Filamentous Fungi Other than Aspergillus and Zygomycetes in Transplant Recipients

Authors: Sanjay G. Revankar, MD


The incidence of invasive fungal infections has been rising in recent years due to increased numbers of immunocompromised patients at risk. Along with this trend, unusual fungal species are being seen as well. Outside the commonly recognized filamentous fungi such as Aspergillus and zygomycetes are a large and heterogenous group of fungi. These are difficult to classify into a simple framework and represent dozens of unique organisms (43, 44, 56). For the purposes of this discussion, we will consider the dematiaceous fungi, Scedosporium species, and Fusarium species. For dematiaceous fungi, their distinguishing characteristic is the presence of melanin in their cell walls, which imparts the dark color to their conidia or spores and hyphae (66). Scedosporium species are emerging as important causes of invasive and refractory mycoses in immunocompromised patients (57, 64, 67). The two main species are Scedosporium apiospermum (i.e. Pseudallescheria boydii) and Scedosporium prolificans. Fusarium spp. are often associated with plants and traumatic inoculation and are often drug resistant (43). As the number of patients immunocompromised from diseases and medical therapy increases, additional species are being reported as causes of human disease, expanding an already long list of potential pathogens. As many of these are rarely seen clinically, referral to a mycology reference lab may be needed to accurately identify isolates to species level.

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These filamentous fungi are generally found in soil or associated with plants and distributed worldwide. Occasionally, species appear to be geographically restricted, such as Rhinocladiella (R.) (formerly Ramichloridium mackenzei) , which has primarily been seen in patients from the Middle East (78). Exposure is thought to be from inhalation or minor trauma, which may not even be noticed by the patient. Surveys of outdoor air for fungal spores routinely observe dematiaceous fungi (72). As these are widespread in the environment, individuals are constantly exposed to them, though they remain uncommon causes of disease. Most life-threatening infections due to these unusual fungi are seen in immunocompromised patients, with the possible exception of CNS infection caused by dematiaceous fungi. However, infections due to certain species, such as Scedosporium (S.) prolificans, have an extremely high mortality in immunocompromised patients despite aggressive therapy (64, 67).

Clinical Manifestations

A variety of infectious syndromes can be seen with these fungi, from superficial infections such as keratitis and subcutaneous nodules to invasive infections such as brain abscess and disseminated disease (61). In particular, phaeohyphomycosis encompasses many clinical syndromes due to a wide variety of dematiaceous fungi (61, 66). Clinical presentation may be indolent, particularly in solid organ transplant patients.

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Laboratory Diagnosis

Unlike other more common fungal infections, there are no simple diagnostic tests to identify these fungi, particularly to the species level. No specific serologic, antigen or polymerase chain reaction (PCR) methods are routinely available, which is at least partly due to the tremendous diversity of these pathogens. However, studies have begun to examine the potential of identifying species within this diverse group of fungi using PCR of highly conserved regions of ribosomal DNA(1). Antigen tests primarily used for Aspergillus and Candida, such as galactomannan and beta-D-glucan, occasionally may be cross-reactive with other filamentous fungi, but this is not consistent (10, 23). Currently, the diagnosis initially relies on pathologic examination of clinical specimens and careful gross and microscopic examination of cultures, occasionally requiring the expertise of a mycology reference lab for unusual or newly described pathogens. Scedosporium apiospermum is indistinguishable from aspergillosis on histologic morphology. In contrast, the histologic appearance of phaeohyphomycosis is often characterized by irregular hyphal elements and beaded, yeast-like forms (66).  However, it may still be difficult to differentiate this pathologically from infection due to other moulds. In such cases, the Fontana-Masson stain, which is specific for melanin, can usually be used to confirm the presence of dematiaceous hyphae (66).


Relatively little is known regarding the pathogenic mechanisms by which many of these fungi cause disease. Invasive disease is uncommon in immunocompetent individuals; most are considered opportunists. In dematiaceous fungi, one of the likely candidate virulence factors is the presence of melanin in the cell wall, which is common to all these fungi. Disruption of specific genes involved in melanin production leads to markedly reduced virulence in animal models (8,15). There are several mechanisms proposed by which melanin may act as a virulence factor including scavenging free radicals and hypochlorite that are produced by phagocytic cells in their oxidative burst that would normally kill most organisms (32).

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Drugs of Choice

There is no single antifungal agent that is effective against all these fungal species in all clinical situations. The choice of drug is made more difficult by the fact that these are rare infections, with no randomized clinical trials to guide therapeutic decisions. However, triazole agents demonstrate the broadest in vitro activity, including voriconazole, posaconazole and itraconazole. However, S. prolificans and Scopulariopsis brumptii are generally resistant to all available antifungals (9,47).

