Although it has been occasionally described in otherwise healthy adults,⁵ it is most often diagnosed in patients with renal failure (decreased toxin excretion), immunodeficiency (lack of antibodies against toxins), and overwhelming staphylococcal infection (excessive toxin).² Mortality in treated children is low, but it can reach almost 60% in adults¹; therefore, defining risk factors that may aid in early diagnosis are exceedingly important.

We believe that both our patient’s history of 
AD and her pregnancy contributed to the development of SSSS. The patient had a history of multiple MRSA infections prior to this hospitalization, suggesting MRSA colonization, which is a common complication of AD with more than 75% of 
AD patients colonized with S aureus.⁶ Additionally, 
S aureus superantigen stimulation can result in the loss of regulatory T cells’ natural immunosuppression. Regulatory T cells are remarkably increased in patients with AD; therefore, the inflammatory response to S aureus is likely amplified in an atopic patient, as there is more native immunosuppressive capacity to be affected.⁴ Furthermore, we believe that pregnancy and its associated immunomodulation is a risk for SSSS. Immune changes in pregnancy are still not well understood; however, it is known that there are alterations to allow symbiosis between the mother and fetus. Anti-ET IgG antibodies are thought to play an important role in protecting against SSSS. Historically, studies on serum immunoglobulin levels during pregnancy have had conflicting findings. They have shown that IgG is either unchanged or decreased, while IgA, IgE, and IgM can be increased, decreased, or unchanged.⁷ In a study of immunoglobulins in pregnancy, Bahna et al⁷ showed that IgE is unchanged over the course of pregnancy, but their analysis did not address IgG levels. If IgG levels in fact decrease during pregnancy, the mother could be at risk for SSSS due to her inability to neutralize toxins. Even if total IgG levels remain unchanged, it is possible that specific antitoxin antibodies are decreased. Additionally, there is a documented suppression and alteration in T-cell response to prevent fetal rejection during pregnancy.⁸ Adult SSSS has been documented several times in human immunodeficiency virus–positive patients, suggesting there may be some association between T-cell suppression and SSSS susceptibility.⁹ Interestingly, pregnancy, similar to AD, results in an increase in immunosuppressive T cells,¹⁰ which, if deactivated by superantigens, could potentially contribute to an increased inflammatory response. All of these immune system alterations likely leave the mother vulnerable to toxin-mediated events such as SSSS.

We believe this case highlights the importance of considering SSSS in both atopic and pregnant patients with desquamating eruptions. In the case of pregnant patients, it is important to consider the risks and benefits of any medical treatments for both the mother and infant. Vancomycin is a pregnancy category B drug and was chosen for its known effectiveness and safety in pregnancy. One study compared 10 babies with mothers who were treated with vancomycin during the second and third trimesters for MRSA to 20 babies with mothers who did not receive vancomycin and did not find an increased risk for sensorineural hearing loss or nephrotoxicity.¹¹ There is no known increased risk for preeclampsia with vancomycin, but some studies have suggested that maternal infection independently increases the risk for preeclampsia.¹² Other treatment options were not as safe as vancomycin in this case: doxycycline is contraindicated (pregnancy category D) due to the potential for staining of deciduous teeth and skeletal growth impairment, trimethoprim-sulfamethoxazole is a pregnancy category D drug during the third trimester due to the risk of kernicterus, and linezolid is a pregnancy category C drug.¹³

To the Editor:

Nevus of Ota, also known as oculodermal melanocytosis or nevus fuscoceruleus ophthalmomaxillaris, is a hamartoma of dermal melanocytes that is characterized by a unilateral or bilateral blue-brown, speckled patch usually involving the malar, periorbital, temple, and/or forehead regions of the face.¹ It also may affect the sclera, conjunctiva, retinas, corneas, ocular muscles, periosteum, and retrobulbar fat corresponding to the distribution of the ophthalmic (V1) and maxillary (V2) divisions of the trigeminal nerve.

Examination of the oral cavity in the setting of nevus of Ota is imperative, as it can present as a developmental lesion of the oral mucosa.² Involvement of the hard palate is rare but has been observed.^3-5 We present a case of blue-pigmented macules in the upper right periorbital region with involvement of the hard palate that were diagnosed as nevus of Ota.

A 34-year-old Indian man presented with progressive, asymptomatic, ashy blue macules in the upper right periorbital region that had been present since birth. The pigmented macules had gradually increased to cover the infraorbital, maxillary, and temporal regions of the right side of the face with involvement of the conjunctiva and sclera (Figure 1).

Examination of the mucous membrane of the hard palate revealed several blue-pigmented macules with ill-defined borders merging into the surrounding mucosa (Figure 2). Ocular tension was normal and slit-lamp examination of the right eye did not reveal any abnormalities. Hematoxylin and eosin–stained sections prepared from a biopsy of the oral mucosa on the hard palate showed numerous elongated, fusiform, dendritic melanocytes in small aggregates scattered widely between the bundles of collagen in the papillary to midreticular dermis (Figure 3). On histology, the melanocytes stained positive for S100 protein (Figure 4) and human melanoma black 45. No evidence indicative of malignancy was found. The stratified squamous epithelium was unremarkable except for the presence of mild perivascular lymphocytic infiltrate in the subepithelial tissue. A diagnosis of nevus of Ota with involvement of the hard palate was made.

Cutaneous macules may enlarge slowly, become deeper in color, and persist throughout the patient’s life. Its pathogenesis is not known, but it is speculated that nevus of Ota is caused by faulty migration of melanoblasts from the neural crest to the skin. Nevus of Ito also is a dermal melanocytic aberration that exclusively affects the shoulders and often occurs in association with nevus of Ota.¹

Ashy or slate-blue pigmentation in individuals with skin of color (eg, Fitzpatrick skin type V) is uncommon, as this discoloration usually is seen in fair-skinned individuals (eg, Fitzpatrick skin type II).⁶ Occasionally, blue-pigmented lesions of the oral mucosa may be seen in nevus of Ota (as in our patient) and are considered developmental; therefore, examination of the oral cavity is suggested when patients present with blue-pigmented lesions in the facial region. Although this finding is rare, several other cases of blue-pigmented macules on the palatal mucosa have been reported.^3-5

The diagnosis of nevus of Ota should be confirmed by histopathology and can be classified into 5 types according to the distribution of melanocytes, including (1) superficial, (2) superficial dominant, (3) diffuse, (4) deep dominant, and (5) deep.⁷ The diagnosis of nevus of Ota can be made based on its characteristic morphology; however, nevus of 
Ito, Mongolian spots, melanoma, fixed drug eruptions,⁸ and lichen planus pigmantosus should also 
be ruled out.⁹

Nevus of Ota is a well-established entity that should be considered when ashy or slate-blue pigmentation is noted along the branches of the ophthalmic and maxillary divisions of the trigeminal nerve. Diagnosis is largely clinical, but should be confirmed on histopathology and immunohistochemistry. Possible concomitant involvement of the buccal mucosa and/or the hard palate warrants a thorough examination of the oral cavity in the setting of nevus of Ota to identify oral mucosal lesions. Histopathology is essential to confirm its status as well as to exclude melanoma.

To the Editor:

Nevus of Ota, also known as oculodermal melanocytosis or nevus fuscoceruleus ophthalmomaxillaris, is a hamartoma of dermal melanocytes that is characterized by a unilateral or bilateral blue-brown, speckled patch usually involving the malar, periorbital, temple, and/or forehead regions of the face.¹ It also may affect the sclera, conjunctiva, retinas, corneas, ocular muscles, periosteum, and retrobulbar fat corresponding to the distribution of the ophthalmic (V1) and maxillary (V2) divisions of the trigeminal nerve.

Examination of the oral cavity in the setting of nevus of Ota is imperative, as it can present as a developmental lesion of the oral mucosa.² Involvement of the hard palate is rare but has been observed.^3-5 We present a case of blue-pigmented macules in the upper right periorbital region with involvement of the hard palate that were diagnosed as nevus of Ota.

A 34-year-old Indian man presented with progressive, asymptomatic, ashy blue macules in the upper right periorbital region that had been present since birth. The pigmented macules had gradually increased to cover the infraorbital, maxillary, and temporal regions of the right side of the face with involvement of the conjunctiva and sclera (Figure 1).

Examination of the mucous membrane of the hard palate revealed several blue-pigmented macules with ill-defined borders merging into the surrounding mucosa (Figure 2). Ocular tension was normal and slit-lamp examination of the right eye did not reveal any abnormalities. Hematoxylin and eosin–stained sections prepared from a biopsy of the oral mucosa on the hard palate showed numerous elongated, fusiform, dendritic melanocytes in small aggregates scattered widely between the bundles of collagen in the papillary to midreticular dermis (Figure 3). On histology, the melanocytes stained positive for S100 protein (Figure 4) and human melanoma black 45. No evidence indicative of malignancy was found. The stratified squamous epithelium was unremarkable except for the presence of mild perivascular lymphocytic infiltrate in the subepithelial tissue. A diagnosis of nevus of Ota with involvement of the hard palate was made.

Cutaneous macules may enlarge slowly, become deeper in color, and persist throughout the patient’s life. Its pathogenesis is not known, but it is speculated that nevus of Ota is caused by faulty migration of melanoblasts from the neural crest to the skin. Nevus of Ito also is a dermal melanocytic aberration that exclusively affects the shoulders and often occurs in association with nevus of Ota.¹

Ashy or slate-blue pigmentation in individuals with skin of color (eg, Fitzpatrick skin type V) is uncommon, as this discoloration usually is seen in fair-skinned individuals (eg, Fitzpatrick skin type II).⁶ Occasionally, blue-pigmented lesions of the oral mucosa may be seen in nevus of Ota (as in our patient) and are considered developmental; therefore, examination of the oral cavity is suggested when patients present with blue-pigmented lesions in the facial region. Although this finding is rare, several other cases of blue-pigmented macules on the palatal mucosa have been reported.^3-5

The diagnosis of nevus of Ota should be confirmed by histopathology and can be classified into 5 types according to the distribution of melanocytes, including (1) superficial, (2) superficial dominant, (3) diffuse, (4) deep dominant, and (5) deep.⁷ The diagnosis of nevus of Ota can be made based on its characteristic morphology; however, nevus of 
Ito, Mongolian spots, melanoma, fixed drug eruptions,⁸ and lichen planus pigmantosus should also 
be ruled out.⁹

Nevus of Ota is a well-established entity that should be considered when ashy or slate-blue pigmentation is noted along the branches of the ophthalmic and maxillary divisions of the trigeminal nerve. Diagnosis is largely clinical, but should be confirmed on histopathology and immunohistochemistry. Possible concomitant involvement of the buccal mucosa and/or the hard palate warrants a thorough examination of the oral cavity in the setting of nevus of Ota to identify oral mucosal lesions. Histopathology is essential to confirm its status as well as to exclude melanoma.

