International Journal of Infectious Diseases 14 (2010) e354–e356

Contents lists available at ScienceDirect

International Journal of Infectious Diseases

journal homepage: www.elsevier.com/locate/ijid

Case Report Invasive fusariosis with prolonged fungemia in a patient with acute lymphoblastic leukemia: case report and review of the literature

M. Jossi, J. Ambrosioni, M. Macedo-Vinas, J. Garbino *

Infectious Diseases Division, University Hospitals of Geneva, 24 Rue Micheli-du-Crest, 1211 Geneva 14, Switzerland

ARTICLE INFO ABSTRACT

Article history: spp are rare but important opportunistic pathogens in immunocompromised patients. Received 27 March 2009 Disseminated fusarial infections occur mostly in patients with hematologic malignancies with Received in revised form 17 April 2009 myelosuppressive chemotherapy or in patients with severe immunodeficiency. Although more frequent Accepted 2 May 2009 than Aspergillus fungemia, Fusarium fungemia remains a rare event. We describe the case of a female Corresponding Editor: Meinolf Karthaus, patient with febrile neutropenia and persistent fungemia due to Fusarium solani, treated with Munich, Germany. posaconazole and liposomal amphotericin B. A review of the literature for Fusarium spp fungemia was carried out. Keywords: Invasive fusariosis ß 2009 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. Leukemia Fusarium solani fungemia Posaconazole

1. Introduction 2. Case report

The incidence of invasive fungal infections is increasing and A 44-year-old white woman presented with a medical history Fusarium spp, a common soil mold, are among the emerging fungal of multiple sclerosis since 2000, and invasive breast carcinoma pathogens causing rare but important opportunistic infections in treated in 2007 with three cycles of fluorouracil, epirubicin, and immunocompromised patients.1,2 Members of the genus Fusarium cyclophosphamide chemotherapy (FEC), and three cycles of are halohyphomycetes belonging to the order taxotere chemotherapy, each cycle complicated by febrile neu- (ascomycetes). They are plant pathogens and soil saprophytes tropenia. that cause a broad spectrum of human infection,3,4 including Due to the diagnosis of an acute lymphoblastic leukemia (ALL) mycotoxicosis following ingestion of fusarial toxins, or tissue type B in January 2008, the patient was hospitalized and invasion. In tissue, Fusarium hyphae resemble those of Aspergillus underwent leukocytapheresis and chemotherapy. She received and identification may be difficult. The , biology, and a prophylactic antimicrobial therapy with fluconazole (200 mg clinical aspects of Fusarium spp are well described by Nelson et al.3 PO/day) and valaciclovir (500 mg PO/day), and imipenem Localized infections occur in both immunocompromised and (4 Â 500 mg IV/day) for fever suspected to have an infectious immunocompetent hosts. Disseminated fusarial infections occur origin. On day 4 after the beginning of chemotherapy, the patient mostly in patients with hematologic malignancies with myelo- was still febrile. Between days 4 and 14, the patient became suppressive chemotherapy or in patients with severe immunode- agranulocytic and presented diarrhea caused by Clostridium ficiency. These can affect almost any organ and are defined as the difficile, which was followed by a bacteremia caused by involvement of two non-contiguous sites in association with more Enterococcus faecium. than one positive blood culture.5,6 Fusarium species can be isolated On day 17, the patient was on treatment with fluconazole from cultures of blood samples in 40% of cases.4 Cases in which the (200 mg PO/day), valaciclovir (500 mg PO/day), imipenem has been recovered only from blood have been associated (4 Â 500 mg IV/day), metronidazole (3 Â 500 mg PO/day) for the with a better clinical outcome.7,8 treatment of diarrhea, and vancomycin (2 Â 750 mg IV/day) and gentamicin (3 Â 80 mg IV/day) for the treatment of bacteremia. At this time, a cutaneous erythematous lesion appeared on the first

* Corresponding author. Tel.: +41 22 37 29 839; fax: +41 22 37 29 832. toe. Direct observation of the skin biopsy and blood revealed no E-mail address: [email protected] (J. Garbino). pathogen.