Though there is greater clinical experience associated with itraconazole, particularly against dematiaceous fungi, voriconazole and posaconazole are generally more active in vitro, particularly against Fusarium and Scedosporium. In addition, itraconazole has serious drug interactions and adverse effects which have led to a black box label by the FDA. Voriconazole and posaconazole are generally well-tolerated, though drug interactions are common. Voriconazole may have advantages for central nervous system infections due to its ability to achieve good cerebrospinal fluid levels, unlike itraconazole (41). All likely achieve adequate brain tissue levels (21).  Table 1 shows the drugs and suggested doses.

Voriconazole is available in both oral and IV forms (33). Similar to itraconazole, it has a broad spectrum of activity that includes most dematiaceous fungi; however, it is the only agent FDA approved as salvage therapy for Scedosporium and Fusarium infections as well (12-14, 46). Recent studies have demonstrated clinical activity against a wide variety of filamentous fungi (5, 17, 18, 57, 81).

Posaconazole is the most recent azole with a similar structure to itraconazole, though with more activity, particularly against Aspergillus and other moulds, including Scedosporium and Fusarium (13, 52). It is only available in oral form at present. The published in vitro data is limited for dematiaceous fungi, but good activity is demonstrated against most species tested (62). Clinical experience is limited compared to other agents (3, 22, 26, 51, 60).

Itraconazole is available in oral and intravenous (IV) formulations. Of the oral preparations, the capsules require an acidic environment for absorption, while the suspension with cyclodextrin does not, being more consistently absorbed. Itraconazole has in vitro activity against the vast majority of dematiaceous fungi (12, 13, 45, 46) and extensive clinical experience (40, 41, 64, 65, 71). Antifungal therapy in patients with organ transplantation should generally be continued longer than in other patients, and the use of surgery (when appropriate) should be strongly considered. Management of drug interactions is critically important when using triazole antifungals, as all the above have significant effects on many drugs used in transplant patients, notably calcineurin inhibitors (33, 52). Monitoring of drug levels of both immunosuppressives and triazoles should be routinely performed when possible.

Special Infections

In general, there are no standardized therapies for infections caused by these uncommon fungi. Voriconazole and posaconazole are likely better tolerated than itraconazole with a broader spectrum of activity and would be preferred drugs. One advantage of voriconazole over posaconazole is the availability of an IV formulation for seriously ill patients unable to tolerate oral therapy. Length of therapy is generally based on clinical response, and ranges from several weeks to several months or longer, including possible lifelong suppressive therapy in immunocompromised patients with infections such as brain abscess or endocarditis due to refractory pathogens. The diversity of the pathogens and of the hosts makes it unlikely that a ‘one size fits all’ therapeutic strategy will be effective.

Superficial and Deep Local Infections

Superficial infections are the most common form of infection due to these fungi. Cases are generally associated with minor trauma or other environmental exposure. Although they rarely lead to life-threatening disease, significant morbidity can occur depending on the site of infection and response to therapy.

There are numerous case reports of subcutaneous infection due to a wide variety of species (54, 58, 77). Minor trauma is the usual inciting factor, though it may be unrecognized by the patient. Lesions typically occur on exposed areas of the body and often appear as isolated cystic or papular lesions. Surgical excision alone has been successful in a number of cases (76). Oral systemic therapy with an azole in conjunction with surgery is also frequently employed and has been used successfully, especially in immunocompromised patients (70, 77, 83).

Keratitis is an uncommon, but serious infection due to these fungi. Dematiaceous fungi account for up to 8-17% of cases, particularly in tropical regions (19, 73), though Fusarium is common as well (20). Topical polyenes, such as natamycin and amphotericin B, are commonly employed, but oral and topical itraconazole has been found to be useful as well, particularly in refractory cases (20, 79). Recent clinical experience suggests voriconazole and posaconazole are potentially useful agents as well (24, 82). Penetrating keratoplasty should be considered in those patients failing initial therapy. However, many patients are left with residual visual deficits at the end of therapy (19, 73).

Deep local infection such as septic arthritis and osteomyelitis are rare and often difficult to treat, frequently requiring both surgical and combination medical therapy (37, 39).


This usually occurs in immunocompromised patients, and may be due to a wide variety of species (6, 7, 31). It is unclear what specific risk factors may contribute to pulmonary infection with these fungi (such as dematiaceous fungi), which are commonly found in the environment, though a study by Campos et al found an association between pre-transplant colonization and subsequent pneumonia in lung transplant patients (7).  Mortality rates are high in immunocompromised patients. Experience with voriconazole is relatively limited, but given its activity in pulmonary aspergillosis and its broad spectrum would favor it in this setting as well (30). Posaconazole has also been reported as successful in case reports of Fusarium pneumonia (26).

Central Nervous System Infection

Though this is a rare clinical manifestation of infection with these uncommon fungi, it remains one of the most difficult to cure and mortality rates are high. In contrast to other clinical syndromes, this can often occur in immunocompetent individuals typically involving dematiaceous fungi (65). The pathogenesis may be hematogenous spread from an initial, presumably subclinical pulmonary focus.

