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Journal of Clinical Oncology, Vol 25, No 30 (October 20), 2007: pp. 4844-4845 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.4320
Subcutaneous Zygomycosis in NeutropeniaDepartments of Medicine and Hematology-Oncology, University of Münster, Münster, Germany
Departments of Medicine and Gastroenterology, University of Münster, Münster, Germany
Department of Medicine, Institute of Medical Microbiology, University of Münster, Münster, Germany
Departments of Medicine and Surgery, University of Münster, Münster, Germany A 41-year-old woman was treated for a metastatic Ewing's sarcoma of the right pelvis with intensive induction chemotherapy consisting of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE). On day 12, after initiating the third course, the patient developed febrile neutropenia with elevated inflammatory markers. Physical examination revealed an indurated, dark-red skin lesion of the right dorsal lower leg initially measuring 4 cm in diameter. Empiric broad-spectrum antibiotic therapy with piperacillin-tazobactam and gentamicin was initiated. Within the next 24 hours, a central necrosis developed within the skin lesion. The lesion was surgically removed for suspected Pseudomonas infection. Two days after surgical intervention, the patient's physical status deteriorated progressively and massive necroses developed within the wound area (Fig 1; photograph of the right dorsal lower leg of the patient showing subcutaneous zygomycosis 2 days after surgical resection of the first lesion). Histological analysis of the excised tissue showed subcutaneous mycosis, and microbiological examination revealed infection due to Absidia corymbifera belonging to the order Mucorales group of the class Zygomycetes. Species identification was done by standard taxonomic procedures including examination of the micromorphology (Fig 2; micrograph of Absidia corymbifera recovered from biopsy material of the patient [tape technique with lactophenole cotton blue] showing sporangiophores [Sph] with sporagnium [Sg] including columella [C], [endo-]spores [S], and releases spores [rS]; the diameter of the hyphes [*] varied in a wide range). 1,2 Species identification was confirmed by sequencing of fungal ribosomal RNA.3,4 Systemic antimycotic therapy with liposomal amphotericin B and posaconazole was initiated. Re-emerging necroses were resected extensively on the 2 following days. Daily changes of the bandage including antiseptic wound rinsing and local therapy with amphotericin B was performed. Within 2 days after the last surgical resection and initiating the antimycotic therapy, no further necroses occurred. The patient's physical status improved gradually, fever disappeared, and inflammatory markers declined. Vacuum-assisted closure (VAC) therapy was performed to accelerate wound healing. After sufficient physical and blood cell recovery, the induction chemotherapy was continued with the fourth course.
Zygomycetes constitute a class of ubiquitous fungi that may cause a variety of infections of clinical relevance in humans. Due to the efficacy of the human immune system, zygomycosis is a rare human infection. However, the incidence of this mycosis is globally increasing. Zygomycosis has been detected in up to 8% in autopsied patients with leukemia and in 2% of allogenic bone marrow transplantation patients.5 Zygomycosis is associated with high morbidity and lethality, and therapeutic options are limited. Almost all human infections due to zygomycetes occur in the presence of some underlying disease predisposing the patient to the infection. Risk of zygomycosis is increased by hematological malignancies, solid organ or bone marrow transplantation, neutropenia, diabetes mellitus, metabolic acidosis, corticosteroid or desferioxamine therapy, AIDS, injection drug use (IDU), trauma, burns, and malnutrition.5,6 Nevertheless, there are also rare reports of zygomycosis in the absence of any apparent risk factors.7 Most infections due to zygomycetes are acquired by inhalation, ingestion, or trauma. In humans, rhinocerebral, pulmonary, and cutaneous infections are the most common sites of zygomycosis. Cutaneous zygomycosis results from inoculation of the fungal spores into the dermis. Thus, cutaneous zygomycosis is almost always associated with trauma or wounds. The entry of the fungi into the dermis can result from seemingly innocuous entry sites like intravenous catheter or subcutaneous injection sites. Cutaneous zygomycosis usually appears as a single, painful, indurated skin lesion characterized by rapid infarction and necrosis of host tissues that result from invasion of the vasculature by hyphae.5 Dissemination or deep tissue involvement are unusual complications of cutaneous zygomycosis. Zygomycosis is diagnosed on biopsy or resection of the involved area followed by histopathological tissue examination and microbiological culture. Furthermore, species identification can be confirmed by molecular