Rhodotorula species

Author:  Antonio Ramos

Previous Authors: Gil Redelman-Sidi, MD, Arthur E. Brown, MD, Susan K. Seo, MD

Rhodotorula species are pigmented basidiomycetous yeasts in the family Sporidiobolaceae (21). The genus contains 37 species, of which only three, including R. mucilaginosa (formerly R. rubra), R. minuta, and R. glutinis, have been reported as causes of infection in humans (7). Three novel species, which are non-pathogenic to humans, have recently been described: R. rosulata, R. silvestris and R. straminea (30). Most Rhodotorula species produce colonies that are pink to coral in color but can also be orange to red on Sabouraud agar due to the presence of carotenoid pigments (Figure 1). Colony morphology has been described as soft, smooth, moist, and sometimes mucoid. Rhodotorula species are nutritionally non-fastidious, grow easily on most media, and are characterized by a rapid growth rate. They appear as round or oval budding cells under microscopy, and pseudohyphae are rarely present. A faint capsule is sometimes formed. Rhodotorula species produce the enzyme urease and do not ferment carbohydrates. They can be differentiated from Cryptococcus species by their inability to assimilate inositol and from Candida species by production of pigmented colonies and the lack of pseudohyphae (47).

Rhodotorula species are widespread in nature and can be isolated from a variety of sources including air, soil, seawater, plants, dairy products, and the household environment (e.g., shower curtains, bathtub grout) (1, 45, 85).  It is also possible for laboratory specimens to become contaminated with this organism (35). In humans, Rhodotorula species have been recovered from cultures of skin, nails, and respiratory, gastrointestinal, and urinary tracts and are generally thought to be commensals.

Rhodotorula species were initially thought to be non-pathogenic until 1960 when the first case of fatal endocarditis in a 47-year-old woman with rheumatic heart disease was published (50). Since then, ~215 cases of Rhodotorula species infection in humans have been reported in the literature, primarily over the last two decades (2, 5, 12, 20, 26, 51, 58, 62, 65, 71, 76, 81, 84).  R. mucilaginosa is the most common species involved in human infections, causing 72% of the cases, followed by R. glutinis (8%) and R. minuta (3%); speciation is not reported for the remaining 17% of cases in the literature (Table 1). Rhodotorula Infection appears to be more common in tropical countries than in Northern regions (3). There has been at least one documented R. mucilaginosa outbreak in a neonatal intensive care unit where four premature infants with indwelling catheters developed fungemia over a period of 19 days and fully recovered with intravenous (IV) liposomal amphotericin B therapy. Attempts to identify the environmental source were unsuccessful (65).

Nearly 90% of patients with Rhodotorula species infection have underlying solid or hematologic malignancy, organ/bone marrow transplant, or immunosuppression due to corticosteroid use, neutropenia, Acquired Immunodeficiency Syndrome (AIDS), or malnutrition (9, 81). The most common risk factor is the presence of a central venous catheter (CVC) (12, 42, 51, 82, 88).  One third of the cases are receiving parenteral nutrition when Rhodotorula infection appears (8, 85, 86).  The average length of time that an indwelling catheter is in place prior to diagnosis of fungemia can be short, as in one series by De Almeida and colleagues (86.5 days, range: 4-261 days) (12), or long, as reported by Kiehn et al. (9.3 months, range: 1-22 months) (42).

Although the precise incidence is unknown, infection due to Rhodotorula species is much less common than infection with other yeast species such as Candida and Cryptococcus. Nevertheless, the number of infections has clearly increased during the last few years (86). In a retrospective study at a teaching hospital in Brazil over a 9-year period, only 2.3% of fungal blood isolates were Rhodotorula species, compared to 83.4% and 6.6% for Candida and Cryptococcus species, respectively (12).

