Trichosporon Infections

Background

Trichosporon are yeast-like anamorphic organisms that belong to the basidiomycetes yeasts.^[1]  Trichosporon yeasts are found worldwide, but most commonly in tropical and temperate regions such as South America, the Middle East, India, Southeast Asia, Africa, Europe, Japan, and parts of Southeastern United States.^[2]  Trichosporon spp are distributed mainly in soil, decomposing wood, water, foods, beetles, bird droppings, cattle, and bats. They can form part of the oral and gastrointestinal tract and transiently colonize the respiratory tract. They also may colonize the perianal and inguinal skin.^[3]

Most Trichosporon spp are saprophytic, however some can be pathogenic and cause both superficial and invasive disease.^[3] Historically this organism was known to cause white piedra, which is characterized by soft nodules along the hair shaft. The etiology of this disease was identified as Trichospron ovoides in 1890. Since then, several other species have been described. Trichosporon asahii is the most common species, followed by Trichosporon inkin, Trichosporon faecale, Trichosporon asteroides, and Trichosporon mucoides.^{[3, 4]}  T asahii, T mucoides, and T asteroides tend to cause invasive disease. T cutaneum, T ovoides, and T inkin all cause superficial infections of the skin, scalp and hair, and pubic hair, respectively.^{[3, 4, 5]}

Although first identified as a superficial infection of the skin or hair, Trichosporon is an opportunistic pathogen capable of causing invasive disease in immunocompromised patients or those with invasive medical devices. Trichosporon can adhere to polystyrene on medical devices and subsequently form biofilms, hence the association with peritoneal, bladder, and central venous catheters.^[4]  Similar to Candida, Trichosporon can form biofilms, which are complex, organized structures consisting of dense microbial communities encased in a self-produced extracellular matrix composed mainly of polysaccharides, extracellular DNA, and secreted proteins.^{[4, 6, 7]}

Invasive Trichosporon infections occur mostly in immunosuppressed patients, particularly those with hematological malignancies or AIDS. Unfortunately, diagnosing and treating invasive trichosporonosis can be challenging, and its global incidence is on the rise.^[5]

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Pathophysiology

Trichosporon species can harmlessly exist as commensals on the skin and in the gastrointestinal tract of healthy individuals, where they are monitored by the immune system and interact with the resident microbiome.^[8]  However, changes in the surrounding microenvironment can trigger their pathogenicity and result in clinically signficant disease. The pathophysiology of Trichosporonosis depends on whether the infection is superficial or invasive. 

Superficial infection

The most common superficial Trichosporon infection is known as white piedra (piedra is the Spanish word for “stone”). In this condition, Trichosporin grows beneath the hair cuticle until a stone like nodule is formed which weakens the hair shaft resulting in breakage. Hair texture may be rough or broken as a result. White piedra may be confused with dandruff; however, dandruff appears as white flakes falling from the scalp, whereas white piedra are whitish tan nodules attached to the hair shaft itself.^{[9, 10]}

Invasive infection

In general, invasive infection occurs as three possible syndromes; disseminated disease (the most common invasive disease presentation), invasive disease localized to a major organ (such as the bladder, lungs, or other organ), or an invasive infection that is related to a indwelling catheter. The pathophysiology of invasive Trichosporon infection involves several pathogen virulence factors and host risk factors which may determine which of these three syndromes develop.

Pertinent factors include the following:

• Enzymatic virulence factors: Enzyme products of Trichosporon include proteinases, lipases, and phospholipases, but the specific contribution of an individual enzyme to human disease remains unclear. Trichosporon spp produce phospholipases that disrupt host cell membranes by destruction of cell membrane proteins and lipids.^[11] Cell wall components such as Glucuronoxylomannan (GXM) may confer a survival advantage as they have been shown to impair the phagocytic capability of neutrophils and monocytes.^{[2, 6]}
• Immune evasion: The cell wall of Trichosporon contains a 1,3-linked mannose backbone similar to that of Cryptococcus neoformans that inhibits phagocytosis by macrophages in a murine model.^[12]
• Biofilm production: Biofilm production by Trichosporon facilitates colonization of indwelling devices, permitting both adherence to prosthetic material and reduction of the fungus’s exposure and susceptibility to antifungal drugs.^{[13, 14, 15]}  Some species such as T asahii and T inkin can be highly tolerant to amphotericin B, and produce persistent cells in the biofilm despite treatment with amphotericin B.^{[2, 4]}
• Phenotypic switching: Trichosporin are physiologically complex and adaptable, able to survive in a variety of environmental and host niches including the skin, gut, and oral mucosa. Similar to the dimorphic fungi, T asahii can grow as a budding yeast or have filamentous growth, forming septate hyphae with arthroconidia and blastoconidia.^[11]  They are metabolically flexible and able to utilize a large variety of carbon and nitrogen sources.^[8]
• Host risk factors: In most cases of severe disease, multiple host risk factors favor the development of tissue invasion. Chemotherapy used to treat hematologic malignancies can cause neutropenia and mucosal disruption allowing yeast to invade beyond their normal musocal surface sites. Patients with hematologic malignancies are the most common host for invasive trichosporonosis. These include patients with acute myeloid leukemia (AML), followed by acute lymphoid leukemia (ALL) and myelodysplastic syndrome (MDS).              Trichosporon peritonitis is described in association with peritoneal dialysis catheters and related to the combination of disrupted barrier immunity and immune dysfunction seen in end-stage renal disease.^[16]  This invasion of mucosal barriers appears to be followed by vascular invasion and dissemination to other sites. Occasionally, Trichosporon infections are limited to a single organ system (eg, the lungs), but scattered visceral lesions similar to those observed in hepatosplenic candidiasis also can occur, often in patients who are recovering from neutropenia and cannot clear the infection.^[5]

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Epidemiology

Frequency

Trichosporon infections are rare, even among patients with impaired host defenses.

Overall the number of cases of Trichosporon spp has grown. One systematic review noted a 74% increase in the number of invasive disease due to Trichosporon spp between 2005 to 2015 compared with 1994 to 2004.^[5]  Trichsporon spp causes invasive disease and deep-seated infections predominantly in immunocompromised hosts. Immunocompetent hosts usually present with superficial infections of the skin/hair or summer-type hypersensitivity pneumonitis.^[4]

Corticosteroid use, solid tumors, HIV/AIDS, and intravascular devices, including catheters and prosthetic heart valves,^[17] are other major risk factors. In one retrospective series, trichosporonosis (including B capitatus infections) developed in only 0.9% of patients with acute leukemia.^[18] In another review of yeast bloodstream infection in patients with cancer at a major referral center, Trichosporon was identified in only 8 of 2,984 isolates (0.27%). Hematologic malignancy is the best-described risk factor.^[19]

Despite the small number of cases, B capitatus may have a geographic predilection for Europe, with most reported cases arising there (especially in Spain and Italy).

T asahii may be a more common cause of breakthrough fungemia in neutropenic patients from Japan than other regions,^[20] and this organism is the cause of summer-type hypersensitivity pneumonitis, a condition reported exclusively in Japan.^{[21, 22]}

Mortality/Morbidity

The mortality rate of acute disseminated trichosporonosis previously has been documented at between 50% and 80% in most case series.^{[23, 24, 25]}  Other series have reported mortality rates of 40-50% in patients with invasive disease.^{[26, 27]}

Benelli et al reviewed a series of 10 cases with severe COVID-19 who also developed invasive Trichosporonosis. Most of these cases were found in South America and the Middle East, and all required systemic steroids and mechanical ventilation. Outcomes in this group were fairly poor; all but one patient died.^[28]

Sex

Trichosporonosis is much more common in males, with a 2:1 male-to-female predominance reported in multiple series.^{[24, 29]}

Age

Invasive disease has been noted among all age groups, but most commonly adults between ages 40 to 50 years.^{[5, 26]}

Diseases that confer susceptibility to Trichosporon infections are most prevalent in adults, with a median age of 44 years in one report.^[24]

A small number of neonatal and pediatric invasive Trichosporon infections have been reported, including nosocomial outbreaks within neonatal intensive care units.^{[5, 30, 31]}

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History

The typical patient with trichosporonosis presents with neutropenia and fever, usually in the setting of cytotoxic chemotherapy for a hematologic malignancy. Patients with hematologic disease are the most common host for invasive trichosporonosis. These include patients with acute myeloid leukemia (AML), followed by acute lymphoid leukemia (ALL) and myelodysplastic syndrome (MDS). Among these subgroups, invasive disease has been noted in those with neutropenia, graft versus host disease, and during post stem cell transplant and pre-engraftment period. Patients with solid organ tumor, transplant and autoimmune disorders are the next most common host. Those with renal transplant and lung cancer tend to be affected more commonly than others.^{[6, 26, 32, 33]}  Having been diagnosed with white piedra is not a significant risk factor.^[32]

