Purpureocillium lilacinum, a ubiquitous mold found in soil and vegetation, has emerged as a pathogen in immuno- competent and immunocompromised patients¹. Although no standard antifungal regimen has been established for P. lilacinum, it has been known for possessing resistance to typical antifungals, such as amphotericin B, fluconazole, and flucytosine. Therefore, P. lilacinum infections are hard to manage given their frequent recurrence with conventional antifungal agents. Nevertheless, several cases have shown that monotherapy or combination therapy with itraconazole, ketoconazole, terbinafine, and surgical debridement can be used to treat cutaneous P. lilacinum infections. Given the con- flicting results of in vitro tests for susceptibility to itraconazole, recurrence or treatment failure has also often been reported with itraconazole treatment for P. lilacinum². Therefore, new second-generation triazole antifungals, including voriconazole, posaconazole, and isavuconazole, have been used to treat cutaneous P. lilacinum infections.

Posaconazole (Noxafil®) had been approved by the Food and Drug Agency (FDA) in 2005 for the treatment of inva- sive aspergillosis and candida infections. However, emerging studies have shown that the effects of posaconazole can extend to various fungal and mold infections³. Herein, we report the use of posaconazole in a patient with cutaneous P. lilacinum infection who failed to achieve complete remission with itraconazole in our last report².

A 72-year-old female presented with an asymptomatic, peripherally spreading, well-demarcated, scaly, and erythema- tous patch on her forehead that had persisted for 4 months (Fig. 1A). Approximately 2 years prior to presentation, she was been diagnosed with a subcutaneous P. lilacinum infection confirmed through skin biopsy, fungal culture, and sequence analysis of the internal transcribed spacer region of the rRNA gene. She had been treated with oral itraconazole (200 mg/day) for 4 months, with most of the skin lesions improving after 4 months of treatment. However, 2 months after ceasing itraconazole, the lesion recurred in her forehead. Despite repeated use of itraconazole for each recurrence, complete remission could not be achieved. Skin biopsy and fungal culture were then conducted. Hematoxylin and eosin staining revealed superficial, interstitial, and perifollicular lympho- histiocytic infiltration and granulomatous inflammation with multinucleated giant cells (Fig. 2A). Periodic acid-Schiff staining with diastase revealed fungal elements and mixed inflam- matory and granulomatous infiltration in the dermis (Fig. 2B). Matrix-assisted laser desorption ionization time-of-flight mass spectrometry analysis identified P. lilacinum. The patient was then prescribed oral posaconazole (100 mg/day) for 10 weeks. Her skin lesions had dramatically decreased after 10 weeks of treatment, with no adverse events having been reported during this period (Fig. 1B). Approximately 2 months after stopping posaconazole, her lesions were entirely resolved without any recurrence.

Figure 1. (A) Peripherally spreading, well-demarcated, asymptomatic, scaly, and erythematous patch on the patient's forehead; (B) The lesion disappeared after 10 weeks of treatment with posaconazole.

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Figure 2. (A) Histopathologic findings revealing superficial, interstitial, and perifollicular lymphohistiocytic infiltration and granulo- matous inflammation with multinucleated giant cells (H&E, ×200); (B) Special periodic acid-Schiff staining with diastase showing fungal elements and mixed inflammatory and granulomatous infiltration in the dermis (×400)

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P. lilacinum causes a variety of clinical manifestations in immunocompetent and immunocompromised patients, ranging from superficial mycoses to life-threatening systemic infections⁴. Thus far, the Korean literature has reported nine cases of cutaneous P. lilacinum infections2. Five of the cases were successfully treated with itraconazole monotherapy. However, two cases showed resistance to itraconazole and required alternative therapy with voriconazole or terbinafine. Our patient also experienced treatment failure with itracona- zole2. Therefore, alternative antifungal agents are necessary for the treatment of cutaneous P. lilacinum infections.

Although a standard treatment guideline has yet to be established, new azoles, such as voriconazole, posaconazole, and isavuconazole, have been used to treat cutaneous P. lilacinum infections. In fact, two recently reported guidelines^5,6 have moderately recommended voriconazole and marginally recommended posaconazole for the treatment of P. lilacinum infections.

