Dematiaceous fungi: Chromoblastomycosis, Mycetoma, Phaeohyphomycosis

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MICROBIOLOGY

Over 100 species and 60 genera of dematiaceous, or pigmented fungi have been implicated in human disease (78). The vast majority are filamentous fungi or moulds, though a few yeast species are also important pathogens. Though they represent a very heterogeneous group of fungi, the distinguishing characteristic common to all these various species is the presence of melanin in their cell walls, which imparts the dark color to their conidia or spores and hyphae (109). The colonies are typically brown to black in color as well. 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

Dematiaceous fungi are generally found in soil or associated with plants and distributed worldwide. Those causing the specific conditions of mycetoma and chromoblastomycosis are primarily found in tropical regions. Occasionally, species appear to be geographically restricted, such as Ramichloridium mackenzei, which has only been seen in patients from the Middle East (123). 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 (117). As these are widespread in the environment, individuals are constantly exposed to them, though they remain uncommon causes of disease.

CLINICAL MANIFESTATIONS

A variety of infectious syndromes are attributed to dematiaceous fungi (Table 1). Two unique conditions, mycetoma and chromoblastomycosis, are caused by a small number of species and are usually seen in tropical regions (79). Mycetoma may be caused by a variety of other pathogens as well, including Nocardia and non-dematiaceous fungi, though they will not be discussed here. It is commonly associated with chronic swelling and draining sinus tracts, usually of the lower extremities. It can be debilitating and difficult to treat. Chromoblastomycosis often presents with verrucous lesions that may occur anywhere on the body, but usually on the lower extremities. This is a chronic, slowly progressive subcutaneous mycosis. Minor trauma typically precedes the lesions. Initially, nodular lesions are present, which may progress over years to form large, verrucous plaques. In contrast, phaeohyphomycosis is a catch-all term that encompasses many clinical syndromes due to a wide variety of fungi (109). Conditions include superficial infections such as keratitisand subcutaneous nodules, allergic diseases, and invasive infections such as brain abscess and disseminated disease. In general, these diseases have been reported worldwide.

LABORATORY DIAGNOSIS

Unlike other more common fungal infections, there are no simple diagnostic tests to identify these fungi, particularly to the species level. No routine serologic, antigen or polymerase chain reaction (PCR) methods are 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). Currently, the diagnosis of infection due to dematiaceous fungi 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. In the case of mycetoma and chromoblastomycosis, pathognomonic histologic findings are very useful (79). The presence of black mycotic granules or grains can establish the diagnosis of mycetoma due to dematiaceous fungi. Histologically, they appear to be composed of fungal cells surrounded by a dense extracellular matrix composed primarily of a melanin compound, which gives it a dark color. Chromoblastomycosis is characterized by the production of characteristic dark sclerotic bodies in tissue, which are thick walled with septae. Phaeohyphomycosis does not have such pathognomonic features, though the histologic appearance is often characterized by irregular hyphal elements and beaded, yeast-like forms (109). However, it may still be difficult to differentiate this pathologically from infection due to other moulds such as Aspergillus. In such cases, the Fontana-Masson stain, which is specific for melanin, can usually be used to confirm the presence of dematiaceous hyphae (109).

PATHOGENESIS

Relatively little is known regarding the pathogenic mechanisms by which many of these fungi cause disease, particularly in immunocompetent individuals. One of the likely candidate virulence factors is the presence of melanin in the cell wall, which is common to all dematiaceous fungi. Melanin has been found to be an important virulence factor in certain fungi, including Cryptococcus (C.) neoformans and Wangiella (W.) dermatitidis, which is a dematiaceous yeast (24, 40). In these fungi, disruption of specific genes involved in melanin production leads to markedly reduced virulence in animal models (24, 40).There are several mechanisms proposed by which melanin may act as a virulence factor (29, 52, 61). It is thought to confer a protective advantage by scavenging free radicals and hypochlorite that are produced by phagocytic cells in their oxidative burst that would normally kill most organisms (61). In addition, melanin may bind to hydrolytic enzymes, thereby preventing their action on the plasma membrane (61). These multiple functions may help explain the pathogenic potential of some dematiaceous fungi, even in immunocompetent hosts. Another pathogenic mechanism is the production of allergic disease. It is interesting to note that most allergic disease and eosinophilia is caused by two genera, Bipolaris andCurvularia (106). These organisms are very common in the environment, so exposure is practically universal. The virulence factors in these fungi that are responsible for eliciting allergic reactions are unclear at present, though certain HLA-types have been associated (113).

