Rare and Emerging Opportunistic Fungal Pathogens: Concern for Resistance beyond Candida albicans and Aspergillus fumigatus

C. glabrata. C. glabrata has emerged as an important and potentially resistant opportunistic fungal pathogen (84, 88, 101). Trick et al. (101) have demonstrated that among the Candida spp. C. glabrata alone has increased in incidence as a cause of BSIs in U.S. intensive care units since 1993. Likewise, in certain regions of the United States C. glabrata both is a common cause of BSI and is also often resistant to fluconazole (35, 88). Surveys from other parts of the world, however, suggest that C. glabrata has not increased as a cause of BSIs to the same extent as that seen in the United States and, furthermore, may not be as resistant to fluconazole as U.S. isolates (84, 88, 91, 100).

In a recent study of clinically invasive isolates of C. glabrata from four different geographic regions (North America, Europe, Latin America, and the Asia-Pacific region), we confirmed that the azoles were less active against isolates from North America than those from other regions of the world (84). We have also shown that azoles have the greatest activities against C. glabrata isolates from the Asia-Pacific region (84, 88).

C. glabrata is innately less susceptible to fluconazole and amphotericin B than most other species of Candida (77, 81, 84) and displays the capacity to rapidly develop resistance to all azoles via induction of CgCDR1 and PDH1 efflux pumps (4, 92). Exposure of C. glabrata to subtherapeutic concentrations of fluconazole may result in resistance (4), and clinical studies have shown that the frequency of colonization and infection of patients with C. glabrata may be increased in populations subjected to fluconazole prophylaxis (52). However, the reason for the emergence of C. glabrata as an important cause of BSIs is likely not as simple as selection by drug pressure (e.g., fluconazole) but may be influenced by patient age, underlying diseases, geographic location, or other unknown factors (84, 88).

The data in Table 2 demonstrate the decreased susceptibility of C. glabrata to fluconazole (61.9% susceptible [S] at ≤8 μg/ml) and amphotericin B (75.2% S at ≤1 μg/ml). Amphotericin B MICs were >2 μg/ml for 12 of the 601 isolates tested (2%) by the Etest method (84). The activities of the new extended-spectrum triazoles against C. glabrata were considerably better than that of fluconazole. This is because the vast majority of isolates for which fluconazole MICs are 16 to 32 μg/ml (susceptible-dose dependent) appear to be susceptible to voriconazole, posaconazole, and ravuconazole (87 to 97% S at MIC ≤1 μg/ml).

It has been suggested that the new triazoles may be active against strains of C. glabrata that are resistant to fluconazole (43); however, a strong positive correlation can be seen between voriconazole (R = 0.9) and posaconazole (R = 0.8) MICs and fluconazole MICs (Fig. 1). We have also noted a similar correlation between ravuconazole MICs and fluconazole MICs, suggesting cross-resistance (86). Isolates resistant to fluconazole are less susceptible to voriconazole, ravuconazole, and posaconazole, with MICs ≥2 μg/ml for 83, 89, and 92% of isolates, respectively. Although the clinical significance of these in vitro data has yet to be determined, cross-resistance among the azoles should not be surprising with C. glabrata, given the ability of this species to rapidly upregulate CDR drug efflux pumps and the effectiveness of these pumps against all of the azoles (4).

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FIG. 1.

Scattergram comparing fluconazole and voriconazole MICs (R = 0.9) (A) and fluconazole and posaconazole MICs (R = 0.8) (B) for C. glabrata. The strong correlations suggest considerable cross-resistance.

Caspofungin (MIC at which 90% of isolates are inhibited [MIC₉₀] = 0.06 μg/ml; 100% S at MIC ≤1 μg/ml) and flucytosine (MIC₉₀ = 0.12 μg/ml; 99.2% S) were the most active against C. glabrata (Table 2). All fluconazole-resistant strains were also susceptible to both of these agents (MICs ≤ 0.25 μg/ml). Although it may not be unexpected that a novel newly introduced agent such as caspofungin would be active against this species, the excellent potency of flucytosine against C. glabrata is not widely appreciated (82, 84). Both of these agents may be useful therapeutic options in regions where azole resistance is a concern.

