Treatment Options in Emerging Mold Infections

Patricia Muñoz, MD, PhD, Jesús Guinea, PharmD, PhD, and Emilio Bouza, MD, PhD

Corresponding authorPatricia Muñoz, MD, PhDServicio de Microbiología Clínica y Enfermedades Infecciosas, Hospital General Universitario Gregorio Marañón, Calle del Doctor Esquerdo, 46, 28007 Madrid, Spain. E-mail: pmunoz@micro.hggm.es

Current Fungal Infection Reports 2008, 2:74–80Current Medicine Group LLC ISSN 1936-3761Copyright © 2008 by Current Medicine Group LLC

Although Zygomycetes, Fusarium spp, and Scedosporium spp are far less frequent causes of invasive fungal dis-ease than Aspergillus and Candida, they are emerging. These types of infections in severely immunocompro-mised patients have a common feature: a poor clinical response to antifungal therapy. Infection is usually air-borne, although local infections in cases of skin trauma are also possible. These fungi are resistant to some common antifungal agents; therefore, surgical debride-ment of the necrotic tissue, when possible, should be combined with specific systemic antifungal treatment in immunocompromised patients. In the absence of randomized clinical trials, most experience in the treatment of these infections is with amphotericin B. Experience with new antifungal agents is still limited, and recovery from neutropenia remains the main pre-dictor of a favorable outcome.

IntroductionInvasive fungal infections (IFIs), a growing cause of mor-bidity and mortality in developed countries, usually occur in patients with severe immunodeficiency, possibly due to the longer survival of hospitalized patients. Invasive candidiasis, caused by Candida spp yeasts, is the most common type of fungal infection, whereas Aspergillus spp cause most invasive mold infections. Although other fila-mentous fungi—such as Zygomycetes, Fusarium spp, and Scedosporium spp—are still far from Aspergillus in terms of frequency, they are currently considered an emerging cause of IFI [1]. Zygomycosis (or “mucormycosis”) is the third most frequent IFI after candidiasis and aspergillosis. Traditionally considered a community-acquired disease,

nosocomial infections frequently appear, and several recent reports from single institutions describe an increase in the number of cases of invasive zygomycosis as a result of new antifungal and immunosuppressive therapies.

This article reviews the therapeutic options available for the management of patients with severe, deep infections caused by Zygomycetes, Fusarium, and Scedosporium.

Infections Caused by ZygomycetesEcology, microbiology, and clinical aspectsZygomycetes are ubiquitous airborne fungi that are fre-quently found outdoors and in hospitals. Like most molds, Zygomycetes play an important role in the decomposition of dead organic material. Invasive zygomycosis is mainly opportunistic. Hosts can become infected after inhaling spores and by traumatic inoculation. Zygomycetes are divided in two orders: Mucorales and Entomophthorales. Members of Mucorales are the etiologic agents of invasive zygomycosis and are distributed into six different fami-lies: Mucoraceae, Cunninghamellaceae, Mortierellaceae, Saksenaceae, Syncephalastraceae, and Thamnidaceae. Genera and species from Mucoraceae more frequently cause zygomycosis, especially Rhizopus arrhizus (oryzae), Rhizopus microsporus var Rhizopodiformis, Rhizomucor pusillus, Cunninghamella bertholletiae, Apophysomyces elegans, and Saksenaea.

Zygomycetes typically cause invasive, rapidly progres-sive, destructive infections that originate in a number of ways (eg, rhinocerebral, pulmonary, cutaneous, gastroin-testinal, disseminated, etc.). The patients most at risk of zygomycosis are those with diabetic ketoacidosis, those with hematologic malignancies, and those receiving des-ferrioxamine therapy.