However, we recommend using posaconazole as the first alternative therapeutic option in P. lilacinum infections refrac- tory to itraconazole given its potentially better effectiveness and safety. First, we assert that posaconazole could be more effective than voriconazole in treating P. lilacinum infection. The effectiveness of posaconazole for P. lilacinum infections can be implied from the results of the antifungal susceptibility test. Although many cases have reported successful treat- ment of cutaneous P. lilacinum infections with itraconazole, itraconazole showed only intermediate antifungal activity against P. lilacinum. Overall, posaconazole showed the best in vitro activity against P. lilacinum, with MICs ≤0.5 mg/L. In addition, posaconazole was effective at a lower range (0.06~ 0.5 mg/L) than voriconazole (0.06~4 mg/L). Therefore, posa- conazole could more effectively treat P. lilacinum infections than voriconazole.

Moreover, posaconazole could be safer than voriconazole due to fewer treatment-related adverse events. A controlled study comparing posaconazole with voriconazole for the treatment of invasive aspergillosis by Maertens et al.⁸ revealed that the overall incidence of treatment-related adverse event rates was 30% for posaconazole and 40% for voriconazole. Also, the American FDA suggests that isavuconazole and posaconazole are better tolerated than voriconazole with fewer neurological disorders (hallucinations, peripheral neuro- pathies), skin toxicities, and interactions with immunosup-pressive treatment⁹.

Nowadays, studies have reported the successful treatment of cutaneous P. lilacinum infections with voriconazole and posaconazole. In fact, over 30 cases of voriconazole use and 9 cases of posaconazole use have been reported for cutaneous /subcutaneous P. lilacinum infections^9-16. We reviewed the demographic characteristics of these cases, including their age, sex, relevant history, treatment, complications related to posaconazole, and outcomes (Table 1). Seven of the nine cases were associated with underlying immunosuppression, including organ transplantation, Evans's syndrome, and long-term use of systemic corticosteroids. Six cases first used other antifungal agents, such as itraconazole and voriconazole. In particular, two cases who failed to respond to voriconazole treatment for P. lilacinum infection were subsequently cured after posaconazole treatment. One case could not continue using voriconazole because of adverse events.

Posaconazole is often connected with the following adverse drug reactions: neutropenia, electrolyte dysfunction, head- ache, vomiting, nausea, stomachache, diarrhea, dyspepsia, and hepatic disturbances including elevation of alanine transaminase (ALT) and aspartate aminotransferase (AST)¹⁷. Physicians need to carefully monitor the electrolyte levels of patients, including hypokalemia and hepatic function, through- out the course of therapy. Nevertheless, all of these adverse drug reactions, except for neutropenia, can be managed by reducing the dose or adding histamine-2 blockers or proton pump inhibitors. In the case reported by Hu et al.¹², the patient showed elevated AST and ALT levels during oral posaconazole treatment. The plasma concentration of posa- conazole was 3.04 μg/mL, whereas its MIC in vitro was 1 μg /mL. After reducing the dosage of posaconazole to 200 mg /day, the patient's AST and ALT levels normalized, with a considerable decrease in her skin lesions also having been observed. In our case, we showed that posaconazole had a sufficient effect on cutaneous P. lilacinum infection without elevating AST and ALT levels despite using a posaconazole dose (100 mg/day) lower than that reported in other case studies. Given that posaconazole is often accompanied by gastric disturbances, famotidine (20 mg/day) can be added as a preventive measure. Our patient did not show any adverse reactions to posaconazole during treatment. Taken together, our experience suggests that the safety of posaconazole can be more reliable and easily managed.

In conclusion, we report a case involving a patient who developed recurrence of cutaneous P. lilacinum infection after itraconazole treatment. Posaconazole exhibited sub- stantial efficacy and good tolerability in this case. We believe posaconazole can be a therapeutic option for cutaneous P. lilacinum infections refractory to itraconazole.