Geotrichum capitatum septicemia in patients with acute myeloid leukemia. Report of three cases

Abstract

Geotrichum capitatum infection is uncommon, and has been exclusively reported in immunocompromised patients. The prognosis is poor with a mortality rate ranging from 50 to 90%. We report 3 cases of Geotrichum capitatum fungemia in neutropenic patients receiving chemotherapy for acute myeloblastic leukemia.

The infection was successfully cured with voriconazole in 1 case and was fatal in the 2 remaining cases despite treatment with amphotericin B.

1. Introduction

Invasive fungal infections are one of the major causes of morbidity and mortality in patients with malignancies and undergoing aplastic chemotherapy [1–3]. Although Candida and Aspergillus species are still the most frequent causes of invasive fungal infections in these patients, less common fungi are causing growing concern due to their increasing incidence and the limited available options for therapy [4–7].

Invasive Geotrichum capitatum infection is relatively rare, as approximately 100 cases have been reported in patients with hematological malignancies [2,8–11]. It mainly presents as septicemia with occasionally secondary localizations [2,11]. Despite appropriate antifungal therapy, the disease has been associated with unfavorable outcome and a mortality rate exceeding 50% [6,7].

We report herein 3 cases of Geotrichum (G.) capitatum fongemia in patients with acute myeloid leukemia (AML) and discuss the epidemiological, clinical and prognostic features of this infection with comparison with published data.

2. Patient one

A 47-year-old man with AML was hospitalized in June 2010 in the Hematology department of Farhat Hached teaching hospital in Sousse, Tunisia, for induction chemotherapy based on idarubicin (12 mg m²/day for 3 days) and cytarabine (200 mg m²/day for 7 days). The patient was neutropenic since admission with a neutrophil count of 354/mm³.

On day 20 of hospital admission, the patient presented fever at 39.5–40 °C without any additional clinical signs, while white blood cells (WBC) count was 400/mm³ with zero neutrophil/mm3. He was treated empirically with tazocillin for 4 days without any response. Fever persisted together with the onset of a dry cough and impaired general condition. The chest X-ray showed diffuse reticular interstitial infiltrates. Aspergillus serology and galactomannan antigenemia were both negative. Antibiotics therapy was changed by imipenem and ciprofloxacin and supplemented with amphotericin B (1 mg/kg/day) for 14 days.

Candida (C.) albicans and C. tropicalis were isolated in repeated cultures of sputum. Blood cultures yielded C. tropicalis and G. capitatum. A total of 10 blood cultures were performed, 2 of them were positive yielding C. tropicalis and G. capitatum after 4 days of incubation. G. capitatum was identified on the basis of morphological characteristics on PCB medium (non budding arthrospores) and biochemical patterns an Auxacolor2^® (Bio-Rad, France) and ID32C^® (bioMérieux, France) with assimilation of D-glucose and Glycerol and non assimilation of D-saccharose, D-mannitol, D-lactose, D-xylose and D-cellulose.

The in vitro susceptibility testing by E-test^® (bioMérieux, France) showed the isolate to be susceptible to both amphotericin B and voriconazole with a minimum inhibitory concentration (MIC) of 0.064 μg ml⁻¹ and 0.094 μg ml⁻¹ respectively.

On day 26 of hospital admission corresponding to day 7 of antifungal treatment, blood cultures were still positive for G. capitatum.

The patient developed renal failure on day 14 of antifungal treatment (cumulative dose of 840 mg) and his clinical condition rapidly deteriorated. Amphotericin B was changed by voriconazole 200 mg twice daily. The patient died 1 day later due to a septic shock. Neutropenia has not been recovered and lasted until death. No autopsy was performed.

3. Patient two

A 11-year-old child was admitted on August 2009 for the treatment of relapsed AML (M7). A reinduction therapy based on the association of mitoxantrone (12 mg/m²for 5 days), etoposid (100 mg/m² for 3 days) and cytarabine (200 mg/m² for 7days) was administered.

On day 11 of hospital admission while WBC count was 200/mm³ with zero neutrophil, the patient presented fever at 39 °C, and was treated empirically by amikacin and ceftazidim. After 3 days of continuous high fever, treatment with tienam and targocid was started. Aspergillus serology and galactomannan antigenemia were both negative. Blood culture isolated a Klebsiella pneumonia strain found sensitive to the prescribed antibiotics. Chest X-ray showed no abnormalities.

On day 17 of hospital admission the patient became very dyspneic and died of a cardiovascular and respiratory failure. A total of 3 blood cultures was performed, one of them proved to be positive for G. capitatum after 3 days of incubation.

G. capitatum identification was based on morphological characteristics on PCB medium and biochemical pattern on Auxacolor2^® (Bio-Rad, France) and ID32C^® (bioMérieux, France) assimilation test systems. No autopsy was performed.

