Filamentous Fungi Other than Aspergillus and Zygomycetes in Transplant Recipients

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History

Mycology

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.

Epidemiology

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.

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).

Pathogenesis

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).

ANTIFUNGAL THERAPY

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).

Pneumonia

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).

ALTERNATIVE THERAPY

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).

ADJUNCTIVE THERAPY

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.

ENDPOINTS FOR MONITORING THERAPY

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.

VACCINES

No vaccines are available for any of these fungi.

ANTIFUNGAL PROPHYLAXIS

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.

INFECTION CONTROL MEASURES

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

Drug	Dose(s)	Duration of therapy	Comments
Voriconazole	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
Posaconazole	200mg PO QID, then 400 mg PO BID.	Variable, see text	Oral form only
Itraconazole	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

Drug

Dose(s)

Duration of therapy

Comments

Voriconazole

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

Posaconazole

200mg PO QID,

then 400 mg PO BID.