 Rhodotorula species are associated with several distinct infections. The relative frequencies of these are shown in Table 1. There are no relevant differences in the clinical presentation of different Rhodotorula species (69). The most common infection is fungemia, which accounts for 73% of all Rhodotorula species infections. It frequently presents as fever of unknown etiology unresponsive to antibacterial treatment and can be associated with sepsis and other life-threatening complications. Endocarditis is present in about 6% of the cases associated with fungemia (Table 1). The vast majority of patients with bloodstream infection due to Rhodotorula species have an indwelling CVC, which in most cases is removed as part of the treatment (12, 41, 42, 43, 51, 82, 88). In some cases, in addition to Rhodotorula, other microorganisms (mainly gram-negative bacilli) have been isolated in blood cultures (69). Patients receiving concomitant fluconazole, voriconazole, echinocandin treatment may be at risk for breakthrough Rhodotorula species fungemia (8, 22, 26, 29, 51, 55, 65) and reported mortality ranges from 14 to 17% (12, 51, 81).

Rhodotorula species have a clear tendency to produce central nervous system (CNS) infection, of which twenty-three cases have been reported to date (8). These included 20 cases of meningitis and three cases of ventriculitis (due to CSF drainage catheter or shunt). Although a case of meningitis has been described in an immunocompetent adult (46), patients with Rhodotorula species meningitis generally have a predisposing condition, such as AIDS, malignancy, or autoimmune disease (e.g., systemic lupus erythematosus) (5, 33, 62, 68, 76, 79, 80). In the case of ventriculitis, the underlying factor was the use of an intraventricular catheter, which was removed as an adjunct to antifungal treatment (18). Presentation may be acute (55, 46), subacute (79, 80) or chronic (33). Symptoms include fever, headache, altered sensorium, and nuchal rigidity. The cerebrospinal fluid usually shows lymphocytic pleocytosis with decrease of glucose and increased protein (80). MRI imaging may show foci of increased signal throughout the brain and brain-stem without hemorrhage (80). Although Rhodotorula is a rapid growing yeast, prolonged periods of incubation have been observed prior to the appearance of symptoms. This entails either low fungal load or quiescent infection (61, 80). The identification of microcalcifications in the brain biopsy may be indicative of a subjacent indolent course (80). On the other hand, the extensive brain edema observed in some cases may suggest immune reconstitution inflammatory syndrome (4). Although the organism can generally be recovered from the cerebrospinal fluid (CSF) culture, it may initially be considered to be a laboratory contaminant resulting in the institution of antifungal therapy being delayed (5, 46).

Unlike fungemia, localized infections, including skin, ocular, meningeal, prosthetic joint and peritoneal infections, are not necessarily related to immunosuppression or to the use of CVCs. Thirteen cases of ocular infection due to Rhodotorula species have been reported in the literature and include keratitis and endophthalmitis (81). A predisposing cause can often be elicited. Keratitis may occur after trauma, keratoplasty and corneal grafting (6, 27, 48, 70, 72) and endophthalmitis has been described in patients with a history of injected drug use (54, 67).  In comparison to keratitis, endophthalmitis is associated with a worse prognosis with some patients requiring either a vitrectomy or enucleation (32, 54, 67).

 Nine cases of peritonitis caused by Rhodotorula species have been described in the literature, seven of which were caused by R. mucilaginosa. Symptoms are usually mild and include fever, abdominal pain, and anorexia (15,16, 19, 64, 77). At least one case has been reported in a liver transplant recipient who required a peritoneal drain for ascites management (2). Peritonitis is almost invariably associated with an infected peritoneal dialysis catheter for continuous ambulatory peritoneal dialysis (CAPD). Dialysate fluid is typically described as being cloudy. Treatment of fungal peritonitis often requires removal of the dialysis catheter, and failure to return to continuous ambulatory peritoneal dialysis is common (16).

Anecdotal presentations of Rhodotorula species causing infection have included orthopedic prosthesis infections (11, 74), hydrosalpingitis (28), lymphadenitis (23), skin infection (10, 39, 53), onychomycosis (13, 83), infected oral ulcers (14, 40) and disseminated infection with bone marrow isolation of the organism (13, 56, 83, 86). The two reported cases of orthopedic prosthesis infection required hardware removal to cure the infection (11, 74).