C. krusei. C. krusei accounts for 2 to 3% of all Candida BSIs (88). This species is best known for its propensity to emerge in settings where fluconazole is used for prophylaxis (110, 111); however, it is worth noting that colonization and infection among those with hematologic malignancies were apparent in certain medical centers well in advance of the use of fluconazole (41, 109). The antifungal susceptibility profile of C. krusei is that of a multidrug-resistant (MDR) pathogen with decreased susceptibility to fluconazole (2.9% S; all isolates should be considered resistant), amphotericin B (the MIC was ≤1 μg/ml for 8.0% of isolates), and flucytosine (4.0% S) (Table 2). This MDR pattern is well recognized for C. krusei and is the basis for continuing concern regarding this species as a possible emerging pathogen (77). Importantly, this resistance profile does not extend to the newer triazoles or the echinocandins. Cross-resistance among azoles does not appear to be an issue with C. krusei, as ≥99% of clinical isolates are susceptible to voriconazole, posaconazole, and ravuconazole (MICs = 1 μg/ml or less). Likewise, caspofungin has excellent activity against this species (MIC₉₀ = 0.25 μg/ml; 99% S at ≤1 μg/ml).

C. lusitaniae. C. lusitaniae most often causes fungemia in patients with malignancies or other serious comorbid conditions (36). C. lusitaniae is often mentioned in the literature as being capable of developing resistance to amphotericin B during the course of therapy (36, 76, 77) and may present as breakthrough fungemia in immunocompromised patients (36). Among the 103 BSI isolates tested for amphotericin B resistance by Etest (Table 2), 96.7% were susceptible at concentrations of ≤1 μg/ml and two appeared to be highly resistant (MICs = 8 and 16 μg/ml, respectively). This level of susceptibility to amphotericin B is comparable to that seen with C. albicans (95% S) (81). In contrast to broth microdilution testing, the Etest method has been shown to be both sensitive and specific for the detection of resistance to amphotericin B in isolates of C. lusitaniae and other species of Candida (80, 107). On the basis of these data, it appears that primary resistance to amphotericin B is uncommon among incident BSI isolates of C. lusitaniae (i.e., those from the first positive blood culture); however, if amphotericin B is used to treat infections due to this species, the patient should be monitored closely for the emergence of secondary resistance (77). C. lusitaniae may exhibit resistance to flucytosine (89.3% susceptible, 6% resistant) but is highly susceptible to both triazoles (96.1 to 100% susceptible) and caspofungin (100% susceptible).

C. dubliniensis. C. dubliniensis is a recently identified opportunistic yeast pathogen that is closely related to, but genetically distinct from, C. albicans (12). This species is now recognized as a minor constituent of the normal human oral microbial flora and a cause of oral thrush in human immunodeficiency virus (HIV)-infected individuals (12). With the development of methods to detect and identify this species (29, 44), it has become evident that C. dubliniensis may also cause oral and vaginal candidiasis in HIV-negative persons (12). Although the incidence of BSIs due to C. dubliniensis is unknown, fungemia due to this species has been reported in North America, Europe, and Australia (7, 54, 59).

Although the majority of C. dubliniensis isolates are susceptible to azoles (83), fluconazole resistance has been observed in clinical isolates from AIDS patients with prior exposure to fluconazole (56, 66). In addition, stable fluconazole resistance is rapidly induced following exposure to the drug in vitro (65). Fluconazole-resistant strains of C. dubliniensis exhibit increased expression of multidrug transporter genes, especially CdMDR1 (66). These findings suggest that antifungal resistance may be a factor in the emergence of C. dubliniensis infections.

Despite concerns regarding the ability of C. dubliniensis to become resistant to fluconazole, most studies have found clinical isolates to be quite susceptible to this agent (7, 54, 59, 83). Only 3 (2.9%) of 101 isolates tested in our laboratories were resistant to fluconazole, and 98% were highly susceptible to the extended-spectrum triazoles (Table 2). Likewise, 100% of the isolates tested were susceptible to amphotericin B, flucytosine, and caspofungin. Thus, it appears that there are several treatment options should resistance to fluconazole become an issue with C. dubliniensis.

