INTRODUCTION — During the past few decades, opportunistic fungal pathogens have become increasingly recognized as a cause of infection in severely ill or immunocompromised patients [1,2]. Although Aspergillus species remain the most common mold to cause invasive infection, other pathogens are becoming more common [1-3]. Two of these, Scedosporium apiospermum (the asexual form of Pseudoallescheria boydii) and Lomentospora prolificans, are considered major human pathogens .
This topic will discuss the diagnosis and treatment of Scedosporium and Lomentospora infections. The epidemiology, mycology, and clinical manifestations of Scedosporium and Lomentospora infections are discussed elsewhere (see "Epidemiology, clinical manifestations, and diagnosis of Scedosporium and Lomentospora infections"). Other emerging fungal infections are discussed elsewhere. (See "Epidemiology and clinical manifestations of Talaromyces (Penicillium) marneffei infection" and "Mycology, pathogenesis, and epidemiology of Fusarium infection".)
SUSCEPTIBILITY TESTING — Given the varying in vitro activity of antifungal agents against S. apiospermum and especially L. prolificans, we typically ask for susceptibility testing of isolates from patients with infections caused by these pathogens. Results of susceptibility testing should be interpreted along with multiple factors that impact drug activity in vivo. Factors that also play a role in determining the outcome of fungal infection include: immune status of the patient (immunocompetent versus immunosuppressed) and possible modulation of immunosuppression, timing of diagnosis (early versus late), extent of disease (localized versus disseminated), amenability to surgical intervention (eg, drainage, debridement, debulking), bioavailability and efficacy of antifungal drug at site of infection (pharmacokinetic and pharmacodynamic parameters), and host metabolic parameters, among others .
Definitions — The term "MIC" refers to the minimum inhibitory concentration of an antifungal agent required to inhibit growth of an organism. MIC50 refers to 50 percent inhibition; MIC90 refers to 90 percent inhibition.
The term "MEC" refers to the lowest concentration of an antifungal agent that leads to aberrant growth, which is the growth of small, rounded, compact hyphal forms as compared with the hyphal growth seen in the growth control well . MECs are generally used for the echinocandins. MEC50 is the concentration at which 50 percent of isolates showed aberrant growth, and MEC90 is the concentration at which 90 percent of isolates showed aberrant growth.
The Clinical and Laboratory Standards Institute (CLSI; formerly NCCLS) has approved a standard method (M38-A2) for antifungal susceptibility testing of filamentous fungi . The M38-A2 method is applicable to Aspergillus, Fusarium, Scedosporium, Lomentospora, and the Mucorales for testing amphotericin B and the azole antifungal agents. Reference ranges for amphotericin B, voriconazole, and posaconazole (MICs) and anidulafungin (MECs) have been proposed for two quality-control strains of S. apiospermum (ATCC MYA-3635 and ATCC MYA-3634) . However, interpretive clinical breakpoints for antifungal MICs/MECs and Scedosporium spp are not available.
Antifungal susceptibility testing is discussed in detail separately. (See "Antifungal susceptibility testing".)
In vitro data — A summary of in vitro activities of selected antifungal agents against Scedosporium is provided in the table (table 1).
Scedosporium apiospermum complex — The azoles and amphotericin B have varying levels of activity against the members of the S. apiospermum complex, with the extended-spectrum azoles (eg, voriconazole) typically having the lowest MICs among the antifungal agents (table 1) [8-12].
●Isavuconazole, a broad-spectrum triazole approved by the US Food and Drug Administration in 2015 for the treatment of invasive aspergillosis and invasive mucormycosis, has shown in vitro activity against some isolates of S. apiospermum [13-15]. In vitro testing of clinical isolates of Scedosporium spp (including S. apiospermum/S. boydii, S. aurantiacum, and S. dehoogii) using CLSI broth microdilution suggests that isavuconazole was less potent that voriconazole based on MIC values [16,17]. Higher MICs were also reported for isavuconazole against Scedosporium spp isolates from Australia and Spain [18,19]. Determination of individual Scedosporium susceptibility is necessary as variable resistance may preclude treatment with isavuconazole for different Scedosporium species.
