Treatment and prevention of Fusarium infection

INTRODUCTION — Fusarium species cause a broad spectrum of infections in humans, including superficial infections such as keratitis and onychomycosis, as well as locally invasive and disseminated infections [1]. Invasive and disseminated infections occur almost exclusively in severely immunocompromised patients, particularly among those with prolonged and profound neutropenia and/or severe T cell immunodeficiency. Among patients with hematologic malignancy, the infection predominates during periods of neutropenia, typically among patients with leukemia receiving induction chemotherapy.

Fusarium species may also cause allergic diseases, such as sinusitis in immunocompetent individuals [2], and mycotoxicosis following ingestion of food contaminated by toxin-producing Fusarium species [3]. Fusarium species are also important plant pathogens that cause various diseases on cereal grains [3] and occasionally cause infection in animals [4].

The treatment and prevention of fusariosis will be reviewed here. The mycology, pathogenesis, epidemiology, clinical manifestations, and diagnosis of fusariosis are discussed separately. (See "Mycology, pathogenesis, and epidemiology of Fusarium infection" and "Clinical manifestations and diagnosis of Fusarium infection".)

ANTIFUNGAL SUSCEPTIBILITY — Fusarium species are relatively resistant in vitro to most antifungal agents. Although antifungal susceptibility testing results have varied in different studies, the following general patterns have been observed [1,5-22]:

●Most Fusarium isolates have higher amphotericin B minimum inhibitory concentrations (MICs) than do Aspergillus species.

●Susceptibility to amphotericin B is usually higher than to the azoles voriconazole, posaconazole, and isavuconazole.

●F. solani and F. verticillioides (previously F. moniliforme) have higher azole MICs than other Fusarium species.

●However, compared with F. solani, the MICs for F. oxysporum and F. verticillioides are lower for amphotericin B, voriconazole, and posaconazole.

●Susceptibility within a species complex may vary from one species to another [22].

●Older azoles, such as itraconazole and fluconazole, have high MICs to Fusarium.

●The echinocandins (caspofungin, micafungin, and anidulafungin) lack activity against Fusarium spp.

Epidemiologic cutoff value (ECV) definitions for 1050 isolates of various species from laboratories from different countries have been reported [23]. The ECV for F. solani species complex was 8 mcg/mL for amphotericin B and 32 mcg/mL for itraconazole, voriconazole, and posaconazole. For F. oxysporum, the ECV was 8 mcg/mL for amphotericin B and posaconazole, 16 mcg/mL for voriconazole, and 32 mcg/mL for itraconazole. The use of ECVs and antifungal susceptibility testing is discussed in detail separately. (See "Antifungal susceptibility testing".)

The clinical relevance of these in vitro data is not clear. Interpreting the MICs of antifungal agents for molds is difficult with no established breakpoints for defining susceptibility or resistance [24]. Differences in testing methods are likely responsible for the differences in susceptibility testing results [9,11,12,14]. A multicenter study analyzed the correlation between MIC and the outcome in 88 cases of fusariosis, 74 with hematologic diseases. The MIC50 was 8 mcg/mL (range 0.5 to 64) for voriconazole, 2 mcg/mL (range 0.25 to 64) for amphotericin B, 16 mcg/mL (range 0.5 to 64) for posaconazole, 32 mcg/mL (range 4 to 64) for itraconazole, and 32 mcg/mL (range 8 to 64) for isavuconazole. There was no difference in MIC50 and MIC distribution among survivors and patients who died. By contrast, persistent neutropenia and receipt of corticosteroids were strong predictors of 6-week mortality [25]. Considering the lack of correlation between MIC and outcome, we cannot recommend routine in vitro susceptibility testing. When testing is performed, the results must be interpreted with caution, and treatment decisions should be based mostly upon the individual patient's response to therapy.

Certain antifungal agents, such as terbinafine and the echinocandins, have little in vitro activity alone but appear synergistic with other antifungal agents in vitro when tested in combination. However, their role in the treatment of invasive disease is not clear. (See 'Combination therapy' below.)