Antifungal susceptibility testingMost data are from studies based on the Clinical and Laboratory Standards Institute M38-A broth microdilu-tion procedure. Data from studies using other methods still need validation. Amphotericin B has proven to be the most active antifungal agent against Zygomycetes, with a minimum inhibitory concentration for 90% of

Treatment Options in Emerging Mold Infections Muñoz et al. 75

isolates (MIC90) of 2 μg/mL. This is consistent with its role as first-line therapy for invasive zygomycosis [2,3••,4,5]. Echinocandins are considered inactive against Zygomycetes, with MICs consistently above 128 μg/mL, regardless of the endpoint and the antifungal susceptibility testing method chosen [6]. However, some studies in vitro suggest a possible role for combinations of antifungals, such as caspofungin plus posaconazole, which is synergistic [7]. Other in vitro combinations have also proven effective, such as amphotericin plus rifampicin and amphotericin plus terbinafine. However, the clinical effectiveness of these combinations should be demonstrated in the clinical setting. The antifun-gal activity of azoles against Zygomycetes is variable. Voriconazole has always shown very high MICs against Zygomycetes, indicating poor activity [6,8]. Itracon-azole has shown variable species-specific activity, with MICs between 0.25 and 16 μg/mL [6]. Posaconazole is a promising drug with good antifungal activity against Zygomycetes; different in vitro studies have shown MICs of between 0.25 and 2 μg/mL [6]. Isavuconazole (BAL4815), a promising new azole with good activity against Candida and Aspergillus, has shown a limited antifungal effect when the endpoint was partial inhi-bition of fungal growth (MIC90 and MIC50 of 8 and 1 μg/mL, respectively) [8].

The lack of breakpoints to classify clinical isolates of zygomycetes as “susceptible” or “resistant” is one of the main shortcomings of the Clinical and Laboratory Standards Institute M-38 A procedure and makes the value of antifungal susceptibility testing against zygo-mycetes controversial. Nevertheless, in vitro activity of these antifungal agents may yield information about their behavior in vivo.

Treatment of zygomycosisThe treatment of zygomycosis rests on five main prin-ciples: rapid diagnosis, correction of predisposing factors, surgical debridement, resection of necrotic tissue, and adequate antifungal treatment. Surgery is mandatory and should always be combined with sys-temic antifungal agents [9].

The most effective antifungal agent for the treat-ment of zygomycosis remains controversial due to the lack of well-designed, multicenter, randomized clini-cal trials, which are difficult to organize because of the low incidence of the disease. In addition, variables such as the type and extent of surgery may interfere with the interpretation of results. Thus, the selection of a suitable antifungal agent depends on the interpretation of in vitro data, results from animal models, and anecdotal experi-ence collected from the case reports of small series with limited numbers of patients [10]. In addition, only a small number of available antifungal agents are active against Zygomycetes, and these could prove to be a valid alterna-tive for the treatment of invasive zygomycosis.

Different formulations of amphotericin BCurrent data suggest, albeit indirectly, that liposomal amphotericin B (AmBisome; Gilead US, Foster City, CA) is the drug of choice for the treatment of invasive zygomy-cosis. It has good antifungal activity, is better tolerated than conventional amphotericin B [1], and has higher bioavailability in the central nervous system than that of the other formulations of amphotericin B (amphotericin B lipid complex). In a retrospective series of 120 cases of invasive zygomycosis in patients with hematologic malignancies, liposomal amphotericin B showed higher survival rates than conventional amphotericin B (67% vs 39%) [11]. The correct dose of liposomal amphotericin B for the treatment of invasive zygomycosis has not been established, although doses greater than 3 mg/kg should be administered with caution.

Azole derivativesThe clinical effectiveness of itraconazole for the treatment of invasive zygomycosis is variable and limited to a small number of studies [4,12]. Although it has been observed in only a few patients, prophylactic use of itraconazole may predispose to infection because of its variable in vitro activity against zygomycetes [13]. Given available alternatives, itraconazole is not the drug of choice for treating zygomycosis.

Voriconazole is quite inactive in vitro against Zygo-mycetes and is clinically inefficient in the treatment of invasive zygomycosis [6,14]. Therefore, it is not recom-mended for this indication. The prophylactic use of voriconazole has been considered “responsible” for a recent increase in the incidence of invasive zygomycosis in oncohematology units in European and North Ameri-can hospitals. Because voriconazole is not highly effective in vitro, invasive zygomycosis breakthroughs have been reported among populations where it had been used pro-phylactically to prevent invasive aspergillosis [15••,16].