●Olorofim (formerly F901318) is the first member of the orotomide class of antifungals. It inhibits dihydroorotate dehydrogenase, a key enzyme in the de novo biosynthesis of pyrimidine, possibly affecting fungal cell wall and cell cycle regulation . In vitro testing of clinical isolates from the United States, Australia, Europe, and India reported low MICs for this agent against all Scedosporium spp tested [18,19,22-24]. F901318 is in phase IIb clinical trials against L. prolificans, Scedosporium spp, Aspergillus spp, and other resistant fungi lacking alternative antifungal treatments .
●Fosmanogepix, also known as APX001 (formerly E1211), is another first-in-class antifungal agent. This small-molecule antifungal is metabolized to the active moiety manogepix or APX001A (formerly E1210). APX001A targets a highly conserved fungal enzyme, Gwt1, inhibiting a step in fungal cell wall protein synthesis, affecting cell wall integrity . APX001A was tested in vitro against clinical isolates originating from North America, Europe, Asia-Pacific, and Latin America and exhibited low MECs (0.015 to 0.08 mg/L) against Scedosporium spp [26-28]. In an immunosuppressed murine model of pulmonary scedosporiosis (S. apiospermum) mice treated with fosmanogepix (plus 1-aminobenzotriazole, a P450 inhibitor) had overall prolonged survival compared with treatment with other antifungals . Conidial tissue burden in lung, kidney, and brain was also lower in the fosmanogepix-treated mice compared with placebo. Brain tissue showed no signs of fungal dissemination in mice treated with fosmanogepix or liposomal amphotericin B. Fosmanogepix is being evaluated in a multicenter phase II clinical trial for invasive fungal infections caused by Aspergillus species or rare molds .
Lomentospora (formerly Scedosporium) prolificans — L. prolificans is resistant to most antifungal agents, with high MICs documented for amphotericin B, flucytosine, fluconazole, itraconazole, ketoconazole, voriconazole, posaconazole, and isavuconazole (table 1) [8,9,11,12,14,18]. In vitro activity has been demonstrated against L. prolificans by the experimental triazole, albaconazole (UR-9825) [11,30]; however, this agent is not available for clinical use.
Anidulafungin and micafungin demonstrated lower MEC50 and MEC90 results compared with caspofungin for L. prolificans by broth microdilution , but the relevance of this observation is unclear. Ibrexafungerp, formerly SCY-078 (MK3118), a glucan-synthase inhibitor that interferes with the cell wall polymer beta-(1,3)-D-glucan, has displayed modest in vitro activity against L. prolificans, with an MEC90 of 4 mcg/mL . A second-generation fungerp antifungal, SCY-247, has also shown in vitro activity against Scedosporium isolates with slightly lower MICs compared with the parent compound, ibrexafungerp, warranting further studies .
The orotomide antifungal agent, olorofim, in phase IIb clinical trials , has potent in vitro activity against L. prolificans. In vitro testing of clinical L. prolificans isolates from the United States, Australia, and Europe revealed low MICs for olorofim, particularly against panresistant L. prolificans isolates [18,19,22,23].
Fosmanogepix, the inositol acyltransferase Gwt1 inhibitor also known as APX001, is metabolized to its active moiety manogepix or APX001A. The latter has been tested against clinical isolates of L. prolificans from North America, Europe, Asia-Pacific, and Latin America and exhibited low MECs. MECs ranged from 0.03 to 0.06 mg/L [26-28]. Fosmanogepix is being evaluated in a multicenter phase II clinical trial for invasive fungal infections caused by Aspergillus spp or rare molds .
Synergistic studies — There is no standardized CLSI-approved guideline for performing synergy testing in vitro. Furthermore, no clinical correlation has been demonstrated between in vitro synergy and synergistic activity in vivo. Nevertheless, several antifungal combinations have been tested in vitro to evaluate for synergy, especially for L. prolificans given its high resistance profile.
●Synergy against L. prolificans has been demonstrated with voriconazole plus terbinafine, voriconazole plus miltefosine, and itraconazole plus terbinafine with in vitro testing of a small number of isolates [33-35].
●The combination of voriconazole and micafungin appeared synergistic in vitro in one study, but the number of isolates tested was small, and some isolates demonstrated indifference to the combination .
ANTIFUNGAL THERAPY — Scedosporium and Lomentospora infections are associated with a high incidence of disseminated disease and high mortality rates in hematopoietic cell and solid organ transplant recipients; mortality rates have ranged from 40 to 100 percent [37-41]. The outcome of these infections depends on the infecting strain, location of infection, choice of antifungal therapy, feasibility of surgical debridement, and, most importantly, the underlying immune status of the patient.