According to the results of E-test^® (bioMérieux, France), the strain was susceptible to amphotericin B and voriconazole with a MIC of 0.002 μg ml⁻¹ and 0.125 μg ml⁻¹ respectively.

4. Patient three

A 51 year-old man with AML was admitted at the Hematology department of our hospital on October 2010 for an induction chemotherapy course consisting of idarubicin (12 mg m²/day for 3 days) and cytarabine (200 mg m²/day for 7 days). On day 2 of hospital admission corresponding to day 1 of chemotherapy the patient presented a first febrile episode that was treated empirically and resolved after ceftazidime and amikacin treatment. WBC was 900/mm³ with 54 neutrophils/mm³.

On day 9 of hospital admission, a second fever episode count exceeding 39 °C developed despite antibiotic therapy. The physical examination only revealed a venite whereas chest X-ray showed diffuse reticular and interstitial infiltrates in both lungs. Antibiotics regimen was supplemented with vancomycine without any response. Ceftazidime and amikacin were changed with imipinem and ciprofloxacin, and amphotericin B (1 mg/kg/j) was administred for 21 days. A total of 8 blood cultures were performed. One of them yielded G. capitatum after 4 days of incubation. In addition, G. capitatum was isolated from sputum.

G. capitatum identification was based on morphological characteristics on PCB medium and biochemical patterns on Auxacolor2^® (Bio-Rad, France) and ID32C^® (bioMérieux, France) assimilation test systems.

The strain was susceptible to amphotericin B (MIC: 0.008 μg ml⁻¹) and voriconazole (MIC: 0.032 μg ml⁻¹).

Amphotericin B therapy was discontinued, and oral voriconazole was instituted at 200 mg twice daily and maintained for 3 weeks. The outcome was favorable and subsequent blood cultures were sterile. Neutropenia was recovered on day 14 of antifungic treatment and day 19 post chemotherapy. Later, the patient was preventively treated with antifungals on each course of chemotherapy. He is still alive and in complete remission with a follow up of 20 months.

5. Discussion

Systemic G. capitatum infections in patients with hematological malignancies are uncommon as compared to invasive aspergillosis and candidiasis [1,2,6,8]. Risk factors are nearly the same and mainly include deep and prolonged neutropenia, broad-spectrum antibiotics, cytotoxic chemotherapy and catherization [1,4,9].

Most of these predisposing factors occurred in our 3 patients as they all were suffering of AML and received induction (patient 1 and 3) or reinduction (patient 2) chemotherapy course and all showed neutropenia lasting for up to 18 days. In addition they all received antibiotics for presumed bacterial sepsis.

G. capitatum (formerly Trichosporon capitatum) is known to be a part of the normal flora of the human digestive and respiratory tracts and skin, all of them acting as a potential portal entry of the disease [1–3]. In our patients however, no clear portal of entry could be defined but the occurrence of respiratory symptoms and infiltrates on chest X-ray in 2 of them argue for a respiratory route.

Overall, clinical presentation of geotrichosis is very similar to that of other invasive fungal infections. Most often, geotrichosis presents as a fever unresponsive to antibiotics [5,6]. Involvement of deep organs, skin and digestive mucosea occur in 60–80% of patients [10–12]. In our 3 patients, diagnosis of the disease was evidenced by the recovery of the fungus from blood and the occurrence of pulmonary infiltrates in 2 of them, even through the responsibility of G. capitatum in respiratory symptoms could not be ascertained in the first patient because of the concomitant isolation of C. tropicalis and C. albicans in sputum.

Treatment and outcome of G. capitatum infection are dependent on the degree of invasion of the organism and the immune status of the host [8,9,11]. In early reports, the rarity of disseminated G. capitatum disease has been attributed at least in part to the low virulence of the fungus [8,9,11]. However further reports together with our own study showed that the prognosis of disseminated G. capitatum infection is very poor with a mortality rate exceeding 50% despite antifungal therapy [6,7,13,14].

Treatment of G. capitatum infection remains debatable, even though the combination of amphotericin B and flucytosin are seemingly the more efficient regimens. Voriconazole and micafungin were succeful in some reported cases [8,15–17]. In our study, only the patient 3, treated with a 3 weeks voriconazole course, survived whereas amphotericin B was inefficient in the first patient despite the in vitro susceptibility of the strain to this antifungal agent. This finding underlines the importance of the immune status of the patient for a favorable outcome. Conventional amphotericin B is used as a first-line treatment in our hospital setting because of its large spectrum, but its major drawbacks is its renal toxicity. This makes the voriconazole an interesting therapeutic alternative owing to its efficiency on G. capitatum and its good tolerance. This is well illustrated by the favorable outcome in our third patient.

The last patient did not receive any antifungal treatment because diagnosis of G. capitatum infection was only established after death.

Our study highlights the emergence of G. capitatum as an opportunistic fungus in leukemia patients of our region, the poorness of prognosis and the difficulties encountered in treatming the patients.

Conflict of interest statement

The authors declare that they have no competing interests.