To the Editor:

Nevus of Ota, also known as oculodermal melanocytosis or nevus fuscoceruleus ophthalmomaxillaris, is a hamartoma of dermal melanocytes that is characterized by a unilateral or bilateral blue-brown, speckled patch usually involving the malar, periorbital, temple, and/or forehead regions of the face.¹ It also may affect the sclera, conjunctiva, retinas, corneas, ocular muscles, periosteum, and retrobulbar fat corresponding to the distribution of the ophthalmic (V1) and maxillary (V2) divisions of the trigeminal nerve.

Examination of the oral cavity in the setting of nevus of Ota is imperative, as it can present as a developmental lesion of the oral mucosa.² Involvement of the hard palate is rare but has been observed.^3-5 We present a case of blue-pigmented macules in the upper right periorbital region with involvement of the hard palate that were diagnosed as nevus of Ota.

A 34-year-old Indian man presented with progressive, asymptomatic, ashy blue macules in the upper right periorbital region that had been present since birth. The pigmented macules had gradually increased to cover the infraorbital, maxillary, and temporal regions of the right side of the face with involvement of the conjunctiva and sclera (Figure 1).

Examination of the mucous membrane of the hard palate revealed several blue-pigmented macules with ill-defined borders merging into the surrounding mucosa (Figure 2). Ocular tension was normal and slit-lamp examination of the right eye did not reveal any abnormalities. Hematoxylin and eosin–stained sections prepared from a biopsy of the oral mucosa on the hard palate showed numerous elongated, fusiform, dendritic melanocytes in small aggregates scattered widely between the bundles of collagen in the papillary to midreticular dermis (Figure 3). On histology, the melanocytes stained positive for S100 protein (Figure 4) and human melanoma black 45. No evidence indicative of malignancy was found. The stratified squamous epithelium was unremarkable except for the presence of mild perivascular lymphocytic infiltrate in the subepithelial tissue. A diagnosis of nevus of Ota with involvement of the hard palate was made.

Cutaneous macules may enlarge slowly, become deeper in color, and persist throughout the patient’s life. Its pathogenesis is not known, but it is speculated that nevus of Ota is caused by faulty migration of melanoblasts from the neural crest to the skin. Nevus of Ito also is a dermal melanocytic aberration that exclusively affects the shoulders and often occurs in association with nevus of Ota.¹

Ashy or slate-blue pigmentation in individuals with skin of color (eg, Fitzpatrick skin type V) is uncommon, as this discoloration usually is seen in fair-skinned individuals (eg, Fitzpatrick skin type II).⁶ Occasionally, blue-pigmented lesions of the oral mucosa may be seen in nevus of Ota (as in our patient) and are considered developmental; therefore, examination of the oral cavity is suggested when patients present with blue-pigmented lesions in the facial region. Although this finding is rare, several other cases of blue-pigmented macules on the palatal mucosa have been reported.^3-5

The diagnosis of nevus of Ota should be confirmed by histopathology and can be classified into 5 types according to the distribution of melanocytes, including (1) superficial, (2) superficial dominant, (3) diffuse, (4) deep dominant, and (5) deep.⁷ The diagnosis of nevus of Ota can be made based on its characteristic morphology; however, nevus of 
Ito, Mongolian spots, melanoma, fixed drug eruptions,⁸ and lichen planus pigmantosus should also 
be ruled out.⁹

Nevus of Ota is a well-established entity that should be considered when ashy or slate-blue pigmentation is noted along the branches of the ophthalmic and maxillary divisions of the trigeminal nerve. Diagnosis is largely clinical, but should be confirmed on histopathology and immunohistochemistry. Possible concomitant involvement of the buccal mucosa and/or the hard palate warrants a thorough examination of the oral cavity in the setting of nevus of Ota to identify oral mucosal lesions. Histopathology is essential to confirm its status as well as to exclude melanoma.

To the Editor:

Contact sensitivity to drugs that are systemically administered can occur among health care workers.¹ We report the case of a 28-year-old nurse who developed eczema on the dorsal aspect of the hand (Figure 1A) and the face (Figure 1B) in the workplace. The nurse was working in the hematology department where she usually handled and administered antibiotics such as imipenem, ertapenem, piperacillin, vancomycin, anidulafungin, teicoplanin, and ciprofloxacin. She was moved to a different department where she did not have contact with the suspicious drugs and the dermatitis completely resolved.

One month after the resolution of the eczema she was referred to our allergy department for an allergological evaluation. A dermatologic evaluation was made and a skin biopsy was performed from a lesional area of the left hand. The patient underwent delayed skin test and patch tests with many β-lactam compounds including penicilloyl polylysine, minor determinant mixture, penicillin G, penicillin V, ampicillin, amoxicillin, bacampicillin, piperacillin, mezlocillin and ticarcillin, imipenem-cilastatin, aztreonam, meropenem, ertapenem, and cephalosporins (eg, cephalexin, cefaclor, cefalotin, cefadroxil, cephradine, cefuroxime, ceftriaxone, cefixime, cefoperazone, cefamandole, ceftazidime, cefotaxime). Undiluted solutions of commercial drugs (parenteral drugs when available were used) were used for skin prick test, and if negative, they were tested intradermally as described by Schiavino et al.² The concentrations used for the skin test and for the patch test are reported in the Table. Histamine (10 mg/mL) and saline were employed as positive and negative controls, respectively. Immediate reactions of at least 3 mm greater in diameter compared to the control for the skin prick test and 5 mm greater for intradermal tests were considered positive. Immediate-type skin tests were read after 20 minutes and also after 48 hours should any delayed reaction occur. An infiltrated erythema with a diameter greater than 5 mm was considered a delayed positive reaction.

Patch tests were applied to the interscapular region using acrylate adhesive strips with small plates. They were evaluated at 48 and 72 hours. Positivity was assessed according to the indications of the European Network for Drug Allergy.³ Patch tests were carried out using the same drugs as the skin test. All drugs were mixed in petrolatum at 
25% wt/wt for ampicillin and amoxicillin, 5% for penicillin G, and 20% for the other drugs as recommended by Schiavino et al.² We also performed patch tests with ertapenem in 20 healthy controls.

A skin biopsy from lesional skin showed a perivascular infiltrate of the upper dermis with spongiosis of the lesional area similar to eczema. Patch tests and intradermal tests were positive for ertapenem after 48 hours (Figure 2). Imipenem-cilastatin, ampicillin, piperacillin, mezlocillin, and meropenem showed a positive reaction for patch tests. We concluded that the patient had delayed hypersensitivity to carbapenems (ertapenem, imipenem-cilastatin, and meropenem) and semisynthetic penicillins (piperacillin, mezlocillin, and ampicillin).

Drug sensitization in nurses and in health care workers can occur. Natural and semisynthetic penicillin can cause allergic contact dermatitis in health care workers. We report a case of occupational allergy to ertapenem, which is a 1-β-methyl-carbapenem that is administered as a single agent. It is highly active in vitro against bacteria that are generally associated with community-acquired and mixed aerobic and anaerobic infections.⁴ Occupational contact allergy to other carbapenems such as meropenem also was reported.⁵ The contact sensitization potential of imipenem has been confirmed in the guinea pig.⁶ Carbapenems have a bicyclic nucleus composed by a β-lactam ring with an associated 5-membered ring. In our patient, patch tests for ertapenem, imipenem, and meropenem were positive. Although the cross-reactivity between imipenem and penicillin has been demonstrated,² data on the cross-reactivity between the carbapenems are not strong. Bauer et al⁷ reported a case of an allergy to imipenem-cilastatin that tolerated treatment with meropenem, but our case showed a complete cross-reactivity between carbapenems. Patch tests for ampicillin, mezlocillin, and piperacillin also were positive; therefore, it can be hypothesized that in our patient, the β-lactam ring was the main epitope recognized by T lymphocytes. Gielen and Goossens¹ reported in a study on work-related dermatitis that the most common sensitizers were antibiotics such as penicillins, cephalosporins, and aminoglycosides.

Health care workers should protect their hands with gloves during the preparation of drugs because they have the risk for developing an occupational contact allergy. Detailed allergological and dermatological evaluation is mandatory to confirm or exclude occupational contact allergy.

To the Editor:

Contact sensitivity to drugs that are systemically administered can occur among health care workers.¹ We report the case of a 28-year-old nurse who developed eczema on the dorsal aspect of the hand (Figure 1A) and the face (Figure 1B) in the workplace. The nurse was working in the hematology department where she usually handled and administered antibiotics such as imipenem, ertapenem, piperacillin, vancomycin, anidulafungin, teicoplanin, and ciprofloxacin. She was moved to a different department where she did not have contact with the suspicious drugs and the dermatitis completely resolved.

One month after the resolution of the eczema she was referred to our allergy department for an allergological evaluation. A dermatologic evaluation was made and a skin biopsy was performed from a lesional area of the left hand. The patient underwent delayed skin test and patch tests with many β-lactam compounds including penicilloyl polylysine, minor determinant mixture, penicillin G, penicillin V, ampicillin, amoxicillin, bacampicillin, piperacillin, mezlocillin and ticarcillin, imipenem-cilastatin, aztreonam, meropenem, ertapenem, and cephalosporins (eg, cephalexin, cefaclor, cefalotin, cefadroxil, cephradine, cefuroxime, ceftriaxone, cefixime, cefoperazone, cefamandole, ceftazidime, cefotaxime). Undiluted solutions of commercial drugs (parenteral drugs when available were used) were used for skin prick test, and if negative, they were tested intradermally as described by Schiavino et al.² The concentrations used for the skin test and for the patch test are reported in the Table. Histamine (10 mg/mL) and saline were employed as positive and negative controls, respectively. Immediate reactions of at least 3 mm greater in diameter compared to the control for the skin prick test and 5 mm greater for intradermal tests were considered positive. Immediate-type skin tests were read after 20 minutes and also after 48 hours should any delayed reaction occur. An infiltrated erythema with a diameter greater than 5 mm was considered a delayed positive reaction.