Posaconazole is a promising third-generation azole that shows antifungal activity against Zygomycetes [6]. In the absence of multicenter, randomized clinical trials, the use of posaconazole as first-line therapy for zygomy-cosis remains controversial. Greenberg et al. [17] studied 24 patients with invasive zygomycosis who were enrolled in two open-label, nonrandomized, multicenter, compas-sionate trials that evaluated oral posaconazole as salvage therapy for IFIs. Eleven (46%) patients had rhinocerebral zygomycosis. Duration of posaconazole therapy ranged from 8 to 1004 days (mean, 292 days; median, 182 days). Rates of successful treatment (complete cure and partial response) were 79% in 19 patients with invasive zygo-mycosis refractory to standard therapy and 80% in five patients were intolerant of standard therapy. Overall, 19 of 24 patients (79%) survived infection. Survival was also associated with surgical resection of the affected tissue and stabilization or improvement of the patients’ underly-ing illnesses. Failure was associated with the worsening of

76 Current Approaches to Prophylaxis and Clinical Management

underlying illnesses or withdrawal of all therapy [17]. van Burik et al. [18••] retrospectively evaluated the efficacy of posaconazole as salvage therapy in 91 patients with proven or probable zygomycosis. Patients had infection that was refractory to prior antifungal treatment (n = 81) or were intolerant of such treatment (n = 10) and partici-pated in the compassionate-use posaconazole (800 mg/d) program. The rate of complete or partial response at 12 weeks after treatment initiation was 60%, and 21% of patients had stable disease.

Combination of antifungal drugsThe combination of antifungal agents aims to increase clinical efficacy, reduce toxicity, and expand the spectrum of activity. Due to the limited number of drugs with anti-fungal activity against these fungi, only a few possibilities currently exist. The logical combination of amphotericin B with posaconazole has proven to be effective in single case reports. However, its effectiveness should be demon-strated in a randomized trial (or at least in more cases) before its wide use can be recommended [19]. No in vitro information for this combination is available.

Clinical and animal data indicate that the presence of elevated available serum iron predisposes the host to invasive zygomycosis. Iron availability is necessary to the pathogenesis of zygomycosis. The use of iron chelators, other than deferoxamine, may play a role in the preven-tion of zygomycosis. Hyperbaric oxygen (HBO) could be a potential adjuvant for the treatment of invasive zygomyco-sis, especially in patients with rhinocerebral forms. A recent review of 28 published cases of zygomycosis indicated that adjunctive HBO may be beneficial in patients with diabe-tes (94% survival), whereas its benefit in the small group of patients with hematologic malignancies or bone mar-row transplants was doubtful (33% survival; P = 0.02). Prolonged courses of HBO were associated with a higher survival (100% survival; P = 0.003) [20]. An in vitro study showed that gamma interferon and colony-stimulating factor increased the hyphal damage of Zygomycetes, sug-gesting a role in the management of invasive zygomycosis.

Fusarium spp InfectionsEcology, microbiology, and clinical aspectsFusarium spp are ubiquitous fungi that are widely dis-tributed in decaying plant debris and other organic substrates, soil, and water [21]. Fusarium spp have also caused contamination in hospital water tanks [22]. The genus includes approximately 50 different species that potentially can cause plant and animal diseases. However, only 12 cause invasive infection in humans. F. solani and F. oxysporum are responsible for 70% of cases [23••]. Other rare causes of fusariosis are F. dimerum, F. proliferatum, F. chlamydosporum, F. sacchari, F. nyg-amai, F. napiforme, F. antophilum, and F. vasinfectum.

Fusarium causes a wide variety of infections, and clini-cal presentation ranges from superficial involvement (skin, nails) that typically occur in immunocompetent individu-als to disseminated, deep infections (pulmonary disease, sinusitis, deep wound infections, and other organs) in neu-tropenic patients. In contrast to other molds (Aspergillus), Fusarium is usually recovered from the bloodstream of patients with disseminated disease.

Antifungal susceptibility testingFusarium spp are resistant to most antifungal agents; in vitro data show high MICs to different antifungal agents, regardless of the antifungal susceptibility testing proce-dure chosen [8]. In a study including 67 different isolates of Fusarium spp, the MIC90 obtained for amphotericin B, itraconazole, voriconazole, and posaconazole was 32 μg/mL, indicating resistance to all of these agents [3]. Isavuconazole (BAL4815) also showed limited antifungal activity against Fusarium [8]. However, dif-ferences between species have been found in terms of susceptibility. Although F. solani and F. verticilloides showed higher MICs for azoles and amphotericin B, F. oxysporum and F. moniliforme tended to be more susceptible to voriconazole and posaconazole [23]. The three echinocandins show little activity against Fusar-ium spp, with minimal effective concentrations greater than 32 μg/mL [24]. Terbinafine, an allylamine anti-fungal agent used in the treatment of dermatophytosis, also has limited activity against Fusarium, although species-specific variations exist, with F. solani being the least susceptible [25].