In a retrospective analysis of 101 reported cases due to dematiaceous fungi, over half occurred in immunocompetent patients, with C. bantiana the most common species isolated (65). Brain abscess was the primary clinical manifestation in 87 cases. Overall results of therapy suggested that the combination of amphotericin B, flucytosine and itraconazole may be associated with improved survival, though it was not frequently used. Therapy varied widely depending on the case report. Complete excision of brain abscesses appeared to have better outcomes than aspiration or partial excision. Outcomes were poor, with an overall mortality >70%.

Voriconazole was not used in the above case series but has been used in four subsequent reports of C. bantiana brain abscess (16, 38, 42, 80). Only one of the cases, in an immunocompetent patient, was successfully treated (42). However, clinical improvement was seen in one of the severely immunosuppressed patients while receiving voriconazole, despite later succumbing to the infection (80). Posaconazole has also been used successfully, including cases of Rhinocladiella and Scedosporium brain abscess (3, 51).

Disseminated Infection

This is the most uncommon manifestation of infection seen with filamentous fungi. In a recent review of dematiaceous fungi, most patients were immunocompromised, though occasional patients without known immunodeficiency or risk factors developed disseminated disease as well (64).  In contrast to most invasive mould infections, blood cultures were positive in over half the cases, usually seen with S. prolificans (64, 67). Infection with this species was also associated with septic shock. The mortality rate was >70%, despite aggressive antifungal therapy. There were no antifungal regimens associated with improved survival in disseminated infection, including multiple combination therapies (64, 67). Infection with S. prolificans was associated with nearly 100% mortality in the absence of recovery from neutropenia. A case of disseminated E. spinifera infection was treated successfully with posaconazole after failing itraconazole and amphotericin B (55). Fusarium and Scedosporium may also cause disseminated infection, though primarily in hematopoetic stem cell transplant patients (22, 67). Anecdotal cases in solid organ transplant recipients have been treated with voriconazole (68), posaconazole (22) and liposomal amphotericin B (40), though one study found improved outcomes with voriconazole compared to amphotericin B (30).

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 There are few useful alternatives to triazole antifungal agents against these uncommon fungal infections. Amphotericin B may be useful for severe disease given its broad fungicidal activity against most pathogens, though isolates of Fusarium and Scedosporium are frequently resistant (13, 46, 47). However, use of lipid AmB preparations allows for much higher doses than possible with standard AmB, which may improve their efficacy against these fungi. The pharmacodynamics of these formulations are different from standard AmB and may also affect their overall efficacy for specific infections (11). However, given the need for parenteral administration, use of these agents is mostly confined to serious infections in unstable patients. Once the infection is under control, longer term therapy with a broad spectrum oral azole is often reasonable until complete response is achieved.

Terbinafine also inhibits ergosterol synthesis, but acts on a different target than azoles. It is also considered fungistatic, and its clinical role has been relegated to treatment of dermatophyte infections. However, in vitro activity is quite broad and includes many non-dermatophyte moulds (25, 45). There has been recent interest in potentially expanding its clinical spectrum (25, 63). However, its extensive binding to serum proteins and distribution into skin and adipose tissue have diminished enthusiasm for its use in treating serious systemic fungal infections (28, 69). In vitro studies against dematiaceous fungi are emerging and fairly broad spectrum activity is seen, though it was found to be inactive in murine models despite good in vitro activity (45). However, terbinafine was used to successfully treat a case of E. jeanselmei subcutaneous infection in a heart transplant patient after failing itraconazole (2).

Miltefosine, originally developed as an anti-neoplastic agent and used in protozoal infections, also has significant antifungal activity against a broad range of pathogens (83). Clinical experience is anecdotal, though a case of refractory infection due to Scedosporium prolificans appeared to respond to the addition of miltefosine (34).

Combination therapy is a potentially useful strategy for refractory infections from dematiaceous fungi, though it has not been studied extensively and is not routinely recommended (53). Terbinafine in particular appears to provide synergistic activity with azole antifungals, and this may be a useful strategy against refractory subcutaneous infections (35).The mechanism is presumably potent inhibition of ergosterol synthesis at two different steps of the pathway by these agents. In addition, recent case reports have suggested that the combination of itraconazole or voriconazole with terbinafine may be synergistic against S. prolificans and improve outcomes (29, 48). However, this should be interpreted with caution, as terbinafine is not generally used for systemic infections.

Echinocandins do not have significant activity against filamentous fungi other than Aspergillus and would not be recommended as single agents. However, a case of refractory bone and joint infection due to S. prolificans were treated effectively with the combination of voriconazole and caspofungin (74).

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There are no controlled trials to determine when surgery is most effective for these infections. However, for several of the above clinical presentations, surgery may be curative or significantly improve outcomes. For subcutaneous abscess in particular, surgery alone has been effective, though in immunocompromised patients follow-up antifungal therapy is often given (83). Outcomes for brain abscess may be improved with the use of surgical drainage and/or excision, if possible (65). Frequently, single lesions are present, which may make surgical resection more feasible.