SUSCEPTIBILITY IN VITRO AND IN VIVO

Single Drugs

In vitro antifungal testing has only recently become standardized, and the first standardized method for filamentous fungi was not available until 2002 (89). As such, the available in vitro data for dematiaceous fungi is relatively sparse, and often relies on small numbers of isolates per species. The past several years have seen an increased interest in dematiaceous fungi, and reports of in vitro testing. An important caveat is that much of the older literature is often inconsistent with regards to methodology, leading to difficulties in comparing data. In addition, interpretive breakpoints are not available for most drugs and any of the dematiaceous fungi, and clinical correlation data is practically non-existent. Therefore, suggestions regarding susceptibility are guidelines only. Compared with in vitro data, animal studies with dematiaceous pathogens are even more scarce, and only a few species have been studied.

Amphotericin B

Amphotericin B has in vitro activity against many clinically important dematiaceous fungi. However, some species have been consistently resistant (minimum inhibitory concentration (MIC) ≥2 μg/mL), including Scedosporium (S.) prolificans and Scopulariopsis (S.) brumptii (81). Other species have occasionally found to be resistant, including Chaetomium spp., Curvularia spp., Phialemonium spp.,Exophiala spp. and Ramichloridium (R.) mackenzei (81, 123). 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 (32). Animal studies have also suggested that amphotericin B is active against some species, including murine models of infection with W. dermatitidis, F. pedrosoi C. bantiana, andOchroconis (O.) gallopavum (31, 102). In a study of murine infection with S. prolificans, use of liposomal amphotericin B with granulocyte colony stimulating factor (G-CSF) was found to significantly prolong survival (93).

Flucytosine (5- fluorocytosine; 5-FC)

5-FC is unique in its mechanism of action, inhibiting DNA and RNA synthesis. Concerns over the development of resistance during monotherapy have resulted in its almost exclusive use in combination therapy for systemic mycoses, most notably cryptococcal meningitis [33]. Resistance is suggested with MICs ≥32 μg/mL (32). In vitro studies with dematiaceous fungi are limited, though activity has been shown against C. bantiana, Exophiala spp., and W. dermatitidis (21, 31, 123). In particular, good activity is present againstFonsecaea (F.) pedrosoi, the major etiologic agent of chromoblastomycosis (21). Early animal studies demonstrated activity in murine models of infection with W. dermatitidis, C. bantiana, Ochroconis (O.) gallopavum and F. pedrosoi (31, 102).

Azoles

Azoles were the first oral, broad spectrum antifungal agents available, and are widely used. As a group, they are well-tolerated, but often have multiple drug interactions. Fluconazole will not be discussed below, as it has negligible activity against dematiaceous moulds, and essentially no role in therapy given the variety of other options available.

Ketoconazole: Sparse in vitro data are available for this agent against dematiaceous fungi, but good activity is noted for the most common fungi causing chromoblastomycosis and mycetoma (8, 128). However, side-effects have significantly limited its current use compared with the availability of newer agents that are much better tolerated. In certain areas, due to the expense and lack of availability of newer agents, ketoconazole remains a useful drug.

Itraconazole: There has been extensive experience with itraconazole (116), though it is currently only available in oral formulations in the U.S. Of the oral preparations, the capsules require an acidic environment for absorption, while the suspension with cyclodextrin does not, being more consistently absorbed. Clinical use has declined due lack of the intravenous form and an FDA black box warning regarding congestive heart failure and significant drug interactions. Itraconazole has in vitro activity against the vast majority of dematiaceous fungi, with MICs generally ≤0.125 μg/mL (8, 37, 39, 63, 80, 81, 82, 92, 128). Almost all the recent in vitro data with dematiaceous fungi includes itraconazole. S. prolificans and S. brumptii are resistant (82).