The geographic prevalence of different Fusarium species is discussed separately. (See "Mycology, pathogenesis, and epidemiology of Fusarium infection", section on 'Species prevalence'.)

ANTIFUNGAL AGENTS — As discussed above, different Fusarium species exhibit variable in vitro susceptibility to antifungal agents, and the clinical relevance of these data is not known. This section describes what is known about the clinical use of antifungal agents for Fusarium infections; most data come from case reports and observational studies in immunocompromised patients with invasive fusariosis.

Treatment recommendations based upon the immune status of the host and the site(s) of infection are presented below. (See 'Treatment' below.)

Amphotericin B — Lipid formulations of amphotericin B have been successful in the treatment of some patients and have been used most extensively for invasive fusariosis [26,27]. In the Collaborative Exchange of Antifungal Research database, 28 of 3514 patients developed fusariosis and were treated with amphotericin B lipid complex either as primary or salvage therapy [27]. Of the 26 evaluable patients, 12 (46 percent) were cured or improved, and 3 (12 percent) stabilized after receiving therapy. Patients with normal absolute neutrophil counts at the end of therapy had better outcomes than those who did not, regardless of neutrophil status at baseline.

Azoles — Voriconazole is fungicidal for filamentous fungi, including Fusarium spp, and is approved in many parts of the world, including the United States, Europe, and Brazil, for the treatment of Fusarium infections in patients who are not responding to or are intolerant of other therapies. This recommendation was based upon a series of only 11 patients [28]. Additional publications have since extended the observations of the use of voriconazole among patients with fusariosis. These include a review of 102 cases [29] and a composite review of 73 cases from the Pfizer database and the French National Reference Center for Mycoses database [30]. In the latter study, the overall response rate (complete or partial) was 47 percent and 52 percent when data were limited to those patients who received at least five days of therapy [30]. The response rate did not differ among different species. The most significant parameter that predicted success was resolution of neutropenia; a 63 percent response rate was observed among patients whose neutropenia resolved, compared with only 5 percent among patients who remained neutropenic. None of the four patients with brain lesions caused by Fusarium spp survived.

More recently, the outcomes of 233 cases of invasive fusariosis from 44 centers in 11 countries were analyzed [31]. Compared with cases reported between 1985 and 2000, cases reported from 2001 to 2011 had a better 90-day survival rate (43 versus 22 percent). Differences in treatment practices between the earlier period and the later period included a reduction in the use of amphotericin B deoxycholate and an increase in the use of voriconazole and combination therapy. During the later period, the 90-day survival was 60 percent with voriconazole treatment, 53 percent with a lipid formulation of amphotericin B, and 28 percent with amphotericin B deoxycholate.

Posaconazole possesses in vitro activity against Fusarium spp, although results differed among studies; as noted with voriconazole, the susceptibility pattern is species dependent [6]. The clinical experience using posaconazole salvage therapy is somewhat limited. In a retrospective analysis, 21 patients with proven or probable invasive fusariosis who were not responding to or were intolerant of other therapies received oral posaconazole suspension salvage therapy at 800 mg orally per day in divided doses [32]. Most patients (76 percent) had an underlying hematologic malignancy. A 48 percent complete or partial response to posaconazole was seen. Case reports have also suggested that posaconazole is effective for fusariosis [33]. On the other hand, cases of disseminated fusariosis have been reported in patients receiving posaconazole prophylaxis [34].

Isavuconazole is a broad-spectrum azole approved for the treatment of invasive aspergillosis and mucormycosis. Clinical experience in the primary treatment of invasive fusariosis is limited; among nine reported cases, three had a complete or partial response [35].

Because older azoles (eg, itraconazole and fluconazole) do not have activity against Fusarium species, they do not have a role in the treatment of invasive fusariosis [17,36].