There are no reliable laboratory tests for monitoring infections due to these fungi. While specific tests are not available, B-glucan and occasionally galactomannan antigen are positive, particularly in disseminated infection (10, 23). It may be reasonable to follow such tests as additional measures of clinical response, though no prospective studies have been done. As a result, one must rely primarily on clinical response, and if relevant, radiologic improvement. Given that many of these infections require prolonged therapy, treatment should probably be continued until objective criteria have improved and/or remained stable for several weeks to months. Firm recommendations for timelines are not possible due to the varied nature of infections and hosts seen.


No vaccines are available for any of these fungi.

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There are no studies that specifically examine outcomes of prophylaxis for these fungi. However, the newer azoles with activity against Aspergillus would be expected to be effective in prophylaxis for these fungi as well. As these are uncommon infections, even large trials are unlikely to show a significant trend in these infections.


Prevention is difficult as well, as these are often acquired from minor trauma that may go unnoticed by the patient, or presumably from inhalation. Dematiaceous fungi are routinely found in ambient air, and prevention from this source is not practical, except perhaps in immunocompromised patient units with HEPA filtration precautions for other, more common fungi such as Aspergillus (36, 59). In one hospital study, Fusariumwas isolated from over half of water system samples, with patient isolates matching some environmental isolates by molecular typing (4). No person-to-person transmission has been demonstrated.

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1. Abliz P, Fukushima K, Takizawa K, Nishimura K. Identification of pathogenic dematiaceous fungi and related taxa based on large subunit ribosomal DNA D1/D2 domain sequence analysis. FEMS Immunol Med Microbiol 2004;40:41-49. [PubMed]

2. Agger WA, Andes D, Burgess JW. Exophiala jeanselmei infection in a heart transplant recipient successfully treated with oral terbinafine. Clin Infect Dis 2004;38:e112-e115. [PubMed]

3. Al Abdely HM, Alkhunaizi AM, Al Tawfiq JA, Hassounah M, Rinaldi MG, Sutton DA. Successful therapy of cerebral phaeohyphomycosis due to Ramichloridium mackenziei with the new triazole posaconazole. Med Mycol 2005;43:91-95. [PubMed]

4. Anaissie EJ, Kuchar RT, Rex JH, Francesconi A, Kasai M, Müller FM, Lozano Chiu M, Summerbell RC, Dignani MC, Chanock SJ, Walsh TJ. Fusariosis associated with pathogenic Fusarium species colonization of a hospital water system: a new paradigm for the epidemiology of opportunistic mold infections. Clin Infect Dis. 2001;33:1871-8. [PubMed]

5. Baden LR, Katz JT, Fishman JA, Koziol C, DelVecchio A, Doran M, Rubin RH. Salvage therapy with voriconazole for invasive fungal infections in patients failing or intolerant to standard antifungal therapy. Transplantation. 2003;76:1632-7. [PubMed]

6. Burns KE, Ohori NP, Iacono AT. Dactylaria gallopava infection presenting as a pulmonary nodule in a single-lung transplant recipient. J Heart Lung Transplant 2000;19:900-902. [PubMed]

7.  Campos S, Caramori M, Teixeira R, Afonso J Jr, Carraro R, Strabelli T, Samano M, Pêgo-Fernandes P, Jatene F. Bacterial and fungal pneumonias after lung transplantation. Transplant Proc. 2008;40:822-4.  [PubMed]

8. Casadevall A, Rosas AL, Nosanchuk JD. Melanin and virulence in Cryptococcus neoformans. Curr Opin Microbiol 2000;3:354-358. [PubMed] 

9. Cuenca-Estrella M, Gomez-Lopez A, Mellado E, Buitrago MJ, Monzon A, Rodriguez-Tudela JL. Head-to-head comparison of the activities of currently available antifungal agents against 3,378 Spanish clinical isolates of yeasts and filamentous fungi. Antimicrob Agents Chemother. 2006;50:917-21. [PubMed] 

10. Cuétara MS, Alhambra A, Moragues MD, González-Elorza E, Pontón J, del Palacio A. Detection of (1-->3)-beta-D-glucan as an adjunct to diagnosis in a mixed population with uncommon proven invasive fungal diseases or with an unusual clinical presentation. Clin Vaccine Immunol. 2009;16:423-6. [PubMed] 

11.  Dodds ES, Drew RH, Perfect JR. Antifungal pharmacodynamics: review of the literature and clinical applications. Pharmacotherapy 2000;20:1335-1355. [PubMed] 

12. Espinel-Ingroff A. In vitro fungicidal activities of voriconazole, itraconazole, and amphotericin B against opportunistic moniliaceous and dematiaceous fungi. J Clin Microbiol 2001;39:954-958. [PubMed] 