A history of corticosteroid use is common, often as part of a chemotherapeutic regimen for leukemia, lymphoma. As in patients with invasive candidiasis, empiric broad-spectrum antibacterial therapy without clinical improvement may be included in the history. Prophylactic antifungal therapy with echinocandins may precede a breakthrough Trichosporon infection.^[34]  Recent steroid use for COVID-19 has also been reported in cases of trichosporonosis.^[28]

Past medical history may include any of the already discussed medical risk factors including hematologic malignancy, HIV/AIDS, or renal disease resulting in need for a dialysis catheter. Cases have also been reported in patients with hemochromatosis^[29] or prosthetic heart valve placement.^[17]  Benelli et al reviewed a series of 10 cases with severe COVID-19 who also developed invasive Trichosporonosis. Most of these cases were found in South America and the Middle East, and all required systemic steroids and mechanical ventilation.^[28]

Syndromic presentations: Patients with disseminated disease tend to have fungemia. The next most common site of isolation is lungs, followed by skin, a combination of skin and lung. Other sites of involvement that are less common include liver, spleen, prosthetic valves and the central nervous system. Patients with trichosporonosis may have a variable constellation of historical features, depending on the organs involved, and often have fever and chills. 

• Pulmonary trichosporonosis: Trichosporon spp is a known cause of invasive lung disease in patients with underlying malignancy.^[5] This tends to present with bilateral patchy lung infiltrates.^{[3, 35, 36]}  However, cases of invasive lung disease have been found in patients with cystic fibrosis (CF).^{[35, 36]}  There have been cases of fatal pneumonia in some patients with CF, whereas others have developed a decline in lung function, patient weight, and worsening inflammation over several years after colonization with Trichosporon spp These patients also had more CF flares after colonization with Trichosporon. Radiologic changes over time showed increasing hyperinflation, bronchiectasis, and mucus plugging and increasingly thickened bronchial walls.^{[35, 36]}  
• Pulmonary hypersensitivity pneumonitis: As part of a less invasive pulmonary syndrome, Trichosporon can manifest as summer-type hypersensitivity pneumonitis found mainly in Japan.^[37]  Living under the same roof was implicated as a risk factor per one case series of 50 familial cases.^[21] In some cases, Trichosporon spores were isolated from the house itself. Damp housing environment was noted in most cases. The most common symptom was cough, followed by dyspnea on exertion and fever. Diagnosis was established by presence of T asahii antibodies in the serum and bronchoalveolar lavage fluid.^[37]
• Endocarditis: Although less common, endocarditis of prosthetic valve has been reported.^{[38, 39]}  Most cases were caused by T asahii and T mucoides; T inkin was noted in a minority of cases. Most patients presented between several months to years after valve replacement, and tend to have involvement of the aortic or mitral valve. Vegetations also tend to be of a larger size >2 cm, and complications such as embolic phenomenon and heart failure have been noted in a significant portion of the patients. In one literature review blood cultures were positive in only 60% of the cases, and the diagnosis was made by tissue cultures that revealed Trichosporon spp.^[38]  Of note, at least two cases of prosthetic valve endocarditis have been reported in immunocompetent hosts.^{[38, 39]}  
• Central nervous system (CNS) infection: Rarely Trichosporon can invade the CNS and present in a variety of syndromes including acute meningitis, chronic meningoencephalitis, fungal balls, and brain abscess.^{[40, 41]}  Most cases were noted in patients with underlying immunocompromise, such as chronic steroid use, aplastic anemia, advanced HIV, malignancy such as ALL and lung cancer. Most commonly reported species includes T asahii, followed by T cutaneum (formerly known as T beigelii), and T inkin. By and large the outcomes have been poor, and fatality rates tend to be high, about 60% per multiple case series, despite surgical intervention. Just as in endocarditis, blood cultures were sterile in several of these cases.^{[40, 41]}  
• Superficial white piedra: Superficial infection usually manifests as white piedra that is characterized by light brown or white soft nodules along the hair shaft.^[4]  White piedra can be seen in multiple areas with body hair such as scalp, eyebrows, moustache, genital hairs. Other superficial infections such as onychomycosis and tinea pedis have also been reported. Hair texture may be rough or broken as a result.^{[9, 10]}

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Physical

General: Immunocompromised patients with fungemia or disseminated disease may generally appear ill. Some patients have infection localized to only one organ, and fungemia may not occur in all of these patients.^[32]  Localized disease has been described in the lungs, peritoneum,^[16]  eye, brain, and stomach.

Eye: Ocular involvement is well-described and occurs in the uveal tissues; chorioretinitis has been described.^[29]  

HENT: Lesions may be found along the entire length of the GI tract, usually in the form of erosions or ulcers. Patients with hematologic malignancies may have coexisting mucositis.