Patch tests were applied to the interscapular region using acrylate adhesive strips with small plates. They were evaluated at 48 and 72 hours. Positivity was assessed according to the indications of the European Network for Drug Allergy.³ Patch tests were carried out using the same drugs as the skin test. All drugs were mixed in petrolatum at 
25% wt/wt for ampicillin and amoxicillin, 5% for penicillin G, and 20% for the other drugs as recommended by Schiavino et al.² We also performed patch tests with ertapenem in 20 healthy controls.

A skin biopsy from lesional skin showed a perivascular infiltrate of the upper dermis with spongiosis of the lesional area similar to eczema. Patch tests and intradermal tests were positive for ertapenem after 48 hours (Figure 2). Imipenem-cilastatin, ampicillin, piperacillin, mezlocillin, and meropenem showed a positive reaction for patch tests. We concluded that the patient had delayed hypersensitivity to carbapenems (ertapenem, imipenem-cilastatin, and meropenem) and semisynthetic penicillins (piperacillin, mezlocillin, and ampicillin).

Drug sensitization in nurses and in health care workers can occur. Natural and semisynthetic penicillin can cause allergic contact dermatitis in health care workers. We report a case of occupational allergy to ertapenem, which is a 1-β-methyl-carbapenem that is administered as a single agent. It is highly active in vitro against bacteria that are generally associated with community-acquired and mixed aerobic and anaerobic infections.⁴ Occupational contact allergy to other carbapenems such as meropenem also was reported.⁵ The contact sensitization potential of imipenem has been confirmed in the guinea pig.⁶ Carbapenems have a bicyclic nucleus composed by a β-lactam ring with an associated 5-membered ring. In our patient, patch tests for ertapenem, imipenem, and meropenem were positive. Although the cross-reactivity between imipenem and penicillin has been demonstrated,² data on the cross-reactivity between the carbapenems are not strong. Bauer et al⁷ reported a case of an allergy to imipenem-cilastatin that tolerated treatment with meropenem, but our case showed a complete cross-reactivity between carbapenems. Patch tests for ampicillin, mezlocillin, and piperacillin also were positive; therefore, it can be hypothesized that in our patient, the β-lactam ring was the main epitope recognized by T lymphocytes. Gielen and Goossens¹ reported in a study on work-related dermatitis that the most common sensitizers were antibiotics such as penicillins, cephalosporins, and aminoglycosides.

Health care workers should protect their hands with gloves during the preparation of drugs because they have the risk for developing an occupational contact allergy. Detailed allergological and dermatological evaluation is mandatory to confirm or exclude occupational contact allergy.

To the Editor:

Contact sensitivity to drugs that are systemically administered can occur among health care workers.¹ We report the case of a 28-year-old nurse who developed eczema on the dorsal aspect of the hand (Figure 1A) and the face (Figure 1B) in the workplace. The nurse was working in the hematology department where she usually handled and administered antibiotics such as imipenem, ertapenem, piperacillin, vancomycin, anidulafungin, teicoplanin, and ciprofloxacin. She was moved to a different department where she did not have contact with the suspicious drugs and the dermatitis completely resolved.

One month after the resolution of the eczema she was referred to our allergy department for an allergological evaluation. A dermatologic evaluation was made and a skin biopsy was performed from a lesional area of the left hand. The patient underwent delayed skin test and patch tests with many β-lactam compounds including penicilloyl polylysine, minor determinant mixture, penicillin G, penicillin V, ampicillin, amoxicillin, bacampicillin, piperacillin, mezlocillin and ticarcillin, imipenem-cilastatin, aztreonam, meropenem, ertapenem, and cephalosporins (eg, cephalexin, cefaclor, cefalotin, cefadroxil, cephradine, cefuroxime, ceftriaxone, cefixime, cefoperazone, cefamandole, ceftazidime, cefotaxime). Undiluted solutions of commercial drugs (parenteral drugs when available were used) were used for skin prick test, and if negative, they were tested intradermally as described by Schiavino et al.² The concentrations used for the skin test and for the patch test are reported in the Table. Histamine (10 mg/mL) and saline were employed as positive and negative controls, respectively. Immediate reactions of at least 3 mm greater in diameter compared to the control for the skin prick test and 5 mm greater for intradermal tests were considered positive. Immediate-type skin tests were read after 20 minutes and also after 48 hours should any delayed reaction occur. An infiltrated erythema with a diameter greater than 5 mm was considered a delayed positive reaction.

Patch tests were applied to the interscapular region using acrylate adhesive strips with small plates. They were evaluated at 48 and 72 hours. Positivity was assessed according to the indications of the European Network for Drug Allergy.³ Patch tests were carried out using the same drugs as the skin test. All drugs were mixed in petrolatum at 
25% wt/wt for ampicillin and amoxicillin, 5% for penicillin G, and 20% for the other drugs as recommended by Schiavino et al.² We also performed patch tests with ertapenem in 20 healthy controls.

A skin biopsy from lesional skin showed a perivascular infiltrate of the upper dermis with spongiosis of the lesional area similar to eczema. Patch tests and intradermal tests were positive for ertapenem after 48 hours (Figure 2). Imipenem-cilastatin, ampicillin, piperacillin, mezlocillin, and meropenem showed a positive reaction for patch tests. We concluded that the patient had delayed hypersensitivity to carbapenems (ertapenem, imipenem-cilastatin, and meropenem) and semisynthetic penicillins (piperacillin, mezlocillin, and ampicillin).

Drug sensitization in nurses and in health care workers can occur. Natural and semisynthetic penicillin can cause allergic contact dermatitis in health care workers. We report a case of occupational allergy to ertapenem, which is a 1-β-methyl-carbapenem that is administered as a single agent. It is highly active in vitro against bacteria that are generally associated with community-acquired and mixed aerobic and anaerobic infections.⁴ Occupational contact allergy to other carbapenems such as meropenem also was reported.⁵ The contact sensitization potential of imipenem has been confirmed in the guinea pig.⁶ Carbapenems have a bicyclic nucleus composed by a β-lactam ring with an associated 5-membered ring. In our patient, patch tests for ertapenem, imipenem, and meropenem were positive. Although the cross-reactivity between imipenem and penicillin has been demonstrated,² data on the cross-reactivity between the carbapenems are not strong. Bauer et al⁷ reported a case of an allergy to imipenem-cilastatin that tolerated treatment with meropenem, but our case showed a complete cross-reactivity between carbapenems. Patch tests for ampicillin, mezlocillin, and piperacillin also were positive; therefore, it can be hypothesized that in our patient, the β-lactam ring was the main epitope recognized by T lymphocytes. Gielen and Goossens¹ reported in a study on work-related dermatitis that the most common sensitizers were antibiotics such as penicillins, cephalosporins, and aminoglycosides.

Health care workers should protect their hands with gloves during the preparation of drugs because they have the risk for developing an occupational contact allergy. Detailed allergological and dermatological evaluation is mandatory to confirm or exclude occupational contact allergy.

Review the PDF of the fact sheet on dermatoses of pregnancy

After, test your knowledge by answering the 5 practice questions.

Practice Questions

1. Which dermatosis of pregnancy occurs during the third trimester and is associated with multiple gestation pregnancies?

a. atopic eruption of pregnancy

b. gestational pemphigoid

c. intrahepatic cholestasis of pregnancy

d. prurigo of pregnancy

e. pruritic urticarial papules and plaques of pregnancy

2. Which dermatosis of pregnancy frequently flares after delivery?

a. atopic eruption of pregnancy

b. gestational pemphigoid

c. polymorphic eruption of pregnancy

d. prurigo gravidarum

e. prurigo of pregnancy

3. Which dermatosis of pregnancy has lesions that have a predilection for the abdominal striae?

a. cholestasis of pregnancy

b. gestational pemphigoid

c. prurigo gestationis

d. prurigo of pregnancy

e. pruritic urticarial papules and plaques of pregnancy

4. Which dermatosis of pregnancy has a risk for the development of hydatidiform moles and choriocarcinomas?

a. atopic eruption of pregnancy

b. cholestasis of pregnancy

c. gestational pemphigoid

d. pruritic urticarial papules and plaques of pregnancy

e. toxic erythema of pregnancy

5. Intrahepatic cholestasis of pregnancy has been associated with:

a. fetal mortality as high as 13%

b. jaundice in 20% of cases

c. onset in the third trimester of pregnancy

d. recurrence in subsequent pregnancies

e. all of the above
 

The answers appear on the next page.

1. Which dermatosis of pregnancy occurs during the third trimester and is associated with multiple gestation pregnancies?

a. atopic eruption of pregnancy

b. gestational pemphigoid

c. intrahepatic cholestasis of pregnancy

d. prurigo of pregnancy

e. pruritic urticarial papules and plaques of pregnancy

2. Which dermatosis of pregnancy frequently flares after delivery?

a. atopic eruption of pregnancy

b. gestational pemphigoid

c. polymorphic eruption of pregnancy

d. prurigo gravidarum

e. prurigo of pregnancy

3. Which dermatosis of pregnancy has lesions that have a predilection for the abdominal striae?

a. cholestasis of pregnancy

b. gestational pemphigoid

c. prurigo gestationis

d. prurigo of pregnancy

e. pruritic urticarial papules and plaques of pregnancy

4. Which dermatosis of pregnancy has a risk for the development of hydatidiform moles and choriocarcinomas?

a. atopic eruption of pregnancy

b. cholestasis of pregnancy

c. gestational pemphigoid

d. pruritic urticarial papules and plaques of pregnancy

e. toxic erythema of pregnancy

5. Intrahepatic cholestasis of pregnancy has been associated with:

a. fetal mortality as high as 13%

b. jaundice in 20% of cases

c. onset in the third trimester of pregnancy

d. recurrence in subsequent pregnancies

e. all of the above

Review the PDF of the fact sheet on dermatoses of pregnancy

After, test your knowledge by answering the 5 practice questions.