C. guilliermondii.Although C. guilliermondii is most often associated with onychomycosis, it has been shown to cause osteomyelitis and hematogenously disseminated candidiasis (19, 98). Dick et al. (19) reported on a case of disseminated candidiasis due to C. guilliermondii in which the patient died, despite amphotericin B therapy. The organism was subsequently shown by in vitro testing to be resistant to amphotericin B. Aside from this case report, resistance to amphotericin B has not been widely appreciated for this species. Among the 102 isolates of C. guilliermondii tested by Etest, only two (MICs = 2 and 32 μg/ml, respectively) appeared to be resistant to amphotericin B. Fluconazole resistance was implicated in a case of osteomyelitis of the finger caused by C. guilliermondii (98). The infection failed to respond, despite prolonged administration of fluconazole (400 mg/day), and partial amputation of the infected finger was ultimately required. The isolate of C. guilliermondii obtained from cultures of infected bone was resistant to both fluconazole and itraconazole. In support of these observations, C. guilliermondii does appear to be less susceptible to fluconazole than the more common BSI isolates of Candida (85.3% of C. guilliermondii isolates were susceptible [Table 2], whereas 97 to 99% of C. albicans, C. tropicalis, and C. parapsilosis isolates were susceptible) (24, 25, 88). Although the new triazoles appear to be quite active against this species (96.7 to 97.1% susceptibility to voriconazole, ravuconazole, and posaconazole at an MIC ≤1 μg/ml), one isolate was resistant to all three of these agents (MIC > 8 μg/ml) as well as to fluconazole. The MICs of caspofungin tend to be 2- to 16-fold higher for C. guilliermondii than for other Candida species (87); however, 96.7% of the isolates tested were susceptible at ≤1 μg/ml, and limited experience suggests that this species may respond clinically to treatment with caspofungin (64) (Table 2). All of the isolates tested were susceptible to flucytosine at the NCCLS breakpoint of ≤4 μg/ml (Table 2).

C. rugosa.Decreased susceptibility to amphotericin B, nystatin, and fluconazole has been reported for C. rugosa (22, 24). Dube et al. (22) reported on 15 episodes of candidemia due to C. rugosa in burn patients receiving topical nystatin treatment. Although the source of the outbreak was not identified, the isolates were all shown to be resistant to nystatin. More recently, a cluster of six episodes of candidemia caused by C. rugosa was reported from Brazil (13). Two of the episodes represented breakthrough infections during treatment with amphotericin B, and all four patients receiving this agent died. Thus, resistance to polyenes and nosocomial spread have been reported for C. rugosa (13, 22). Amphotericin B is clearly less active in vitro against this species than against most other Candida species (Table 2). Similarly, decreased susceptibility to flucytosine (84.6% S) and fluconazole (78.9% S) was observed. This profile resembles that of C. krusei, in that resistance to the three established antifungal agents may be seen with C. rugosa. As with C. krusei, C. rugosa is highly susceptible to voriconazole, posaconazole, and ravuconazole as well as caspofungin (100% of the isolates were susceptible to concentrations ≤1 μg/ml).

Trichosporon spp.The genus Trichosporon consists of six species at present: Trichosporon asahii and T. mucoides are known to cause deep invasive infections, T. asteroides and T. cutaneum cause superficial skin infections, T. ovoides causes white piedra of the scalp, and T. inkin causes white piedra of the pubic hair (26). Unfortunately, most of the literature on serious opportunistic trichosporonosis refers to the older nomenclature of T. beigelii.

Trichosporon causes catheter-associated fungemia in neutropenic patients but may gain entrance to the bloodstream via the respiratory or gastrointestinal tract as well (103, 104, 106). Widespread hematogenous dissemination may manifest as positive blood cultures and multiple cutaneous lesions. Chronic hepatic trichosporonosis mimics hepatic candidiasis and may be seen upon recovery from neutropenia (26).