13. Espinel-Ingroff A. In vitro antifungal activities of anidulafungin and micafungin, licensed agents and the investigational triazole posaconazole as determined by NCCLS methods for 12,052 fungal isolates: review of the literature. Rev Iberoam Micol 2003;20:121-136. [PubMed] 

14. Espinel-Ingroff A, Boyle K, Sheehan DJ. In vitro antifungal activities of voriconazole and reference agents as determined by NCCLS methods: review of the literature. Mycopathologia 2001;150:101-115. [PubMed] 

15. Feng B, Wang X, Hauser M, Kaufmann S, Jentsch S, Haase G, Becker JM, Szaniszlo PJ. Molecular cloning and characterization of WdPKS1, a gene involved in dihydroxynaphthalene melanin biosynthesis and virulence in Wangiella (Exophiala) dermatitidis. Infect Immun 2001;69:1781-1794. [PubMed] 

16. Fica A, Diaz MC, Luppi M, Olivares R, Saez L, Baboor M, Vasquez P. Unsuccessful treatment with voriconazole of a brain abscess due to Cladophialophora bantiana. Scand J Infect Dis 2003;35:892-893. [PubMed] 

17. Fortún J, Martín-Dávila P, Sánchez MA, Pintado V, Alvarez ME, Sánchez-Sousa A, Moreno S. Voriconazole in the treatment of invasive mold infections in transplant recipients. Eur J Clin Microbiol Infect Dis. 2003;22:408-13. [PubMed] 

18. Garbino J, Uckay I, Rohner P, Lew D, Van Delden C. Fusarium peritonitis concomitant to kidney transplantation successfully managed with voriconazole: case report and review of the literature. Transpl Int. 2005;18:613-8. [PubMed] 

19.  Garg P, Gopinathan U, Choudhary K, Rao GN. Keratomycosis: clinical and microbiologic experience with dematiaceous fungi. Ophthalmology 2000; 107:574-580. [PubMed] 

20. Gopinathan U, Garg P, Fernandes M, Sharma S, Athmanathan S, Rao GN. The epidemiological features and laboratory results of fungal keratitis: a 10-year review at a referral eye care center in South India. Cornea 2002;21:555-559. [PubMed] 

21. Groll AH, Piscitelli SC, Walsh TJ. Clinical pharmacology of systemic antifungal agents: a comprehensive review of agents in clinical use, current investigational compounds, and putative targets for antifungal drug development. Adv Pharmacol 1998; 44:343-499. [PubMed]    

22. Gupta S, Almyroudis NG, Battiwalla M, Bambach BJ, McCarthy PL, Proefrock AD, Ball D, Paplham P, Varma A, Kwon-Chung J, Segal BH. Successful treatment of disseminated fusariosis with posaconazole during neutropenia and subsequent allogeneic hematopoietic stem cell transplantation. Transpl Infect Dis. 2007;9:156-60. [PubMed] 

23. Hachem RY, Kontoyiannis DP, Chemaly RF, Jiang Y, Reitzel R, Raad I. Utility of galactomannan enzyme immunoassay and (1,3) beta-D-glucan in diagnosis of invasive fungal infections: low sensitivity for Aspergillus fumigatus infection in hematologic malignancy patients. J Clin Microbiol. 2009;47:129-33. [PubMed] 

24. Hariprasad SM, Mieler WF, Lin TK, Sponsel WE, Graybill JR. Voriconazole in the treatment of fungal eye infections: a review of current literature. Br J Ophthalmol. 2008;92:871-8. [PubMed] 

25. Hay RJ. Therapeutic potential of terbinafine in subcutaneous and systemic mycoses. Br J Dermatol 1999;141(Supplement 56):36-40. [PubMed] 

26. Herbrecht R, Kessler R, Kravanja C, Meyer MH, Waller J, Letscher-Bru V. Successful treatment of Fusarium proliferatum pneumonia with posaconazole in a lung transplant recipient. J Heart Lung Transplant. 2004;23:1451-4. [PubMed] 

27. Hernandez PC, Llinares TF, Burgos SJ, Selva OJ, Ordovas Baines JP. Voriconazole in fungal keratitis caused by Scedosporium apiospermum. Ann Pharmacother 2004;38:414-417. [PubMed] 

28. Hosseini-Yeganeh M, McLachlan AJ. Physiologically based pharmacokinetic model for terbinafine in rats and humans. Antimicrob Agents Chemother 2002;46:2219-2228. [PubMed] 

29. Howden BP, Slavin MA, Schwarer AP, Mijch AM. Successful control of disseminated Scedosporium prolificans infection with a combination of voriconazole and terbinafine. Eur J Clin Microbiol Infect Dis 2003;22:111-113. [PubMed] 

30. Husain S, Muñoz P, Forrest G, Alexander BD, Somani J, Brennan K, Wagener MM, Singh N. Infections due to Scedosporium apiospermum and Scedosporium prolificans in transplant recipients: clinical characteristics and impact of antifungal agent therapy on outcome. Clin Infect Dis. 2005;40:89-99. [PubMed] 