Cardiac: Murmurs may be ausculatated if there is endocarditis

Pulmonary: Pulmonary infiltrates are common, occurring in about 25% of patients but with no specific pattern of involvement.^[32]  Hypoxemia has been described in association with these lesions. An isolated pulmonary infiltrate may be the only demonstrable manifestation of trichosporonosis in some patients. What proportion of patients have pulmonary physical exam findings is unclear.

Gastrointestinal: Lesions may be found along the entire length of the GI tract, usually in the form of erosions or ulcers. Patients with hematologic malignancies may have coexisting mucositis or perirectal pain. Patients undergoing peritoneal dialysis with a PD catheter infection may present with abdominal pain, abdominal distension, and cloudy peritoneal fluid.^{[16, 33]}

Genitourinary: Flank tenderness or hematuria may be present and suggests renal involvement in disseminated disease. Flank pain, azotemia, hematuria, or red blood cell casts may signal renal involvement.^[29]

Dermatologic: Cutaneous findings occur in one third of patients with disseminated Trichosporon disease.^[42] The most commonly described lesions are nontender erythematous nodules of varying number,^[31] which are located mainly on the extremities but also are found on the trunk and face. The lesions may become ulcerated,^[42] with an appearance similar to that of ecthyma gangrenosum. Skin involvement often begins as a discrete maculopapular rash and may progress to purpuric or hemorrhagic manifestations.^[29]  (The presence of skin lesions may represent a site for biopsy, aiding in the diagnosis.) For patients with a superficial scalp infection (white piedra) this may be confused with dandruff, however, dandruff appears as white flakes falling from the scalp, whereas white piedra are whitish tan nodules attached to the hair shaft itself.^{[9, 10]}

Neurologic: and spondylodiscitis also have been described.^[43]

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Causes

Most literature prior to 1995 refers to pathogenic Trichosporon species as T beigelii. Subsequent articles usually describe specific species under the newer nomenclature.

Etiologic agents, in order of reported frequency, include the following:

• T asahii
• B capitatus (Trichosporon capitum)
• T inkin
• Trichosporon dermatis
• Trichosporon montevideense

Trichosporon is a normal colonizer of mucous membranes in the GI and respiratory epithelium, as well as the skin; invasive disease usually requires significant host compromise of both anatomic and neutrophilic defenses.

In nearly all patients, the source of the invasive organism is the host’s flora. Trichosporon is not often isolated from hospital environments, although outbreaks due to contaminated hospital equipment have been reported. Unlikely sources of nosocomial spread, such as infected urinary catheters and aerosolization of the fungus, have been described.^{[30, 44]}

Risk factors include the following:

• Neutropenia is the greatest single risk factor.^[45]
• Additional risk factors include corticosteroid use, cytotoxic chemotherapy, diabetes,^[46] and hemochromatosis.^[29]
• Trichosporonosis has been described in patients with prosthetic heart valves,^[47] those with HIV infection, patients on dialysis, and neonates.
• Trichosporonosis has been reported in patients with severe COVID-19 who required invasive mechanical ventilation and systemic steroids. ^[28]
• Many of these risk factors directly contribute to deficiencies in the host immune system. Hemochromatosis may be a risk factor owing to excess iron stores, as in vitro data suggest improved fungal growth in iron-supplemented media.^[29]

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Approach Considerations

The diagnosis of trichosporonosis usually is confirmed by a positive blood culture result obtained in the evaluation of a febrile (typically neutropenic) patient. Most patients with disseminated disease tend to have fungemia. The next most common site of isolation is lungs, followed by skin, a combination of skin and lung. Other sites of involvement that are less common include liver, spleen, prosthetic valves and the central nervous system.^{[2, 5, 32]}  Ultimately, the appropriate work up should include blood cultures; however, additional testing should be focused based on the presenting syndromic illness.

Invasive trichosporonosis is defined as either proven, probable, or possible per the European Organization for Research and Treatment of Cancer/Invasive Fungal Infection Cooperative Group (EORTC/IFICG) and the National Institute of Allergy and Infectious Disease Mycoses Study Group (NIAID/MSG) guidelines.^{[3, 48]}

Proven disease applies to all patients regardless of immune status. Proven disease requires at least one of the following criteria: (1) histopathologic, cytopathologic, or direct microscopy exam of a sterile site demonstrating yeast; (2) recovery of yeast on culture from a normally sterile site with a clinical or radiologic syndrome of an infectious process; (3) blood cultures positive for yeast; or (4) amplification of fungal DNA by PCR on a tissue sample.