The overall crude mortality of infections caused by Rhodotorula species is 12.6% (81). However, it is difficult to estimate how much of this mortality is directly attributable. In fact, some cases of fungemia have evolved favorably without antifungal treatment (66).

Isolation of Rhodotorula species from non-sterile sites such as skin, sputum, or stool is more likely to be due to colonization or contamination, and treatment in such cases should only be started in the presence of symptoms strongly suggestive of infection and after other causes have been excluded. The clinician should also be aware that pseudo-outbreaks have occurred due to specimen contamination (35). One communicated pseudo-outbreak was due to fungal contamination of brushes used to clean bronchoscopes (37).

The recovery of Rhodotorula species from a sterile site, such as blood, peritoneal fluid or CSF, is usually indicative of infection. The clinician should maintain a high degree of suspicion in such cases, especially if the patient has no suggestive symptoms of infection. Morphological and biochemical confirmation of the diagnosis as described in the preceding ‘Microbiology’ section should be sought since yeast cells can usually be seen on microscopic examination (47).

In cases of meningitis, the CSF typically shows lymphocytic pleocytosis, and India ink stain can reveal encapsulated budding yeast cells (5, 76, 79). It may be difficult to morphologically differentiate Rhodotorula species meningitis from cryptococcal meningitis, and an instance of false-positive latex agglutination test (LAT) for cryptococcal antigen has been reported (79). Characteristic pigmentation of the colonies, confirmatory biochemical tests (e.g., absence of carbohydrate fermentation, production of urease), and absence of ballistospore formation should lead to a specific microbial identification (5, 79). The mainstay in the diagnosis of invasive Rhodotorula spp. infection is blood culture as 78% of the systemic infections present as fungemia (81). It should be noted that that isolates of Rhodotorula have been found to cross react with the Candida glabrata/ Candida krusei probe in the commercially available fluorescence in situ hybridization (FISH) test for species identification in positive blood cultures, which could lead to inappropriate echinocandin treatment (36). Panfungal PCR allows for highly sensitive, specific detection and identification of a wide spectrum of fungal pathogens in blood samples, including Rhodotorula (40, 78), however it is difficult to predict when these techniques will be incorporated into conventional clinical practice (40).

Since the CVC is often involved, the catheter tip should be cultured when removed so as to capture cases where blood cultures are falsely negative (86). Rhodotorula isolates are easily recognizable in the laboratory due to their distinctive orange to salmon-colored colonies, morphology, formation of rudimentary hyphae and urease production.

Antigen detection has not been reported in clinical cases of systemic Rhodotorula infections. ß1-3-D-glucan has been detected in the supernatant from isolates of R. mucilaginosa at an average concentration of two-thirds of that of Candida spp (60). Whether the ß 1-3-D-glucan test would be useful as a surrogate marker for invasive Rhodotorula infection remains to be investigated (60). As could be expected, Cryptococcal antigen, Aspergillus galactomannan and Candida mannan are usually negative in biologic fluids (80).

The pathogenesis of infection due to Rhodotorula species has not been studied. As mentioned previously, in almost all cases there is underlying immunosuppression and/or the presence of a foreign body. The low pathogenicity of Rhodotorula spp. is probably related to its reduced ability to grow at 37°C. Immunocompromised individuals form few epithelioid cells or multinucleated giant cells thereby promoting yeast growth (87). It has been demonstrated that Rhodotorula species are able to form biofilms which could play a role in the pathogenesis of infections caused by these species (73). According to one study, R. minuta and R. mucilaginosa are able to produce more biofilm than R. glutinis (59). It can be speculated that invasive infections may occur as a result of environmental contamination of an inserted prosthetic device (16, 18, 19), but it seems more likely that the organism is an opportunist that takes advantage of immunocompromising conditions, indwelling devices, and exposure to broad-spectrum antibiotics to colonize and infect at-risk patients (12, 42, 52). Antibiotics and exposure to cytotoxic agents may increase gastrointestinal colonization and intestinal mucosa damage. Few studies have investigated the role of the digestive tract as a source of Rhodotorula spp (82).

