Our institution is a 950-bed tertiary hospital in northern Spain that attended 282 admissions to the haematology ward, corresponding to 176 adult patients with acute leukaemia or Burkitt's lymphoma between the years 2004 and 2010. Five proven IFIs by S. capitata occurring during this period were retrospectively evaluated in 3 women and 2 men, aged between 41 and 74 years. Four patients were diagnosed acute leukaemia, and one Burkitt's lymphoma. All of them were undergoing intensive chemotherapy in single rooms equipped with HEPA (High Efficiency Particulate Air) filters and positive pressure air flow at the time they developed the IFI. Diagnostic and therapeutic protocols of the institution were followed. The study was approved by the ethics committee of the hospital.

The diagnosis of IFI was established according to the criteria of the consensus group of the EORTC/MSG.19 The clinical and microbiological relevant data of the patients are summarized in Table 1.

Patient 4

A 66-year-old man was admitted to our unit from the intensive care unit (ICU) in November 2009. He had been admitted in the ICU due to severe respiratory failure, pulmonary infiltrates and bilateral pleural effusion that required non-invasive mechanical ventilation (bi-level positive airway pressure). He was diagnosed of acute monocytic leukaemia (WHO classification), and chemotherapeutical induction treatment was initiated with idarubicin, cytarabine and etoposide. The utilization of chemotherapy, supporting measures and broad spectrum antibiotics achieved certain degree of clinical stability that permitted the transfer of the patient to the haematology unit. At that time (day −4) he had fever and distal areas of cyanosis on the toes on both feet with biological data of disseminated intravascular coagulation. Continuous perfusion of sodium heparin was added, together with broad spectrum antibiotic coverage including meropenem, amikacin and teicoplanin. CNS was identified in blood cultures of days −3 and −2 as well as in the tip of the CVC that was removed and replaced on day +2. Since the fever persisted, caspofungin was added on day +2, but despite this, Candida tropicalis was isolated in blood cultures obtained from peripheral blood and through the CVC on days +4 and +7. However, the culture of the removed CVC tip was negative. At day +6 a generalized erythema appeared, and despite all the measures set out the patient died on day +10. The necropsy study revealed filamentous structures in all the studied parenchyma (liver, spleen, kidney, lung, intestine and bone) (Fig. 1), and S. capitata was isolated in the culture of a lung sample. A 13-day neutropenia period was registered.

Fig. 1.

Periodic-acid-Schiff stained sections of Saprochaete capitata infected organs from Patient 4. (a) Histological section of liver showing a colony of S. capitata (original magnification ×40); (b) histological section of spleen showing lymphoid depletion and abundant colonies of S. capitata mimicking “fireworks” (original magnification ×40); (c) histological section of spleen showing lymphoid depletion and abundant colonies of S. capitata (original magnification ×100); (d) large power field of fungal filaments of S. capitata in the spleen, showing occasional branching (original magnification ×400).

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Saprochaete capitata is an emerging fungal pathogen, especially in the Mediterranean area.28 Since early disseminated infections were described in the 1960s, new cases are being reported with increasing frequency.1,3,11,21–23,34,41,57,59 In our haematological unit, between the years 2004 and 2010, 5 cases of proven IFI by S. capitata were registered among 176 adult patients diagnosed of acute leukaemia or related diseases. The differential profiles of randomly amplified DNA bands helped to discard an epidemiologic relationship of the isolated strains. The S. capitata isolate of patient 3 showed the most differentiated bands patterns for all the assayed primers, while the rest of isolates exhibited differences for at least one of the assayed primers within the group. It is odd that the most similar strains belonged to patients 1 and 2, if we consider that their isolation dates were five years apart.

The incidence rate of S. capitata IFI for the whole group of patients was 2.84%, well above the 0.5% rate reported for an Italian multicenter retrospective study conducted on 3000 patients with acute leukaemia, between the years 1992 and 2000.28 As reproduced frequently in the literature, S. capitata infection was registered in patients with a very precarious clinical situation (patient 3) or in those undergoing salvage therapy as a consequence of the advanced state of their illness (patients 1, 2 and 5).1,11,20,34,41 These patients had accumulated long periods of profound neutropenia from previous chemotherapy cycles (at least 73d, 119d and 67d for patients 1, 2 and 5, respectively) that entailed complications such as bacterial infections, antibiotics administration and above all, repetitive handling of CVCs and previous treatment with antifungal agents not active against S. capitata. All these factors may have contributed to the development of the IFIs. In our group of patients, the higher mortality due to S. capitata when compared to that reported for Candida spp.28,40 is difficult to explain because patients with advanced haematological malignancies have inherent higher rates of mortality.

Three out of 5 patients (patients 1, 2 and 5) presented a clinical syndrome of S. capitata IFI indistinguishable from Candida IFI. Coinciding with the isolation of S. capitata in blood cultures, patient 1 presented a generalized very itchy maculopapular rash and patient 2 ileo-pancolitis with identification of C. albicans in the oral mucosa. Few cases such as patient 5 have been described, in which the participation of an endovascular device could be identified as the source of sepsis caused by S. capitata.28 The fungus was isolated from the tip of the catheter and from the membrane of the device, but even though the catheter was removed it was not possible to prevent the death of the patient. The ability of S. capitata and Candida parapsilosis to generate biofilms within the endovascular devices has recently been described.17 In contrast, patient 3 presented another typical manifestation of S. capitata IFI with lung involvement, as it has been frequently reported.39,40 This patient presented severe respiratory failure with faint pulmonary infiltrates which could easily be confused with a trichosporonosis or aspergillosis. Patient 4 had a mixed presentation including erythema without papula, blood culture isolation of C. tropicalis and alveolar infiltrates with respiratory failure. S. capitata was identified in every parenchyma studied, including lung, although the two fungi were likely to have contributed to his death (Fig. 1). All IFIs occurred during the period of profound neutropenia.

