mycoses 42, 507–511 (1999) Accepted: September 20, 1998

LETTER TO THE EDITOR

Case Report. Atypical cutaneous pseudallescheriosis refractory to antifungal agents

Fallbericht: Atypische therapierefrakta¨re kutane Pseudallescheriose

Gabriele Ginter1, B. Petutschnig2, G. Pierer2, H. P. Soyer1, S. Reischle1, T. Kern1 and S. de Hoog3

Key words. , cutaneous infection, heart transplant, antimycotic chemotherapy, itraconazole, miconazole, surgical debridement. Schlu¨ sselwo¨rter. Pseudallescheria boydii, Hautinfektion, Herztransplantation, antimykotische Chemotherapie, Itraconazol, Miconazol, chirurgisches Debridement.

Summary. We report on a 65-year-old male Zusammenfassung. Bei einem 65-ja¨hrigen heart transplant recipient who was otherwise in herztransplantierten Patienten kam es unter good condition. The patient was immunocom- Immunsuppression mit Cyclosporin, Kortikoste- promised secondarily due to cyclosporin, predniso- roiden und Azathioprin 3 Monate nach Herztrans- lone and azathioprine when widespread pustular plantation bei gutem Allgemeinzustand zur skin lesions with erythematous margins sub- Entwicklung von Pusteln auf erythemato¨sem sequently developed on his left forearm. There Grund am linken Unterarm. Anamnestisch ergab was no history of trauma or septic temperature. sich kein Anhalt fu¨r ein zuvor erfolgtes Trauma Bacterial cultures were sterile and the results of oder febrile Temperaturen. Die mikrobiologische native and cultural investigation studies were nega- Exploration erbrachte weder nativ noch kulturell tive. A biopsy specimen of the lesion demonstrated einen Erregernachweis. In der feingeweblichen hyalohyphomycosis with numerous septate hyphae Untersuchung einer Hautbiopsie fanden sich im within granulomas throughout the dermis. Bereich der Dermis innerhalb von Granulomen Subcutaneous tissues were not involved. Culture zahlreiche septierte Hyphen als Ausdruck einer plates inoculated with pus and skin from the punch Hyalohyphomykose, die Subkutis war unauffa¨llig. biopsy showed growth of a mould yielding Im Kulturversuch mit bioptischem Material entwi- Pseudallescheria boydii. Sensitivity testing was per- ckelte sich wiederholte Male ein rasch wachsender formed with miconazole, ketoconazole and itra- Schimmelpilz, Pseudallescheria boydii. Gema¨ß der im conazole showing the best in vitro activity against Antimykogramm niedrigen Hemmkonzentration P. boydii. In spite of treatment with itraconazole, von Azolen wurde eine orale Therapie mit the erythema and pustules continued to spread Itraconazol eingeleitet, die Behandlung jedoch and therapy was changed to intravenous micona- wegen Progredienz der La¨sion auf intraveno¨ses zole. Due to ongoing progression after 3 months Miconazol umgestellt. Weiteres therapierefrakta¨res of antifungal therapy surgical debridement was Verhalten veranlasste nach 3-monatiger antimyze- required. After 2 years of follow up, he had no tischer Therapie das chirurgische Debridement recurrence. der kutanen Infektion. Der Patient pra¨sentiert sich bis heute ru¨ckfall- und erscheinungsfrei. 1Department of Dermatology, 2Division of Surgery, Department of Transplantation, University of Graz, Austria, and 3Centraalbureau voor Schimmelcultures, Baarn, The Introduction Netherlands. Fungal infection has emerged as a leading cause Correspondence: Prof. Dr Gabriele Ginter, Universita¨tsklinik fu¨r Dermatologie, Auenbruggerplatz 8, A-8036 Graz, Austria. of death among immunosuppressed and cancer Tel.: ++43/316 385 2371; Fax: ++43/316 385 2466 patients. Whereas Candida spp., spp. and 508 G. Ginter et al.

Cryptococcus neoformans are common opportunistic fungal organisms causing infections in compro- mised hosts, Pseudallescheria boydii has emerged as an infrequently appearing that may become more frequent and threatening in the future [1]. Pseudallescheria boydii (Petriellidium boydii, Allescheria boydii) is an ubiquitous soil-inhabiting that can be recovered from polluted water and sewage. Human infection can follow traumatic implant- ation or aspiration of contaminated water. Pseudallescheria boydii is the most frequent cause of fungal mycetoma in temperate regions. This chronic infection results from the traumatic implantation of the fungus into subcutaneous tissue [2]. Sinus tract formation with discharge of grains and spreading into adjacent tissue and bone are typical findings. The lung is the second most common site of P. boydii infection in humans with development of abscess formation or necrotizing in immunosuppressed patients [3]. Fatal dissemi- nation may develop with infection of the central nervous system, , endocarditis, arthritis, osteomyelitis, soft tissue abscesses, kidney and eye infections [4].