The optimal choice and duration of therapy is unknown. A large retrospective study provides support for the use of voriconazole for the treatment of Scedosporium and Lomentospora infections [40,41], whereas the data regarding the use of other antifungals come from case reports and small observational studies.
Choice of regimen — The choice of empiric antifungal regimen depends in part upon which species of Scedosporium is causing the infection. Given the rarity of Scedosporium and Lomentospora infections and the relative antifungal resistance of these pathogens, particularly L. prolificans, clinicians should consult with an infectious diseases specialist with experience managing these infections.
Scedosporium apiospermum — The antifungal agent with the greatest efficacy against S. apiospermum is voriconazole [40,42]. Many experts empirically treat patients with S. apiospermum infections with voriconazole monotherapy. We agree with this approach. We do not use amphotericin B to treat S. apiospermum infections. The antifungal regimen should be tailored according to in vitro susceptibility results while also factoring in nonpharmacologic parameters as noted above. In patients receiving immunosuppressive therapy (eg, hematopoietic cell and solid organ transplant recipients), we reduce immunosuppression when feasible.
Most clinical data on the treatment of Scedosporium infections are related to the use of voriconazole:
●A large retrospective study reviewed 107 patients treated for Scedosporium infection with voriconazole, 70 of whom had S. apiospermum infection . Forty-five of 70 patients (66 percent) with S. apiospermum infection had successful responses. The most common underlying conditions were solid organ transplant (22 percent), hematologic malignancy (21 percent), and surgery or trauma (15 percent). Cancer patients and hematopoietic cell transplant recipients had the worst outcomes.
●Another case series of 13 transplant recipients with scedosporiosis and an additional 67 cases reported in the literature between 1985 and 2003 were analyzed regarding treatment outcomes . A logistic regression model, using amphotericin B as the comparator, demonstrated that voriconazole was associated with a trend toward better survival; however, mortality remained greater than 50 percent in those with disseminated disease .
●In a salvage study that included patients who were refractory or intolerant of antifungals, voriconazole demonstrated a response rate of only 30 percent in the subgroup with Scedosporium infections . Several case reports have suggested potential efficacy of systemic voriconazole in the treatment of disseminated S. apiospermum infection [44,45].
●Based upon a review of the literature from 2000 to 2018 and Fungiscope (an internal registry of rare invasive fungal infections), including >200 patients with Scedosporium infection, patients who were treated with voriconazole-based regimens had overall longer survival time and lower 42-day mortality compared with those treated with amphotericin B . Surgical interventions, debridement, or drainage were also performed where feasible, though a survival benefit was not noted.
In clinical trials, isavuconazole, which has been approved for treating invasive aspergillosis and invasive mucormycosis, was shown to be noninferior to voriconazole for invasive mold disease caused by Aspergillus spp and other filamentous fungi [61,62]. Isavuconazole was also better tolerated by patients and exhibited an improved safety profile. However, only three patients with Scedosporium infection participated, thus precluding conclusions about efficacy for these infections. Individualized care of the patient with Scedosporium, including susceptibility testing of the isolate along with infectious disease consultation and careful monitoring, is crucial for managing these complex infections.
Although amphotericin B has been used to treat Scedosporium infection, a retrospective analysis of patients who received amphotericin B lipid complex for invasive fungal infections showed very poor response rates in patients who were infected with Scedosporium . Animal studies also do not support the use of amphotericin B .
Lomentospora prolificans — We typically initiate combination antifungal therapy for patients with L. prolificans infection. In general, we suggest voriconazole plus terbinafine with or without an echinocandin. However, this fungus is generally resistant to most available antifungals, and there are no definitive data to suggest that these regimens should be preferred over others. In all cases, we check in vitro susceptibilities because the relative efficacy antifungal agents varies among strains.
Although voriconazole appears to have some activity against this organism, minimum inhibitory concentrations (MICs) tend to be high, and the response to therapy varies depending on the site and extent of infection and the underlying immune status of the host. Patients with L. prolificans infection who are not severely immunocompromised and have skin and soft tissue or bone infection have better outcomes with voriconazole than patients with severe immunosuppression (eg, cancer, hematopoietic cell transplantation) or those with respiratory, central nervous system, or disseminated disease.