Echinocandins — The echinocandins (caspofungin, micafungin, anidulafungin) should not be used to treat invasive infection with Fusarium spp because they lack activity against these pathogens [18]. (See 'Antifungal susceptibility' above.)

Combination therapy — Because of species-dependent variability in in vitro susceptibility profiles of Fusarium spp and the poor prognosis of fusariosis in immunocompromised hosts, particularly those with disseminated disease, some have recommended combination antifungal regimens initially in such settings in order to ensure activity of at least one agent [37,38]. A small number of in vitro studies have suggested that certain antifungal combinations may be synergistic (eg, voriconazole plus terbinafine [39,40] or amphotericin B plus voriconazole [39,40]), although possible antagonism remains a potential concern, particularly with the latter combination.

The clinical significance of these in vitro data is unclear. Single case reports have described successful outcomes using the following combinations: amphotericin B plus voriconazole [37,41-43], amphotericin B plus terbinafine [44,45], or amphotericin B plus caspofungin [46]. However, potential publication bias limits the usefulness of these findings. In a retrospective review of 73 patients with invasive fusariosis treated with voriconazole, 13 received another agent (liposomal amphotericin B, terbinafine, caspofungin, or posaconazole) in combination with or immediately following voriconazole; the response rate among these patients was similar to that reported with voriconazole monotherapy [30]. In an analysis of the outcomes of 233 cases of invasive fusariosis, a benefit of combination therapy was not observed, possibly because patients who received combination therapy were very sick with advanced disease and severe immunosuppression [31].

TREATMENT — Because Fusarium species exhibit limited and species-dependent susceptibility to antifungal agents and because of the lack of randomized trials, the optimal treatment of fusariosis is not well established [47]. Amphotericin B and voriconazole are the most commonly used agent for invasive disease.

Localized disease — Localized disease, such as keratitis and onychomycosis, are the most common manifestations of Fusarium infection in immunocompetent patients.

Keratitis — Fusarial keratitis may develop following the traumatic inoculation of Fusarium-contaminated soil or plant material or related to poor hygiene practices in soft contact lens wearers. (See "Mycology, pathogenesis, and epidemiology of Fusarium infection", section on 'Keratitis'.)

The treatment of Fusarium keratitis is challenging because of the limited and variable susceptibility of Fusarium spp to antifungal agents, the poor tissue penetration of topical antifungal agents, and the potential seriousness of infection by this pathogen, which can result in corneal perforation and even endophthalmitis. In one study, keratitis due to F. solani was associated with longer time to cure and worse follow-up best-corrected visual acuity compared with non-F. solani cases [48].

First-line therapy for fusarial keratitis includes a topical antifungal agent either alone or in combination with systemic antifungal medications. We favor a combination of topical plus systemic therapy in immunocompromised patients and in those with severe infections. Natamycin suspension (5 mg/mL) has been the traditional drug of choice for topical therapy, although amphotericin B drops (1.5 mg/mL) have also been used [49,50]. Topical voriconazole is increasingly favored among ophthalmologists [51,52]. However, one randomized trial comparing topical natamycin with topical voriconazole for the treatment of fungal keratitis (24.6 percent of which were caused by Fusarium spp) suggested that natamycin may be more effective in healing corneal ulcers and improving visual acuity [53]. Topical agents should initially be applied hourly with subsequent modification based upon response.

The addition of systemic therapy with voriconazole is commonly used, particularly in severe cases [49,54]. In hospitalized patients, the loading dose of voriconazole is 6 mg/kg intravenously (IV) every 12 hours for two doses, followed by 4 mg/kg IV every 12 hours. For outpatients, oral voriconazole may be given as a loading dose of 400 mg orally every 12 hours for two doses, followed by 200 mg orally twice daily. Oral posaconazole has been used successfully in three patients who did not respond to systemic and/or topical voriconazole [55].