Case report Figure 1. Pseudallescheriosis. Development of painless widespread miliary, partial pustular skin lesions with erythematous margins on the left forearm. The patient described here was a 65-year-old man with a history of severe dilating cardiopathy; for this reason he was treated with heart transplan- tation in March 1996. The patient was immuno- compromised secondary to cyclosporin, pred- nisolone and azathioprine but otherwise in good condition. Three months after transplantation, painless widespread miliary, partial pustular skin lesions with erythematous margins developed on his left forearm to the extent of about 8 cm×12 cm (Fig. 1). There was no history of trauma or septic temperature. Radiographic examination of the affected part revealed no bone involvement. When the patient was admitted to our clinic microbiological investigations were carried out: Figure 2. Histopathological examination (12×) of an excisional bacterial cultures were sterile and mycological biopsy from the left forearm revealed several granulomas within the investigation studies, i.e. potassium hydroxide upper dermis. There was no involvement of the subcutaneous fat. preparation and fungal culture of the skin were performed and yielded negative results. layer probably representing the remnant of a To establish a diagnosis a punch biopsy was dilated follicular infundibulum. The granulomas obtained on the left forearm lesion and the speci- consisted of a peripheral rim of epithelioid cells men was bisected for histopathological examin- intermingled with some multinuclear giant cells ation and repeated cultivation. Histopathological and a large central core with masses of neutrophils evaluation revealed several granulomas within the and nuclear dust (Fig. 3). Within this central upper dermis (Fig. 2). Remarkably, one of these abscess formation numerous septate hyphae, granulomas was surrounded by a thin epithelial 2–7 mm in diameter could already be easily

mycoses 42, 507–511 (1999) Pseudallescheria boydii infection 509

Mc.Ginnis et al.(Graphium synanamorph) and con- firmed by de Hoog and Samson at CBS, Baarn. Sensitivity testing was performed by F. Odds from Janssen Research Foundation in Belgium with miconazole, ketoconazole and itraconazole showing best in vitro activity against Pseudallescheria boydii (Table 1).

Treatment

In accordance with the sensitivity testing values which showed the best in vitro activity with azoles, Figure 3. Histopathological examination (100×): The granulomas systemic treatment with itraconazole (200 mg p.o. consisted of a peripheral rim of epithelioid cells interminged with daily) was initiated first and an initial improvement some multinuclear giant cells and a large central core with masses of seemed to occur. However, after 8 weeks and in neutrophils and nuclear dust. spite of the treatment, the erythema and pustules were spreading and so itraconazole was changed to miconazole (600–1800 mg i.v. daily). detected with HE-stain (Fig. 4). These septate hyphae were found in a very large number especi- Due to ongoing progression—culture growth remained positive all the time (Table 2)—after ally within the epithelial cyst. There was no involvement of the subcutaneous fat. 3 months of therapy surgical debridement was required with the removal of at least 1.5 cm in These histopathological findings could be stated diameter of healthy tissue (Fig. 5). as dermal absceding granulomas with numerous septate hyphae resembling hyalohyphomycosis [5]. After 2 years of follow up, he had no recurrence. Culture plates (Sabouraud glucose agar, SGA) inoculated with pus and skin from the punch biopsy showed a rapid growth of a mould 3 days Conclusion after inoculation with colonies maturing within In patients undergoing immunosuppression due to 7 days. The colonies were fluffy, initially whitish, and later on mousehair grey to brownish in colour. cancer chemotherapy or organ transplant a high The reverse was white to grey, and finally black. Microscopic examination of the mycelial colon- Table 1. Pseudallescheria boydii: sensitivity testing* with ies showed characteristic hyaline branching septate miconazole, ketoconazole and itraconazole showing best hyphae with one-celled pale brown ovoid conidia in vitro activity. (*With request to F. C. Odds, PhD, MRC developing either singly or in clusters on short Path, JANSSEN Research Foundation) conidiophores. These findings were compatible MIC mg/ml with identification of Pseudallescheria boydii (Shear) >8 >64 4 Ketoconazole 0.25 Itraconazole 0.50 Miconazole 0.063 Terbinafine >16