Voriconazole: Voriconazole is one of the most widely used azoles due to its indication for aspergillosis, and is available in both oral and IV forms (64). Similar to itraconazole, it has a broad spectrum of activity that includes most dematiaceous fungi (37, 39, 81, 128). Recently it has supplanted itraconazole as the drug of choice for these infections. However, MICs for these fungi are usually slightly higher for voriconazole than itraconazole, though the clinical significance of this is unclear. S. prolificans is generally resistant (82).

Posaconazole: Posaconazole is a broad spectrum azole similar in structure to itraconazole, though with more activity, particularly against Aspergillus and other moulds (55). The published in vitro data is limited for dematiaceous fungi, but good activity is demonstrated against most species tested, including Bipolaris spp., C. bantiana, Phialophora spp. and R. mackenzei (6, 36, 101). As with other azoles, S. prolificans and S. brumptii are resistant (82). Murine models have shown activity of posaconazole against R. mackenzei and Wangiellainfection (6, 47).

Ravuconazole: Ravuconazole is an investigational, broad-spectrum azole with activity against a wide variety of moulds. In vitro activity is demonstrated against Chaetomium spp., F. pedrosoi, and Phialophora spp. (43, 114). S. prolificans is resistant (22).

Isavuconazole: Isavuconazole is another investigational azole for which limited data have been published regarding dematiaceous fungi (45).

Terbinafine

Terbinafine also inhibits ergosterol synthesis, but acts on squalene epoxidase, an enzyme two steps before the target of 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 (53). There has been recent interest in potentially expanding its clinical spectrum (53, 105). 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 (59, 111). In vitro studies against dematiaceous fungi are emerging and fairly broad spectrum activity is seen. Genera affected include Alternaria, Curvularia, Phialophora, and Bipolaris (62, 80). C. bantiana, Ochroconis (O.) gallopavum, and W. dermatitidis were studied in mice though terbinafine was found to be inactive in vivo, despite good in vitro activity (31).

Echinocandins

The echinocandins are the latest group of antifungals agents to be developed and have a unique mechanism of action, inhibiting β-1,3 glucan synthesis and thereby disrupting the fungal cell wall (29). They are generally well-tolerated.

Caspofungin: Caspofungin was the first of the class available for clinical use. In vitro studies with dematiaceous fungi are limited, though some activity is demonstrated against Curvularia, Bipolaris, and F. pedrosoi (36). C. bantiana has higher MICs and S. prolificans appears resistant (39, 82). In general, MICs for dematiaceous fungi are higher than for Aspergillus sp.

Micafungin: Micafungin has been evaluated against only a few species in vitro, with activity shown against C. bantiana, F. pedrosoi, andExophiala (E.) spinifera (38). MICs may be somewhat lower than for caspofungin.

Anidulafungin: Anidulafungin is the most recently approved echinocandin and little in vitro data is available. There appears to be some activity against Bipolaris and C. bantiana (38).

Combination Drugs

This is a potentially useful strategy for refractory infections, though it has not been studied extensively in dematiaceous fungi. The combination of itraconazole or voriconazole with terbinafine was found to be synergistic against S. prolificans, which is otherwise generally resistant to all agents (84, 85). The mechanism is presumably potent inhibition of ergosterol synthesis at two different steps of the pathway by these agents. However, this should be interpreted with caution, as terbinafine is not generally used for systemic infections. Another report suggested synergy for S. prolificans with voriconazole and caspofungin (119). Animal studies with C. bantiana show benefit with combination antifungal therapy over monotherapy, though it is unclear which is the optimal combination (76). Older literature also suggests additive activity and synergy with 5-FC and ketoconazole or amphotericin B for a variety of dematiaceous fungi (28, 102). This may be applicable to other azoles as well.

ANTIFUNGAL THERAPY

Drug of Choice

V oriconazole, posaconazole and itraconazole demonstrate the most consistent in vitro activity against this group of fungi. Oral itraconazole had been considered the drug of choice for most situations, given its extensive clinical experience (116). However, voriconazole is now preferred due to better tolerability, safety and the availability of an intravenous formulation, and may have advantages for central nervous system infections due to its ability to achieve good cerebrospinal fluid levels, unlike itraconazole (74). Posaconazole is a broad-spectrum alternative that is well-tolerated, though with less clinical experience. All likely achieve adequate brain tissue levels (49).