Probable disease criteria are applicable to those with underlying immunocompromise. Probable disease requires the presence of at least 1 host criteria, clinical criteria, and microbiologic criteria (Table 1).^{[3, 48]}

Table. Risk Factors for Invasive Trichosporonosis

View Table

See Table

Possible disease is defined by the presence of host and clinical criteria, but without any microbiologic evidence as defined in Table 1.^[3]

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Laboratory Studies

Important laboratory tests include the following:

• Blood culture (ideally two sets including one from any indwelling catheters): Patients with disseminated disease tend to have fungemia, and disseminated disease has been associated with invasive intravascualr devices.
• Blood chemistries including and hepatic transaminases, alkaline phosphatase, bilirubin, lactic acid dehydrogenase (LDH)
• Urinalysis with urine culture. Urine cultures may be the first to grow Trichosporon in the setting of disseminated disease,^[49] and it should not be presumed to be a contaminant or colonizer in the high-risk host (ie, in the setting of neutropenic fever).^[32]
• Cryptococcal serum antigen: Trichosporon and C neoformans are closely related organisms and share a number of surface antigens. As such, the latex agglutination test results for serum cryptococcal antigen often are positive in the setting of disseminated trichosporonosis^[45] (except trichosporonosis due to B capitatus.^[50] ) This widely used, rapid, and inexpensive test may provide an early clue about a Trichosporon infection. Because of changes in cell wall conformation, these test results may become negative during antifungal therapy, but newly negative test results do not imply a response to therapy.^[32]

Investigational methods of rapid molecular diagnostics, such as DNA-based microarrays,^[51] polymerase chain reaction (PCR), and pyrosequencing,^[52] are in development but are not widely available for clinical use.^{[53, 54]}

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Imaging Studies

Radiologic evaluation should include a chest radiograph and CT scans of the abdomen and pelvis. A CT scan of the chest is also frequently useful in the evaluation of the pulmonary infiltrate in the patient population at risk for Trichosporon infection, but confirmation of the diagnosis should rely on a tissue sample or on another useful clinical sample. Depending on the clinical picture, a CT scan or MRI of the brain may be indicated.

Endocarditis rarely is reported^{[17, 47]} but is associated with high mortality rate (82% in a single series). Patients with prosthetic heart valves or persistently positive blood culture results should undergo echocardiography.

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Procedures

Bronchoscopy

When pulmonary infiltrates are present, bronchoscopy is a useful means of obtaining samples if the patient can tolerate the procedure. Positive culture results from a bronchial lavage support the diagnosis.^[31]

Biopsy

Open-lung biopsy may be required for definitive diagnosis because of the large number of viral, bacterial, protozoal, and fungal pathogens that can cause disease in patients with pulmonary infiltrates.

Lesions of the GI tract may be accessible for biopsy and may yield a diagnosis before blood cultures return positive findings.

Skin lesions occur in roughly 10% of patients with disseminated trichosporonosis. Biopsy of suspicious lesions in immunocompromised patients with fever may facilitate early diagnosis.

Liver lesions or other visceral lesions may also require biopsy for diagnosis and optimal management.

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Histologic Findings

Histopathology and fungal stain of the tissue are the gold standard for diagnosis. Histopathologic features of Trichosporon spp include pseudohyphae, hyphae. Blastoconidia and arthroconidia can also be found; the presence of these elements along with a urease positive test allows for presumptive identification of Trichosporon.^{[3, 4]} Fungal culture of blood or tissue are well supported for diagnostics and show white or cream-colored colonies with a cerebriform pattern on Saboraud-dextrose agar. Colonies may be dry after 24 to 48 hours.^[3]

Grossly, infected tissues may contain micronodules (0.5-1.0 cm), occasionally surrounded by red rims. The GI tract may demonstrate ulceration and erosion associated with hemorrhage and hemorrhagic infarction.^[45]

Microscopic examination of a nodule may reveal a necrotic center with fungal elements either in a starburst pattern or more loosely organized. Fungal elements may be observed invading the vasculature. Visualization of blastoconidia, arthroconidia, hyphae, and pseudohyphae in a histologic section supports the diagnosis of invasive Trichosporon infection.^{[29, 45]}  The cellular inflammation surrounding the fungal elements may vary, occasionally associated with hemorrhage. Granulomatous inflammation with multinucleated giant cells has been reported.^[55]

Histopathology and fungal cultures should be pursued whenever possible; however results may be delayed and culture may not distinguish colonization from true disease. History and clinical suspicion are of paramount importance in these cases.^{[3, 4]} Considering the limitations of pathology and culture, several biomarkers and molecular testing have come to light..