Practice Questions

1. Which dermatosis of pregnancy occurs during the third trimester and is associated with multiple gestation pregnancies?

a. atopic eruption of pregnancy

b. gestational pemphigoid

c. intrahepatic cholestasis of pregnancy

d. prurigo of pregnancy

e. pruritic urticarial papules and plaques of pregnancy

2. Which dermatosis of pregnancy frequently flares after delivery?

a. atopic eruption of pregnancy

b. gestational pemphigoid

c. polymorphic eruption of pregnancy

d. prurigo gravidarum

e. prurigo of pregnancy

3. Which dermatosis of pregnancy has lesions that have a predilection for the abdominal striae?

a. cholestasis of pregnancy

b. gestational pemphigoid

c. prurigo gestationis

d. prurigo of pregnancy

e. pruritic urticarial papules and plaques of pregnancy

4. Which dermatosis of pregnancy has a risk for the development of hydatidiform moles and choriocarcinomas?

a. atopic eruption of pregnancy

b. cholestasis of pregnancy

c. gestational pemphigoid

d. pruritic urticarial papules and plaques of pregnancy

e. toxic erythema of pregnancy

5. Intrahepatic cholestasis of pregnancy has been associated with:

a. fetal mortality as high as 13%

b. jaundice in 20% of cases

c. onset in the third trimester of pregnancy

d. recurrence in subsequent pregnancies

e. all of the above
 

The answers appear on the next page.

1. Which dermatosis of pregnancy occurs during the third trimester and is associated with multiple gestation pregnancies?

a. atopic eruption of pregnancy

b. gestational pemphigoid

c. intrahepatic cholestasis of pregnancy

d. prurigo of pregnancy

e. pruritic urticarial papules and plaques of pregnancy

2. Which dermatosis of pregnancy frequently flares after delivery?

a. atopic eruption of pregnancy

b. gestational pemphigoid

c. polymorphic eruption of pregnancy

d. prurigo gravidarum

e. prurigo of pregnancy

3. Which dermatosis of pregnancy has lesions that have a predilection for the abdominal striae?

a. cholestasis of pregnancy

b. gestational pemphigoid

c. prurigo gestationis

d. prurigo of pregnancy

e. pruritic urticarial papules and plaques of pregnancy

4. Which dermatosis of pregnancy has a risk for the development of hydatidiform moles and choriocarcinomas?

a. atopic eruption of pregnancy

b. cholestasis of pregnancy

c. gestational pemphigoid

d. pruritic urticarial papules and plaques of pregnancy

e. toxic erythema of pregnancy

5. Intrahepatic cholestasis of pregnancy has been associated with:

a. fetal mortality as high as 13%

b. jaundice in 20% of cases

c. onset in the third trimester of pregnancy

d. recurrence in subsequent pregnancies

e. all of the above

Review the PDF of the fact sheet on dermatoses of pregnancy

After, test your knowledge by answering the 5 practice questions.

Practice Questions

1. Which dermatosis of pregnancy occurs during the third trimester and is associated with multiple gestation pregnancies?

a. atopic eruption of pregnancy

b. gestational pemphigoid

c. intrahepatic cholestasis of pregnancy

d. prurigo of pregnancy

e. pruritic urticarial papules and plaques of pregnancy

2. Which dermatosis of pregnancy frequently flares after delivery?

a. atopic eruption of pregnancy

b. gestational pemphigoid

c. polymorphic eruption of pregnancy

d. prurigo gravidarum

e. prurigo of pregnancy

3. Which dermatosis of pregnancy has lesions that have a predilection for the abdominal striae?

a. cholestasis of pregnancy

b. gestational pemphigoid

c. prurigo gestationis

d. prurigo of pregnancy

e. pruritic urticarial papules and plaques of pregnancy

4. Which dermatosis of pregnancy has a risk for the development of hydatidiform moles and choriocarcinomas?

a. atopic eruption of pregnancy

b. cholestasis of pregnancy

c. gestational pemphigoid

d. pruritic urticarial papules and plaques of pregnancy

e. toxic erythema of pregnancy

5. Intrahepatic cholestasis of pregnancy has been associated with:

a. fetal mortality as high as 13%

b. jaundice in 20% of cases

c. onset in the third trimester of pregnancy

d. recurrence in subsequent pregnancies

e. all of the above
 

The answers appear on the next page.

1. Which dermatosis of pregnancy occurs during the third trimester and is associated with multiple gestation pregnancies?

a. atopic eruption of pregnancy

b. gestational pemphigoid

c. intrahepatic cholestasis of pregnancy

d. prurigo of pregnancy

e. pruritic urticarial papules and plaques of pregnancy

2. Which dermatosis of pregnancy frequently flares after delivery?

a. atopic eruption of pregnancy

b. gestational pemphigoid

c. polymorphic eruption of pregnancy

d. prurigo gravidarum

e. prurigo of pregnancy

3. Which dermatosis of pregnancy has lesions that have a predilection for the abdominal striae?

a. cholestasis of pregnancy

b. gestational pemphigoid

c. prurigo gestationis

d. prurigo of pregnancy

e. pruritic urticarial papules and plaques of pregnancy

4. Which dermatosis of pregnancy has a risk for the development of hydatidiform moles and choriocarcinomas?

a. atopic eruption of pregnancy

b. cholestasis of pregnancy

c. gestational pemphigoid

d. pruritic urticarial papules and plaques of pregnancy

e. toxic erythema of pregnancy

5. Intrahepatic cholestasis of pregnancy has been associated with:

a. fetal mortality as high as 13%

b. jaundice in 20% of cases

c. onset in the third trimester of pregnancy

d. recurrence in subsequent pregnancies

e. all of the above

To the Editor:

A 52-year-old man presented to the emergency department with skin pain. Although he felt well overall, he reported that he had developed skin sores 3 weeks prior to presentation that were progressively causing skin pain and sleep loss. He acknowledged smoking cigarettes and snorting cocaine but denied intravenous use of cocaine or using any other drugs. His usual medications were lisinopril and tramadol, and he had no known drug allergies. His history was remarkable for methicillin-resistant Staphylococcus aureus (MRSA) septic arthritis of the shoulder and MRSA prepatellar bursitis within the last 2 years. During examination in the emergency department he was alert, afebrile, nontoxic, generally healthy, and in no acute distress. Extensive necrotic skin lesions were present on the trunk, extremities, and both ears. The lesions were large necrotic patches with irregular, sharply angulated borders with thin or ulcerated epidermis surrounded by a bright halo of erythema (Figure 1). Ulcers were noted on the tongue (Figure 2).

Figure 1. Extensive skin necrosis on the leg from levamisole-contaminated cocaine (A). Necrotic skin lesions also were present on the trunk, arm (B), and ear (C).

Figure 2. Ulcers were noted on the tongue.

The clinical diagnosis was probable thrombosis of skin vessels with skin necrosis due to cocaine that was likely contaminated with levamisole. Pertinent laboratory results included the following: mild anemia and mild leukopenia; values within reference range for liver function, serum protein electrophoresis, hepatitis profile, human immunodeficiency virus 1 and 2, rapid plasma reagin, and antinuclear antibody; normal thrombotic studies for antithrombin III, protein C, protein S, factor V Leiden, prothrombin mutation G20210A, anticardiolipin IgG, IgM, and IgA; erythrocyte sedimentation rate of 
26 mm/h (reference range, 0–15 mm/h); perinuclear antineutrophil cytoplasmic antibody greater than 1:320 (reference range, <1:20) with normal proteinase 3 
and myeloperoxidase antibodies; urine positive for cocaine but blood negative for cocaine; normal chest radiograph; and normal electrocardiogram.

The patient was stable with good family support and was discharged from the emergency department to be followed in our dermatology office. The following day his skin biopsies were interpreted as neutrophilic vasculitis with extensive intravascular early and organizing thrombi involving all small- and medium-sized blood vessels consistent with levamisole-induced necrosis or septic vasculitis (Figure 3). With his history of MRSA septic arthritis and bursitis, he was hospitalized for treatment with intravenous vancomycin pending further studies. Skin biopsy for direct immunofluorescence revealed granular deposits of IgM and linear deposits of C3 at the dermoepidermal junction and in blood vessel walls. Two tissue cultures for bacteria and fungi were negative and 2 blood cultures were negative. An echocardiogram was normal and without evidence of emboli. The patient remained stable and antibiotics were discontinued. He was released from the hospital and his skin lesions healed satisfactorily with showering and mupirocin ointment.

Figure 3. Thrombotic occlusion of blood vessels was seen on histopathology (A and B)(H&E, original magnifications ×100 and ×400).

Cocaine is a white powder that is primarily derived from the leaves of the coca plant in South America. It is ingested orally; injected intravenously; snorted intranasally; chewed; eaten; used as a suppository; or dissolved in water and baking soda then heated to crystallization for smoking, which is the most addictive method and known as freebasing. When smoked, crack cocaine produces a crackling sound. Cocaine stimulates the central nervous system similar to amphetamine but may harm any body organ through vasoconstriction/vasospasm and cause skin necrosis without any additive. Perhaps less known is its ability to produce smooth muscle hyperplasia of small vessels and premature atherosclerosis.¹

Levamisole has been used to treat worms, cancer, and stimulation of the immune system but currently is used only by veterinarians because of agranulocytosis and vasculitis in humans. As of July 2009, the Drug Enforcement Agency reported that 69% of seized cocaine lots coming into the United States contained levamisole.² By January 2010, 73.2% of seized cocaine exhibits contained levamisole according to the California Poison Control System, with reports of contamination rates from across the country ranging from 40% to 90%.³ Levamisole is an inexpensive additive to cocaine and may increase the release of brain dopamine.⁴ It is difficult to detect levamisole in urine due to its short half-life of 
5.6 hours and only 2% to 5% of the parent compound being found in the urine.⁵