Special Infections

In general, there are no standardized therapies for infections caused by dematiaceous fungi. Length of therapy is generally based on clinical response, and ranges from several weeks to several months or longer. The diversity of the pathogens and of the hosts (immunocompetent and immunocompromised) makes it unlikely that a ‘one size fits all’ therapeutic strategy will be effective. A summary is presented in Table 2.

Superficial and Deep Local Infections

Superficial infections are the most common form of infection due to dematiaceous fungi. These cases are generally associated with minor trauma or other environmental exposure. Although many pathogens have been reported, relatively few are responsible for the majority of infections. Although they rarely lead to life-threatening disease, significant morbidity can occur depending on the site of infection and response to therapy.

Tinea nigra: This is a rare infection seen primarily in tropical areas with high salinity (115). The most common cause is Hortaea werneckii. It presents as a pigmented macule, typically on the palms and soles, and is confined to the stratum corneum. As such, topical therapy (azoles or keratolytics) is usually effective (14,100).

Onychomycosis: Dematiaceous fungi are rare causes of onychomycosis. Clinical features may include a history of trauma, involvement of only one or two toenails, and lack of response to standard systemic therapy (50). Neoscytalidium and Alternaria have been reported, with the former being highly resistant to therapy (10, 50, 126). Itraconazole and terbinafine are the most commonly used systemic agents, and may be combined with topical therapy for refractory cases (126). No published data is available for newer azole agents.

Subcutaneous Lesions: There are numerous case reports of subcutaneous infection due to a wide variety of species, though Alternaria is the most common cause (2, 7, 65, 88, 122, 97). 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, including in immunocompromised patients (99, 121). Oral systemic therapy with an azole in conjunction with surgery is also frequently employed and has been used successfully, especially in immunocompromised patients (122,131).

Chromoblastomycosis: This chronic infection is often difficult to cure, and relapses are common. There is no standard therapy, though in several studies, cryotherapy, i traconazole, or the combination resulted in the largest number of cures (15, 103). In developing countries, where systemic antifungals are not easily available or too expensive, use of cryotherapy alone in a systematic manner over several months has led to good cure rates as well (25). The exact mechanism of this effect is unclear. For small lesions, surgery alone may be effective (9). As a single agent, itraconazole appears to be the most effective (15, 103, 104). Pulse therapy of one week per month for 7 months has also been successful, though in a small number of patients (71). A variety of other treatments have also been successful, includingketoconazole, flucytosine, local heat therapy and amphotericin B (86). However, the overall cure rate was only 57% in one large series of 100 cases from Brazil, despite use of multiple modalities (86). In refractory cases, the combination of itraconazole with terbinafine or flucytosine has been found to be useful (51, 70). Posaconazole has also been used in refractory cases (90).

Mycetoma: Mycetoma in general, and due to dematiaceous fungi in particular, can be refractory to therapy. Unlike chromoblastomycosis and subcutaneous phaeohyphomycosis, which may be cured with surgical techniques alone, mycetoma almost always requires prolonged systemic antifungal therapy in addition to surgery (4). The most experience has been with ketoconazole and itraconazole, though itraconazole appears to have more consistent clinical activity (4, 54). Anecdotal reports using voriconazole and posaconazole have been successful (72, 90). As with chromoblastomycosis, amphotericin B is largely ineffective (110). Surgery can help to reduce disease burden and occasionally cure small, localized lesions that do not involve bone. There is very limited experience with the use of combination therapy for this disease, but the addition of flucytosine to azoles may not be effective, in contrast to chromoblastomycosis (12).

Keratitis: Dematiaceous fungi account for up to 8-17% of cases, particularly in tropical regions (118). Some of the largest case series with dematiaceous fungi have come from India (13, 26, 44). In a large experience of keratitis due to dematiaceous fungi, 88 cases were examined (44). Almost half the cases were associated with trauma. Most patients received topical agents only (5% natamycin +/- azole), though more severe cases also received oral ketoconazole. Overall response was 72% in those available for follow-up. Surgery was needed in 13 patients, with an additional 6 requiring enucleation due to poor response.