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Other Tests

Molecular methods such as Ribosomal DNA sequencing are reliable and strongly recommended. Matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) is being increasingly utilized and able to identify at least 10 species of Trichosporon.^{[2, 3, 4]}  Genus or species cannot be inferred from histopathology; direct microscopy is recommended instead.^[3]

Glucuronoxylomannan (GXM) is a cell wall component of both Trichosporon and Cryptococcus species. The GXM components of both organisms have structural differences but can cross react with the cryptococcal antigens resulting in a positive test in patients with invasive Trichosporonosis. ^[4] However, not many studies exploring the sensitivity of this test, therefore it should be used with caution in screening for invasive Trichosporonosis.^[4]  Likewise, (1→3)-β-d-glucan (BDG) has limited utility for screening purposes as per one study that noted around 50% sensitivity in patients with invasive Trichosporonosis.^[56]

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Approach Considerations

Most data regarding treatment of Trichosporon spp is derived from in-vitro studies and patients with hematologic malignancies. Per both European Confederation of Medical Mycology (ECMM) and American Society of Microbiology (ASM) guidelines, voriconazole or posaconazole are recommended as the first line of therapy. Fluconazole is the alternative regimen dependent on minimum inhibitory concentration (MIC).^[3]  

There is some data for use of isavuconazole. Liposomal amphotericin B or amphotericin B deoxycholate may be used as a second line therapy; overall azoles are preferred over amphotericin B. Combination therapy with Azole-amphotericin B is not recommended as initial regimen, but may be used as salvage therapy. Echinocandins alone have not conferred any therapeutic advantage against Trichosporon and should be avoided. ^{[2, 3]}

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Medical Care

Azoles

Voriconazole and posaconazole show excellent in vitro activity against Trichosporon.^{[17, 27, 31, 57]} In particular, voriconazole seems to have better in vitro activity than amphotericin B.^{[27, 58, 59]} Indeed, successful clearance of fungemia with voriconazole has been reported when liposomal amphotericin B treatment was failing.^[31] Posaconazole is approved by the US Food and Drug Administration for prophylaxis of invasive Aspergillus and Candida infections in patients at high risk because of severe immunosuppression and has activity against Trichosporon, although human clinical data are both limited and mixed in terms of results.^{[60, 61]}  Most azoles can prolong the QT interval. Voriconazole can contribute to hepatocellular injury, visual disturbances (most commonly hallucinations), and photosensitivity.

Voriconazole also has several drug interactions particularly in patients post organ and stem cell transplant.^[56]  These drugs are both a substrate and an inhibitor of the cytochrome P-450 system and so can lead to decreased metabolism and increased toxicity of several medications such as calcium-channel blockers, warfarin, rifabutin, phenytoin, tacrolimus and cyclosporin. Posaconazole can also interact with several medications such as rifabutin, rifampin, statins and various immunosuppressive medications.^{[62, 63]}

Amphotericin

High-dose amphotericin B deoxycholate (1-1.5 mg/kg/d) historically has been the most common treatment for invasive trichosporonosis, but many breakthrough cases have occurred on this therapy.^{[12, 25]}  Because of high rates of resistance to amphotericin B^[58] and the toxicity of this regimen, alternate therapies are often necessary. Lipid preparations of amphotericin B (eg, liposomal amphotericin B, 5 mg/kg/d) are commonly used in place of amphotericin B deoxycholate, although treatment failures have also been reported with these agents.^[23] Bcapitatus infections appear to respond better to amphotericin B than those due to Trichosporon species.^[25]  Amphotericin B is classically associated with infusion-related events such as fevers, chills, headaches, nausea, vomiting and nephrotoxicity. Liposomal formulation of amphotericin B can lessen but not completely ameliorate the possibility of these adverse effects. Nephrotoxicity can be prevented by IV fluid administration before infusion of the medication along with avoidance of nephrotoxic medication such as diuretics. Most patients develop tolerance to infusion-related side effects; but supportive measures such as diphenhydramine and acetaminophen can be used if necessary.^{[62, 63]}

Echinocandins

Lone echinocandin should be avoided. The echinocandins caspofungin and micafungin have poor in vitro activity against Trichosporon when used alone.^[20] One report describes successful treatment of T inkin peritoneal catheter–associated peritonitis using caspofungin monotherapy.^[16] However, cases of breakthrough T asahii infections have been reported in patients with hematologic malignancies receiving micafungin^[20] and caspofungin^[46] for empiric treatment of neutropenic fever. Combination therapy with caspofungin and liposomal amphotericin B may be effective,^[23] and micafungin and amphotericin B appear synergistic against Trichosporon in vitro. One in vivo murine model of trichosporonosis showed a significant reduction in fungal burden in multiple infected organ systems when amphotericin B was combined with micafungin. 