1201-9712/$36.00 – see front matter ß 2009 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ijid.2009.05.004 M. Jossi et al. / International Journal of Infectious Diseases 14 (2010) e354–e356 e355

infection.2 Disseminated Fusarium infection carries a poor prog- nosis, which is related to the angiotropism of Fusarium and its capacity for adventitious sporulation in tissues,17 as well as the underlying disease, the presence of neutropenia (<500 cells/l), and late diagnosis and treatment. Recovery is furthermore very difficult if neutropenia persists.14,18 Fusarium species are relatively resistant to treatment with antifungal agents. In vitro, amphotericin B is the most effective of the antifungal agents. Fluconazole, itraconazole, and flucytosine have no activity against Fusarium species, and ketoconazole, miconazole, terbinafine, and echinocandins have limited activ- ity.19–22 F. solani, in particular, is intrinsically resistant to echinocandins.23 Amphotericin B is the agent of choice, but high doses are required and may increase side effects. The liposomal formulations are less toxic, but costly. The new triazole agents (voriconazole, posaconazole, and ravuconazole) exhibit activity Figure 1. Cutaneous lesions caused by Fusarium solani. against these fungi24 and are used for the treatment of fusariosis. On day 22, she was still febrile with a worsening general state Voriconazole has been reported as a successful treatment for and the appearance of other cutaneous lesions, which thereafter disseminated fusariosis in patients with hemato-oncologic malig- turned necrotic in the center (Figure 1). Fluconazole, gentamicin, nancies25 or refractory fungal infections.26 It has also been used imipenem, and metronidazole were stopped, and treatment was successfully for the treatment of Fusarium peritonitis concomitant completed with amikacin (1 g IV/day), meropenem (3 Â 1 g IV/ to kidney transplantation.1 day), vancomycin (4 Â 125 mg PO/day), and voriconazole Nucci and Anaissie2 reported 12 Fusarium species associated (2 Â 300 mg IV/day) for suspicion of an invasive fungal infection. with infections. The most frequent species causing infections in To enlarge the antifungal spectrum, voriconazole was finally humans are F. solani, F. oxysporum, and F. moniliforme.3,7 A reported stopped at the end of day 22 and replaced with posaconazole case of F. sacchari fungemia in an immunosuppressed patient (2 Â 400 mg PO/day) and liposomal amphotericin B (5 mg/kg/day shows that the pattern of infection, as well as the prognosis, may IV). Direct observation on blood samples performed between days vary according to the species involved.27 After renal transplanta- 22 and 26 revealed neither bacteria nor fungi. However, tion, the patient presented a prolonged Fusarium fungemia from filamentous fungi were observed in conjunctival secretions on postoperative days 11 to 24. He had no central venous catheter, day 25. At this time, an abdominal computed tomography scan also was clinically well, and had no skin lesions or other complaints revealed hypodense splenic lesions considered to be related to during infection. A small dose of amphotericin B (0.5 mg/kg daily) fungal emboli. Within the next few days, the general state of the was sufficient to render blood cultures negative. The patient was patient decreased dramatically, agranulocytosis was always discharged after administration of a cumulative dose of 500 mg.27 persistent, C-reactive protein increased up to 364 mg/l, and she Our patient described in the present report