In a study from the U.S. of 43 cases of Curvularia keratitis, topical natamycin was used almost exclusively, with only a few severe cases requiring adjunctive therapy, usually with an azole (130). Surgery, including penetrating keratoplasty, was required in 19% of patients. At the end of therapy, only 78% had a visual acuity of 20/40 or better.

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 (46, 125). Voriconazole is a potentially useful agent, but published clinical experience is limited, though topical preparations are available (34, 56, 94). 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, suggesting that further advances in therapy are needed for this debilitating disease.

Allergic Disease

Fungal Sinusitis: Previously, Aspergillus was thought to be the most common fungus responsible for allergic sinusitis, but it is now appreciated that disease due to dematiaceous fungi actually comprises the majority of cases (41, 112). The most common are Bipolaris spp, Curvularia spp., Exserohilum spp. and Alternaria spp. This is a hypersensitivity phenomenon and does not involve invasive disease. Diagnosis generally depends on demonstration of allergic mucin, with or without actual culture of the organism. Therapy consists of surgery to remove the mucin, which is often tenacious, and systemic steroids. Antifungal therapy, usually in the form of itraconazole, may play a role in reducing the requirement for steroids, but this is not routinely recommended (69). Other azoles have only rarely been used for this disease (35). Immunotherapy with weekly injections of fungal antigens have shown promise in preliminary studies (11, 77).

Allergic Bronchopulmonary Mycosis (ABPM): This is a fairly recent concept, similar in presentation to allergic bronchopulmonary aspergillosis (ABPA), which is typically seen in patients with asthma or cystic fibrosis (48). The most common fungi are Bipolaris spp. andCurvularia spp. (Table 1). Therapy is primarily systemic steroids, usually prednisone at 0.5 mg/kg/day for 2 weeks, followed by a slow taper over 2-3 months or longer, if necessary. Itraconazole has been used as a steroid sparing agent, but its efficacy is not clear and routine use of itraconazole is not generally recommended (48, 129).

Sinus Fungus Balls

Black fungi are also commonly responsible for sinus fungus balls, including Bipolaris spp, Curvularia spp., Exserohilum spp., and Alternaria spp. Therapy consisting of surgical resection of the fungus ball, and aeration of the sinus is generally curative. Unless invasion of the surrounding mucosa or bone is demonstrated, antifungal agents do not appear to be of additional benefit (27, 66).

Pneumonia

Non-allergic pulmonary disease usually occurs in immunocompromised patients, and may be due to a wide variety of species (including Bipolaris spp., Ochroconis, Galloparum, and Chaetomium spp.); in contrast to allergic disease (17, 18, 19, 58, 124) (Table 1). However, cases in immunocompetent patients may also be seen (16). It is unclear what specific risk factors may contribute to pulmonary infection with these fungi, which are commonly found in the environment. Therapy usually consists of intravenous amphotericin B or oralitraconazole initially, followed by itraconazole for a more prolonged period. Mortality rates are high in immunocompromised patients. Experience with voriconazole and posaconazole is accumulating (30, 57, 87).

Central Nervous System Infection

This is a rare, but frequently fatal manifestation of phaeohyphomycosis, often in immunocompetent individuals (23). The pathogenesis may be hematogenous spread from an initial, presumably subclinical pulmonary focus. It remains unclear why these fungi preferentially cause CNS disease. A retrospective analysis of 101 reported cases of CNS phaeohyphomycoses found that over half occurred in immunocompetent patients, with Cladophilalophora bantiana the most common species isolated (108). Ramichloridium mackenzei and Ochroconis gallopavum were less common. 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 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 (42,73, 75, 127). Only one of the cases, in an immunocompetent patient, was successfully treated (75). However, clinical improvement was seen in one of the severely immunosuppressed patients while receiving voriconazole, although the patient ultimately died from the infection (127). In that case, caspofungin (Cancidas®)was also added late in the course so it was not clear what role it played. Posaconazole has also been used successfully, notably in a case of R. mackenziei brain abscess, which previously had been associated with 100% mortality (5).