Contrarily to other authors,4,26 no positive data for Platelia Aspergillus EIA test were registered during the follow-up of patients, as reported by Schuermans et al.,59 By contrast, the β-glucan determination performed in patients 2 and 4, resulted positive throughout the S. capitata IFI monitoring, which is in agreement with a previous work of our group14 that pointed at β-glucan as a useful biomarker for this type of infections.

Following institutional protocols, patients 2 and 5 were under prophylactic fluconazole treatment, and patients 1, 2, 3 and 4 were receiving caspofungin as empiric treatment, when S. capitata IFI was diagnosed. As shown in Table 2, the MIC values of echinocandins and fluconazole were high for most S. capitata isolates, with the exception of patient 2 isolate, which showed fluconazole MIC 2 mg/ml. In addition, strains from patients 4 and 5 were likely to be resistant to AMB (MIC=2μg/ml46). On the contrary, all the S. capitata isolates showed very low MIC values for voriconazole and posaconazole. These breakthrough fungemia cases, which we found in four of our five patients, have been reported by other authors.39,40,59 In our opinion, the lack of susceptibility of S. capitata to fluconazole and/or echinocandins facilitated its dissemination, given that these antifungal compounds were administered to prevent or treat empirically infections by Candida spp. or Aspergillus spp., which are more prevalent than S. capitata infections in this group of patients.

Patients 1, 2, 3 and 4 had received caspofungin treatment for 29, 15, 10 and 8 days, respectively, before the identification of S. capitata in blood cultures or necropsy, and patients 2 and 5 had received prophylactic fluconazole treatment for prolonged periods in the previous chemotherapy courses as well as when S. capitata was isolated. A similar situation has been previously described with other yeasts due to selective pressure exerted by azoles such as fluconazole that is commonly used in patients with haematological malignancies facilitating the emergence of less susceptible species such as Candida glabrata or Candida krusei.33 Lately, it has been suggested that recent exposure to fluconazole or caspofungin, both as prophylaxis and empirical treatment, leads with increasing frequency to the isolation of species less susceptible to these antifungals, such as C. parapsilosis, C. glabrata or C. krusei. These yeasts are capable of causing serious infections in patients at high risk, and therefore they are bringing about a major change in the frequency of the different species of Candida involved in candidemia.38

The emergence of S. capitata strains, which are non susceptible to caspofungin, makes this infection especially dangerous in those haematological units where this echinocandin is routinely used for the empirical treatment of febrile neutropenia, especially in those units where an increased prevalence of this organism has been registered. Moreover, the clinical resemblance with acute invasive candidiasis could make one believe that the infection is been treated adequately when, in fact, it is not. However, the literature reports two cases of S. capitata IFI that had a good clinical response to the combination of caspofungin and voriconazole,22,23 even though the first case showed high echinocandin MIC. In the surviving patients of the present study (patients 1 and 2), in addition to recovering from neutropenia and regaining clinical stability, caspofungin was replaced by voriconazole and liposomal amphotericin B once S. capitata was identified and susceptibility tests were performed. At present the treatment of this rare infection is not clearly defined but, in our experience, to perform of the antifungal susceptibility test of the isolated organism is highly recommended. If there is no microbial isolation and the patient presents with clinical symptoms compatible with disseminated candidiasis, trichosporonosis or aspergillosis that do not respond favourably to antifungal treatment, especially if covered with caspofungin and/or fluconazole, the use of voriconazole and liposomal amphotericin B is advised.

In our group of patients the four cases of fungemia by S. capitata accounted for 20% of total fungemia registered between 2004 and 2010, while other isolates were 7 C. parapsilosis, 4 C. tropicalis, 3 C. krusei, 1 Candida guilliermondii and 1 Fusarium solani. Interestingly, two more isolates of S. capitata were reported in our unit during this period. The first one was isolated in a stool culture of a patient who underwent an autologous HSCT for multiple myeloma one year earlier, and was adequately solved with voriconazole. By contrast, the second one was found in a urine culture of a patient with an advanced chronic lymphoid leukaemia, who died of multiorgan failure with a profound neutropenia. Necropsy was not accomplished. These cases were not analyzed in this study because they were not proven IFIs, however they should be taken into account if we are thinking of S. capitata as an emerging pathogen in our region.

In conclusion, in our institution, S. capitata is an emerging agent responsible for IFIs especially in acute leukaemia or advanced haematological malignancies. The limited extension of this series precludes the categorical conclusion that the IFIs caused by this fungus were facilitated by the previous antifungal treatment with fluconazole or caspofungin, but we found that S. capitata isolates showed low in vitro susceptibility to these antifungals, which in turn did not behave favourably in the clinical set. Therefore, in our opinion, the prophylactic and empirical use of fluconazole and/or caspofungin respectively is not advisable for the treatment of neutropenic fever in high-risk patients, particularly in institutions with high prevalence of this microorganism. From our experience, treatment with voriconazole and liposomal amphotericin B, and early removal of presumably infected CVCs are the most effective measures to control infections by S. capitata, although recovery from neutropenia and clinical improvement of patients are indispensable for success.

The authors declare that they have no conflict of interest.