developed a died 16 days after the appearance of the first cutaneous lesion. disseminated F. solani infection after receiving fluconazole, Blood cultures were performed daily from days 22 to 32. The valaciclovir, imipenem, metronidazole, vancomycin, and genta- first positive blood culture for Fusarium spp was recovered on day micin. She received an empiric treatment with posaconazole and 27 and all following samples were also positive. Growth detection, liposomal amphotericin B. However, after a persistent fungemia, identification, and the fungigram of the pathogenic organism, the patient died while microbiological cultures were pending. The Fusarium solani, were achieved only after the patient’s death. fungigram revealed that the pathogenic agent, F. solani, was resistant to fluconazole, itraconazole, and flucytosine, presented an 3. Discussion intermediate resistance to amphotericin B and ketoconazole, and was sensitive to voriconazole and posaconazole. The widespread prophylactic use of fluconazole has led to a This case highlights the poor outcome of an invasive fungal decline in Candida infections.9,10 However, the subsequent disease caused by one of the most frequent Fusarium species. It also changes in Candida epidemiology have resulted in the emergence provides evidence of the importance of the delay necessary to of other less susceptible fungal pathogens. In addition to typify the pathogenic fungi and the need to start empiric treatment aspergillosis, infections caused by other molds have increased in at the earliest stages of the infection. Fungemia was prolonged and immunocompromised patients. Fusarium, Scedosporium, and persistent in the final stage of the disease in this patient. zygomycetes are examples of these pathogens. Fusarium infections The association of antifungal drugs plays also an important role remain rare, but tend to be disseminated, and the prognosis is poor when Fusarium infection is suspected. New drugs, particularly the as these fungi are resistant to many available antifungal agents. new triazoles, may have a role in the treatment and prophylaxis of The skin is often the initial clue to diagnosis, as cutaneous Fusarium infections, but available data remain scarce. At present, lesions are observed in approximately 85% of patients with treatments with voriconazole (IV) + amphotericin B (IV) or disseminated Fusarium infections and often occur at an early stage posaconazole (PO) + amphotericin B (IV) are the two main of the disease.5,6,11 While fusariosis in solid organ transplant alternatives. As mentioned, amphotericin B is the most active recipients is very rare with a lower incidence than zygomycosis agent against this fungus but, in this case, new azoles were more (<1–9%),12 it is more frequent in neutropenic cancer patients.13 active. In addition to antifungal treatment, strategies to improve Fusarium spp are emerging as pathogens that can cause serious the host defenses and surgical intervention to remove necrotic opportunistic infections in patients with bone marrow suppression tissue are important measures that may improve the prognosis of and neutropenia.6,14,15 They have also been reported to cause 15% these infections. of invasive fungal infections occurring in patients with hemato- logic malignancies.16 Conflict of interest The mortality rate among patients with disseminated Fusarium infection (75%) is twice as high as among patients with local No conflict of interest to declare. e356 M. Jossi et al. / International Journal of Infectious Diseases 14 (2010) e354–e356

