Introduction

Rhodotorula species are commensal yeasts that belong to Urediniomycetes class of Basidiomycota phylum and are distributed in Microbotryum, Sporidiobolus and Erythrobasidium clades [1]. Members of the genus Rhodotorula show a marked ubiquity and have been isolated from human feces, urine, nails, skin, sputum, digestive tract and adenoids [2]. Although the first report on Rhodotorula fungemia dates back to 1960 [3], during the last two decades Rhodotorula spp have emerged as cause of catheter-related fungemia, sepsis, and invasive disease in severely immunocompromised patients [4]. In the ARTEMIS surveillance project, Rhodotorula spp were the fourth most common non-candidal of yeasts isolated from clinical specimens, whereas R. mucilaginosa (formerly R. rubra) was the commonest cause of Rhodotorula spp fungemia followed by R. glutinis and R. minuta [5]. In this study, a fatal case of R. mucilaginosa fungemia at a critically ill ICU patient and review of all published cases of Rhodotorula spp fungemia during the last decade is presented.

Case Report

A 48-year-old woman was admitted to emergency department complaining for abdominal pain and distension (ileus). Symptoms originated from colorectal invasion and obstruction due to ovarian cancer. The patient was nursed in the General Surgery department. Extensive surgery was performed, and the affected part of the bowel was removed. Unfortunately, bowel necrosis complicated the post-surgery clinical course resulting in bowel perforation and fecal peritonitis. Additional bowel excision was performed, and the patient was transferred to intensive care unit with mechanical ventilization. After 2 weeks of stay in ICU, Klebsiella pneumoniae was isolated from blood. The isolate produced carbapenemases and among all other agents tested (Vitek2, Biomerieux, Marcy l’Etoile, France) was susceptible only to colistin (MIC < 0.5 mg/L) and tigecycline (MIC = 2 mg/L). In spite of antibiotic administration (colistin), K. pneumoniae continued to be isolated from consecutive blood cultures for the following 3 weeks. Additionally, the patient was receiving fluconazole as prophylaxis due to immunosupression. Finally, 2 days after the last K. pneumoniae-positive blood culture, a fungus was isolated. Creamy, coral red-colored colonies were visible after 2 days of incubation on blood agar and Sabouraud agar plates at 37 °C. Germ tubes test was negative, while urease test was positive. The strain was identified as R. rubra by API 20C AUX (Biomerieux, Marcy l’Etoile, France) and R. mucilaginosa in Vitek2 YST (code number 4116141413121511; probability of species identification 90 %) (Biomerieux, Marcy l’Etoile, France). Susceptibility test was performed with E test strips, and MICs were the following: 1.5 mg/L for amphotericin B, 0.064 mg/L for flucytocine, over 256 mg/L for fluconazole, 0.032 mg/L for ketoconazole, 0.75 mg/L for itraconazole, 0.25 mg/L for posaconazole, 1.5 mg/L for voriconazole and over 32 mg/L for caspofungin, anidulafungin and micafungin, respectively (Figs. 1, 2). Unfortunately, the patient did not receive any antifungal agent besides fluconazole and she died 1 day after fungus retrieval from blood cultures.

Fig. 1
figure 1

Susceptibility testing to azoles

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Fig. 2
figure 2

Susceptibility testing to amphotericin B, flucytosine and echinocandins

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Discussion

Although Rhodotorula is of low virulence organism as compared to Candida and Trichosporon, it must be considered a potential pathogen in patients with immunosupression and central venous catheters (CVCs) [6, 7]. Most cases of Rhodotorula infections (79 %) are presented as catheter-related fungemia [6, 8], endocarditis and meningitis [5]. From 1960, over 134 cases of Rhodotorula fungemia have been described. Such cases have been extensively presented on several studies until 2001 [9, 10]. In addition, reviews on selected groups of patients, such as those having central catheter (8), hematological malignancy patients [11] and patients undergoing hematopoietic stem cell transplantation [12] have been conducted. In Table 1, clinical presentation, underlying disease, risk factors, microbiological data, therapeutic approach and outcome of seventy cases published between 2001 and 2011 is presented [10, 12–32]. During the last decade, 46 cases are reported in adults, seventeen in children below 18 years, and seven in neonates.

Table 1 Published cases of Rhodotorula spp fungemia (2001–2011)
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Patients with solid tumors and hematological malignancies [11], especially those undergoing bone marrow transplantation [12] as well as patients with AIDS, are considered as those at high risk of systemic Rhodotorula infection [5, 33]. As presented in Table 1, the majority of adults had malignancies; specifically, twenty-one patients had hematological malignancies and six solid tumors, whereas four patients had undergone solid organ transplantation.

Published cases involving children are few and involve almost exclusively children with hematological malignancies or solid tumors.