Trichosporon has been reported to be the most common cause of noncandidal yeast infection in patients with hematological malignancies, and infection carries a mortality rate in excess of 80% (26, 103, 104, 106). Susceptibility to amphotericin B is variable, and this agent lacks fungicidal activity against Trichosporon. Clinical failures with amphotericin B, fluconazole, and combinations of the two have been reported; and the outcome is generally dismal in the absence of neutrophil recovery (26, 103, 104, 106). The multiresistant nature of T. asahii makes it a threat for nongranulocytopenic patients as well, as evidenced by a report of apparent nosocomial transmission of a strain resistant to amphotericin B, fluconazole, itraconazole, and flucytosine (112). Notably, the new triazoles appear to be more active than fluconazole against Trichosporon (75), and voriconazole has successfully been used to treat disseminated T. asahii infection in a patient with acute myeloid leukemia (27).

In vitro susceptibility studies of Trichosporon species by NCCLS methods are limited and generally include only a small number of isolates (Table 3). Arikan and Hascelik (2) reported elevated amphotericin B MICs and moderate susceptibility to fluconazole and itraconazole for 43 isolates of T. asahii (Table 3). Similar results for these agents were reported by Paphitou et al. (75), whereas good activity was seen with the extended-spectrum triazoles, especially posaconazole (MIC₅₀, 0.12 μg/ml) and voriconazole (MIC₅₀, 0.06 μg/ml). Paphitou et al. (75) found non-T. asahii isolates to be more susceptible than T. asahii isolates to amphotericin B, fluconazole, and itraconazole, whereas the new triazoles gave activity comparable to that seen against T. asahii (Table 3). Espinel-Ingroff (24, 25) reported results for T. beigelii that were similar to those reported by Arikan and Hascelik (2) and Paphitou et al. (75) for amphotericin B and the azoles and, in addition, showed the lack of activity of the echinocandins, caspofungin, and anidulafungin (Table 3). On the basis of the results of these in vitro studies, it appears that the azoles in general, and voriconazole and posaconazole in particular, have activities superior to that of amphotericin B. Similar to flucytosine, the echinocandins lack any useful activity against this organism. On the basis of the limited amount of data available at present, treatment of disseminated trichosporonosis in a persistently neutropenic patient should include an azole in conjunction with granulocyte-macrophage colony-stimulating factor (26).

Rhodotorula spp.Species of Rhodotorula include Rhodotorula glutinis, R. mucilaginosa, R. rubra, and R. minuta. These yeast-like fungi are found as commensals in skin, nails, and mucous membranes as well as in cheese and milk products and environmental sources, including air, soil, shower curtains, bathtub grouts, and toothbrushes. Rhodotorula species are emerging as important human pathogens in immunocompromised patients and those with indwelling devices (8, 23, 40, 46). Rhodotorula has been implicated as a cause of central venous catheter infection and fungemia (40, 113), ocular infections (34), peritonitis (23), and meningitis (46).

There are very few studies in the literature dealing with the in vitro susceptibility of Rhodotorula to systemically active antifungal agents (21, 28, 113). When clinical isolates of Rhodotorula are tested by NCCLS methods (67), the isolates are the most susceptible to amphotericin B (MIC₉₀ = 0.5 μg/ml, 100% of isolates S at ≤1 μg/ml) and flucytosine (MIC₉₀ = 0.25 μg/ml, 100% S at ≤4 μg/ml) (Table 3). The MICs of fluconazole (MIC₉₀ = 256 μg/ml), caspofungin (MIC₉₀ > 8 μg/ml), and micafungin (MIC₉₀ > 64 μg/ml) were all high, representing resistance to these agents. Both itraconazole and ravuconazole were moderately active (MIC₉₀ = 1 μg/ml). The MICs of posaconazole and voriconazole were fourfold higher than those of ravuconazole and itraconazole.

Amphotericin B has excellent activity against Rhodotorula and, coupled with catheter removal, is an optimal therapeutic approach to infections with this organism (8, 113). Flucytosine has excellent in vitro activity but should not be considered for monotherapy. Neither fluconazole nor the echinocandins should be used to treat infections due to Rhodotorula species, and the role of the extended-spectrum triazoles is uncertain pending additional clinical data. Of the extended-spectrum triazoles, ravuconazole is the most potent.