In a secondary analysis of a randomized trial that compared adjuvant oral voriconazole to placebo in 72 patients with fusarial keratitis who also received topical antifungal therapy, oral voriconazole was associated with a 0.43-fold reduced hazard of perforation or therapeutic penetrating keratoplasty [56].

Small case series have reported success in some patients, but not others, with the addition of intracorneal (intrastromal) injections of voriconazole in patients who responded poorly to topical and systemic therapy [57-59].

The total duration of antifungal therapy depends upon the patient's response, which should be assessed frequently by ophthalmologic examinations. Many patients require several months of therapy. In a retrospective study of fungal keratitis, Fusarium was the most common pathogen, occurring in 29 of 78 eyes (37 percent) [60]. The average duration of therapy was 81 days (range 20 days to 1 year). The time to healing, defined as resolution of infiltrate and epithelial healing, was a mean of 57 days but ranged from 8 to 300 days.

Patients who do not respond to antifungal therapy usually require corneal transplantation. Patients with keratitis should be managed by an ophthalmologist with expertise in corneal infections.

The management of endophthalmitis caused by molds is discussed separately. (See "Treatment of endophthalmitis due to molds", section on 'Treatment Modalities'.)

Onychomycosis — Fusarium onychomycosis is difficult to treat, with high failure rates even after long courses of systemic antifungal or topical therapy, with or without nail avulsion [61]. Despite limited in vitro activity, oral itraconazole and terbinafine are commonly used as therapy for fusarial onychomycosis and have been observed to be effective in immunocompetent patients in some [62-64] but not all reports [65]. The newer triazoles, voriconazole and posaconazole, have greater in vitro activity against Fusarium spp than itraconazole. We favor the use of oral voriconazole in immunocompromised patients with onychomycosis caused by Fusarium spp. Voriconazole is administered as a loading dose of 400 mg orally every 12 hours for two doses, followed by 200 mg orally twice daily. Adjunctive nail avulsion with topical amphotericin B can be used in patients who do not respond to systemic antifungal therapy, but it is usually avoided in severely immunocompromised patients. The infection often requires months of therapy, and the duration depends on the patient's overall state of immunosuppression and the response to therapy. (See 'Duration' below.)

The management of onychomycosis in immunocompetent patients is discussed separately. (See "Onychomycosis: Management" and "Onychomycosis: Management", section on 'Yeast and nondermatophyte mold onychomycosis'.)

Invasive disease — Because Fusarium infections are almost always invasive in immunocompromised hosts and are often disseminated, treatment should be multifaceted; although systemic antifungal agents represent the cornerstone of therapy, surgical debridement of infected tissues and/or removal of infected foreign bodies should be performed when possible. Therapy usually starts without knowing the infecting species because identification to the species level is typically performed only at reference laboratories, and results may not be rapidly available to the treating clinician. Cases of catheter-related fusariosis usually resolve with antifungal therapy and catheter removal [66-70].

Choice of antifungal therapy — The optimal treatment strategy of patients with fusariosis remains unclear because of the lack of clinical trials and the critical role that immune reconstitution plays in the outcome of this infection. Successful outcomes have been reported with various antifungal agents including amphotericin B deoxycholate [71], liposomal amphotericin B [71], amphotericin B lipid complex [27], and the triazole antifungals, voriconazole [28,30], posaconazole [32], and isavuconazole [35]. Combination antifungal therapy has also been described in single case reports and a retrospective study, as discussed above. (See 'Combination therapy' above.)