Skin necrosis due to cocaine-contaminated levamisole usually occurs in younger individuals who have characteristic skin lesions and a history of cocaine use. Skin lesions usually are multiple, purpuric or necrotic with irregular angulated edges and a halo of erythema. Ear involvement is common but not invariable.⁶ Descriptive adjectives include branched, netlike, retiform, and stellate, all revealing the compromised underlying dermal and subcutaneous vascular anatomy. Supportive evidence includes a decreased white blood cell count (neutropenia in up to 50%),⁵ positive antineutrophilic cytoplasmic antibodies,^5,7 and/or positive drug screen. Skin biopsy may reveal thrombosis,⁴ fibrin thrombi without vasculitis,⁸ or leukocytoclastic vasculitis,^4,5 or may suggest septic vasculitis.⁹ Direct immunofluorescence may suggest an immune complex-mediated vasculitis.⁵

The differential diagnosis for a patient with 
purpuric/necrotic skin lesions should be broad and include vasculitis (eg, inflammatory, antineutrophil cytoplasmic antibody positive, septic), hypercoagulopathy (eg, antiphospholipid syndrome, antithrombin III, prothrombin mutation G20210A, 
factor V Leiden, protein C, protein S), drugs 
(eg, heparin, warfarin, cocaine with or without levamisole, intravenous drug use, hydroxyurea, ergotamine, propylthiouracil¹⁰), calciphylaxis, 
cold-induced thrombosis, emboli (eg, atheroma, cholesterol, endocarditis, myxoma, aortic angiosarcoma, marantic), febrile ulceronecrotic Mucha-Habermann disease, infection especially if immunosuppressed (eg, disseminated Acanthamoeba/Candida/histoplasmosis/strongyloides/varicella-zoster virus, 
S aureus, streptococcus, ecthyma gangrenosum, gas gangrene, hemorrhagic smallpox, lues maligna with human immunodeficiency virus, Meleney ulcer, Rocky Mountain spotted fever, Vibrio vulnificus), idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, thrombocythemia, Waldenström hyperglobulinemic purpura, pyoderma gangrenosum, cancer (eg, paraneoplastic arterial thrombi), oxalosis, paraproteinemia (eg, multiple myeloma), and lupus with generalized coagulopathy. Less likely diagnoses might include Degos disease, factitial dermatitis, foreign bodies, multiple spider bites, paroxysmal nocturnal hemoglobinuria, sickle cell anemia, Buruli ulcer, or thromboangiitis obliterans. Branched, angulated, retiform lesions are an important finding, and some of these diagnostic possibilities are not classically retiform. However, clinical findings are not always classical, and astute physicians want to be circumspect. Had more ominous findings been present in our patient (eg, fever, hemodynamic instability, progressive skin lesions, systemic organ involvement), prompt hospitalization and additional considerations would have been necessary, such as septicemia (eg, meningococcemia, bubonic plague [Black Death], necrotizing 
fasciitis, purpura fulminans), catastrophic antiphospholipid syndrome, or disseminated intra-
vascular coagulation.

The prognosis for skin necrosis caused by 
levamisole-contaminated cocaine generally is good without long-term sequelae.⁵ Autoantibody 
serologies normalize within weeks to months after stopping levamisole.^5,8 Our patient recovered with conservative measures.

To the Editor:

A 52-year-old man presented to the emergency department with skin pain. Although he felt well overall, he reported that he had developed skin sores 3 weeks prior to presentation that were progressively causing skin pain and sleep loss. He acknowledged smoking cigarettes and snorting cocaine but denied intravenous use of cocaine or using any other drugs. His usual medications were lisinopril and tramadol, and he had no known drug allergies. His history was remarkable for methicillin-resistant Staphylococcus aureus (MRSA) septic arthritis of the shoulder and MRSA prepatellar bursitis within the last 2 years. During examination in the emergency department he was alert, afebrile, nontoxic, generally healthy, and in no acute distress. Extensive necrotic skin lesions were present on the trunk, extremities, and both ears. The lesions were large necrotic patches with irregular, sharply angulated borders with thin or ulcerated epidermis surrounded by a bright halo of erythema (Figure 1). Ulcers were noted on the tongue (Figure 2).

Figure 1. Extensive skin necrosis on the leg from levamisole-contaminated cocaine (A). Necrotic skin lesions also were present on the trunk, arm (B), and ear (C).

Figure 2. Ulcers were noted on the tongue.

The clinical diagnosis was probable thrombosis of skin vessels with skin necrosis due to cocaine that was likely contaminated with levamisole. Pertinent laboratory results included the following: mild anemia and mild leukopenia; values within reference range for liver function, serum protein electrophoresis, hepatitis profile, human immunodeficiency virus 1 and 2, rapid plasma reagin, and antinuclear antibody; normal thrombotic studies for antithrombin III, protein C, protein S, factor V Leiden, prothrombin mutation G20210A, anticardiolipin IgG, IgM, and IgA; erythrocyte sedimentation rate of 
26 mm/h (reference range, 0–15 mm/h); perinuclear antineutrophil cytoplasmic antibody greater than 1:320 (reference range, <1:20) with normal proteinase 3 
and myeloperoxidase antibodies; urine positive for cocaine but blood negative for cocaine; normal chest radiograph; and normal electrocardiogram.

The patient was stable with good family support and was discharged from the emergency department to be followed in our dermatology office. The following day his skin biopsies were interpreted as neutrophilic vasculitis with extensive intravascular early and organizing thrombi involving all small- and medium-sized blood vessels consistent with levamisole-induced necrosis or septic vasculitis (Figure 3). With his history of MRSA septic arthritis and bursitis, he was hospitalized for treatment with intravenous vancomycin pending further studies. Skin biopsy for direct immunofluorescence revealed granular deposits of IgM and linear deposits of C3 at the dermoepidermal junction and in blood vessel walls. Two tissue cultures for bacteria and fungi were negative and 2 blood cultures were negative. An echocardiogram was normal and without evidence of emboli. The patient remained stable and antibiotics were discontinued. He was released from the hospital and his skin lesions healed satisfactorily with showering and mupirocin ointment.

Figure 3. Thrombotic occlusion of blood vessels was seen on histopathology (A and B)(H&E, original magnifications ×100 and ×400).

Cocaine is a white powder that is primarily derived from the leaves of the coca plant in South America. It is ingested orally; injected intravenously; snorted intranasally; chewed; eaten; used as a suppository; or dissolved in water and baking soda then heated to crystallization for smoking, which is the most addictive method and known as freebasing. When smoked, crack cocaine produces a crackling sound. Cocaine stimulates the central nervous system similar to amphetamine but may harm any body organ through vasoconstriction/vasospasm and cause skin necrosis without any additive. Perhaps less known is its ability to produce smooth muscle hyperplasia of small vessels and premature atherosclerosis.¹

Levamisole has been used to treat worms, cancer, and stimulation of the immune system but currently is used only by veterinarians because of agranulocytosis and vasculitis in humans. As of July 2009, the Drug Enforcement Agency reported that 69% of seized cocaine lots coming into the United States contained levamisole.² By January 2010, 73.2% of seized cocaine exhibits contained levamisole according to the California Poison Control System, with reports of contamination rates from across the country ranging from 40% to 90%.³ Levamisole is an inexpensive additive to cocaine and may increase the release of brain dopamine.⁴ It is difficult to detect levamisole in urine due to its short half-life of 
5.6 hours and only 2% to 5% of the parent compound being found in the urine.⁵

Skin necrosis due to cocaine-contaminated levamisole usually occurs in younger individuals who have characteristic skin lesions and a history of cocaine use. Skin lesions usually are multiple, purpuric or necrotic with irregular angulated edges and a halo of erythema. Ear involvement is common but not invariable.⁶ Descriptive adjectives include branched, netlike, retiform, and stellate, all revealing the compromised underlying dermal and subcutaneous vascular anatomy. Supportive evidence includes a decreased white blood cell count (neutropenia in up to 50%),⁵ positive antineutrophilic cytoplasmic antibodies,^5,7 and/or positive drug screen. Skin biopsy may reveal thrombosis,⁴ fibrin thrombi without vasculitis,⁸ or leukocytoclastic vasculitis,^4,5 or may suggest septic vasculitis.⁹ Direct immunofluorescence may suggest an immune complex-mediated vasculitis.⁵

The differential diagnosis for a patient with 
purpuric/necrotic skin lesions should be broad and include vasculitis (eg, inflammatory, antineutrophil cytoplasmic antibody positive, septic), hypercoagulopathy (eg, antiphospholipid syndrome, antithrombin III, prothrombin mutation G20210A, 
factor V Leiden, protein C, protein S), drugs 
(eg, heparin, warfarin, cocaine with or without levamisole, intravenous drug use, hydroxyurea, ergotamine, propylthiouracil¹⁰), calciphylaxis, 
cold-induced thrombosis, emboli (eg, atheroma, cholesterol, endocarditis, myxoma, aortic angiosarcoma, marantic), febrile ulceronecrotic Mucha-Habermann disease, infection especially if immunosuppressed (eg, disseminated Acanthamoeba/Candida/histoplasmosis/strongyloides/varicella-zoster virus, 
S aureus, streptococcus, ecthyma gangrenosum, gas gangrene, hemorrhagic smallpox, lues maligna with human immunodeficiency virus, Meleney ulcer, Rocky Mountain spotted fever, Vibrio vulnificus), idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, thrombocythemia, Waldenström hyperglobulinemic purpura, pyoderma gangrenosum, cancer (eg, paraneoplastic arterial thrombi), oxalosis, paraproteinemia (eg, multiple myeloma), and lupus with generalized coagulopathy. Less likely diagnoses might include Degos disease, factitial dermatitis, foreign bodies, multiple spider bites, paroxysmal nocturnal hemoglobinuria, sickle cell anemia, Buruli ulcer, or thromboangiitis obliterans. Branched, angulated, retiform lesions are an important finding, and some of these diagnostic possibilities are not classically retiform. However, clinical findings are not always classical, and astute physicians want to be circumspect. Had more ominous findings been present in our patient (eg, fever, hemodynamic instability, progressive skin lesions, systemic organ involvement), prompt hospitalization and additional considerations would have been necessary, such as septicemia (eg, meningococcemia, bubonic plague [Black Death], necrotizing 
fasciitis, purpura fulminans), catastrophic antiphospholipid syndrome, or disseminated intra-
vascular coagulation.

The prognosis for skin necrosis caused by 
levamisole-contaminated cocaine generally is good without long-term sequelae.⁵ Autoantibody 
serologies normalize within weeks to months after stopping levamisole.^5,8 Our patient recovered with conservative measures.