Disseminated Infection

This is the most uncommon manifestation of infection seen with dematiaceous fungi. In a recent review, most patients were immunocompromised, though occasional patients without known immunodeficiency or risk factors developed disseminated disease as well (107). In contrast to most invasive mould infections, blood cultures were positive in over half the cases, usually seen with S. prolificans. 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. Infection with S. prolificans was associated with nearly 100% mortality in the absence of recovery from neutropenia, as it is generally resistant to all available antifungal agents. Therapy with the newer azoles has been successful with other fungi (33, 67, 91, 95).

Underlying Diseases

Most life-threatening infections due to dematiaceous fungi are seen in immunocompromised patients, with the possible exception of CNS infection. Therapy in patients with underlying diseases should be continued longer than in other patients and the use of surgery (when appropriate) should be strongly considered. However, infections due to certain species, such as Scedosporium prolificans, have an extremely high mortality in immunocompromised patients despite aggressive therapy.

Alternative Therapy

Amphotericin B may be useful for severe disease, though some species are resistant. Lipid formulations will likely play an important role for such infections, as reduced toxicity combined with the potential for increased efficacy using high doses makes them an attractive therapeutic choice. 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.

Other drugs have a more limited role in therapy of infections caused by dematiaceous fungi. Susceptibility testing may be useful in determining which alternative agents may be useful for specific infections. Echinocandins appear to have some activity, though clinical experience as single agents is very limited to date. Terbinafine and flucytosine may have a role in treating chromoblastomycosis as single agents. Terbinafine was used to successfully treat a case of E. jeanselmei subcutaneous infection in a heart transplant patient after failing itraconazole (3).

Anecdotal reports suggest that posaconazole may be effective as well. A case of disseminated E. spinifera infection was treated successfully with posaconazole after failing itraconazole and amphotericin B (91). Posaconazole successfully treated a case of R. mackenzei brain abscess, which represents the first reported survival of infection due to this species (5).

Combination Therapy

Terbinafine in particular appears to provide synergistic activity with azole antifungals, and this may be a useful strategy against refractory subcutaneous infections such as chromoblastomycosis and mycetoma that do not respond to conventional therapy (51). Use of this combination in serious systemic infections, however, is unproven, limited to anecdotal reports, and cannot be generally recommended. However, recent case reports have suggested that the combination of itraconazole or voriconazole with terbinafine may be synergistic against highly refractory S. prolificans infections and improve outcomes (60, 83).

Echinocandins may be considered in combination therapy of difficult cases, though with only anecdotal reports. Two cases of refractory bone and joint infection due to S. prolificans were treated effectively with voriconazole and the combination of voriconazole andcaspofungin (Cancidas®) (119, 120).

In a refractory case of chromoblastomycosis, the combinations of amphotericin B and itraconazole with 5-FC resulted in dramatic improvement after failure of itraconazole, terbinafine, and Amphotericin B (96).

In the setting of CNS infection, combination therapy appears to be associated with improved outcomes vs. monotherapy, though which is the optimal antifungal combination remains unclear, and will likely depend upon the individual case.

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. Complete wide and deep margin resection is critical for the optimal management of chromoblastomycosis, mycetoma, and subcutaneous phaeohyphomycosis. For subcutaneous abscess in particular, surgery alone has been effective, though in immunocompromised patients follow-up antifungal therapy is often given. In allergic syndromes, antifungal therapy is usually not recommended, and systemic steroids are the mainstay of therapy. In addition, surgical removal of allergic mucin, which is often tenacious, is essential for treatment of allergic fungal sinusitis. Outcomes for brain abscess may be improved with the use of surgical drainage and/or excision, if possible. Frequently, single lesions are present, which may make surgical resection more feasible.

ENDPOINTS FOR MONITORING THERAPY

There are no useful laboratory tests for monitoring infections due to dematiaceous fungi. Serologic and antigen tests are not available. As a result, reliance must be 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.

PREVENTION OR INFECTION CONTROL MEASURES

General

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 (68, 98).

Antifungal Agent 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 dematiaceous fungi as well. As these are uncommon infections, even large trials are unlikely to show a significant trend in these infections.

Infection Control

No specific infection control measures are recommended for these fungi. No person-to-person transmission has been demonstrated.