Table 2. Growth of Pseudallescheria boydii in spite of treat- ment with itraconazole and miconazole for a 3-month period

Date Therapy

10/07/96 positive Itraconazole 200 mg/day p.o. 29/08/96 positive Itraconazole 200 mg/day p.o. 06/09/96 positive Itraconazole 200 mg/day p.o. 16/09/96 positive Miconazole 600–1800 mg/day i.v. Figure 4. Histopathological examination (500×): Within central 01/10/96 positive Miconazole 600–1800 mg/day i.v. abscess formations numerous septate hyphae, 2–7 mm in diameter, 15/10/96 positive Surgery+miconazole resembling hyalohyphomycosis could already be detected with HE- 28/10/96 Discontination of miconazole stain mycoses 42, 507–511 (1999) 510 G. Ginter et al.

Paecilomyces spp., Penicillium spp., Scopulariopsis spp. and Trichoderma spp. are known to be common causative organisms, whereas Pseudallescheria boydii is less prevalent [7]. Aspergilli also have hyaline hyphae, but infection with these organisms is termed ‘‘’’ instead. Histologically, Pseudallescheria boydii resembles other fungi in tissue specimens, most notably Aspergillus. That means it may be impossible to differentiate between these organisms—both appear as branched septate hyphae—on mor- phology alone. To determine the causative fungal agent special culture techniques are required for Figure 5. Surgical debridement with removal of at least a 1,5 cm rapid diagnosis and appropriate varied or com- in diameter of healthy tissue. bined modes of therapy [4, 8, 9]. In addition to the use of cultivation methods in the diagnostic procedure, mycetomas reveal a index of clinical suspicion for opportunistic therapeutic challenge in relation to their causative mycoses should be maintained. Whereas systemic agent. According to present reports P. boydii is and disseminated candidosis have emerged as the often resistant to amphotericin B, and patients most frequent complications, aspergillosis is sus- usually exhibit a poor in vivo response to this agent pected to show the highest mortality rate [6]. [9–11]. Nielson et al. measured the sensitivities of Many other fungi may infect the immunocom- 15 isolates to amphotericin B and found only three promised patient infrequently. These miscel- (20%) that were sensitive to <2mgml−1, the laneous fungi are categorized into two groups: the maximum achievable blood level [11]. dematiaceous moulds and (phaeohypho- In most cases miconazole and ketoconazole ) and the hyaline moulds and yeasts (hya- have shown the best in vitro activity against lohyphomycosis) [7]. Pseudallescheria boydii with miconazole considered Besides the opportunity for different fungi to by many to be the drug of choice [12]. cause mycotic infections in the immunocom- The reported MICs of miconazole to P. bodii promised hosts, their clinical appearance may also are close to 0.2 mgml−1; with our isolate not be specific. 0.063 mgml−1 was noted. The achievable peak Our case illustrates an unusual clinical picture serum levels of miconazole exceed 1 mgml−1 with of without the formation of sinus intravenous doses of >9mgkg−1 [13]. tracts and extrusion of grains. Furthermore, subcu- Ketoconazole offers the advantage of prolonged taneous tissue and the bones were not involved. oral therapy but the MICs of ketoconazole to We suspect that the typical findings for mycetoma P. boydii are higher than those of miconazole and were not present in our patient due to his under- often exceed the achievable serum concentrations. lying immunosuppression. Therefore we agree However, in vitro susceptibilities to miconazole and the term ‘‘cutaneous pseudallescheriosis’’ or ketoconazole do not always correlate with clinical ‘‘mycetoma-like disease’’. response as successful therapy has been reported Patterson et al. [8] described the epidemiology in patients with strains showing in vitro resistance of two cases of pseudallescheriosis in organ trans- [14]. In transplant recipients the use of miconazole patients. Similar to our patient one of them, and ketoconazole may be complicated because a heart transplant recipient who was generally in these agents can increase serum cyclosporin levels good condition developed localized disease, and in liver transplant recipients may not be namely multiple cystic lesions on the medial aspect properly metabolized [8]. of his right knee following soil contamination of Itraconazole is probably a good alternative to soft tissue trauma. As in our patient he failed to miconazole for treatment of Pseudallescheria boydii develop sinus tracts or grains and radiographs especially in the immunocompromised host showed no bone involvement. The infection was because there is less interference with cyclosporin cured with surgical resection and miconazole therapy. In vitro susceptibilities suggest itraconazole therapy. typically has activity against P. boydii [8, 9, 15] The term ‘‘hyalohyphomycosis’’ implies dis- furthermore, this broad spectrum triazole has the seminated infection of hyaline (non-pigmented) advantage of oral bioavailability. Itraconazole has moulds and is characterized by displaying hyaline been effective in some cases of pseudallescheriosis hyphae in tissue. Acremonium spp., spp., with failure of surgical debridements and intra-