31. Issakainen J, Salonen JH, Anttila VJ, Koukila-Kahkola P, Castren M, Liimatainen O, Vuento R, Ojanen T, Koivula I, Koskela M, Meurman O. Deep, respiratory tract and ear infections caused by Pseudallescheria (Scedosporium) and Microascus (Scopulariopsis) in Finland. A 10-year retrospective multi-center study. Med Mycol. 2009;11:1-9. [PubMed] 

32. Jacobson ES. Pathogenic roles for fungal melanins. Clin Microbiol Rev 2000;13:708-717. [PubMed] 

33. Johnson LB, Kauffman CA. Voriconazole: a new triazole antifungal agent. Clin Infect Dis 2003; 36:630-637. [PubMed] 

34. Kesson AM, Bellemore MC, O'Mara TJ, Ellis DH, Sorrell TC. Scedosporium prolificans osteomyelitis in an immunocompetent child treated with a novel agent, hexadecylphospocholine (miltefosine), in combination with terbinafine and voriconazole: a case report. Clin Infect Dis. 2009;48:1257-61.   [PubMed] 

35. Krishnan-Natesan S, Chandrasekar PH, Manavathu EK, Revankar SG. Successful treatment of primary cutaneous Aspergillus ustus infection with surgical debridement and a combination of voriconazole and terbinafine. Diagn Microbiol Infect Dis. 2008;62:443-6. [PubMed] 

36. Kruger WH, Zollner B, Kaulfers PM, Zander AR. Effective protection of allogeneic stem cell recipients against Aspergillosis by HEPA air filtration during a period of construction--a prospective survey. J Hematother Stem Cell Res 2003; 12:301-307. [PubMed] 

37.  Kumashi PR, Safdar A, Chamilos G, Chemaly RF, Raad II, Kontoyiannis DP. Fungal osteoarticular infections in patients treated at a comprehensive cancer centre: a 10-year retrospective review. Clin Microbiol Infect. 2006;12:621-6.[PubMed]  

38. Levin TP, Baty DE, Fekete T, Truant AL, Suh B. Cladophialophora bantiana brain abscess in a solid-organ transplant recipient: case report and review of the literature. J Clin Microbiol 2004;42:4374-4378. [PubMed] 

39. Li JY, Yong TY, Grove DI, Coates PT. Successful control of Scedosporium prolificans septic arthritis and probable osteomyelitis without radical surgery in a long-term renal transplant recipient. Transpl Infect Dis. 2008;10:63-5. [PubMed] 

40. Lodato F, Tamé MR, Montagnani M, Sambri V, Liguori G, Azzaroli F, Costigliola P, Grazi G, Roda E, Mazzella G. Systemic fungemia and hepatic localizations of Fusarium solani in a liver transplanted patient: an emerging fungal agent. Liver Transpl. 2006;12:1711-4. [PubMed] 

41. Lutsar I, Roffey S, Troke P. Voriconazole concentrations in the cerebrospinal fluid and brain tissue of guinea pigs and immunocompromised patients. Clin Infect Dis 2003;37:728-732. [PubMed] 

42.  Lyons MK, Blair JE, Leslie KO. Successful treatment with voriconazole of fungal cerebral abscess due to Cladophialophora bantiana. Clin Neurol Neurosurg 2005;107:532-534. [PubMed] 

43. Malani AN, Kauffman CA. Changing epidemiology of rare mould infections: implications for therapy. Drugs. 2007;67:1803-12. [PubMed] 

44. Matsumoto T, Ajello L, Matsuda T, Szaniszlo PJ, Walsh TJ. Developments in hyalohyphomycosis and phaeohyphomycosis. J Med Vet Mycol 1994; 32 Suppl 1:329-349. [PubMed] 

45. McGinnis MR, Pasarell L. In vitro evaluation of terbinafine and itraconazole against dematiaceous fungi. Med Mycol 1998;36:243-246. [PubMed] 

46. McGinnis MR, Pasarell L. In vitro testing of susceptibilities of filamentous ascomycetes to voriconazole, itraconazole, and amphotericin B, with consideration of phylogenetic implications. J Clin Microbiol 1998;36:2353-2355. [PubMed] 

47. Meletiadis J, Meis JF, Mouton JW, Rodriquez-Tudela JL, Donnelly JP, Verweij PE. In vitro activities of new and conventional antifungal agents against clinical Scedosporium isolates. Antimicrob Agents Chemother 2002;46:62-68. [PubMed] 

48. Meletiadis J, Mouton JW, Meis JF, Verweij PE. Combination chemotherapy for the treatment of invasive infections by Scedosporium prolificans. Clin Microbiol Infect 2000;6:336-337. [PubMed] 

49. Meletiadis J, Mouton JW, Meis JF, Verweij PE. In vitro drug interaction modeling of combinations of azoles with terbinafine against clinical Scedosporium prolificans isolates. Antimicrob Agents Chemother 2003;47:106-117. [PubMed] 

