Dermatology Online Journal

Unique presentations of epidermal growth factor receptor inhibitor-induced papulopustular eruption related to bacterial superinfection
Lauren Elyse Wiznia BA, Jennifer Nam Choi MD
Dermatology Online Journal 19 (3): 8

Yale University School of Medicine, New Haven, Connecticut

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Abstract

Epidermal growth factor receptor (EGFR) inhibitors have been reported to induce numerous cutaneous side effects, the most notable of which is a papulopustular eruption on the face, scalp, and central chest. The typical presentation consists of inflamed papules, often with pustules, favoring a seborrheic distribution. The pustules of the EGFR inhibitor-induced papulopustular eruption are commonly sterile but bacterial superinfection is not uncommon. We report two unique presentations of the papulopustular eruption that were found to be associated with Staphylococcus aureus superinfection. One patient presented with an abrupt onset of nearly confluent red plaques on the cheeks, forehead, chin, and neck, with innumerable studded pinpoint pustules. The other patient had a long-standing untreated papulopustular eruption on the scalp, which resulted in widespread erythema, large thick plaques of serous crust, pustular exudate, and associated alopecia. Both patients quickly resolved with non-tetracycline oral antibiotics combined with topical steroid treatment.

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Introduction

Epidermal growth factor receptor inhibitors (EGFRI) induce numerous cutaneous adverse events, including papulopustular eruption, xerosis, fissures, pruritus, nail changes including paronychia and periungual granulation tissue, and hair changes including hair loss, inflammatory hair loss, hypertrichosis, trichomegaly, and trichiasis. The papulopustular eruption related to EGFRIs typically occurs in a seborrheic distribution, primarily on the face, scalp, neck, and upper torso during the first two weeks of treatment. The typical presentation consists of inflamed papules and pustules that can resemble acne vulgaris clinically, but has a distinct lack of comedones. Prior reports on the EGFRI-induced papulopustular eruption have not frequently described the altered appearance of the eruption related to bacterial superinfection. In this report, we describe two patients in whom the presence of Staphylococcus aureus led to unique presentations of the EGFRI-induced papulopustular eruption.

Case 1

Figure 1	Figure 2

Figure 3

A 74-year-old female was treated with erlotinib 150 mg daily for stage IV non-small cell lung adenocarcinoma. Within 2 weeks of treatment initiation, with a recurrence 16 months later, she developed a typical EGFRI-induced papulopustular eruption composed of pink papules and pustules on her scalp, central face, and chest. Treatment with oral minocycline 100 mg twice daily and topical aluminum acetate astringent soaks, clindamycin 1 percent lotion and clobetasol cream twice daily led to resolution. One year later (28 months after starting erlotinib), she presented with a sudden onset eruption limited to her face and neck, consisting of a nearly confluent plaque of 2 to 3 mm red papules and hundreds of <1 mm pinpoint pustules (Figures 1 and 2). A 3 mm punch biopsy revealed numerous Gram positive bacteria within the inflamed follicle and a histologic pattern of suppurative folliculitis typical of that seen in patients treated with EGFRIs (Figure 3). Bacterial culture of the pustules revealed moderate growth of Staphylococcus aureus resistant to erythromycin and susceptible to amoxicillin/clavulanate, ampicillin/sulbactam, clindamycin, gentamicin, levofloxacin, oxacillin, tetracycline, trimethoprim/sulfamethoxazole, and vancomycin. Treatment with oral amoxicillin/clavulanate 500 mg twice daily and halobetasol propionate 0.05 percent cream twice daily for 2 weeks led to resolution. Three months later, the patient presented with a recurrence of an identical eruption confined to the face, slightly extending onto her neck. Bacterial culture revealed moderate growth of Staphylococcus aureus with identical sensitivities. After treatment with oral amoxicillin/clavulanate 500 mg twice daily for 2 weeks, she was started on a maintenance regimen of trimethoprim/sulfamethoxazole 500 mg three times weekly with no further recurrences.

Case 2

Figure 4	Figure 5

A 47-year-old female with stage IV non-small cell lung adenocarcinoma was initiated on oral erlotinib 150 mg daily. Twenty-six months after initiating erlotinib therapy, she presented with a large, confluent, red erythematous patch with several < 1 mm studded pustules on her scalp. Within this patch was notable extensive alopecia, along with numerous areas covered with thick matted down yellow serous crust (Figure 4). She was treated with oral doxycycline 100 mg twice daily and a topical regimen consisting of aluminum acetate astringent soaks, clindamycin 1 percent lotion, and clobetasol propionate 0.05 percent cream three times daily. Three weeks later, there was complete resolution (Figure 5), with subsequent hair regrowth. At three subsequent time points, including 3, 11, and 16 months later, she developed acute recurrences of the papulopustular eruption on her scalp, resulting in similar erythematous patches with overlying thickened, matted down serous crust and pustules. Her erlotinib dose was reduced to 100 mg daily after her first recurrence. Bacterial cultures of her scalp on all three occasions showed moderate to heavy growth of Staphylococcus aureus resistant to erythromycin and clindamycin in all of the cultures and resistant to tetracycline in two of the cultures. The patient was treated with amoxicillin/clavulanate 500 mg twice daily for 2 weeks and the same topical regimen in all three instances, which led to resolution each time. After her third recurrence, she was started on trimethoprim/sulfamethoxazole three times a week as maintenance therapy with no further recurrences.

Discussion

The severity of EGFR-inhibitor induced papulopustular eruptions often decreases with continued use of the drug [1]. Our patients experienced distinct eruptions after many months of continuous EGFRI treatment. Our first patient’s plaque-like presentation with innumerable studded pinpoint pustules 28 months into treatment is distinct from the typical EGFRI-induced appearance of discrete papules and pustules within 2 to 4 weeks of treatment initiation. Our second patient experienced a total of three eruption flares within 17 months, with two occurring even after erlotinib dose reduction. Each flare was associated with Staphylococcus aureus infection, which was notably resistant to tetracyclines.

Whereas earlier studies demonstrated that the EGFRI-induced papulopustular eruption is usually sterile, [2, 3] more reports are indicating the prevalence of infection in this rash [4, 5, 6]. Amitay-Laish et al [5] found that among 20 patients with a papulopustular reaction, in whom bacterial cultures were tested, 14 (70%) of them showed positive Staphylococcus aureus infection. The data was further divided into patients with an “early phase” rash, which started within the first 2 weeks of EGFRI treatment (median, 8 days; range, 4-14 days) and patients with a “late phase” rash, which started at a median of 200 days (range, 150-300 days) after initiation of EGFRI treatment. Fifty-five percent of the patients with early phase rash and 100 percent of the patients with late phase rash showed cultures with methicillin-sensitive Staphylococcus aureus.

The standard of care for management of the EGFRI-induced papulopustular eruption includes the initiation of a second-generation tetracycline for rash severity grades 2 or higher [7]. Our second patient demonstrates that pustules showing bacterial growth resistant to tetracyclines requires treatment with appropriate antibiotics according to susceptibility profile of the organism. In our patients, initiation of trimethoprim/sulfamethoxazole as maintenance therapy resulted in prevention of eruption recurrences.

These cases describe unique variants in the presentation of the EGFRI-induced papulopustular eruption owing to the significant presence of bacteria, Staphylococcus aureus in our cases. These cases emphasize the importance of obtaining bacterial cultures in the presence of any pustules or crusting associated with the EGFRI-induced papulopustular eruption and the potential utility of maintenance with non-tetracycline antibiotics to prevent recurrences of the eruption.

References

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