G. capitatum.Among the emerging opportunistic yeast pathogens, Geotrichum capitatum (formerly Blastoschizomyces capitatus; teleomorph, Dipodascus capitatus) is a rarely described yeast-like fungus that produces severe systemic infection in immunocompromised patients, especially those with hematological malignancies (6, 9, 17, 57). It is widely distributed in nature and may be found as part of the normal skin flora. Infection with G. capitatum presents similarly to that with Trichosporon in neutropenic patients, with breakthrough infection (36% of episodes), frequent fungemia with multiorgan (including brain) dissemination, and a mortality rate of 60 to 80% (57). Blood cultures are usually positive. As with Trichosporon, a chronic disseminated form of G. capitatum infection, similar to chronic disseminated candidiasis, may be seen upon resolution of neutropenia.

Data on the antifungal susceptibilities of G. capitatum are quite limited; however, resistance to fluconazole and decreased susceptibility to amphotericin B have been described (6, 9, 30). In vitro susceptibilities determined by NCCLS methods (Table 3) indicate high levels of susceptibility to amphotericin B, itraconazole, and voriconazole. Most isolates were susceptible to flucytosine (MIC₉₀ = 4 μg/ml) and fluconazole (MIC₉₀ = 8 μg/ml), although isolates with decreased susceptibilities to both of these agents were observed. Anidulafungin showed only modest activity against the few strains tested.

The optimal approach to therapy is not yet defined. Some investigators believe that G. capitatum has decreased susceptibility to amphotericin B (102); however, the strains tested generally appear to be susceptible (Table 3), and recent clinical experience with patients with leukemia was favorable for treatment with amphotericin B (57). The excellent activity of voriconazole suggests that it may be a useful agent for the treatment of G. capitatum infections. Rapid removal of central venous catheters, adjuvant immunotherapy, and novel antifungal therapies (e.g., either voriconazole or high-dose fluconazole plus amphotericin B) are recommended for treatment of this rare but devastating infection (57).

A. terreus.The frequency of Aspergillus terreus as a cause of invasive aspergillosis varies from 3 to 12.5% (42, 78). Infections due to this species appear to be increasing in recent years and are of concern given its apparent resistance in vitro to amphotericin B and poor clinical response to treatment with this agent (3, 14, 42, 47, 96). Environmental studies have found A. terreus in showerheads, hospital water storage tanks, and potted plants (1, 48).

Invasive aspergillosis caused by A. fumigatus is rarely documented by positive blood cultures (45, 78). In fact, most bloodstream isolates of Aspergillus species have been shown to represent pseudofungemia or terminal events at autopsy (45). Importantly, among all species of Aspergillus, A. terreus has been shown to cause true aspergillemia (45, 78, 93, 105). Similar to other angioinvasive filamentous fungi (e.g., Fusarium spp., Paecilomyces lilacinus, Scedosporium spp., and Acremonium spp.), A. terreus is capable of adventitious sporulation in which yeast-like spores, or aleurioconidia, are formed in tissue and blood and are more likely to be detected in blood collected for culture (78, 105). Recognition of these aleurioconidia on microscopic examination of tissue, fine needle aspirates, or bronchoscopy specimens can allow a rapid presumptive identification of A. terreus (105).

In contrast to A. fumigatus, A. terreus is resistant in vitro and in vivo to the fungicidal effects of amphotericin B (Table 4) (14, 20, 47, 96, 105). Of note, the new triazoles and echinocandins all have excellent activities in vitro against A. terreus (Table 4). Although clinical experience is limited, both voriconazole and caspofungin have successfully been used to treat invasive aspergillosis due to this species.

Zygomycetes.Infections due to the zygomycetes are rare, occurring at an annual rate of 1.7 infections per million population in the United States (89). Unfortunately, when they do occur, infections due to these agents are generally acute and rapidly progressive, with mortality rates of 70 to 100% (31).

The most common etiologic agents of zygomycosis include members of the genera Rhizopus, Mucor, and Absidia. These organisms cause infections in immunocompromised individuals, especially those with diabetic ketoacidosis, neutropenia, and corticosteroid therapy (31). Zygomycetes have a marked predilection for blood vessels and produce multiple emboli with concomitant infarction and necrosis of surrounding tissues. The classic clinical presentation of zygomycosis is that of rhinocerebral and pulmonary involvement; however, cutaneous, gastrointestinal, and disseminated infections are well documented (31, 94, 99).