Combination therapy

Combination therapy should be the cornerstone of treatment for trichosporonosis. The combination of high-dose amphotericin B (deoxycholate or liposomal) with either or both 5-flucytosine or voriconazole is commonly prescribed, although failure rates remain high. Amphotericin B plus an echinocandin is a potentially promising regimen, and synergy has been suggested in vitro^[64] and in a murine model,^[65] with a small number of successful reports of salvage therapy in the current literature.^{[66, 67]}

Source Control and Other Considerations

Regardless of the therapeutic options, patients’ clinical responses may not be optimal until they recover from their predisposing immunocompromised states. Possible strategies include the addition of granulocyte colony-stimulating factor (G-CSF) in patients with neutropenia^[45] and the reduction of glucocorticoid doses as much as possible in patients receiving these agents. Persistence of positive blood culture findings on amphotericin B monotherapy suggests resistance, and modification of the regimen is indicated. Catheter-associated infections, such as peritonitis in patients undergoing peritoneal dialysis, generally require removal of the catheter.

In patients who do not respond to high-dose amphotericin B, an azole or flucytosine (5-FC) should be added. Unfortunately, all of these therapies have significant failure rates in patients with neutropenia. levels of 5-FC must be carefully monitored. Do not use 5-FC if levels cannot be measured expeditiously. Liposomal amphotericin has been successfully used in trichosporonosis but may not necessarily offer greater efficacy over standard therapy. Miconazole has significant in vitro activity; however, this does not translate to useful in vivo results, and it should not be used.

Fungemia and superficial infections without organ involvement should be treated for 2 weeks. Whereas with organ involvement 4 to 6 weeks of therapy are recommended, along with source control strategies such as CVAD removal and valve replacement, and removal of central venous catheter. Patients may also be treated until radiologic resolution.^[3]

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Consultations

Patients with trichosporonosis are often critically ill, complicated, and immunosuppressed.Infectious diseases consultation is paramount, preferibily with a transplant infectious diseases specialist if possible.

Due to the severity of disseminated fungal infections infection and their frequent underlying illnesses, a critical care unit admission is warranted in most cases.

Consultation with an ophthalmologist is generally advised for diagnostic purposes and to evaluate for fungal retinitis.

Because of the many organ systems involved, input from a number of other specialists may be required. Pulmonologists, intensivists, gastroenterologists, dermatologists, and general surgeons commonly assist in the diagnosis and management of patients with trichosporonosis.

• References

Global guideline for diagnosis and management of rare yeast infections by ECMM, ISHAM, and ASM

A global guideline for the diagnosis and management of rare yeast infections by the European Confederation for Medical Mycology (ECMM) in cooperation with the International Society for Human and Animal Mycology (ISHAM) and the American Society for Microbiology (ASM) was published in 2021.^[3] Recommendations for Trichosporon infection are summarized below^[3] :

• Trichosporon spp yeasts commonly are found in the environment and can colonize human skin, respiratory, and gastrointestinal tracts.
• Invasive trichosporonosis commonly affects immunocompromised patients, particularly those with hematological conditions and exposure to antifungals.
• Diagnosis of trichosporonosis involves imaging studies, histopathology examination, and molecular methods such as panfungal PCR for accurate identification.
• Susceptibility testing for antifungal drugs is recommended due to variable resistance patterns among Trichosporon spp.
• Voriconazole and fluconazole-based regimens are preferred over amphotericin B for treatment, with posaconazole and isavuconazole also showing efficacy.
• Combination therapy with echinocandins and azoles is not recommended as initial therapy.
• Central venous access device (CVAD) removal and cardiac valve surgery may be necessary for source control in certain cases.
• The duration of antifungal therapy should be tailored based on the extent of organ involvement, with longer durations for patients with organ involvement compared to fungemia alone.

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Medication Summary

The goals of pharmacotherapy are to eradicate the infection, to reduce morbidity, and to prevent complications. In general, empiric monotherapy should be avoided without specific testing of fungal sensitivity to available drugs.

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Amphotericin B (Amphocin, Fungizone)

• Dosing, Interactions, etc.

Clinical Context:  Amphoteric polyene antifungal with activity against many fungal pathogens. Administered in solution only and is well known for a variety of toxic side effects. May be injected intrathecally or into a joint space, or it may be used as an irrigant, although it is usually administered IV. Dose should be adjusted for the indication. For trichosporonosis, high doses are required. Lipid formulations of amphotericin B (see below) are generally preferred, however.