Although in vitro data correlate well with the refrac-toriness of disseminated Fusarium infections to antifungal treatment, there are not enough data to establish strong cor-relations between antifungal susceptibility and outcome.

Treatment of fusariosisThe limited number of fusariosis cases makes it nearly impossible to develop randomized, double-blind clinical trials to establish the optimal treatment of the infection. In addition, immune reconstitution plays a role in outcome in immunocompromised patients. Thus, experience with the treatment of fusariosis is based on case reports and series with a limited number of patients. In general, the treatment of Fusarium infections depends on the immune status of the host, the site and extent of the infection, and the species involved.

Cases of localized infection in normal hosts usually benefit from surgical debridement of necrotic tissue. How-ever, in the case of Fusarium keratitis, topical treatment with natamycin (eye drops) is standard and sometimes is combined with an oral antifungal, such as itraconazole. Medical response rates are above 60% [26]. Disseminated infections in immunocompromised hosts deserve special attention because of their poor prognosis. In these situ-

Treatment Options in Emerging Mold Infections Muñoz et al. 77

ations, infected patients should always receive systemic antifungal therapy. Most reports focus on patients with different hematologic malignancies [23••].

Different formulations of amphotericin BVariable rates of success have been achieved with high-dose amphotericin B, lipid formulations of amphotericin B, and the combination of amphotericin B with other anti-fungal agents. In a multicenter, retrospective study, Nucci et al. [27] reviewed patients with hematologic cancers and invasive fusariosis who were treated at a single institution in the United States and 11 centers in Brazil. Of the 84 patients evaluated, neutropenia was present in 83% at the time of diagnosis, and 33 patients had undergone stem cell transplantation. The patients received amphotericin B deoxycholate or a lipid formulation of amphotericin B. Twenty-seven patients (32%) responded to treatment, but only 18 patients (21%) had survived 90 days after the diagnosis. Fifty-nine patients died of fusariosis, and seven died of the underlying disease. The median survival of all 84 patients was 32 days.

The Collaborative Exchange of Antifungal Research database [28] includes large, retrospective data on the treatment and outcome of cases of IFI caused by non-Aspergillus molds that were treated with amphotericin B lipid complex. Perfect [28] subanalyzed 28 of the 3514 patients registered in the database who met the criteria for fusariosis. The patients had variable neutrophil counts at baseline, and the most frequent underlying conditions were hematologic malignancies (n = 12) and allogeneic hematopoietic stem cell transplant (n = 8). Amphotericin B lipid complex was administered as first-line treatment to eight (29%) of 28 patients and as a second-line treatment to 20 (71%) of 28 patients. Most patients had infec-tions that were refractory to prior antifungal treatment. Amphotericin B lipid complex improves the outcome of 46% of the 26 patients who were intolerant of or lacked response to primary therapy with other antifungals.

New triazolesIn a study by Perfect et al. [29], voriconazole was admin-istered to 11 patients with fusariosis who were intolerant of or refractory to primary therapy. The authors found a response rate of 45%. Survival 90 days after diagnosis was 71%. Raad et al. [30] showed that posaconazole was an effective salvage therapy in patients with fusariosis refrac-tory to amphotericin B. This study included 21 patients, collected retrospectively from three open-label clinical tri-als, who had proven or probable fusariosis. They received oral posaconazole suspension (800 mg/d in divided doses). Outcome was successful in 48%, and the response rate in patients with disseminated infection was 30% [30].

Combination therapySeveral combinations of antifungal agents have been chosen in case reports: caspofungin plus amphotericin B,

amphotericin B plus voriconazole, amphotericin B plus terbinafine, and voriconazole plus terbinafine [23••]. However, due to limited experience, strong conclusions and recommendations for combinations cannot be made at this time [23••].