Amphotericin B is the first-line therapy of choice for zygomycosis, often supplemented by surgical debridement and immune reconstitution (31). Most of the zygomycetes appear to be quite susceptible to amphotericin B in vitro and are generally not susceptible to the triazoles or echinocandins (Table 4). Among the extended-spectrum triazoles, however, posaconazole stands apart from both voriconazole and ravuconazole in that it appears to be active against most of the zygomycetes (Table 4) (15, 16, 20, 95). Furthermore, posaconazole has documented efficacy in murine models of zygomycosis (15, 95) and for the treatment of infections in humans, although the experience has been limited (99). In contrast, voriconazole is inactive against these agents (Table 4), and breakthrough zygomycosis has recently been reported in BMT patients receiving voriconazole prophylaxis (58, 94). The latter experience serves to emphasize the fact that in very high risk patients, such as BMT recipients, the organism with the greatest intrinsic resistance to the antifungal agent used will ultimately emerge as a cause of infection (94). Broad usage of any antifungal agent in this population carries a risk of superinfection with an unusual, drug-resistant opportunistic fungus.

Other hyaline molds.The list of hyaline molds that have been shown to cause opportunistic infections is quite long, and it is well beyond the scope of this minireview to discuss them all (26, 106). The taxonomically diverse agents of hyalohyphomycosis do share several characteristics, in that many exhibit decreased susceptibilities to a number of antifungal agents, and when they are present in tissue, they appear as hyaline (nonpigmented), septate, branching filamentous fungi that may be indistinguishable from Aspergillus (106). Culture is necessary to identify these agents and may be critical in determining the most appropriate therapy.

Among the vast numbers of hyaline molds that may serve as opportunists, there are a handful that deserve special mention, given that they are relatively more common and/or that they exhibit antifungal resistance profiles that should be recognized. These organisms are Fusarium spp., Acremonium spp., Scedosporium spp., Paecilomyces spp., and Trichoderma spp. These organisms tend to cause infections in neutropenic patients that are often disseminated in nature and that are almost uniformly fatal in the absence of immune reconstitution (106). Several of these organisms are capable of adventitious conidiation (generation of spores in tissue) with concomitant hematogenous dissemination, positive blood cultures, and multiple cutaneous lesions (26, 106).

The agents of hyalohyphomycosis as a whole tend to be considerably less susceptible than Aspergillus spp. to virtually all of the systemically active antifungal agents (Fig. 2) (20, 24, 25, 72). Fusarium spp. often appear to be resistant to amphotericin B in vitro (Table 4), and breakthrough infections occur frequently in patients treated with this agent (71, 106). Among the new triazoles, only modest activity is seen in vitro (Table 4); however, voriconazole has successfully been used in some patients with amphotericin B-refractory fusariosis (79). Primary therapy with either a lipid formulation of amphotericin B or voriconazole plus vigorous efforts at immune reconstitution is recommended at this time (71, 106).

Within the genus Scedosporium, Scedosporium apiospermum (teleomorph, Pseudallescheria boydii) and S. prolificans represent two important antifungal-resistant opportunistic pathogens. S. apiospermum is a well-known cause of mycetoma and may cause deep-seated infections (e.g., central nervous system [CNS] abscesses) and disseminated infection in BMT recipients and other neutropenic, immunosuppressed individuals (61, 70). This organism is generally considered resistant to amphotericin B, the MICs of which are elevated (Table 4) and to which the clinical response is very poor, despite the use of high doses (106). The extended-spectrum triazoles are active in vitro against S. apiospermum, and both posaconazole and voriconazole have successfully been used for the treatment of CNS abscesses (61, 70). In addition to antifungal therapy, restoration of immune competence is essential for survival in these often fatal infections (106).