Single Drug

There are few publications reporting on in vitro susceptibility testing of Rhodotorula species with Clinical and Laboratory Standard Institute (CLSI) methodology. In general, flucytosine and amphotericin B appear to be the most active agents in vitro against R. mucilaginosa, R. glutinis, and other Rhodotorula species. Table 2 summarizes the susceptibilities of Rhodotorula species to antifungals as assessed in four studies (17, 24, 31, 88). Zaas and colleagues determined antifungal susceptibilities for eight R. mucilaginosa and two R. glutinis blood isolates identified over a 9-year period at their institution. Flucytosine MICs ranged from 0.125-0.25 µg/mL, and amphotericin B MICs ranged from 0.25-1 µg/mL (88). Diekema et al. studied 64 isolates between 1987 and 2003 (17). All isolates were inhibited by flucytosine at <0.5 µg/mL. Amphotericin B MICs by broth dilution were < 1µg/mL, but interestingly, Etest detected 8 isolates with MICs >1 µg/mL, raising the possibility that some Rhodotorula isolates may be less susceptible in vitro or in vivo. One Spanish study utilized a somewhat modified European Committee on Antibiotic Susceptibility Testing (EUCAST) protocol for yeast and found a wider MIC range for flucytosine (0.06 to >64 µg/mL) and amphotericin B (0.06 to 8 µg/mL) in their collection of 29 Rhodotorula species isolates (25 R. mucilaginosa, 4 R. glutinis) (31). However, the authors concluded that both drugs showed good in vitro activity against Rhodotorula species.

Rhodotorula species appear to be resistant to the echinocandins with high MICs. Reported MICs ranged from 8 to 16 µg/mL in one study (17) and were >16 µg/mL in another (88). MICs >64 µg/mL have been reported for micafungin (88). Fluconazole can also be predicted to be ineffective against Rhodotorula species since the majority of isolates exhibit MICs >64 µg/mL (17, 31, 88). The resistance mechanism is unknown, but the repeated pattern of high MICs suggests intrinsic resistance (81). The newer triazoles show variable degrees of potency. In the largest study of 64 Rhodotorula species isolates, 17% of isolates had MICs >4 µg/mL when tested against posaconazole in contrast to itraconazole (33%) and voriconazole (31%) (17). Ravuconazole, an investigational agent, appeared to be the most active with MICs ranging from <0.06 to 2 µg/mL.

No significant differences in the activities of any of the tested antifungal agents according to Rhodotorula species have been noted in the cited studies (17, 31, 88). The majority of the patients presented were receiving antifungal prophylaxis, mainly fluconazole, when fungemia was noticed (55, 86). This fact could be related to the intrinsic resistance of Rhodotorula to fluconazole (and echinocandins) (17, 31, 51). Some strains also show resistance to voriconazole and posaconazole, although these drugs may be effective. According to laboratory results and clinical experience in HSCT recipients, amphotericin B appears to be the drug of choice for Rhodotorula infection (22, 25, 55).

One study tested 35 different strains of Rhodotorula species utilizing the Sensititre YeastOne MIC Susceptibility Test (AccuMed International Ltd, UK), a commercial broth microdilution test that correlates highly with reference procedures (24). All strains were considered to be susceptible to amphotericin B (MIC range: 0.125 to 0.5 µg/mL), flucytosine (MIC range: 0.064 to 0.25 µg/mL), ketoconazole (MIC range: 0.125 to 0.25 µg/mL), and itraconazole (MIC range: 0.25 to 1 µg/mL), and resistant to fluconazole (MICs >32 µg/mL). It is worth noting that MIC results for ketoconazole and itraconazole are lower than what has been reported with the CLSI and EUCAST protocols. Gomez-Lopez and colleagues found similar results when reviewing MIC data between reference and Sensititre YeastOne methods (31). Further studies are needed to clarify the role of extended-spectrum triazoles.