50. Meletiadis J, Mouton JW, Rodriguez-Tudela JL, Meis JFGM, Verweij PE. In vitro interaction of terbinafine with itraconazole against clinical isolates of Scedosporium prolificans. Antimicrob Agents Chemother 2000;44470-472. [PubMed] 

51. Mellinghoff IK, Winston DJ, Mukwaya G, Schiller GJ. Treatment of Scedosporium apiospermum brain abscesses with posaconazole. Clin Infect Dis. 2002;15;34:1648-50. [PubMed]   

52. Morris MI. Posaconazole: a new oral antifungal agent with an expanded spectrum of activity. Am J Health Syst Pharm. 2009;66:225-36. [PubMed] 

53. Muñoz P, Singh N, Bouza E. Treatment of solid organ transplant patients with invasive fungal infections: should a combination of antifungal drugs be used? Curr Opin Infect Dis. 2006;19:365-70. [PubMed] 

54. Murayama N, Takimoto R, Kawai M, Hiruma M, Takamori K, Nishimura K. A case of subcutaneous phaeohyphomycotic cyst due to Exophiala jeanselmei complicated with systemic lupus erythematosus. Mycoses 2003;46:145-148. [PubMed] 

55. Negroni R, Helou SH, Petri N, Robles AM, Arechavala A, Bianchi MH. Case study: posaconazole treatment of disseminated phaeohyphomycosis due to Exophiala spinifera. Clin Infect Dis 2004;38:e15-e20. [PubMed] 

56. Nucci M. Emerging moulds: Fusarium, Scedosporium and Zygomycetes in transplant recipients. Curr Opin Infect Dis. 2003;16:607-12. [PubMed] 

57. O'Bryan TA. Pseudallescheriasis in the 21st century. Expert Rev Anti Infect Ther. 2005;3:765-73. [PubMed] 

58. Ogawa MM, Galante NZ, Godoy P, Fischman-Gompertz O, Martelli F, Colombo AL, Tomimori J, Medina-Pestana JO. Treatment of subcutaneous phaeohyphomycosis and prospective follow-up of 17 kidney transplant recipients. J Am Acad Dermatol. 2009;61:977-85. [PubMed] 

59. Patterson JE, Peters J, Calhoon JH, Levine S, Anzueto A, Al Abdely H, Sanchez R, Patterson TF, Rech M, Jorgensen JH, Rinaldi MG, Sako E, Johnson S, Speeg V, Halff GA, Trinkle JK. Investigation and control of aspergillosis and other filamentous fungal infections in solid organ transplant recipients. Transpl Infect Dis 2000; 2:22-28. [PubMed] 

60. Raad II, Hachem RY, Herbrecht R, Graybill JR, Hare R, Corcoran G, Kontoyiannis DP. Posaconazole as salvage treatment for invasive fusariosis in patients with underlying hematologic malignancy and other conditions. Clin Infect Dis. 2006;42:1398-403. [PubMed] 

61. Revankar SG. Dematiaceous fungi. Mycoses. 2007;50:91-101. [PubMed] 

62. Revankar SG. Therapy of infections caused by dematiaceous fungi. Expert Rev Anti Infect Ther. 2005;3:601-12. [PubMed] 

63. Revankar SG, Nailor MD, Sobel JD. Use of terbinafine in rare and refractory mycoses. Future Microbiol. 2008;3:9-17. [PubMed] 

64. Revankar SG, Patterson JE, Sutton DA, Pullen R, Rinaldi MG. Disseminated phaeohyphomycosis: review of an emerging mycosis. Clin Infect Dis 2002;34:467-476. [PubMed] 

65. Revankar SG, Sutton DA, Rinaldi MG. Primary central nervous system phaeohyphomycosis: a review of 101 cases. Clin Infect Dis 2004;38:206-216. [PubMed] 

66. Rinaldi MG. Phaeohyphomycosis. Dermatol Clin 1996;14:147-153. [PubMed] 

67. Rodriguez-Tudela JL, Berenguer J, Guarro J, Kantarcioglu AS, Horre R, de Hoog GS, Cuenca-Estrella M. Epidemiology and outcome of Scedosporium prolificans infection, a review of 162 cases. Med Mycol. 2009;47:359-70.[PubMed]  

68. Rogasi PG, Zanazzi M, Nocentini J, Fantoni E, Trotta M, Faggi E, Fontanelli A, Bertoni E, Salvadori M, Leoncini F. Disseminated Scedosporium apiospermum infection in renal transplant recipient: long-term successful treatment with voriconazole: a case report. Transplant Proc. 2007;39:2033-5. [PubMed] 

69. Ryder NS, Frank I. Interaction of terbinafine with human serum and serum proteins. J Med Vet Mycol 1992; 30:451-460. [PubMed] 

70. Segner S, Jouret F, Durant JF, Marot L, Kanaan N. Cutaneous infection by Alternaria infectoria in a renal transplant patient. Transpl Infect Dis. 2009;11:330-2. [PubMed] 