Scedosporium spp InfectionsEcology, microbiology, and clinical aspectsThe filamentous fungus Scedosporium consists of two spe-cies, S. prolificans and S. apiospermum. S. apiospermum (formerly Monosporium apiospermum) is the anamorph state of Pseudallescheria boydii (formerly Petriellidium boydii and Allescheria boydii). Both can cause invasive infections in immunocompromised patients with a very poor prognosis. Therapy of these infections is especially difficult due to their broad resistance to many antifungal agents, including amphotericin B.

S. prolificans is the most common cause of disseminated phaeohyphomycosis and infections caused by dematiaceous fungi. Although it is found in soil worldwide, most cases have been reported in Spain and Australia. S. prolificans may cause locally invasive infections in immunocompetent hosts, such as osteoarticular infections after trauma or surgery, keratouveitis associated with contact lenses, or pulmonary infections secondary to bronchiectasis. In the immunocompromised population, it usually affects the lung, central nervous system, and skin in neutropenic patients or transplant recipients, although disseminated scedosporiosis can affect almost every organ [31–33]. Two small outbreaks related to air contamination have been reported in patients with leukemia [34]. Phenotypic and genotypic assessment of samples from clinical material and ambient air from the iso-lation rooms where the patients were being treated showed that the epidemic was caused by a single strain. S. pro-lificans is considered an emerging pathogen in solid organ transplant recipients, accounting for approximately 25% of all non-Aspergillus mold infections [35]. Infection by S. prolificans can be differentiated from invasive aspergil-losis because of its higher tendency to produce skin lesions and to be recovered from blood cultures. Diagnosis requires isolation in culture, as it is histologically similar to Asper-gillus, showing angioinvasive branching hyphae in tissue.

S. apiospermum is a hyaline filamentous fungus present in soil, sewage, and polluted waters. The propor-tion of positive blood cultures is much lower than for S. prolificans. The correct diagnosis of S. apiospermum infection must be confirmed by the isolation of this fun-gus in culture because both its histologic appearance and clinical presentation are similar to that of Aspergillus. A misdiagnosis based only on these data can result in delayed or inappropriate treatment, considering that S. apiospermum is almost always resistant to amphoteri-cin B. However, microbiologic diagnosis is easy due to its characteristic macroscopic and microscopic appearance in culture.

78 Current Approaches to Prophylaxis and Clinical Management

The main portal of entry for S. apiospermum is the respiratory tract or the skin (by trauma) from where it may disseminate. In normal hosts, it produces localized disease after penetrating trauma or disseminated infec-tion after aspiration of polluted water [36]. However, in immunocompromised patients, it may cause severe pulmonary or disseminated infections. Involvement of the central nervous system is disproportionately more common in patients with pseudallescheriasis than other mycoses. Many patients are already receiving systemic antifungal therapy when the infection is diagnosed [37], classifying it as a breakthrough mycosis.

S. apiospermum should be included in the differential diagnosis of any manifestation compatible with invasive mycosis in immunosuppressed patients, especially when treatment with amphotericin B or itraconazole has failed. Therefore, the importance of biopsy-driven diagnosis with culture of the organism must be stressed.

Antifungal susceptibility testingS. prolificans is resistant to most antifungal agents, includ-ing amphotericin B, flucytosine, and most azoles [38]. Voriconazole, albaconazole, and caspofungin have some activity in vitro [39,40], although breakthrough infections have been described in patients receiving voriconazole. As for antimicrobial susceptibility, S. apiospermum isolates are more susceptible in vitro than S. prolificans, with the best activity exhibited by voriconazole (MIC90, 0.5 μg/mL) followed by miconazole (MIC90, 1 μg/mL), UR-9825 and posaconazole (MIC90, 2 μg/mL), and itraconazole (MIC90, 4 μg/mL). The high MICs of terbinafine, amphotericin B, and the two formulations of nystatin against S. apio-spermum isolates indicate poor activity. Cross-resistance was observed among all the azoles, except for posacon-azole, and among all the polyenes, except for the lipid formulations [41]. Terbinafine has in vitro activity against dematiaceous fungi. The combination of terbinafine and the azoles voriconazole, miconazole, and itracon-azole against five clinical S. prolificans isolates showed a synergistic effect in vitro [42]. This interaction may be explained by both drugs’ mechanisms of action, which block different steps of fungal ergosterol synthesis.