CONTROVERSIES, CAVEATS, OR COMMENTS

Dematiaceous fungi are becoming increasingly recognized as important opportunists and pathogens, though the clinical setting in which they are isolated should always be carefully considered before making decisions regarding therapy. Much additional work is needed in order to better understand the pathogenic mechanisms underlying infection with dematiaceous fungi and to optimize therapy for these often refractory infections.

Unfortunately, there are no new classes of drugs in the near future that are expected to have significant activity against dematiaceous fungi. Currently available agents have excellent activity, particularly voriconazole and posaconazole, though some may have specific advantages for certain types of infections and fungal species. Progress in therapy is likely to come from accumulating clinical experience over time, as large, randomized trials are impractical for any of the clinical syndromes described. This implies that reporting of individual cases, particularly for rare infections, will be important to advance our understanding, regardless of whether therapy was successful or not. This relates both to the use of single agents and to combinations. It is likely that combination therapy will be utilized more often, and that additional clinical experience will drive future therapeutic options.

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Table 1. Disease Entities Caused by Black Fungi [Download PDF]

Entity	Common Pathogens	Clinical Manifestations	Histopathologic characteristics	Prognosis
Chromoblastomycosis	Fonsecaea pedrosoi Cladosporium carrionii F. compacta Phialaphora verrucosa Rhinocladiella aquaspersa	Chronic wart- or caulfilower-like lesions of skin and subcutaneous tissue	Sclerotic bodies ("copper pennies")	Limited infections: cure is possible; Extensive infections: cure is rare
Mycetoma	Madurella mycetomatis M. grisea Pyrenochaeta romeroi Exophiala jeanselmei	Chronic skin and subcutaneous lesions with swelling and draining sinus tracts	Mycotic granules	Worse than chromoblastomycosis; Limited infections: cure is possible; Extensive infections: cure is very rare
Subcutaneous phaeohyphomycosis	E. jeanselmei Wangiella dermatitidis Phialophora spp. Bipolaris spp.	Heterogenous: well-formed cysts; subcutaneous tissue invasion; extensive sinus tracts	Fungi within non-keratinized tissue beneath the dermal layer; no granules or sclerotic bodies	Cystic form: good Non-encapsulated form: fair, depends on extent of tissue invasion; cures less likely in immunosuppressed patients
Dermatomycosis and onychomycosis	Alternaria spp. Hendersonula toruloidea Phialophora spp. Onychocola spp.	Indistinguishable from infections by dermatophytes	Fungi within keratinized tissue with extensive host response and tissue damage	Onychomycosis is difficult to eradicate; dermatomycosis has better prognosis
Keratitis	Curvularia spp. Alternaria spp. Exserohilum spp.Lasiodiplodia theobromae	Nodule progressing to ulcer; feathery, branching pattern in cornea	Superficial or deep fungal invasion of cornea; endopthalmitis rare	Fair: residual visual damage common; 25% require penetrating keratoplasty
Sinusitis: Allergic sinusitis	Bipolaris spp., Curvularia spp., Exserohilum spp., Alternaria spp.	Chronic sinusitis	Sparse fungi; eosinophil-rich mucoid material (allergic mucin); Charcot-Leyden crystals	Cure is uncommon; frequent relapses
Sinusitis: Fungus ball	Bipolaris spp., Curvularia spp., Exserohilum spp., Alternaria spp.	Nasal congestion; rhinosinusitis	Fungus ball: abundant fungi within inflammatory mass	Good
Allergic bronchopulmonary mycosis	Bipolaris spp., Curvularia spp.	Cough, wheezing	Airway inflammation	Good
Pneumonia	Bipolaris spp. Ochroconis gallopavum Chaetomium spp.	Chronic pneumonia	Granulomas	Immunocompetent pts: good Immunocompromised pts: fair
Central nervous system infection	Cladophialophora bantiana Ramichloridium mackenzei Ochroconis gallopavum	Brain abscess (usually single) Meningitis Encephalitis (rare)	Acute and chronic (granulomatous) inflammation	Poor
Disseminated infection	Scedosporium prolificans Bipolaris spp. Wangiella dermatitidis	Fever, skin lesions, septic shock	Depends on sites of infection	Poor, despite aggressive therapy

