SHORT COMMUNICATION

Corticosteroid-resistant Terbinafine-induced Acute Generalized Exanthematous Pustulosis: Therapeutic Challenges and Clinical Infection Overlap

Alessandro SVIZZERO^1,2†, Camilla VASSALLO^1,2, Andrea MICHELERIO^1,2, Arber SELIMI², Marco NISI², Giacomo FIANDRINO³ and Valeria BRAZZELLI^1,2*†

¹Dermatology Clinic, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, ²Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy, and ³Pathology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. ^*Email: v.brazzelli@smatteo.pv.it

^†These authors contributed equally to this work.

 

 

Terbinafine is an uncommon, yet increasingly recognized, cause of acute generalized exanthematous pustulosis (AGEP) (1, 2). We report a corticosteroid-resistant case complicated by severe Staphylococcus aureus infection, illustrating the therapeutic and diagnostic challenges that may arise in this setting.

A 56-year-old woman developed an itchy, rapidly progressive pustular rash approximately 2 weeks after starting to take 250 mg of oral terbinafine daily for onychomycosis caused by Trichophyton rubrum. She was initially evaluated at another hospital, where Stevens–Johnson syndrome was suspected. High-dose systemic corticosteroids (prednisone 75 mg daily) were administered and terbinafine was discontinued; however, there was only partial improvement, with repeated flares whenever corticosteroid was tapered. The ongoing disease activity despite treatment prompted referral to our department. At this time, she was receiving prednisone 50 mg daily.

Upon examination, she exhibited a fever, generalized erythema and edema, and numerous pinhead-sized, nonfollicular pustules, primarily on her trunk and intertriginous areas (Fig. 1). The mucous membranes were spared. Laboratory tests revealed leukocytosis with neutrophilia, normal liver and renal function. A skin biopsy revealed spongiform and subcorneal pustules, papillary dermal edema, a perivascular neutrophilic infiltrate with scattered necrotic keratinocytes and foci of leukocytoclastic vasculitis, which is consistent with AGEP (Fig. 2) (3). According to the EuroSCAR scoring system, the validation score was 10, which supports a definitive diagnosis of drug-induced AGEP related to terbinafine.

Fig. 1. Widespread erythema and edematous skin covered with numerous non-follicular pustules, predominantly affecting the trunk and intertriginous areas.

Fig. 2. Histopathological findings showed spongiform subcorneal and intraepidermal pustules, perivascular neutrophilic infiltrate, scattered necrotic keratinocytes, and foci of leukocytoclastic vasculitis, consistent with AGEP.

In our unit, attempts to further taper systemic prednisone led to rapid pustular relapses, rendering the eruption functionally corticosteroid-dependent. Due to the severity and extent of the eruption, cyclosporine was introduced at a dosage of 3 mg/kg daily while maintaining a low dose of prednisone. Within a few days, the pustules resolved, and progressive desquamation ensued.

Despite the dermatologic response, the patient developed sudden severe lumbar back pain, persistent fever and rising inflammatory markers. Blood cultures yielded methicillin-sensitive S. aureus, consistent with bacteremia. Intravenous daptomycin, 850 mg daily, was promptly initiated. Two days later, the patient developed dyspnea and hypoxemia. A chest CT scan revealed pulmonary consolidations consistent with septic pneumonia, prompting an adjustment to the antibiotic regimen to ensure adequate lung penetration. Daptomycin was therefore discontinued and the antibiotic regimen was changed to ceftriaxone, 2 g daily, oxacillin, 2 g intravenously every 4 h and clindamycin, 600 mg 3 times daily.

Due to persistent lumbar pain, spinal magnetic resonance imaging revealed vertebral osteomyelitis and discitis with paravertebral soft tissue involvement. A prolonged combined course of intravenous and then oral antibiotics with good bone penetration was instituted. Because of persistent bacteremia and spinal involvement, ceftriaxone was subsequently discontinued, oxacillin was maintained, and daptomycin, 850 mg daily, was reintroduced. After 15 days of combined antimicrobial therapy, blood cultures became negative. During this phase, cyclosporine was discontinued, whereas low-dose prednisone, 5 mg daily, was maintained. Blood cultures became negative and both respiratory and spinal symptoms resolved. About 1 month after admission, the patient was discharged in good general condition, with complete clearance of the pustular eruption and oral moxifloxacin, 400 mg daily, for 8 weeks.

AGEP is a rare, usually drug-induced pustular eruption characterized by acute onset of diffuse nonfollicular sterile pustules on an edematous erythematous base, accompanied by fever and neutrophilia. It typically follows a rapid course, resolving within days after the offending drug is withdrawn. Terbinafine has been increasingly associated with AGEP, likely due to its long half-life of approximately 200 to 400 h and its tendency to accumulate in the skin and keratinized tissues (1, 2). This can result in a delayed onset of symptoms and a prolonged disease course, even after discontinuing the drug. This case highlights the importance of promptly recognizing and withdrawing terbinafine as a potential cause of AGEP, especially given its widespread use in treating onychomycosis (4). The case also suggests that cyclosporine may be an effective second-line, steroid-sparing option for treating severe or corticosteroid-resistant AGEP (5). Finally, the development of systemic symptoms in patients receiving immunosuppressive treatment for severe AGEP should prompt a careful clinical and microbiological reassessment to exclude invasive infections and avoid delays in diagnosing and managing potentially life-threatening complications.

REFERENCES

1. Ross CL, Shevchenko A, Mollanazar NK, Hsu S, Motaparthi K. Acute generalized exanthematous pustulosis due to terbinafine. Dermatol Ther 2018; 31: e12617. https://doi.org/10.1111/dth.12617
2. Carnio LR, Johnson Shaw ME, Schnur J, Casadesus D. Concurrent terbinafine-induced acute generalised exanthematous pustulosis and hepatitis. BMJ Case Rep 2021; 60: e238930. https://doi.org/10.1136/dtb.2021.238930
3. Sidoroff A, Halevy S, Bavinck JN, Vaillant L, Roujeau JC. Acute generalized exanthematous pustulosis (AGEP)--a clinical reaction pattern. J Cutan Pathol 2001; 28: 113–119. https://doi.org/10.1034/j.1600-0560.2001.028003113.x
4. de Oliveira GV, Maia MLP, Leão FAA, Sad EF, Miotto IZ, Silva MR, et al. What to expect when AGEP is induced by terbinafine? Case report and critical review of the literature. Mycoses 2022; 65: 918–925. https://doi.org/10.1111/myc.13506
5. Yanes D, Nguyen E, Imadojemu S, Kroshinsky D. Cyclosporine for treatment of acute generalized exanthematous pustulosis: a retrospective analysis. J Am Acad Dermatol 2020; 83: 263–265. https://doi.org/10.1016/j.jaad.2020.02.069