The presence of central venous catheters has been closely associated with Rhodotorula fungemia [8]. Rhodotorula, as a fungus that is normally present on the skin, adheres to the catheter and colonizes it [33]. Administration of chemotherapeutic agents, immunosuppressive agents, steroids and associated neutropenia represents major risk factors [8, 28]. Patients who have abdominal surgery, cirrhosis, autoimmune diseases or burns are also at risk [5]. Previous antibiotic use and parenteral nutrition is also associated with Rhodotorula infection [6, 19, 28]. Use of broad spectrum antibiotics and exposure to cytotoxic agents probably contribute to the increase in gastrointestinal colonization and to damage of the intestinal mucosa, although the role of gastrointestinal tract as a source of Rhodotorula fungemia is not well documented [10, 28]. In a report of R. mucilaginosa outbreak in a neonatal intensive care unit [22], all neonates were premature and had a vascular central line. Also, three out of four neonates were on fluconazole prophylaxis. Although cultures were taken from hands of personnel, parenteral nutrition bags and objects, no source was found; even cultures of catheter tips were negative. Of the patients reported with Rhodotorula fungemia during the last decade, 81.4 % had a central line in place, 38.6 % were receiving chemotherapy, immunosuppressive agents, steroids or had neutropenia, 30 % were receiving antibiotics, and 20 % had a concomitant infection, most commonly bloodstream infection. Furthermore, a considerable number (four) of patients had gastrointestinal malformations, such as short-bowel syndrome. Our patient had several risk factors such as solid organ neoplasm, abdominal surgery, presence of CVC, total parenteral nutrition and prolonged antibiotic administration.

Our isolate was identified as R. mucilaginosa, which is the most common species causing fungemia (74–75 %), followed by R. glutinis (6–7.7 %) [6, 8]. Also, among the reviewed seventy cases, 59 were identified as R. mucilaginosa, eight as R. glutinis, whereas three were unidentified.

Overall mortality is reported to be 15 % [5]. During the last decade, ten out of seventy patients with Rhodotorula fungemia died, corresponding to a mortality rate of 14.3 %. In addition, in two cases, death was not attributed to Rhodotorula infection.

Several in vitro studies have been carried out in order to predict in vivo response of Rhodotorula fungemia to antifungal agents. Susceptibility testing of twenty-nine Rhodotorula strains revealed that only one was resistant to amphotericin B having MIC > 1 mg/L, whereas 27 strains were susceptible to flucytosine [34]. Susceptibility to azoles such as itraconazole and voriconazole was limited; 55 and 72.4 % of strains had MICs > 1 mg/L, respectively, whereas MIC to fluconazole was consistently >4 mg/L [34]. Finally, ravuconazole appeared to be the most active drug of the azoles group; 93 % of strains were inhibited by ≤4 mg/L [34]. In another study where 210 Rhodotorula strains were tested, 49 % were resistant to fluconazole and 37.3 % to voriconazole [35]. Diekema et al. [36] tested 64 Rhodotorula spp strains against eight antifungals and revealed that all strains were susceptible to flucytosine and ravuconazole, 63 (98 %) of strains were susceptible to amphotericin B (most strains were clustered around a value of 1 mg/L), and voriconazole, 25 (39 %) and 16 (25 %) were susceptible to itraconazole and posaconazole, respectively, whereas fluconazole and caspofungin were inactive. Our strain was susceptible to flucytosine. MIC to amphotericin B was relatively high (1.5 mg/L), whereas the strain was resistant to fluconazole, posaconazole and voriconazole according to the revised break points for Candida spp [37]. Echinocandins appeared completely inactive, as previously described [11, 12, 29, 38].

Our patient was also receiving fluconazole as prophylaxis. Antifungal prophylaxis can be administrated to adults in ICUs who are at high risk of invasive candidosis [5]. Because of intrinsic resistance of Rhodotorula spp to triazoles and echinocandins, patients receiving fluconazole and caspofungin are prompt to develop breakthrough Rhodotorula fungemia (23). In a study involving twenty-nine cases of hematological malignancy patients, thirteen were receiving prophylaxis with fluconazole when they developed Rhodotorula fungemia [6].

Resolution of neutropenia, especially chemotherapy induced, is crucial for recovery from the infection [9, 10]. Taking into account that many cases are proven to be catheter related (either positive cultures of catheter tips or recurrence of infection until catheter is removed) [13, 15, 18, 19, 29, 31], catheter removal seems a reasonable choice. As shown in Table 1, catheter removal was adequate for the elimination of infection in five cases. Regarding the use of antifungals, amphotericin B was the agent of choice and was used alone or in combination with catheter removal in 57 % of reported cases. Surprisingly, seven patients were successfully treated with fluconazole; isolated strains were either susceptible to fluconazole [25] or resistant [17, 18, 28]. Voriconazole has been used in some cases alone or with catheter removal with good results [24, 27, 30–32]. Flucytosine has been also used as a second agent because of persistent positive blood cultures, despite several days of monotherapy with amphotericin B [21].

Increasing awareness by physicians and microbiologists along with improved and more aggressive therapeutic approach of critically ill patients or patients with malignancies have led to the emergence of Rhodotorula spp as a noteworthy pathogen. Although the optimal therapy remains to be defined, a conservative approach combining amphotericin B with catheter removal should be considered to prevent serious complications, especially in immunosuppressed patients [28]. Correct identification is obligatory for appropriate management, as Rhodotorula spp are resistant to antifungal agents, such as fluconazole and echinocandins.