Given the aggressive and often fatal nature of infections with L. prolificans, management needs to be tailored to the individual patient. Surgical debridement and optimization of the patient's immune status (eg, reducing immunosuppression when feasible) are key elements that play a role in determining outcome. Some experts give combination antifungal therapy with an extended-spectrum azole (eg, voriconazole) plus terbinafine or an echinocandin or both. We typically give voriconazole plus terbinafine with or without an echinocandin. The antifungal regimen should be tailored according to in vitro susceptibility results when they become available. In cases for which susceptibility testing reveals no good antifungal options, antifungal agents are maintained while management of the infection and underlying condition are re-evaluated. While an optimal outcome is desired, not all of these cases will achieve a successful result.
Case-by-case analysis of the patient's underlying disease, treatment regimen, type of Lomentospora infection, pharmacokinetic/pharmacodynamic data, and MIC of the pathogen help ascertain whether terbinafine may have a role as part of combination therapy. Specific dosing recommendations are not available for terbinafine in L. prolificans infections. In case reports, the combination of terbinafine 250 mg once or twice daily and appropriately dosed voriconazole, along with adjunctive therapies such as surgical debridement, has led to successful outcomes in a few patients [65-70]. Pharmacokinetic modeling shows that terbinafine doses of 500 mg twice daily achieve higher systemic exposure  and higher cure rates in patients with sporotrichosis . Whether this dose would apply to treatment of Lomentospora infections as part of combination therapy remains to be determined.
Mortality rates with L. prolificans infection are high due to resistance to available antifungal agents. A retrospective review showed successful responses to therapy with voriconazole in 16 of 36 patients (44 percent) infected with L. prolificans . Survival rates were significantly lower among patients with L. prolificans compared with those with S. apiospermum infection. However, the specifics regarding underlying disease and site of disease for these cases were not reported.
Based upon a comprehensive review of the literature and Fungiscope (an international registry of invasive fungal infections) which included 56 patients with L. prolificans infection, mortality was very high regardless of treatment type, although mortality was lower in patients who received voriconazole-based regimens when compared with other antifungal agents (52.6 versus 68.8 percent) . The addition of terbinafine to voriconazole did not appear reduce mortality. There were likely multiple contributors to mortality that may confound analysis (eg, degree of immunosuppression, severity of illness, and organs involved in the infection).
In a separate review from the Fungiscope registry spanning 2008 to 2019, both voriconazole and terbinafine based regimens were associated with treatment success. In this review, mortality was reduced with voriconazole-based combination therapy or any combination antifungal therapy when compared with monotherapy . As with the review above, there are multiple contributors to mortality that may confound the analysis.
Sclerokeratitis with L. prolificans has a poor response to therapy with both topical and systemic agents . Endophthalmitis with this mold, be it secondary to trauma or in disseminated infection, also has a poor response to both systemic and intravitreal agents [74,75].
Case series of immunocompetent individuals with L. prolificans septic arthritis [76-78] and osteomyelitis [65,79] treated with prolonged antifungal agents and surgical debridement (plus local irrigation with polyhexamethylene biguanide in one case) reported improvement in several patients.
In some, but not all, animal studies, combination therapy appeared to be more effective than monotherapy. As an example, in a murine model of disseminated L. prolificans infection, the combination of micafungin with either voriconazole or amphotericin B prolonged survival and decreased colony counts in both the kidneys and brain compared with single-agent and triple-agent therapy . However, neutropenic mice with disseminated L. prolificans treated with liposomal amphotericin B, caspofungin, or combination therapy with both agents had poor outcomes . High doses of liposomal amphotericin B reduced colony counts, but toxicity was high and survival shortened. Caspofungin did not reduce colony counts, although, at high doses, it appeared to prolong survival. The combination of liposomal amphotericin B and caspofungin was no better than liposomal amphotericin B alone.
In an immunocompetent rabbit model, albaconazole, a triazole that is not currently available in the United States, significantly reduced fungal tissue burden and resulted in 100 percent survival of the animals at the highest dose tested .