References 14. Hennequin C, Lavarde V, Poirot JL, Rabodonirina M, Datry A, Aractingi S, et al. Invasive Fusarium infections: a retrospective survey of 31 cases. J Med Vet Mycol 1. Garbino J, Uckay I, Rhoner P, Lew D, Van Delden C. Fusarium peritonitis 1997;35:107–14. concomitant to kidney transplantation successfully managed with voricona- 15. Gamis AS, Gudnason T, Giebink GS, Ramsay NK. Disseminated infection with zole: case report and review of the literature. Transpl Int 2005;18:613–8. Fusarium in recipients of bone marrow transplants. Rev Infect Dis 1991;13: 2. Nucci M, Anaissie E. Fusarium infections in immunocompromised patients. Clin 1077–88. Microbiol Rev 2007;20:695–704. 16. Krcmery Jr V, Kunova E, Jesenska Z, Trupl J, Spanik S, Mardiak J, et al. Invasive 3. Nelson PE, Dignani MC, Anaissie EJ. Taxonomy, biology, and clinical aspects of mold infections in cancer patients: 5 years experience with Aspergillus, Mucor, Fusarium species. Clin Microbiol Rev 1994;7:479–504. Fusarium and infections. Support Care Cancer 1996;4:39–45. 4. Dignani MC, Anaissie E. Human fusariosis. Clin Microbiol Infect 2004;10:67–75. 17. Liu K, Howell DN, Perfect JR, Schnell WA. Morphologic criteria for the pre- 5. Bushelman SJ, Callen JP, Roth DN, Cohen LM. Disseminated Fusarium solani liminary identification of Fusarium, Paecilomyces, and Acremonium species by infection. J Am Acad Dermatol 1995;32:346–51. histopathology. Am J Clin Pathol 1998;109:45–54. 6. Boutati EI, Anaissie EJ, Fusarium. a significant emerging pathogen in patients 18. Krcmery Jr V, Jesenska Z, Spanik S, Gyarfas J, Nogova J, Botek R, et al. Fungaemia with hematologic malignancy: ten years experience at a cancer centre and due to Fusarium spp in cancer patients. J Hosp Infect 1997;36:223–8. implications for management. Blood 1997;90:999–1008. 19. McGinnis MR, Pasarell L, Sutton DA, Fothergill AW, Cooper Jr CR, Rinaldi MG. In 7. Guarro J, Gene J. Opportunistic fusarial infections in humans. Eur J Clin Microbiol vitro activity of voriconazole against selected fungi. Med Mycol 1998;36: Infect Dis 1995;14:741–54. 239–42. 8. Velasco E, Martins C, Nucci M. Successful treatment of catheter-related fusarial 20. Pujol I, Guarro J, Gene J, Sala J. In vitro antifungal susceptibility of clinical and infection in immunocompromised children. Eur J Clin Microbiol Infect Dis environmental Fusarium spp strains. J Antimicrob Chemother 1997;39:163–7. 1995;14:697–9. 21. Speeleveld E, Gordts B, Van Landuyt HW, De Vroey C, Raes-Wuytack C. Suscept- 9. Marr KA, Seidel K, Slavin MA, Bowden RA, Schoch HG, Boekh M. Prolonged ibility of clinical isolates of Fusarium to antifungal drugs. Mycoses 1996;39:37–40. fluconazole prophylaxis is associated with persistent protection against 22. Cornely OA. Aspergillus to zygomycetes: causes, risk factors, prevention, and candidiasis-related death in allogeneic marrow transplant recipients: treatment of invasive fungal infections. Infection 2008;36:296–313. long-term follow up of a randomized, placebo-controlled trial. Blood 23. Katyar SK, Edlind TD. Role for Fks1 in the intrinsic echinocandin resistance of 2000;96:2055–61. Fusarium solani as evidenced by hybrid expression in yeast. Antimicrob Agents 10. Winston DJ, Pakrasi A, Busuttil RW. Prophylactic fluconazole in liver transplant Chemother 2009;53:1772–8. recipients: a randomized, doubleblind, placebo-controlled trial. Ann Intern Med 24. Sutton DA. Laboratory evaluation of new antifungal agents against rare and 1999;131:729–37. refractory mycoses. Curr Opin Infect Dis 2002;15:575–82. 11. Mowbray DN, Paller AS, Nelson PE, Kaplan RL. Disseminated Fusarium solani 25. Consigny S, Dhedin N, Datry A, Choquet S, Leblond V, Chosidow O. Successful infection with cutaneous nodules in a bone marrow transplant patient. Int J voriconazole treatment of disseminated Fusarium infection in an immuno- Dermatol 1988;27:698–701. compromised patient. Clin Infect Dis 2003;37:311–3. 12. Singh N, Gayowski T, Singh J, Yu VL. Invasive gastrointestinal zygomycosis in a 26. Perfect JR, Marr KA, Walsh TJ, Greenberg RN, DuPont B, de la Torre-Cisneros J, liver transplant recipient: case report and review of zygomycosis in solid-organ et al. Voriconazole treatment for less-common, emerging, or refractory fungal transplant recipients. Clin Infect Dis 1995;20:617–20. infections. Clin Infect Dis 2003;36:1122–31. 13. Maertens J, Lagrou K, Deweerdt H, Surmont I, Verhoef GE, Verhaegen J, et al. 27. Guarro J, Nucci M, Akiti T, Gene´ J, Barreiro MD, Gonc¸alves RT. Fungemia due to Disseminated infection by Scedosporium prolificans: emerging fatality among Fusarium sacchari in an immunosuppressed patient. J Clin Microbiol hematology patients. Ann Hematol 2000;79:340–4. 2000;38:419–21.