A lipid formulation of amphotericin B (3 to 5 mg/kg IV once daily) is usually the preferable first-line therapy. An alternative is voriconazole (6 mg/kg IV every 12 hours for two doses, followed by 4 mg/kg IV every 12 hours). A combination of a lipid formulation of amphotericin B and voriconazole is often used because of the variable susceptibility of Fusarium spp to antifungal agents and the need to ensure that at least one active antifungal agent is given [72]. Combination therapy with a lipid formulation of amphotericin B and voriconazole should be considered in cases of severe immunosuppression and/or severe disease or in patients with increasing skin lesions or persistently positive blood cultures while on monotherapy. Combination therapy (using intravenous liposomal amphotericin B 5 mg/kg/day and intravenous voriconazole) has been recommended by the Centers for Disease Control and Prevention (CDC) for treatment of confirmed or suspected meningitis due to Fusarium; higher dosages of liposomal amphotericin B (7.5 to 10 mg/kg/day) have been used for refractory cases. Updated CDC recommendations can be found on the CDC website and the fungus education hub [73-75]. Further details about the outbreak can be found separately. (See "Aseptic meningitis in adults", section on 'Fusarium outbreaks'.)

We strongly discourage the use of amphotericin B deoxycholate because it has more toxicities (especially nephrotoxicity) than the lipid formulations and because the response rate was lower compared with a lipid formulation of amphotericin B or voriconazole [31]. (See "Pharmacology of amphotericin B" and "Amphotericin B nephrotoxicity".)

A switch from IV to oral therapy with voriconazole (200 to 300 mg orally twice daily) may be considered upon achievement of a significant response, provided that the patient is compliant and is able to absorb oral medications. Posaconazole delayed-release tablets (300 mg orally once daily) are an alternative option if voriconazole cannot be given. Monitoring serum drug concentration is recommended during oral therapy. This is discussed in detail separately. (See "Pharmacology of azoles", section on 'Voriconazole' and "Pharmacology of azoles", section on 'Posaconazole'.)

Duration — The duration of antifungal therapy depends upon the site and extent of the infection, the patient's underlying disease and immune status, the need for continuous immunosuppression, and the response to therapy. The most important factor in outcome is resolution of neutropenia. Antifungal therapy is generally continued until all signs and symptoms of the infection have resolved, radiographic abnormalities have stabilized, and significant immune reconstitution has occurred. For severely immunosuppressed patients or patients with central nervous system (CNS) infection, antifungal therapy may continue for months or longer in some cases; in patients with Fusarium meningitis, the CDC has made treatment recommendations that can be reviewed on the CDC website and the fungus education hub [73-75]. (See 'Choice of antifungal therapy' above.)

Adjunctive therapies — Because a recovering immune system is essential for the successful outcome of fusariosis, every effort should be made to enhance immunity; this includes decreasing the dose of immunosuppressants when possible and the use of adjunctive immunotherapy, such as granulocyte or granulocyte-macrophage colony-stimulating factors (G-CSF or GM-CSF), G-CSF- or G-CSF plus dexamethasone-stimulated granulocyte transfusions, or interferon-gamma. The efficacy of these therapies for fusariosis has not been established [76,77]. A single-center series of 11 patients with invasive fusariosis treated with antifungal agents and G-CSF plus dexamethasone-stimulated granulocyte transfusions reported a 73 percent 90-day survival. As expected, all survivors had neutrophil recovery [78].

Additional strategies include surgical debridement of infected tissues (eg, sinuses, soft tissues, lung nodules) [79], particularly in immunocompromised patients with localized disease, and removal of central venous catheters in patients with possible catheter-related fusariosis [66].

PREVENTION — Because of the poor prognosis associated with fusariosis and the limited susceptibility of Fusarium species to antifungal agents, preventing this infection is important, when possible.

Primary prophylaxis — General preventive measures that should be employed in patients at significant risk of invasive fusariosis, such as patients with hematologic malignancies undergoing induction chemotherapy or hematopoietic cell transplantation (HCT), include [1,80-82]:

●Avoidance of activities associated with skin breakdown.

●Avoidance of contact of areas of skin breakdown with tap water.

●Careful examination for and treatment of onychomycosis, interdigital intertrigo, and paronychia and surgical debridement of infected wounds prior to commencing anticancer therapies. (See 'Onychomycosis' above.)

●Delaying severely immunosuppressive therapies until areas of skin breakdown are healed, when possible.