Scedosporium aurantiacum — Most clinical cases of S. aurantiacum infection have been reported from Australia, where it has been associated with chronic lung disease . A few invasive cases have been described, but none involved the brain or skin. Low voriconazole and posaconazole MICs suggest that these agents may be effective for S. aurantiacum infections. Some studies have shown that the echinocandins all have higher minimum effective concentrations (MECs) to S. aurantiacum compared with other species in the S. apiospermum complex [15,84-87]. The new antifungal agents, olorofim and fosmanogepix, have both exhibited low in vitro MIC values against S. aurantiacum [18,19,22,23,27,88].
Further studies are needed to correlate MIC data to clinical outcome.
Voriconazole dosing and monitoring — Voriconazole is available in both intravenous (IV) and oral formulations [89-91]. The recommended dosing regimen is 6 mg/kg IV every 12 hours on day 1 followed by 4 mg/kg IV every 12 hours thereafter.
When the patient is able to take oral medications, one can consider switching to the oral form. Optimal oral dosing is a matter of controversy. The currently recommended dose of 200 mg orally every 12 hours has been noted to result in low or even unmeasurable serum concentrations in a substantial proportion of patients, and high concentrations may be associated with excessive toxicities . The dose of oral voriconazole can be increased to 4 mg/kg orally every 12 hours (or 300 mg orally every 12 hours) in patients with disease progression.
We suggest monitoring serum voriconazole trough concentrations in all patients receiving oral or IV voriconazole for invasive Scedosporium or Lomentospora infection. We suggest checking a trough concentration five to seven days into therapy. A goal of achieving serum trough concentrations >1 mcg/mL and <5.5 mcg/mL has been suggested , but we prefer concentrations between 2 and 5.5 mcg/mL. Trough concentrations below 1 mcg/mL warrant an increase in the voriconazole dose and appropriate subsequent monitoring . On the other hand, serum drug concentrations above 5.5 mcg/mL warrant a reduction in the voriconazole dose because they have been associated with an increased risk of toxicity [92,93]. (See "Pharmacology of azoles", section on 'Serum drug concentration monitoring'.)
As with other triazoles, use of this agent requires careful monitoring due to potential interactions with other medications, including calcineurin inhibitors, via inhibition of CYP450 enzymes [94,95]. Details about specific interactions may be obtained by using the Lexicomp drug interactions tool included within UpToDate. An overview of drug interactions with voriconazole is presented elsewhere. (See "Pharmacology of azoles", section on 'Drug interactions'.)
The adverse effects associated with voriconazole are also discussed separately. (See "Pharmacology of azoles", section on 'Adverse effects' and "Pharmacology of azoles", section on 'Voriconazole'.)
Duration — Antifungal therapy is generally continued until all signs and symptoms of the infection have resolved and often longer in patients with persistent immune defects. Radiographic abnormalities should have stabilized and signs of active infection should have disappeared before treatment is discontinued. For most immunocompromised patients, antifungal therapy will continue for months or even years in some cases.
SURGICAL DEBRIDEMENT — Given the poor response to antifungal therapies alone, surgical debridement (in addition to antifungal therapy) is encouraged whenever possible. Surgical debridement can help to decrease the burden of organisms present and has been associated with improved outcomes [37,96]. Adjunctive surgery has been reported for Scedosporium soft tissue infection , osteomyelitis [53,54,65,79], pneumonia [46,49], and brain abscesses [57,97-99].
In a study of 55 pediatric patients with invasive Scedosporium spp and L. prolificans infection, 96 percent were treated with antifungals independent of the causative fungus and 62 percent received surgical intervention . Most patients undergoing surgical intervention were immunocompetent, and procedures included surgical debridement of bone and joint infections, drainage of central nervous system abscess, and surgical management of eye infections. Lower risk of death was noted if voriconazole and surgery were included as part of the treatment regimen.
In adults with L. prolificans infection, surgical intervention was associated with higher 28-day survival rates, though the number of patients was small .
Management of mold endophthalmitis is discussed separately. (See "Treatment of endophthalmitis due to molds".)
ADJUNCTIVE THERAPIES — Adjunctive therapies, including immunomodulatory therapies (eg, granulocyte-colony stimulating factor [G-CSF]) and hyperbaric oxygen therapy require further study.
Immunomodulatory therapies — As noted above, in patients receiving immunosuppressive therapy (eg, hematopoietic and solid organ transplant recipients), we reduce immunosuppression when feasible.