• References

Amphotericin B, liposomal (AmBisome)

• Dosing, Interactions, etc.

Clinical Context:  Lipid formulations of amphotericin B that deliver higher concentrations of the drug, with a theoretical increase in therapeutic potential and decreased nephrotoxicity. Produced from a strain of Streptomyces nodosus. Antifungal activity of amphotericin B results from its ability to insert itself into fungal cytoplasmic membrane at sites that contain ergosterol or other sterols. Aggregates of amphotericin B accumulate at sterol sites, resulting in an increase in cytoplasmic membrane permeability to monovalent ions (eg, potassium, sodium).

At low concentrations, the main effect is increased intracellular loss of potassium, resulting in reversible fungistatic activity; however, at higher concentrations, pores of 40-105 nm in cytoplasmic membrane are produced, leading to large losses of ions and other molecules. A second effect of amphotericin B is its ability to cause auto-oxidation of the cytoplasmic membrane and release of lethal free radicals. Main fungicidal activity of amphotericin B may reside in ability to cause auto-oxidation of cell membranes.

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Voriconazole (Vfend)

• Dosing, Interactions, etc.

Clinical Context:  A triazole antifungal agent that inhibits fungal cytochrome P450-mediated 14 alpha-lanosterol demethylation, which is essential in fungal ergosterol biosynthesis. Commonly used in the treatment of aspergillosis, invasive candidiasis, and neutropenic fever. Has excellent MICs against Trichosporon species and has occasionally been effective as monotherapy.

• References

Posaconazole (Noxafil)

• Dosing, Interactions, etc.

Clinical Context:  Triazole antifungal agent. Blocks ergosterol synthesis by inhibiting the enzyme lanosterol 14-alpha-demethylase and sterol precursor accumulation. This action results in cell membrane disruption. Available as oral susp (200 mg/5 mL). Indicated for prophylaxis of invasive Aspergillus and Candida infections in patients at high risk because of severe immunosuppression.

• References

Fluconazole (Diflucan)

• Dosing, Interactions, etc.

Clinical Context:  Triazole derivative with high enteral bioavailability used for Candida infections and infections with endemic mycoses. Also useful for Trichosporon infections. Dose depends on the indication. For trichosporonosis, the dose should be the maximum dosage.

• References

Flucytosine (Ancobon)

• Dosing, Interactions, etc.

Clinical Context:  Pyrimidine analog available enterally or IV for use against a variety of fungal pathogens but is not generally used as monotherapy owing to emergence of resistance during therapy. Well absorbed orally but should be administered IV to critically ill patients.

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Caspofungin (Cancidas)

• Dosing, Interactions, etc.

Clinical Context:  Routinely used to treat refractory invasive aspergillosis and invasive candidiasis. First of a new class of antifungal drugs (glucan synthesis inhibitors). Inhibits synthesis of beta-(1,3)-D-glucan, an essential component of fungal cell wall.

• References

Micafungin (Mycamine)

• Dosing, Interactions, etc.

Clinical Context:  Member of new class of antifungal agents, echinocandins, that inhibit cell wall synthesis. Inhibits synthesis of 1,3-beta-D-glucan, an essential fungal cell wall component not present in mammalian cells.

Approved indications include (1) prophylaxis of candidal infections in patients undergoing hematopoietic stem cell transplantation and (2) treatment of esophageal candidiasis.

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Further Inpatient Care

Patients with trichosporonosis should be monitored carefully, preferably in the ICU, until recovery of an adequate neutrophil count. Continue active antifungal therapy during the period of neutropenia and after recovery of neutrophil count until the resolution of symptoms.

Monitor blood cultures, urine cultures, and cutaneous or ocular lesions, along with renal and hepatic panel blood chemistries.

CT scanning of the abdomen and pelvis is indicated in most patients for initial evaluation and should be periodically repeated to monitor the progress of disease. For example, the lesions of hepatosplenic disease may become visible only after recovery of neutrophils.

The patient should remain on therapy until clinically stable and afebrile with the resolution of all visceral lesions.

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Prognosis

Trichosporon spp are an emerging opportunistic yeast that tend to cause invasive end-organ disease especially in immunocompromised host. Prognosis is guarded in most patients with invasive disease largely due to delays in diagnosis and treatment. Limited availability of effective antifungal therapy adds to the challenges in managing this disease. Currently, triazoles are first line therapy along with adequate source control measures to maximize successful patient outcomes. 

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