mycoses 42, 507–511 (1999) Pseudallescheria boydii infection 511 venous miconazole therapy. Piper et al. reported on Hyalohyphomycosis. In: Fungal Infection—Diagnosis and a successful treatment of Scedosporium apiospermum Management. Oxford: Blackwell Sc. Publishers, pp. 162–166. suppurative arthritis with itraconazole in an 6 Hummel, M. & Hetzer, R. (1991) Pilzinfektionen nach immunocompetent 6-year-old child after previous Herztransplantation. In: Staib, F. & Huhn, D. (eds) ineffective treatment. However, the question when Pilzinfektionen bei Abwehrgeschwa¨chten Patienten. Berlin, using all these newer drugs in P. boydii infections Heidelberg, New York: Springer-Verlag. S. 64–72. is the dosage as well as treatment duration and 7 Rippon, J. W. (1988) Medical Mycology: the Pathogenic Fungi and the Pathogenic Actinomyces. 3rd edn. Philadelphia: W. B. the mode of administration, namely, whether to Saunders. give the substance alone or in combination with 8 Patterson, T. F., Andriole, V. T., Zervos, M. J., Therasse, amphotericin B. D. & Kauffman, C. A. (1990) The epidemiology of In our case a cure was not achieved with the pseudallescheriasis complicating transplantation: noso- use of selected appropriate systemic antifungals. comial and community-acquired infection. Mycoses 33, The therapeutic challenge may therefore be the 297–302. 9 Sugar, A. M. & Lyman, C. A. (1997) Pseudallescheria coordination of the traditional approach of surgical (Scedosporium). In: Practical Guide to Medically Important Fungi debridement with selection of the most appropriate and the Diseases They Cause. Philadelphia, New York: systemic antifungal agent. Lippincott-Raven, pp. 63–65. In future, clinicians must be aware of 10 Welsh, O. (1991) Mycetoma: current concepts in treat- Pseudallescheria boydii as an emerging opportunistic ment. Int. J. Dermatol. 30, 387–398. 11 Nielson, H. S. (1967) Effects of amphotericin B in vitro on pathogen that can no longer be dismissed as an perfect and imperfect strains of Allescheria boydii. Appl. improbable contaminant or colonizer when iso- Microbiol. 15, 86–91. lated from immunocompromised hosts [16]. 12 Rotowa, N. A., Shadomy, H. J. & Shadomy, S. (1990) In vitro activities of polyene and imidazole antifungal agents against unusual opportunistic fungal . Mycoses References 33, 203–211. 13 Lutwick, L. I., Galgiani, J. J., Johnson, R. H. & Stevens, 1 Bodey, G. P. (1990) Fungal Infections in Cancer Patients—an D. A. (1976) Visceral fungal infections due to. Petriellidium Overview. New York: Pfizer International Inc., pp. 2–18. boydii (Allescheria boydii). Am. J. Med. 61, 632–640. 2 Hay, R. J. (1993) Deep mycoses and the skin: subcutane- 14 Galgiani, J. N., Stevens, D. A., Graybill, J. R., Stevens, ous mycoses. In: R. Hay (ed.) Fungi and Skin Disease. D. L., Tillinghast, A. J. & Levine, H. B. (1984) London, Philadelphia, Milan etc: Mosby-Wolfe, Pseudallescheria boydii infections treated with ketoconazole. pp. 51–54. Chest 86, 219–224. 3 Seale, J. P. & Hudson, J. A. (1986) Successful medical 15 Piper, J. P., Golden, J., Brown, D. & Broestler, J. (1987) treatment of pulmonary petriellidiosis. South. Med. J. 78, Successful treatment of Scedosporium apiospermum suppurat- 473–476. ive arthritis with itraconazole. Pediatr. Infect. Dis. J. 9, 4 Bernstein, E. F., Schuster, M. G., Stieritz, D. D., Heuman, 674–675. P. C. & Uitto, J. (1995) Disseminated cutaneous 16 Anaissie, E. (1992) Opportunistic mycoses in the immuno- Pseudallescheria boydii. Brit. J. Derm. 132, 456–460. compromised host: experience at a cancer center and 5 Richardson, M. D. & Warnock, D. W. (1993) review. Clin. Infect. Dis. 14 (Suppl. 1), 43–53.

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