71. Sharkey PK, Graybill JR, Rinaldi MG, Stevens DA, Tucker RM, Peterie JD, Hoeprich PD, Greer DL, Frenkel L, Counts GW. Itraconazole treatment of phaeohyphomycosis. J Am Acad Dermatol 1990; 23(3:Pt 2):t-86. [PubMed] 

72. Shelton BG, Kirkland KH, Flanders WD, Morris GK. Profiles of airborne fungi in buildings and outdoor environments in the United States. Appl Environ Microbiol 2002; 68:1743-1753. [PubMed] 

73. Srinivasan M. Fungal keratitis. Curr Opin Ophthalmol 2004;15:321-327. [PubMed] 

74. Steinbach WJ, Schell WA, Miller JL, Perfect JR. Scedosporium prolificans osteomyelitis in an immunocompetent child treated with voriconazole and caspofungin, as well as locally applied polyhexamethylene biguanide. J Clin Microbiol 2003; 41:3981-3985. [PubMed]   

75. Studahl M, Backteman T, Stalhammar F, Chryssanthou E, Petrini B. Bone and joint infection after traumatic implantation of Scedosporium prolificans treated with voriconazole and surgery. Acta Paediatr 2003; 92:980-982.  [PubMed] 

76. Summerbell RC, Krajden S, Levine R, Fuksa M. Subcutaneous phaeohyphomycosis caused by Lasiodiplodia theobromae and successfully treated surgically. Med Mycol 2004; 42:543-547.  [PubMed] 

77. Sutton DA, Rinaldi MG, Kielhofner M. First U.S. report of subcutaneous phaeohyphomycosis caused by Veronaea botryosa in a heart transplant recipient and review of the literature. J Clin Microbiol 2004; 42:2843-2846.  [PubMed] 

78. Sutton DA, Slifkin M, Yakulis R, Rinaldi MG. U.S. case report of cerebral phaeohyphomycosis caused by Ramichloridium obovoideum (R. mackenziei): criteria for identification, therapy, and review of other known dematiaceous neurotropic taxa. J Clin Microbiol 1998; 36:708-715.  [PubMed] 

79. Thomas PA. Fungal infections of the cornea. Eye 2003;17:852-862.  [PubMed] 

80. Trinh JV, Steinbach WJ, Schell WA, Kurtzberg J, Giles SS, Perfect JR. Cerebral phaeohyphomycosis in an immunodeficient child treated medically with combination antifungal therapy. Med Mycol 2003;41:339-345.  [PubMed] 

81. Troke P, Aguirrebengoa K, Arteaga C, Ellis D, Heath CH, Lutsar I, Rovira M, Nguyen Q, Slavin M, Chen SC; Global Scedosporium Study Group. Treatment of scedosporiosis with voriconazole: clinical experience with 107 patients. Antimicrob Agents Chemother. 2008;52:1743-50.  [PubMed] 

82. Tu EY, McCartney DL, Beatty RF, Springer KL, Levy J, Edward D. Successful treatment of resistant ocular fusariosis with posaconazole (SCH-56592). Am J Ophthalmol. 2007;143:222-227.  [PubMed] 

83. Widmer F, Wright LC, Obando D, Handke R, Ganendren R, Ellis DH, Sorrell TC. Hexadecylphosphocholine (miltefosine) has broad-spectrum fungicidal activity and is efficacious in a mouse model of cryptococcosis. Antimicrob Agents Chemother. 2006;50:414-21.  [PubMed] 

84. Yehia M, Thomas M, Pilmore H, Van Der MW, Dittmer I. Subcutaneous black fungus (phaeohyphomycosis) infection in renal transplant recipients: three cases. Transplantation 2004;77:140-142.  [PubMed] 

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Table 1.   Drugs of Choice for Filamentous Fungi Other than Aspergillus and Zygomycetes 

 Drug Dose(s) Duration of therapy Comments

6mg/kg IV q12 hrs X 2 doses, then 4mg/kg IV q12 hrs.

May switch to oral therapy at 200mg BID when clinically stable.

Variable, see text First choice for most infectious syndromes

200mg PO QID,

then 400 mg PO BID.

Variable, see text Oral form only

200mg IV BID for 4 doses, then 200mg IV QD.

May switch to oral therapy at 200mg BID when clinically stable.

Variable, see text Poor activity against Fusarium spp. and Scedosporium spp.; adverse effects

Review Articles

Revankar SG. Dematiaceous fungi: Chromoblastomycosis, Mycetoma, Phaeohyphomycosis.

Kiwan EN, Anaissie EJ. Hyalohyphomycosis.

Nucci M, Anaissie E. Fusarium.

Baron EJ. Mold

Javey G, Zuravleff G.  Keratitis. 2007.

Adhikari P, Mietzner T.  Cell Mediated Immunity. 2008.



Clinical Manifestations