Combination Drugs

There are scant data on the susceptibility of Rhodotorula species to combinations of antifungals. A study by Serena et al. evaluated the in vitro activity of combinations of micafungin with amphotericin B or triazole agents against basidiomycetous yeasts including 10 isolates of R. glutinis (75). Drug interactions were assessed by the checkerboard technique using the CLSI microdilution method (M27-A2). The fractional inhibitory concentration index (FICI) was used to classify drug interactions as synergistic (FICI <0.5), null (FICI >0.5 and <4.0), or antagonistic (FICI >4.0). For R. glutinis, the combination of micafungin and fluconazole showed only 20% synergism. Micafungin combined with ravuconazole showed the highest percentage of synergistic interactions (80%), followed by micafungin/amphotericin B (70%), micafungin/itraconazole (60%), and micafungin/voriconazole (60%). Limitations include the small number of isolates available for testing, lack of data for other Rhodotorula species, and lack of clinical data to support these in vitro results.

While there is limited clinical experience using amphotericin B and flucytosine together (81), this combination has been suggested due to good in vitro activity of flucytosine (17).

Drug of Choice

There are no randomized controlled trials that have evaluated treatment for Rhodotorula species infections. Based on the available in vitro susceptibility data, amphotericin B or one of its lipid formulations appears to be the drug of choice (81). Recommended antifungals for treatment of Rhodotorula species infections are listed in Table 3.

Special Infections

Clinical experience in treatment of bloodstream infections has by and large been with conventional amphotericin B administered intravenously at dosages from 0.7 to 1 mg/kg daily (12, 42, 51) or one of its lipid formulations at a dose of 3 to 5 mg/kg daily (26, 65). On occasion, combination therapy with flucytosine has been reported (51, 81). One patient, who was a recipient of simultaneous liver-kidney transplant, received combination treatment using voriconazole (200 mg intravenously twice daily) and micafungin (100 mg intravenously once daily) for catheter-associated C. glabrata and R. glutinis fungemia (71). Treatment was selected on the basis of antifungal susceptibility testing and in consideration of the patient’s underlying renal and hepatic insufficiency. Length of treatment is variable in the literature, ranging from 14 to 41 days (81). One report has suggested two weeks’ duration if the CVC is not removed and one week with CVC removal (42).

There are no data regarding the optimal treatment and duration for endocarditis. One 7-year-old boy with presumptive rheumatic fever and Rhodotorula species endocarditis was treated with 3 months of oral flucytosine 100 mg/kg daily divided into 4 doses. He defervesced within 3 days of starting effective therapy and had normalization of erythrocyte sedimentation rate (ESR) in 2 months (57). In another report, a 53-year-old man with R. mucilaginosa homograft endocarditis was managed surgically in combination with amphotericin B (a total of 2 grams administered over 28 days), followed by oral itraconazole (200 mg twice daily for one month) (52). Two of the reported cases (one with concomitant meningitis) were managed without surgery (49, 57), nevertheless, surgical treatment is strongly indicated in all cases of fungal endocarditis (34).

CNS infections have been treated with conventional amphotericin B (0.7 to 1 mg/kg IV daily) (5, 46, 76), flucytosine monotherapy (25 mg/kg orally every 6 hours) (33), or combination therapy using amphotericin B and flucytosine (18, 79). Treatment is generally for 2 weeks, but it must be taken into account that relapses are possible (33) and mortality may be over 40% despite antifungal treatment (80). For patients with AIDS, consideration should be given to starting antiretroviral therapy as an adjunct (5, 79).

For ocular infections with Rhodotorula, topical or intravitreal amphotericin has commonly been used with or without the addition of systemic antifungals (6, 32, 48, 54, 67). Keratitis generally responds to topical treatment alone, whereas more serious infections like endophthalmitis typically require systemic antifungal administration and surgical drainage as part of management (72, 81). Similarly, intraperitoneal amphotericin B, in combination with removal of the peritoneal catheter, has been used successfully in the treatment of peritonitis due to Rhodotorula species (19, 77). Systemic antifungal therapy with or without catheter removal has also been reported for the treatment of peritonitis. One patient in whom the peritoneal catheter was not removed was successfully treated with one month of oral ketoconazole (16), whereas another patient, who was a liver transplant recipient, was treated initially with catheter removal and concomitant amphotericin B deoxycholate, then liposomal amphotericin B for a total of 10 days (2).