●Following appropriate air and water precautions during periods at risk – These include use of a high-efficiency particulate air filter and positive pressure isolation rooms, avoiding contact with reservoirs of Fusarium spp, such as tap water, and having showers cleaned thoroughly prior to use by high-risk patients. (See "Prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults", section on 'General precautions'.)

One study showed that patients with hematologic malignancies who had interdigital intertrigo and/or onychomycosis at the time of hospital admission and who had cultures of such lesions showing Fusarium spp were at increased risk for development of invasive disease [83]. In a subsequent study of five patients who had positive cultures of skin lesions and who did not receive prophylaxis, four developed invasive fusariosis [84]. By contrast, none of six patients who received prophylaxis with voriconazole or posaconazole developed invasive fusariosis, a difference that was statistically significant.

Considering the high mortality rate associated with invasive fusariosis, we also favor the following approach for patients at significant risk of invasive fusariosis:

●A thorough dermatologic examination of the extremities upon admission

●Culture of any suspicious lesion (especially interdigital intertrigo or onychomycosis), and

●Primary prophylaxis with voriconazole or posaconazole in patients with positive cultures

Since fungi may take a few days to grow in cultures, we initiate prophylaxis if hyaline hyphae are observed on direct microscopy and adjust prophylaxis a few days later, when cultures confirm (or exclude) the diagnosis of superficial fusariosis.

Posaconazole delayed-release tablets should be given as a loading dose of 300 mg (three 100 mg tablets) every 12 hours on the first day, followed by a maintenance dose of 300 mg (three 100 mg tablets) daily starting on the second day.

Voriconazole is administered as a loading dose of 400 mg orally every 12 hours for two doses, followed by 200 mg orally twice daily.

For patients involved in a nosocomial outbreak of Fusarium meningitis associated with epidural anesthesia in Mexico, management of exposures is detailed on the CDC website and the fungus education hub [73-75]. Further information about the outbreak is available separately. (See "Aseptic meningitis in adults", section on 'Fusarium outbreaks'.)

Secondary prophylaxis — In patients who had a prior episode of fusariosis, secondary antifungal prophylaxis should be given to prevent relapse of infection during periods of increased immunosuppression. Secondary prophylaxis should be given when the patient receives chemotherapy, undergoes HCT, or when immunosuppression is significantly increased for the management of graft-versus-host disease (GVHD). Among patients with a history of invasive Fusarium infection, the following measures should be taken [1]:

●Evaluation of residual infection prior to starting immunosuppressive therapy: blood cultures, imaging with computed tomography, others as indicated

●Prophylaxis with an antifungal agent active against the Fusarium species previously isolated (voriconazole, posaconazole, or a lipid formulation of amphotericin B) (see 'Choice of antifungal therapy' above)

●Application of less immunosuppressive therapies when possible (eg, dose reduction of the antineoplastic regimen, reduced intensity rather than myeloablative conditioning regimen for HCT)

●Careful selection of donors in allogeneic HCT to decrease the immunosuppressive effects of GVHD, graft failure, or cytomegalovirus reactivation

●Consideration of granulocyte colony-stimulating factor plus dexamethasone-elicited granulocyte transfusions during periods of expected neutropenia [76,77]

●Documentation of GVHD before empiric therapy with glucocorticoids, when possible, and prompt therapy of GVHD with the lowest immunosuppressive regimen possible and a careful approach to glucocorticoid tapering

A multicenter retrospective study evaluated practices of secondary prophylaxis in 40 patients with fusariosis who were exposed to subsequent periods of immunosuppression following successful treatment of fusariosis [85]. Among 28 patients who had disseminated fusariosis, relapse occurred in 2 of 2 patients who did not receive secondary prophylaxis and in 3 of 26 who received prophylaxis, mostly with voriconazole [85].