Several studies have examined the role of immune modulation in the treatment of fungal infections. These include cellular growth factors (eg, granulocyte-colony stimulating factor), cytokines such as the proinflammatory cytokines interferon (IFN)-gamma or interleukin-12, monoclonal antibodies, granulocyte infusions, immunoglobulin infusions, and active immunization [101,102].
The use of adjunctive G-CSF for recovery of neutropenia [66,103] or the use of IFN-gamma  have been reported in isolated cases, but no firm conclusions can be drawn about their efficacy. In a case series of patients with L. prolificans infections, survival was independently associated with recovery from neutropenia . However, studies in animal models have not demonstrated improved survival or differences in fungal burden with the addition of G-CSF to either amphotericin B formulations or posaconazole [104,105]. Nevertheless, in neutropenic patients with scedosporiosis, adjunctive G-CSF can be considered.
In in vitro studies, Scedosporium and Lomentospora species were vulnerable to polymorphonuclear leukocytes (PMNs) and macrophages, especially when opsonization of hyphae occurred [106,107]. Another in vitro study used the combination of various triazoles (itraconazole, voriconazole, posaconazole) plus PMNs against S. apiospermum and L. prolificans . The combination of posaconazole plus PMNs appeared to have synergistic activity against L. prolificans isolates but additive effects against S. apiospermum.
Hyperbaric oxygen therapy — Another approach that warrants further study is the use of a hyperbaric oxygen therapy. In vitro testing showed that all antifungal agents had low minimum inhibitory concentrations (MICs) when incubated with S. apiospermum and L. prolificans isolates in a hyperbaric atmosphere . However, the MICs reverted to the expected high values when the incubation was performed in a normal atmosphere. It is unknown whether exposing patients with Scedosporium infections to a hyperbaric atmosphere would improve the efficacy of antifungal therapy.
PROGNOSIS — As noted above, Scedosporium and Lomentospora infections are associated with a high incidence of disseminated disease and high mortality rates in hematopoietic cell and solid organ transplant recipients; mortality rates have ranged from 40 to 100 percent [37-40,96,110]. Treatment failures are especially common in patients with L. prolificans infection. The majority of patients with respiratory, central nervous system, or disseminated L. prolificans infections have succumbed regardless of the antifungal regimen used [41,70,100,111-118]. (See 'Lomentospora prolificans' above.)
The outcome of Scedosporium and Lomentospora infection depends upon the immune status of the host, the location and extent of the infection, and whether surgical debridement is possible.
SUMMARY AND RECOMMENDATIONS
●Scedosporium and Lomentospora are filamentous fungi ubiquitous in the environment. The two major human pathogens within this genus are Scedosporium apiospermum (the asexual form of Pseudallescheria boydii) and Lomentospora prolificans. (See 'Introduction' above.)
●We send clinical isolates for susceptibility testing from all patients with Scedosporium or Lomentospora infection. (See 'Susceptibility testing' above.)
●Antifungal therapy should be initiated as soon as possible for Scedosporium or Lomentospora infection.
•L. prolificans is resistant to most of the antifungal agents available. For empiric therapy of L. prolificans infection, we suggest voriconazole plus terbinafine with or without an echinocandin (Grade 2C). (See 'Lomentospora (formerly Scedosporium) prolificans' above.)
•The antifungal regimen should be tailored according to in vitro susceptibility results. (See 'Choice of regimen' above.)
●In patients receiving immunosuppressive therapy (eg, hematopoietic cell and solid organ transplant recipients), we reduce immunosuppression when feasible. (See 'Antifungal therapy' above.)
●Surgical debridement should be performed when feasible (ie, when infection is localized) as it has been associated with improved outcomes. (See 'Surgical debridement' above.)
●In neutropenic patients, granulocyte-colony stimulating factor to hasten recovery from neutropenia can be considered, although further study is needed to establish its efficacy. (See 'Immunomodulatory therapies' above.)
●Scedosporium and Lomentospora infections are associated with a high incidence of disseminated disease and high mortality rates in hematopoietic cell and solid organ transplant recipients; mortality rates have ranged from 40 to 100 percent. The site of infection and underlying immune status of the host play an important role in the response to therapy and survival. Treatment failures are especially common in patients with L. prolificans infection. (See 'Prognosis' above.)
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