Amphotericin B alone is inactive against clinical isolates of S. apiospermum using a checkerboard microdi-lution method. However, amphotericin B was found to act additively or synergistically in combination with micon-azole (76%), fluconazole (88%), and itraconazole (38%). Amphotericin B and pentamidine also showed synergism. The combination was synergistic against 28 of 30 isolates (93.3%–100%, depending on the method), and antago-nism was not observed [43].

Other combinations that have shown synergistic or additive effects in vitro are the combination of vori-conazole or amphotericin B with micafungin against S. prolificans and S. apiospermum (31%–75% of the tested isolates) [44].

Treatment of scedosporiosisFocal infections in immunocompetent hosts respond well to surgery and antifungal drugs, but treatment of invasive Scedosporium infection in immunocompromised hosts is difficult. The disease is usually rapidly fatal; most patients die within 4 days of the first positive blood culture [33].

Optimal treatment of S. prolificans infection remains controversial due to the resistance of the microorganism to most available antifungal agents. Surgical excision should be considered in all cases, although underlying conditions, disease location, or extent of the disease may render this option impossible. The vacuum seal technique has also been used for severe S. apiospermum skin infections [45].

Husain et al. [31] reported Scedosporium infections in 80 transplant recipients and compared them with 190 additional cases of scedosporiosis in patients from the literature who did not undergo transplantation. When adjusted for disseminated infection, voriconazole therapy was associated with a lower mortality rate than amphotericin B (3/11 vs 20/25; P = 0.06). Combination therapy was used in seven patients: amphotericin B with miconazole (n = 5), fluconazole (n = 1), and itraconazole (n = 1). No impact on outcome was observed with combi-nation therapy; however, the combination of voriconazole and terbinafine has proven effective in several cases. This strategy is the best available first option for these infec-tions, although more data are warranted [46]. Recovery from neutropenia is critical, and mortality is essentially 100% in patients with persistent neutropenia [32,47].

Posaconazole was useful rescue therapy in a patient with multiple S. apiospermum brain abscesses refractory to neurosurgical drainage and treatment with itracon-azole, amphotericin B, and ketoconazole [48].

No impact on outcome was observed with combina-tion therapy in Scedosporium infections in solid organ transplant recipients. At present, treatment involves amphotericin B or voriconazole, granulocyte colony-stimulating factors in neutropenic patients, and surgical debridement when feasible. Some authors recommend the combination of voriconazole and terbinafine for S. prolificans infections because of its in vitro synergy in some case reports [49]. This synergistic interaction is explained based on the mechanisms of action of azoles and terbinafine, which block different steps of the same pathway of fungal ergosterol biosynthesis.

Polymorphonuclear leukocytes synergize with anti-fungal agents against this microorganism [49]; therefore, the reversal of neutropenia may have important therapeu-tic implications [50]. Accordingly, the use of granulocyte monocyte colony-stimulating factor has been advocated as a potentially useful tool in the treatment of very severe fungal infections, even in non-neutropenic patients. It increases neutrophil production and enhances poly-morphonuclear leukocyte–mediated killing of fungal pathogens in vivo, implying a possible therapeutic role as a biologic response–modifying agent during opportunis-

Treatment Options in Emerging Mold Infections Muñoz et al. 79

tic fungal infection. It should be considered for short-term treatments in very severe diseases until more information is available.

ConclusionsZygomycetes, Fusarium spp, and Scedosporium spp are still far from Aspergillus and Candida in terms of frequency, but their incidence is increasing in some at-risk populations. Their ubiquitous nature and the poor response of patients to clinical treatment threaten severely immunocompromised patients. In the absence of avail-able and effective antifungal treatment, all effort should be driven toward prevention. Environmental exposure of patients at risk should be reduced by installing high-effi-ciency particle air filters and ensuring positive pressure in the vicinity of these patients. The role of new antifungal drugs for the treatment of these infections is promising but not yet established.

AcknowledgmentsWe would like to thank Thomas O’Boyle for his help in the translation of the article.

DisclosuresDr. Guinea is under contract with Fondo de Investigación Sanitaria CM05/00171.

No further potential conflict of interest information relevant to this article was reported.

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