PROGNOSIS — The prognosis of fusariosis is directly related to the patient's immune status, with very high mortality rates in persistently immunocompromised patients. The overall mortality rate from disseminated Fusarium infection is 60 to 80 percent [1,26,86-88]. In a series of 84 patients with fusariosis and an underlying hematologic malignancy, the 30- and 90-day survival rates were 50 and 21 percent, respectively [71]. Persistent neutropenia and recent glucocorticoid therapy were the only independent factors associated with poor outcome; no patient who had adverse prognostic factors survived, whereas the survival rate was 67 percent among patients who had neither of these factors. In a series of 22 cases of invasive fusariosis in children with hematologic malignancies and/or undergoing HCT, the 90-day probability of survival was 33 percent in patients with relapsed/refractory underlying malignancy versus 94 percent in others, further underscoring the importance of immune reconstitution on the outcome of invasive fusariosis [89].

SUMMARY AND RECOMMENDATIONS

●Spectrum of illness – Fusarium species cause a broad spectrum of infections in humans including superficial infections, such as keratitis and onychomycosis, as well as locally invasive and disseminated infections. Invasive and disseminated infections occur almost exclusively in severely immunocompromised patients. (See 'Introduction' above.)

●Antifungal resistance – Fusarium species usually exhibit high minimum inhibitory concentrations (MICs) to most antifungal agents, with F. solani showing higher MICs than other Fusarium species. (See 'Antifungal susceptibility' above.)

●Clinical management

•Keratitis – Patients suspected of having Fusarium keratitis should be evaluated and treated urgently. Treatment usually involves a combination of topical and systemic antifungal therapy. For patients with Fusarium keratitis, we suggest initial therapy with a topical antifungal agent in combination with systemic voriconazole (Grade 2C). Appropriate topical agents include natamycin, voriconazole, and amphotericin B. Topical agents should be used every hour initially. (See 'Keratitis' above.)

•Onychomycosis – For immunocompromised patients with Fusarium onychomycosis, we suggest treatment with voriconazole (Grade 2C) (see 'Onychomycosis' above and 'Primary prophylaxis' above). The management of onychomycosis in immunocompetent individuals is discussed separately. (See "Onychomycosis: Management" and "Onychomycosis: Management", section on 'Yeast and nondermatophyte mold onychomycosis'.)

•Invasive disease – Immunocompromised patients with invasive fusariosis require aggressive antifungal therapy. In such patients, we suggest initial therapy with a lipid formulation of amphotericin B or voriconazole (Grade 2C). Combination therapy with a lipid formulation of amphotericin B and voriconazole should be considered in cases of severe immunosuppression and/or severe disease, including meningitis. The dosing of lipid formulations of amphotericin B is 3 to 5 mg/kg intravenously (IV) once daily, and the dosing of voriconazole is 6 mg/kg IV every 12 hours for two doses, followed by 4 mg/kg IV every 12 hours. (See 'Choice of antifungal therapy' above.)

●Role of antifungal prophylaxis

•Primary prophylaxis – For patients at significant risk of invasive fusariosis, such as those with hematologic malignancies undergoing induction chemotherapy or hematopoietic cell transplantation (HCT), we suggest a thorough dermatologic examination of the extremities upon admission, culture of any suspicious lesion (especially interdigital intertrigo or onychomycosis), and primary prophylaxis with voriconazole or posaconazole in patients with positive cultures for Fusarium spp (Grade 2C). Other preventive measures are discussed above. (See 'Primary prophylaxis' above.)

•Secondary prophylaxis – In patients who have had a prior episode of fusariosis, we suggest secondary antifungal prophylaxis to prevent relapse of infection during periods of increased immunosuppression (Grade 2C). Secondary prophylaxis should be given when the patient receives chemotherapy, undergoes HCT, or when immunosuppression is significantly increased for the management of graft-versus-host disease. (See 'Secondary prophylaxis' above.)

●Prognosis – Disseminated Fusarium infections are associated with high mortality rates. The prognosis of fusariosis is directly related to the patient's immune status, with high mortality rates in persistently immunosuppressed patients, especially those who remain neutropenic. (See 'Prognosis' above.)