To the Editor:

A 52-year-old man presented to the emergency department with skin pain. Although he felt well overall, he reported that he had developed skin sores 3 weeks prior to presentation that were progressively causing skin pain and sleep loss. He acknowledged smoking cigarettes and snorting cocaine but denied intravenous use of cocaine or using any other drugs. His usual medications were lisinopril and tramadol, and he had no known drug allergies. His history was remarkable for methicillin-resistant Staphylococcus aureus (MRSA) septic arthritis of the shoulder and MRSA prepatellar bursitis within the last 2 years. During examination in the emergency department he was alert, afebrile, nontoxic, generally healthy, and in no acute distress. Extensive necrotic skin lesions were present on the trunk, extremities, and both ears. The lesions were large necrotic patches with irregular, sharply angulated borders with thin or ulcerated epidermis surrounded by a bright halo of erythema (Figure 1). Ulcers were noted on the tongue (Figure 2).

Figure 1. Extensive skin necrosis on the leg from levamisole-contaminated cocaine (A). Necrotic skin lesions also were present on the trunk, arm (B), and ear (C).

Figure 2. Ulcers were noted on the tongue.

The clinical diagnosis was probable thrombosis of skin vessels with skin necrosis due to cocaine that was likely contaminated with levamisole. Pertinent laboratory results included the following: mild anemia and mild leukopenia; values within reference range for liver function, serum protein electrophoresis, hepatitis profile, human immunodeficiency virus 1 and 2, rapid plasma reagin, and antinuclear antibody; normal thrombotic studies for antithrombin III, protein C, protein S, factor V Leiden, prothrombin mutation G20210A, anticardiolipin IgG, IgM, and IgA; erythrocyte sedimentation rate of 
26 mm/h (reference range, 0–15 mm/h); perinuclear antineutrophil cytoplasmic antibody greater than 1:320 (reference range, <1:20) with normal proteinase 3 
and myeloperoxidase antibodies; urine positive for cocaine but blood negative for cocaine; normal chest radiograph; and normal electrocardiogram.

The patient was stable with good family support and was discharged from the emergency department to be followed in our dermatology office. The following day his skin biopsies were interpreted as neutrophilic vasculitis with extensive intravascular early and organizing thrombi involving all small- and medium-sized blood vessels consistent with levamisole-induced necrosis or septic vasculitis (Figure 3). With his history of MRSA septic arthritis and bursitis, he was hospitalized for treatment with intravenous vancomycin pending further studies. Skin biopsy for direct immunofluorescence revealed granular deposits of IgM and linear deposits of C3 at the dermoepidermal junction and in blood vessel walls. Two tissue cultures for bacteria and fungi were negative and 2 blood cultures were negative. An echocardiogram was normal and without evidence of emboli. The patient remained stable and antibiotics were discontinued. He was released from the hospital and his skin lesions healed satisfactorily with showering and mupirocin ointment.

Figure 3. Thrombotic occlusion of blood vessels was seen on histopathology (A and B)(H&E, original magnifications ×100 and ×400).

Cocaine is a white powder that is primarily derived from the leaves of the coca plant in South America. It is ingested orally; injected intravenously; snorted intranasally; chewed; eaten; used as a suppository; or dissolved in water and baking soda then heated to crystallization for smoking, which is the most addictive method and known as freebasing. When smoked, crack cocaine produces a crackling sound. Cocaine stimulates the central nervous system similar to amphetamine but may harm any body organ through vasoconstriction/vasospasm and cause skin necrosis without any additive. Perhaps less known is its ability to produce smooth muscle hyperplasia of small vessels and premature atherosclerosis.¹

Levamisole has been used to treat worms, cancer, and stimulation of the immune system but currently is used only by veterinarians because of agranulocytosis and vasculitis in humans. As of July 2009, the Drug Enforcement Agency reported that 69% of seized cocaine lots coming into the United States contained levamisole.² By January 2010, 73.2% of seized cocaine exhibits contained levamisole according to the California Poison Control System, with reports of contamination rates from across the country ranging from 40% to 90%.³ Levamisole is an inexpensive additive to cocaine and may increase the release of brain dopamine.⁴ It is difficult to detect levamisole in urine due to its short half-life of 
5.6 hours and only 2% to 5% of the parent compound being found in the urine.⁵

Skin necrosis due to cocaine-contaminated levamisole usually occurs in younger individuals who have characteristic skin lesions and a history of cocaine use. Skin lesions usually are multiple, purpuric or necrotic with irregular angulated edges and a halo of erythema. Ear involvement is common but not invariable.⁶ Descriptive adjectives include branched, netlike, retiform, and stellate, all revealing the compromised underlying dermal and subcutaneous vascular anatomy. Supportive evidence includes a decreased white blood cell count (neutropenia in up to 50%),⁵ positive antineutrophilic cytoplasmic antibodies,^5,7 and/or positive drug screen. Skin biopsy may reveal thrombosis,⁴ fibrin thrombi without vasculitis,⁸ or leukocytoclastic vasculitis,^4,5 or may suggest septic vasculitis.⁹ Direct immunofluorescence may suggest an immune complex-mediated vasculitis.⁵

The differential diagnosis for a patient with 
purpuric/necrotic skin lesions should be broad and include vasculitis (eg, inflammatory, antineutrophil cytoplasmic antibody positive, septic), hypercoagulopathy (eg, antiphospholipid syndrome, antithrombin III, prothrombin mutation G20210A, 
factor V Leiden, protein C, protein S), drugs 
(eg, heparin, warfarin, cocaine with or without levamisole, intravenous drug use, hydroxyurea, ergotamine, propylthiouracil¹⁰), calciphylaxis, 
cold-induced thrombosis, emboli (eg, atheroma, cholesterol, endocarditis, myxoma, aortic angiosarcoma, marantic), febrile ulceronecrotic Mucha-Habermann disease, infection especially if immunosuppressed (eg, disseminated Acanthamoeba/Candida/histoplasmosis/strongyloides/varicella-zoster virus, 
S aureus, streptococcus, ecthyma gangrenosum, gas gangrene, hemorrhagic smallpox, lues maligna with human immunodeficiency virus, Meleney ulcer, Rocky Mountain spotted fever, Vibrio vulnificus), idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, thrombocythemia, Waldenström hyperglobulinemic purpura, pyoderma gangrenosum, cancer (eg, paraneoplastic arterial thrombi), oxalosis, paraproteinemia (eg, multiple myeloma), and lupus with generalized coagulopathy. Less likely diagnoses might include Degos disease, factitial dermatitis, foreign bodies, multiple spider bites, paroxysmal nocturnal hemoglobinuria, sickle cell anemia, Buruli ulcer, or thromboangiitis obliterans. Branched, angulated, retiform lesions are an important finding, and some of these diagnostic possibilities are not classically retiform. However, clinical findings are not always classical, and astute physicians want to be circumspect. Had more ominous findings been present in our patient (eg, fever, hemodynamic instability, progressive skin lesions, systemic organ involvement), prompt hospitalization and additional considerations would have been necessary, such as septicemia (eg, meningococcemia, bubonic plague [Black Death], necrotizing 
fasciitis, purpura fulminans), catastrophic antiphospholipid syndrome, or disseminated intra-
vascular coagulation.

The prognosis for skin necrosis caused by 
levamisole-contaminated cocaine generally is good without long-term sequelae.⁵ Autoantibody 
serologies normalize within weeks to months after stopping levamisole.^5,8 Our patient recovered with conservative measures.

The Diagnosis: Allergic Contact Dermatitis to 
Para-phenylenediamine

To darken the color of henna and increase penetrance and staining, para-phenylenediamine (PPD) is added.¹ Allergic contact dermatitis is the most common type of hypersensitivity to PPD.² A retrospective study that examined severe adverse events from applying henna dyes in children found that angioedema of mucosal tissues was the most common severe adverse event; others included renal failure and shock.³

Black henna is associated with multiple cultural practices. For example, Indian weddings contain a henna decoration ceremony for the bride based on the belief that the longer the henna lasts, the longer the marriage lasts. Black henna is favored for this practice, as it lasts longer than red henna.

Henna (Lawsonia inermis) is a plant that contains the molecule lawsone (naphthoquinone). Lawsone has an intense affinity for keratin; as a result, lawsone is frequently added to temporary body tattoos and hair dyes to create a relatively permanent change in skin or hair color.⁴ Henna is mixed with hennotannic acid to release the lawsone from the plant. Lawsone and hennotannic acid rarely cause allergic reactions.^1,5-7 Once applied to skin, henna takes a few hours to dry, and the resulting color is orange to red.⁸ Often, PPD is added to henna paste to create a black color, to speed up the drying process, and to increase its longevity.

Para-phenylenediamine has been repeatedly reported to cause allergic contact dermatitis. We describe a case of allergic contact dermatitis secondary to PPD in black henna. Our patient is a clear example that PPD is the allergen in black henna given that there was no reaction to the natural red henna tattoo that was applied at the same time to the palmar surfaces of the hands (Figure). Aside from the bullous reaction to black henna dye described here, other reported presentations include erythema multiforme–like and exudative erythema reactions.^9,10

Contact dermatitis lesions from black henna dye can be treated with topical corticosteroids. Patients may develop residual postinflammatory hyperpigmentation or hypopigmentation, leukoderma, keloids, or scars.^1,11,12

The Diagnosis: Allergic Contact Dermatitis to 
Para-phenylenediamine

To darken the color of henna and increase penetrance and staining, para-phenylenediamine (PPD) is added.¹ Allergic contact dermatitis is the most common type of hypersensitivity to PPD.² A retrospective study that examined severe adverse events from applying henna dyes in children found that angioedema of mucosal tissues was the most common severe adverse event; others included renal failure and shock.³

Black henna is associated with multiple cultural practices. For example, Indian weddings contain a henna decoration ceremony for the bride based on the belief that the longer the henna lasts, the longer the marriage lasts. Black henna is favored for this practice, as it lasts longer than red henna.