Alternative Therapy

Although fluconazole has been prescribed in some cases with sporadic success (44, 81), it should probably not be used given the high level of in vitro resistance unless susceptibility testing suggests otherwise. There has been one report of successful itraconazole treatment of R. mucilaginosa lymphadenitis in a patient with HIV (200 mg orally once daily for 8 months) (23). Half of the reported cases of onychomycosis evolved favorably with itraconazole (those strains showed MIC <= 0.125 μg/mL) (83). Itraconazole has also successfully employed in one case of an infected oral ulcer (40).

Echinocandins alone should not be used for the treatment of Rhodotorula species infections because of the high level of in vitro resistance. While there is some evidence that micafungin has in vitro synergy when used in combination with several antifungals (see ‘Combination Drugs’), there is limited clinical evidence suggesting that it is of benefit. It has been used successfully in combination with voriconazole in at least one case of R. glutinis fungemia (71).

For patients unable to tolerate amphotericin B or flucytosine, susceptibility testing of extended-spectrum triazole agents may help to guide appropriate therapy. In such cases, special care should be taken to remove any foreign bodies associated with the infection (see ‘Adjunctive Therapy’) in order to maximize the chance of a favorable outcome.

As in candidemia (63), CVC removal should be strongly considered as part of treatment for Rhodotorula species fungemia as it may hasten blood clearance (58, 82). There have even been cases when CVC-related fungemia due to Rhodotorula species was treated successfully with CVC removal alone (42, 51). However, there do not seem to be clear guidelines as to which patients would warrant CVC removal only. Therefore it seems prudent to consider CVC removal in light of concomitant systemic antifungal therapy. For peritonitis, the literature supports the removal of the peritoneal dialysis catheter as part of management (19, 64, 77). CNS infections, particularly ventriculitis, may also require removal of the foreign body (18).

Duration of antifungal therapy should be guided by the patient’s clinical presentation, underlying disease, and degree of immunosuppression.

There are no available vaccines for prevention of Rhodotorula species infection.

General

As with other opportunistic infections, an important aspect of prevention of Rhodotorula species infections is to minimize associated risk factors. CVCs should be used judiciously and should be removed as soon as they are no longer needed. Great care should be taken to maintain sterility when inserting intravascular and intraperitoneal catheters, and sterility should be maintained during the long-term maintenance of these and other devices.

Antifungal Prophylaxis

There are no studies to date evaluating antifungal prophylaxis for prevention of Rhodotorula species infections. Given the rarity of these infections, specific prophylaxis is not recommended. There are no data to suggest that antifungal agents used for prophylaxis in other situations (e.g., after bone marrow transplantation) are effective in the prevention of Rhodotorula species infection. Breakthrough infections have been reported in patients receiving azoles or echinocandin prophylaxis (8, 22, 25, 26, 29, 51, 55, 65, 69).

Infection Control

Patients infected with Rhodotorula species do not require any specific infection control precautions. The organisms are common in the environment and are likely acquired through colonization with environmental strains. There is no evidence of human-to-human transmission of Rhodotorula species. However, health care workers’ hands (as well as any rings) can be contaminated with Rhodotorula spp (41). In the absence of specific data, standard infection control precautions, including hand-washing and proper skin cleansing and preparation prior to invasive procedures, should be emphasized.

FIGURE AND TABLES

Figure 1: Colonies of Rhodotorula glutinis

*Onychomycosis (n=4), Skin infection (n=3), oral ulcer (n=1) Orthopedic prosthesis infections (n=2), hydrosalpingitis (n=1), lymphadenitis (n=1), disseminated infection (n=1)

**Concomitant endocarditis and meningitis in one patient

Table 2: Summary of Five Reports on Susceptibility Data of Rhodotorula Species

 *Now Clinical and Laboratory Standard Institute (CLSI)

Table 3: Recommended Antifungals for Rhodotorula Species

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