S. prolificans causes bone and soft tissue infections in immunocompetent individuals and deeply invasive and disseminated infections in immunocompromised patients. S. prolificans is considered resistant to virtually all of the systemically active antifungal agents, including the extended-spectrum triazoles and the echinocandins (Table 4). Although terbinafine, an inhibitor of squalene epoxidase, does not appear to be active alone, synergy between triazoles and terbinafine against S. prolificans has been demonstrated in vitro (60), and a single patient with disseminated S. prolificans infection has successfully been treated with a combination of voriconazole and terbinafine, in addition to aggressive surgical debridement (39). Despite this apparent success, medical therapy for nonresectable or disseminated disease due to S. prolificans is virtually always ineffective (106). Surgical resection remains the only definitive therapy for infections caused by S. prolificans (106).

Invasive infections due to Acremonuim spp. are almost exclusively seen in patients with neutropenia, transplantation, or some other cause of immunodeficiency (32, 106) and present in a manner similar to that of Fusarium infections, with hematogenously disseminated skin lesions and positive blood cultures (32, 106). The optimal treatment for invasive infections due to Acremonium spp. has not been established. In vitro resistance to amphotericin B, itraconazole, and the echinocandins is seen, whereas the newer triazoles, such as voriconazole, appear to be active in vitro (Table 4). A recent report of successful treatment of a pulmonary infection due to Acremonium strictum with posaconazole suggests that the new triazoles may be useful in treatment of Acremonium infections (37).

Although they are uncommon, Paecilomyces spp. may cause invasive disease in organ and hematopoietic stem cell recipients, individuals with AIDS, and other immunocompromised patients (10, 49, 55, 73). The portal of entry is often breaks in the skin or intravascular catheters; and dissemination, possibly aided by adventitious conidiation in tissue, is common (51, 73). Susceptibility to amphotericin B is variable, with resistance seen in P. lilacinus (Table 4). The triazoles and caspofungin demonstrate good activities (Table 4), and voriconazole has successfully been used to treat both severe cutaneous infections (38) and disseminated disease (55). Given the poor responses of disseminated infections to high-dose amphotericin B therapy that have been reported, the use of voriconazole or lipid formulations of amphotericin B may prove more effective and less toxic (106).

Trichoderma spp. are excellent examples of fungi previously labeled as nonpathogenic that have emerged as important opportunistic pathogens in immunocompromised patients and in patients undergoing peritoneal dialysis (11). Fatal disseminated disease due to Trichoderma longibrachiatum occurs in patients with hematologic malignancies and following BMT or solid-organ transplantation (11). Most Trichoderma spp. show decreased susceptibilities to amphotericin B, itraconazole, fluconazole, and flucytosine (Table 4) (11). Voriconazole appears to be active against the few species tested (Table 4).

Dematiaceous molds.As with the agents of hyalohyphomycosis, the list of dematiaceous fungi is both long and taxonomically diverse. These organisms are characterized by the presence of a pale brown to dark melanin-like pigment in the cell wall. The dematiaceous fungi may cause a variety of cutaneous and subcutaneous infections in immunocompetent individuals and invasive or disseminated infections in both immunocompetent and immunocompromised patients (69, 90, 97).

Infections involving dematiaceous fungi are known as phaeohyphomycoses. The number of dematiaceous molds reported to be etiologic agents of phaeohyphomycosis continues to grow, and several of these organisms appear to be neurotropic (90, 106). Those fungi known to be neurotropic include Cladophialophora bantiana, Bipolaris spicifera, Exophiala spp., Wangiella dermatitidis, Ramichloridium obovoideum, and Chaetomium atrobrunneum (90). Brain abscess is the most common CNS presentation. Bipolaris spp. and Exerohilum rostratum infections may initially present as sinusitis, which then extends into the CNS (90, 106).

The optimal treatment for disseminated or CNS phaeohyphomycosis has not yet been established, although it most often includes early administration of amphotericin B and complete surgical excision (90, 106). Despite these efforts, phaeohyphomycosis does not respond well to therapy and relapses are common (69, 90).

The in vitro activities of the antifungal triazoles (itraconazole, voriconazole, and posaconazole) are superior to that of amphotericin B against many of the dematiaceous molds (Table 4). Posaconazole has successfully been used to treat disseminated infections due to Exophiala spinifera (69). In those patients with brain abscesses, complete excision of the lesion has been associated with improved survival (90). Long-term triazole (posaconazole or voriconazole) therapy coupled with repeat surgical resection may prevent recurrences (106).