Henna (Lawsonia inermis) is a plant that contains the molecule lawsone (naphthoquinone). Lawsone has an intense affinity for keratin; as a result, lawsone is frequently added to temporary body tattoos and hair dyes to create a relatively permanent change in skin or hair color.⁴ Henna is mixed with hennotannic acid to release the lawsone from the plant. Lawsone and hennotannic acid rarely cause allergic reactions.^1,5-7 Once applied to skin, henna takes a few hours to dry, and the resulting color is orange to red.⁸ Often, PPD is added to henna paste to create a black color, to speed up the drying process, and to increase its longevity.

Para-phenylenediamine has been repeatedly reported to cause allergic contact dermatitis. We describe a case of allergic contact dermatitis secondary to PPD in black henna. Our patient is a clear example that PPD is the allergen in black henna given that there was no reaction to the natural red henna tattoo that was applied at the same time to the palmar surfaces of the hands (Figure). Aside from the bullous reaction to black henna dye described here, other reported presentations include erythema multiforme–like and exudative erythema reactions.^9,10

Contact dermatitis lesions from black henna dye can be treated with topical corticosteroids. Patients may develop residual postinflammatory hyperpigmentation or hypopigmentation, leukoderma, keloids, or scars.^1,11,12

The Diagnosis: Allergic Contact Dermatitis to 
Para-phenylenediamine

To darken the color of henna and increase penetrance and staining, para-phenylenediamine (PPD) is added.¹ Allergic contact dermatitis is the most common type of hypersensitivity to PPD.² A retrospective study that examined severe adverse events from applying henna dyes in children found that angioedema of mucosal tissues was the most common severe adverse event; others included renal failure and shock.³

Black henna is associated with multiple cultural practices. For example, Indian weddings contain a henna decoration ceremony for the bride based on the belief that the longer the henna lasts, the longer the marriage lasts. Black henna is favored for this practice, as it lasts longer than red henna.

Henna (Lawsonia inermis) is a plant that contains the molecule lawsone (naphthoquinone). Lawsone has an intense affinity for keratin; as a result, lawsone is frequently added to temporary body tattoos and hair dyes to create a relatively permanent change in skin or hair color.⁴ Henna is mixed with hennotannic acid to release the lawsone from the plant. Lawsone and hennotannic acid rarely cause allergic reactions.^1,5-7 Once applied to skin, henna takes a few hours to dry, and the resulting color is orange to red.⁸ Often, PPD is added to henna paste to create a black color, to speed up the drying process, and to increase its longevity.

Para-phenylenediamine has been repeatedly reported to cause allergic contact dermatitis. We describe a case of allergic contact dermatitis secondary to PPD in black henna. Our patient is a clear example that PPD is the allergen in black henna given that there was no reaction to the natural red henna tattoo that was applied at the same time to the palmar surfaces of the hands (Figure). Aside from the bullous reaction to black henna dye described here, other reported presentations include erythema multiforme–like and exudative erythema reactions.^9,10

Contact dermatitis lesions from black henna dye can be treated with topical corticosteroids. Patients may develop residual postinflammatory hyperpigmentation or hypopigmentation, leukoderma, keloids, or scars.^1,11,12

Sodium sulfacetamide has various uses in the field of dermatology due to its anti-inflammatory and antibacterial properties. It has been shown to be effective in the management of a variety of inflammatory facial dermatoses, including papulopustular rosacea, acne vulgaris, seborrheic dermatitis, and perioral dermatitis. We review the mechanism of action, pharmacology and formulations, clinical uses, and adverse effects of sodium sulfacetamide as a dermatologic treatment.

Mechanism of Action

Sodium sulfacetamide is a sulfonamide-type antibacterial agent. Its mechanism of action is the inhibition of bacterial dihydropteroate synthetase, which prevents the conversion of p-aminobenzoic acid to folic acid. This process causes a bacteriostatic effect on the growth of several gram-negative and gram-positive organisms, including Propionibacterium acnes.^1,2

The effectiveness of sodium sulfacetamide is increased when used in combination with sulfur, which has keratolytic, antibacterial, antifungal, and antiparasitic effects. The addition of hydrocortisone has been reported to increase the effectiveness of both agents.³

Pharmacology

Sodium sulfacetamide is highly soluble at the physiologic pH of 7.4, which contributes to its high level of penetration and absorption.⁴ An in vitro study showed percutaneous absorption of sodium sulfacetamide to be around 4%.⁵ Sulfonamides are metabolized mainly by the liver and are excreted by the kidneys.

Formulations

The most common concentrations of sodium sulfacetamide and sulfur are 10% and 5%, respectively. A wide variety of sulfacetamide-containing products are available, many of which are marketed to treat specific conditions depending on additional ingredients or the type of delivery system.

Clinical Uses

Topical formulations of sodium sulfacetamide and sulfur have proven to be efficacious in the management of rosacea, with a typical regimen consisting of twice-daily application for 8 weeks.⁶ The sulfur in the formulation has the additional benefit of targeting Demodex mites, which are implicated as a contributing factor in some cases of rosacea.⁷ Sodium sulfacetamide 10%–sulfur 5% lotion was more effective in improving the erythema, papulopustules, and overall severity of rosacea as compared to metronidazole gel 0.75%.⁸ Other studies have reported increased efficacy when sodium sulfacetamide and topical sulfur are used along with metronidazole.^9,10                

Sodium sulfacetamide also has shown efficacy against acne. Its antibacterial and drying properties have been shown to decrease the number of inflammatory lesions and comedones, and in the treatment of acne vulgaris, no sensitivity reactions have been observed.² Also, unlike topical antibiotics, cases of P acnes resistance to topical sulfur products have not been widely reported. Studies have demonstrated that twice-daily use of sodium sulfacetamide 10%–sulfur 5% for 12 weeks decreases inflammatory acne lesions by 80.4% to 83%.^11,12

Seborrheic dermatitis is a common chronic infection of the skin caused by Malassezia species. One study investigated the use of sodium sulfacetamide ointment and soap to treat seborrheic dermatitis and found that the condition was either improved or completely controlled in 93% (71/76) of cases.⁴ Sodium sulfacetamide lotion was an effective treatment of seborrheic dermatitis in 89% (54/61) of patients with scalp involvement and 68% (30/44) of patients with glabrous skin involvement.¹³

Perioral dermatitis is characterized by groups of erythematous papules and pustules localized around the mouth. The use of topical sodium sulfacetamide along with oral tetracyclines has been demonstrated to consistently clear lesions in most patients with perioral dermatitis.¹⁴ Sodium sulfacetamide is unique in that it is not associated with the excessive erythema and irritation often found with retinoic acid and benzoyl peroxide.¹⁵ Unfortunately, however, there have been no well-controlled trials to compare the efficacy of sodium sulfacetamide to other topical therapies for this condition.

Adverse Effects

Adverse effects from sodium sulfacetamide are rare and generally are limited to cutaneous reactions including dryness, erythema, pruritus, and discomfort.¹ Periocular use of sodium sulfacetamide can cause conjunctival irritation. One study reported that 19% (6/31) of patients experienced local reactions but most were considered mild.⁹ Rare but serious reactions including erythema multiforme and Stevens-Johnson syndrome have been reported from ophthalmic use.^16,17

A common limiting factor to sodium sulfacetamide preparations that include elemental sulfur is the offensive smell, which has hindered patient compliance in the past; however, pharmaceutical companies have attempted to create more tolerable products without the odor.¹⁰ One study found that the tolerability of a sodium sulfacetamide 10%–sulfur 5% foam using a rinse-off method of application was excellent, with only 33% (8/24) of participants commenting on the smell.¹⁸ Another limiting factor of sodium sulfacetamide preparations containing sulfur is orange-brown discoloration when combined with benzoyl peroxide, which does not affect the skin but may stain clothing.¹⁹

Sodium sulfacetamide is rendered less effective when combined with silver-containing products.²⁰ No other notable drug interactions are known; however, oral sulfonamides are known to interact with several drugs, including cyclosporine and phenytoin.^21,22

Contraindications

Sodium sulfacetamide is contraindicated in patients with known hypersensitivity to sulfonamides, sulfur, or any other component of the preparation. It is a pregnancy category C drug, and pregnant women should only use sodium sulfacetamide if it is the only modality to treat the condition or the benefits outweigh the risks. Although there are no known reports of problems related to topical sodium sulfacetamide during pregnancy, the use of oral sulfonamides during pregnancy can increase the risk for neonatal jaundice.²³ Likewise, caution should be exercised in prescribing this product to nursing women, as systemic sulfonamide antibacterials are well known to cause kernicterus in nursing neonates.¹

Conclusion

The efficacy and safety of sodium sulfacetamide, used alone or in combination with sulfur, has been demonstrated in the treatment of rosacea, acne, seborrheic dermatitis, and perioral dermatitis. Advances in formulation technology to decrease odor and irritation have allowed for more use of this product. Further studies will help elucidate the role that sodium sulfacetamide should play in the treatment of inflammatory dermatoses in comparison to other available products.

Sodium sulfacetamide has various uses in the field of dermatology due to its anti-inflammatory and antibacterial properties. It has been shown to be effective in the management of a variety of inflammatory facial dermatoses, including papulopustular rosacea, acne vulgaris, seborrheic dermatitis, and perioral dermatitis. We review the mechanism of action, pharmacology and formulations, clinical uses, and adverse effects of sodium sulfacetamide as a dermatologic treatment.

Mechanism of Action

Sodium sulfacetamide is a sulfonamide-type antibacterial agent. Its mechanism of action is the inhibition of bacterial dihydropteroate synthetase, which prevents the conversion of p-aminobenzoic acid to folic acid. This process causes a bacteriostatic effect on the growth of several gram-negative and gram-positive organisms, including Propionibacterium acnes.^1,2

The effectiveness of sodium sulfacetamide is increased when used in combination with sulfur, which has keratolytic, antibacterial, antifungal, and antiparasitic effects. The addition of hydrocortisone has been reported to increase the effectiveness of both agents.³

Pharmacology

Sodium sulfacetamide is highly soluble at the physiologic pH of 7.4, which contributes to its high level of penetration and absorption.⁴ An in vitro study showed percutaneous absorption of sodium sulfacetamide to be around 4%.⁵ Sulfonamides are metabolized mainly by the liver and are excreted by the kidneys.

Formulations

The most common concentrations of sodium sulfacetamide and sulfur are 10% and 5%, respectively. A wide variety of sulfacetamide-containing products are available, many of which are marketed to treat specific conditions depending on additional ingredients or the type of delivery system.