methods, such as polymerase chain reaction–based restriction fragment length polymorphism or amplification and direct sequencing of fungal ribosomal RNA genes and their intergenic spacer.2,4,8 Early diagnosis is critical for successful treatment of zygomycosis that requires immediate surgical intervention. For adjunctive antifungal therapy, amphotericin B or its lipid derivatives remain first-line agents, as several antifungal agents, such as voriconazole and caspofungin, are not effective against zygomycetes. However, in vitro data with posaconazole, a novel extended-spectrum triazole, suggested that it may be also effective against these pathogens.9,10 Moreover, posaconazole has been used for successful in vivo salvage therapy in patients who experienced treatment failure or could not tolerate standard therapy.11,12 Antimycotic therapy is often required for long-term periods. Control of predisposing factors is also critical for effective treatment of zygomycosis, whereas for hyperbaric oxygen no benefit for patients with zygomycosis could be demonstrated.13-16 Often, both diagnostic and therapeutic measures are performed too late and are inadequate. Death rates in infected transplantation recipients with zygomycosis are approximately 50%.15 Despite early diagnosis and aggressive combined surgical and antifungal therapy, the prognosis of zygomycosis is not favorable. In the case of zygomycosis, localized disease, absence of pulmonary involvement, neutrophil recovery, and stabilization, or improvement of the patients' underlying diseases, early surgical resection of affected tissues, and therapy with high-dose amphotericin B are assumedly associated with the best chance for survival of cancer patients.15,17 AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
REFERENCES 1. de Hoog GS, Guarro J, Gené J, et al: Atlas of clinical fungi. Centraalbureau voor Schimmelcultures, Utrecht, The Netherlands 2000 2. Dromer F: Zygomycosis, in Anaissie EJ, McGinnis MR, Pfaller MA, et al (eds): Clinical Mycology (ed 1). New York, NY, Churchill Livingstone, 2003, pp 297-308, 2003 3. Breitkopf C, Hammel D, Scheld HH, et al: Impact of a molecular approach to improve the microbiological diagnosis of infective heart valve endocarditis. Circulation 111:1415-1421, 2005 4. White TJ, Bruns T, Lee S, et al: Amplification and direct sequencing of fungal ribosomal RNA genes for phylogenetics. In Innis MA, Gelfand DH, Sninsky JJ, et al (eds.): PCR Protocols: A Guide to Methods and Applications. San Diego, CA, Academic Press, 1990, pp 315-322 5. Greenberg RN, Scott LJ, Vaughn HH, et al: Zygomycosis (mucormycosis): Emerging clinical importance and new treatments. Curr Opin Infect Dis 17:517-525, 2004[CrossRef][Medline] 6. Roden MM, Zaoutis TE, Buchanan WL, et al: Epidemiology and outcome of zygomycosis: A review of 929 reported cases. Clin Infect Dis 41:634-653, 2005[CrossRef][Medline] 7. Radner AB, Witt MD, Edwards JE: Acute invasive rhinocerebral zygomycosis in an otherwise healthy patient: Case report and review of the literature. Clin Infect Dis 20:163-166, 1995[Medline] 8. Machouart M, Larché J, Burton K, et al: Genetic identification of the main opportunistic Mucorales by PCR-restriction fragment length polymorphism. J Clin Microbiol 44:805-810, 2006 9. Spanakis EK, Aperis G, Mylonakis E: New agents for the treatment of fungal infections: Clinical efficacy and gaps in the coverage. Clin Infect Dis 43:1060-1068, 2006[CrossRef][Medline] 10. Sun QN, Fothergill AW, McCarthy DI, et al: In vitro activities of posaconazole, itraconazole, voriconazole, amphotericin B, fluconazole against 37 clinical isolates of zygomycetes. Antimicrob Agents Chemother 46:1581-1582, 2002 11. van Burik JA, Hare RS, Solomon HF, et al: Posaconazole is effective as salvage therapy in zygomycosis: A retrospective summary of 91 cases. Clin Infect Dis 42:e61-e65, 2006[CrossRef][Medline] 12. Greenberg RN, Mullane K, van Burik JA, et al: Posaconazole as salvage therapy for zygomycosis. Antimicrob Agents Chemother 50:126-133, 2006 13. Yohai RA, Bullock JD, Azis AA, et al: Survival factors in rhino-orbital-cerebral mucormycosis. Surv Ophthalmol 39:3-22, 1994[CrossRef][Medline] 14. Ferguson BJ, Mitchell TG, Moon R, et al: Adjunctive hyperbaric oxygen for treatment of rhinocerebral mucormycosis. Rev Infect Dis 10:551-559, 1988[Medline] 15. Almyroudis NG, Sutton DA, Linden P, et al: Zygomycosis in solid organ transplant recipients in a tertiary transplant center and review of the literature. Am J Transplant 6:2365-2374, 2006[CrossRef][Medline] 16. Bentur Y, Shupak A, Ramon Y, et al: Hyperbaric oxygen therapy for cutaneous/soft-tissue zygomycosis complicating diabetes mellitus. Plast Reconstr Surg 102:822-824, 1998[CrossRef][Medline] 17. Kontoyiannis DP, Wessel VC, Bodey GP, et al: Zygomycosis in the 1990s in a tertiary-care cancer center. Clin Infect Dis 30:851-856, 2000[CrossRef][Medline]
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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