Table 2. Recommendations for Antimicrobial Therapy of Infections Caused by Black Fungi [Download PDF]

Clinical entity	First-line therapy	Second-line therapy	Options for refractory infections
Chromoblastomycosis	Itraconazole (oral 200-400 mg daily) for 2 - 3 months or longer	Partial surgical resection and/or cryotherapy combined with itraconazole (200 - 600 mg daily) or voriconazole (400-600mg daily) until 2 - 3 months after apparent mycologic cure	Repeated surgical resection; itraconazole and flucytosine; amphotericin B and flucytosine; ketoconazole; ketoconazole and flucytosine; itraconazole and terbinafine
Mycetoma	Itraconazole (200-400 mg daily) for 2 - 3 months or longer	Partial surgical resection combined itraconazole (200 - 600 mg daily) or voriconazole (400-600mg daily); until 2 - 3 months after apparent mycologic cure	Repeated surgical resection; amphotericin B; ketoconazole and flucytosine; itraconazole and flucytosine; amphotericin B and flucytosine; itraconazole and terbinafine
Subcutaneous phaeohyphomycosis Immunocompetent hosts	Itraconazole (200-400 mg daily) for 2 - 3 months; if organisms are contained within a cyst, adjunctive antifungal therapy is not needed	Partial surgical resection combined with itraconazole (200 - 600 mg daily) or voriconazole (400-600mg daily) until 2 - 3 months after apparent mycologic cure	Repeated surgical resection; amphotericin B; ketoconazole; addition of flucytosine or terbinafine to medical regimen
Immunocompromised hosts	Itraconazole (200 -400mg daily), or amphotericin B (1 mg/kg/day) until 2 - 3 months after apparent mycologic cure	Partial surgical resection combined with itraconazole (200 - 600 mg daily), voriconazole (400-600mg daily), amphotericin B (1 mg/kg/day), or ketoconazole (300 - 400 mg daily) until 2 - 3 months after apparent mycologic cure	Repeated surgical resection; addition of flucytosine or terbinafine to medical regimen
Cutaneous phaeohyphomycosis Dermatomycosis, onychomycosis	Itraconazole (200 mg daily) until 2- 3 months after apparent mycologic cure	Voriconazole (400mg daily)	Terbinafine; Ketoconazole
Keratomycosis	Natamycin (5% solution) topically	Topical natamycin or amphotericin B (0.15%) combined with flucytosine (1% aqueous solution); topical itraconazole, ketoconazole, or miconazole; oral itraconazole (400 mg daily); oral voriconazole (400mg daily); oral ketoconazole (400 mg daily)	Prior therapy with penetrating keratoplasty
Sinusitis Allergic fungal sinusitis	Surgical drainage and debridement, combined with postoperative corticosteroids; postoperative nasal saline irrigations and regular surveillance endoscopy	Itraconazole (200-400mg daily); voriconazole (400mg daily)	Allergen immunotherapy to decrease IgE production
Fungus ball	Resection of fungus ball, with aeration of sinuses	In cases of local invasion of bone, itraconazole or amphotericin B are indicated as adjunctive therapy	Voriconazole
Allergic bronchopulmonary mycosis	Corticosteroids	Corticosteroids with itraconazole (200-400mg daily) or voriconazole (400mg daily)
Pneumonia	Itraconazole (400mg daily) or amphotericin B (1mg/kg daily) for severe disease	Voriconazole (400-600mg daily)	Amphotericin B with flucytosine
Central nervous system infection	Surgical resection (brain abscess) with high dose itraconazole (400-600mg daily) or voriconazole (400-600mg daily) + lipid amphotericin B +/- flucytosine	Repeated surgical resection with high dose azole + echinocandin +/- flucytosine
Disseminated infection	High dose lipid amphotericin B (>5mg/kg daily) with intravenous itraconazole (400-600mg daily) or voriconazole (400-600mg daily) +/- echinocandin; colony stimulating factors if neutropenic	High dose lipid amphotericin B with azole +/- echinocandin +/- flucytosine; colony stimulating factors if neutropenic