Clinical Uses

Topical formulations of sodium sulfacetamide and sulfur have proven to be efficacious in the management of rosacea, with a typical regimen consisting of twice-daily application for 8 weeks.⁶ The sulfur in the formulation has the additional benefit of targeting Demodex mites, which are implicated as a contributing factor in some cases of rosacea.⁷ Sodium sulfacetamide 10%–sulfur 5% lotion was more effective in improving the erythema, papulopustules, and overall severity of rosacea as compared to metronidazole gel 0.75%.⁸ Other studies have reported increased efficacy when sodium sulfacetamide and topical sulfur are used along with metronidazole.^9,10                

Sodium sulfacetamide also has shown efficacy against acne. Its antibacterial and drying properties have been shown to decrease the number of inflammatory lesions and comedones, and in the treatment of acne vulgaris, no sensitivity reactions have been observed.² Also, unlike topical antibiotics, cases of P acnes resistance to topical sulfur products have not been widely reported. Studies have demonstrated that twice-daily use of sodium sulfacetamide 10%–sulfur 5% for 12 weeks decreases inflammatory acne lesions by 80.4% to 83%.^11,12

Seborrheic dermatitis is a common chronic infection of the skin caused by Malassezia species. One study investigated the use of sodium sulfacetamide ointment and soap to treat seborrheic dermatitis and found that the condition was either improved or completely controlled in 93% (71/76) of cases.⁴ Sodium sulfacetamide lotion was an effective treatment of seborrheic dermatitis in 89% (54/61) of patients with scalp involvement and 68% (30/44) of patients with glabrous skin involvement.¹³

Perioral dermatitis is characterized by groups of erythematous papules and pustules localized around the mouth. The use of topical sodium sulfacetamide along with oral tetracyclines has been demonstrated to consistently clear lesions in most patients with perioral dermatitis.¹⁴ Sodium sulfacetamide is unique in that it is not associated with the excessive erythema and irritation often found with retinoic acid and benzoyl peroxide.¹⁵ Unfortunately, however, there have been no well-controlled trials to compare the efficacy of sodium sulfacetamide to other topical therapies for this condition.

Adverse Effects

Adverse effects from sodium sulfacetamide are rare and generally are limited to cutaneous reactions including dryness, erythema, pruritus, and discomfort.¹ Periocular use of sodium sulfacetamide can cause conjunctival irritation. One study reported that 19% (6/31) of patients experienced local reactions but most were considered mild.⁹ Rare but serious reactions including erythema multiforme and Stevens-Johnson syndrome have been reported from ophthalmic use.^16,17

A common limiting factor to sodium sulfacetamide preparations that include elemental sulfur is the offensive smell, which has hindered patient compliance in the past; however, pharmaceutical companies have attempted to create more tolerable products without the odor.¹⁰ One study found that the tolerability of a sodium sulfacetamide 10%–sulfur 5% foam using a rinse-off method of application was excellent, with only 33% (8/24) of participants commenting on the smell.¹⁸ Another limiting factor of sodium sulfacetamide preparations containing sulfur is orange-brown discoloration when combined with benzoyl peroxide, which does not affect the skin but may stain clothing.¹⁹

Sodium sulfacetamide is rendered less effective when combined with silver-containing products.²⁰ No other notable drug interactions are known; however, oral sulfonamides are known to interact with several drugs, including cyclosporine and phenytoin.^21,22

Contraindications

Sodium sulfacetamide is contraindicated in patients with known hypersensitivity to sulfonamides, sulfur, or any other component of the preparation. It is a pregnancy category C drug, and pregnant women should only use sodium sulfacetamide if it is the only modality to treat the condition or the benefits outweigh the risks. Although there are no known reports of problems related to topical sodium sulfacetamide during pregnancy, the use of oral sulfonamides during pregnancy can increase the risk for neonatal jaundice.²³ Likewise, caution should be exercised in prescribing this product to nursing women, as systemic sulfonamide antibacterials are well known to cause kernicterus in nursing neonates.¹

Conclusion

The efficacy and safety of sodium sulfacetamide, used alone or in combination with sulfur, has been demonstrated in the treatment of rosacea, acne, seborrheic dermatitis, and perioral dermatitis. Advances in formulation technology to decrease odor and irritation have allowed for more use of this product. Further studies will help elucidate the role that sodium sulfacetamide should play in the treatment of inflammatory dermatoses in comparison to other available products.

Sodium sulfacetamide has various uses in the field of dermatology due to its anti-inflammatory and antibacterial properties. It has been shown to be effective in the management of a variety of inflammatory facial dermatoses, including papulopustular rosacea, acne vulgaris, seborrheic dermatitis, and perioral dermatitis. We review the mechanism of action, pharmacology and formulations, clinical uses, and adverse effects of sodium sulfacetamide as a dermatologic treatment.

Mechanism of Action

Sodium sulfacetamide is a sulfonamide-type antibacterial agent. Its mechanism of action is the inhibition of bacterial dihydropteroate synthetase, which prevents the conversion of p-aminobenzoic acid to folic acid. This process causes a bacteriostatic effect on the growth of several gram-negative and gram-positive organisms, including Propionibacterium acnes.^1,2

The effectiveness of sodium sulfacetamide is increased when used in combination with sulfur, which has keratolytic, antibacterial, antifungal, and antiparasitic effects. The addition of hydrocortisone has been reported to increase the effectiveness of both agents.³

Pharmacology

Sodium sulfacetamide is highly soluble at the physiologic pH of 7.4, which contributes to its high level of penetration and absorption.⁴ An in vitro study showed percutaneous absorption of sodium sulfacetamide to be around 4%.⁵ Sulfonamides are metabolized mainly by the liver and are excreted by the kidneys.

Formulations

The most common concentrations of sodium sulfacetamide and sulfur are 10% and 5%, respectively. A wide variety of sulfacetamide-containing products are available, many of which are marketed to treat specific conditions depending on additional ingredients or the type of delivery system.

Clinical Uses

Topical formulations of sodium sulfacetamide and sulfur have proven to be efficacious in the management of rosacea, with a typical regimen consisting of twice-daily application for 8 weeks.⁶ The sulfur in the formulation has the additional benefit of targeting Demodex mites, which are implicated as a contributing factor in some cases of rosacea.⁷ Sodium sulfacetamide 10%–sulfur 5% lotion was more effective in improving the erythema, papulopustules, and overall severity of rosacea as compared to metronidazole gel 0.75%.⁸ Other studies have reported increased efficacy when sodium sulfacetamide and topical sulfur are used along with metronidazole.^9,10                

Sodium sulfacetamide also has shown efficacy against acne. Its antibacterial and drying properties have been shown to decrease the number of inflammatory lesions and comedones, and in the treatment of acne vulgaris, no sensitivity reactions have been observed.² Also, unlike topical antibiotics, cases of P acnes resistance to topical sulfur products have not been widely reported. Studies have demonstrated that twice-daily use of sodium sulfacetamide 10%–sulfur 5% for 12 weeks decreases inflammatory acne lesions by 80.4% to 83%.^11,12

Seborrheic dermatitis is a common chronic infection of the skin caused by Malassezia species. One study investigated the use of sodium sulfacetamide ointment and soap to treat seborrheic dermatitis and found that the condition was either improved or completely controlled in 93% (71/76) of cases.⁴ Sodium sulfacetamide lotion was an effective treatment of seborrheic dermatitis in 89% (54/61) of patients with scalp involvement and 68% (30/44) of patients with glabrous skin involvement.¹³

Perioral dermatitis is characterized by groups of erythematous papules and pustules localized around the mouth. The use of topical sodium sulfacetamide along with oral tetracyclines has been demonstrated to consistently clear lesions in most patients with perioral dermatitis.¹⁴ Sodium sulfacetamide is unique in that it is not associated with the excessive erythema and irritation often found with retinoic acid and benzoyl peroxide.¹⁵ Unfortunately, however, there have been no well-controlled trials to compare the efficacy of sodium sulfacetamide to other topical therapies for this condition.

Adverse Effects

Adverse effects from sodium sulfacetamide are rare and generally are limited to cutaneous reactions including dryness, erythema, pruritus, and discomfort.¹ Periocular use of sodium sulfacetamide can cause conjunctival irritation. One study reported that 19% (6/31) of patients experienced local reactions but most were considered mild.⁹ Rare but serious reactions including erythema multiforme and Stevens-Johnson syndrome have been reported from ophthalmic use.^16,17

A common limiting factor to sodium sulfacetamide preparations that include elemental sulfur is the offensive smell, which has hindered patient compliance in the past; however, pharmaceutical companies have attempted to create more tolerable products without the odor.¹⁰ One study found that the tolerability of a sodium sulfacetamide 10%–sulfur 5% foam using a rinse-off method of application was excellent, with only 33% (8/24) of participants commenting on the smell.¹⁸ Another limiting factor of sodium sulfacetamide preparations containing sulfur is orange-brown discoloration when combined with benzoyl peroxide, which does not affect the skin but may stain clothing.¹⁹

Sodium sulfacetamide is rendered less effective when combined with silver-containing products.²⁰ No other notable drug interactions are known; however, oral sulfonamides are known to interact with several drugs, including cyclosporine and phenytoin.^21,22

Contraindications

Sodium sulfacetamide is contraindicated in patients with known hypersensitivity to sulfonamides, sulfur, or any other component of the preparation. It is a pregnancy category C drug, and pregnant women should only use sodium sulfacetamide if it is the only modality to treat the condition or the benefits outweigh the risks. Although there are no known reports of problems related to topical sodium sulfacetamide during pregnancy, the use of oral sulfonamides during pregnancy can increase the risk for neonatal jaundice.²³ Likewise, caution should be exercised in prescribing this product to nursing women, as systemic sulfonamide antibacterials are well known to cause kernicterus in nursing neonates.¹

Conclusion

The efficacy and safety of sodium sulfacetamide, used alone or in combination with sulfur, has been demonstrated in the treatment of rosacea, acne, seborrheic dermatitis, and perioral dermatitis. Advances in formulation technology to decrease odor and irritation have allowed for more use of this product. Further studies will help elucidate the role that sodium sulfacetamide should play in the treatment of inflammatory dermatoses in comparison to other available products.