Mycopathologia DOI 10.1007/s11046-015-9859-4
Fungemia Caused by Yarrowia lipolytica H. Trabelsi • K. Chtara • N. Khemakhem • S. Ne´ji • F. Cheikhrouhou • H. Sellami • R. Guidara • F. Makni • M. Bouaziz • A. Ayadi
Received: 4 September 2014 / Accepted: 6 January 2015 Ó Springer Science+Business Media Dordrecht 2015
Abstract Yarrowia lipolytica is weakly pathogenic yeast, which is rarely isolated from the blood. We report unusual cases of Y. lipolytica fungemia occurred between October 2012 and June 2014 in the intensive care unit (ICU) of the UH Habib Bourguiba Sfax. During this period, 55 cases of Y. lipolytica septicemia were diagnosed. There were 44 men and 11 women (sex ratio = 4).The median age was 43 years. The broadspectrum antibiotics (100 %), the catheterization (96 %), and the prolonged hospitalization in ICU (91 %) were the main risk factors. Patients were hospitalized in ICU, mostly, for polytraumatism (45.4 %), pneumopathy (9 %), and post-operative complications (7 %). Fever unresponsive to broadspectrum antibacterial therapy was the predominant sign of infection (83.6 %). Y. lipolytica was isolated in one or several blood cultures (14.5 %) and in the catheter tip culture of nine patients (16.3 %).Treatment was based on intravenous amphotericin B (58.2 %), fluconazole (45.4 %) and/or removal catheter (69 %).
H. Trabelsi N. Khemakhem S. Ne´ji F. Cheikhrouhou H. Sellami R. Guidara F. Makni A. Ayadi (&) Fungal and Parasitic Molecular Biology Laboratory, School of Medicine-Sfax, Sfax University, 3029 Sfax, Tunisia e-mail:
[email protected] K. Chtara M. Bouaziz Intensive Care Unit, CHU Habib Bourguiba Sfax, Sfax, Tunisia
Apyrexia or blood cultures sterilization was obtained for 34 patients (61.8 %). Y. lipolytica candidemia is an opportunistic and emerging human yeast pathogen. It can reach to the bloodstream of immunocompromised or critically ill patients during hospitalization through intravascular catheterization. Further clinical data need to be evaluated for formulating management strategies of seriously ill patients infected with uncommon fungal agents. Keywords Yarrowia lipolytica Emergent yeast Candidemia Intensive care unit
Introduction Yarrowia lipolytica is the only known species in the teleomorph genus Yarrowia and its anamorph is Candida lipolytica. It is a strictly aerobic and ubiquitous in the environment and having been isolated from refrigerated meat products, petroleum products, agricultural processing plants, and soil [1]. It, also, inhabits the mouth, pulmonary tree and intestines of healthy individuals [2]. It has a high lipolytic and proteolytic activity, and it is widely used in the detergent, food and pharmaceutics industries. Y. lipolytica has rarely been reported as a human pathogen [2, 3]. Y. lipolytica infection was first reported by Wehrspann and Fu¨llbrandt [4] in 1985. Since then, Y. lipolytica candidemia has been
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increasingly reported. It was isolated in four cases (0.07 %) among 6,082 yeast isolates collected from bloodstream infections in 250 medical centers distributed over 32 countries [5]. How such a yeast microorganism invades human hosts, even causing severe bloodstream infections is an interesting issue that is yet to be elucidated [6]. We report 55 cases of fungemia caused by Y. lipolytica. We sought to deepen our understanding of the clinical characteristics and management of Y. lipolytica fungemia.
Patients and Methods We report unusual cases of Y. lipolytica fungemia occurred between October 2012 and June 2014 in the intensive care unit (ICU) of the UH Habib Bourguiba Sfax (Tunisia). For each patient, we collected epidemiological (age, sex, underlying disease, and risk factors), clinical characteristics, treatment, and outcome. Prospective surveillance cultures (oral, nasal, urine, anal, and catheters tip cultures) were also taken in an attempt to further isolate Y. lipolytica from our patients. We collected samples from environmental sources (intravascular injection fluids, floors, tap water supply system, infusion pumps, and other hospital equipment). The hands of all healthcare workers in the unit were sampled using the broth-bag technique [7] and sterile premoistened swabs, respectively. All the blood specimens from the patients were inoculated into Bactec PED bottles (Becton–Dickinson, USA), which were incubated in the BactecÒ 9050 automated culturing system (BD diagnostic Systems 9050, Oxford, UK) at 37 °C for 15 days or until the bottles were positive by the colorimetric detection of CO2. Bottles proven to contain Candida spp. by direct examination were selected and subcultured in Sabouraud dextrose agar (SDA) at 25 °C. Yeasts grown on SDA plates were identified according to their morphological characteristics and biochemical profiles. Biochemical tests were performed by using ID32C (BioMerieux, France). The same methods were used for the others specimens (culture on SDA and identification by using ID32C). Identification of isolates was confirmed by DNA sequence analysis of the intergenic spacer (ITS) region (primers: ITS-1: 50 -TCCGTAGGTGAACCTGCGG-
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30 and ITS-4: 50 -TCCTCCGCTTATTGATATGC-30 ). These primers were designated by White et al. [8]. For antifungal drug susceptibility testing, a microtiter broth dilution method based on the Clinical and Laboratory Standards Institute M27-A2 standard (the sensititre yeast one; TREK Diagnostic Systems, East Grimstead, UK) was performed.
Results During our period of study, 55 cases of Y. lipolytica septicemia were diagnosed among 77 cases of positive yeast blood culture (71.4 %). There were 44 men and 11 women (sex ratio = 4).The median age was 43 years. The broad-spectrum antibiotics (100 %), the catheterization (96 %), and the prolonged hospitalization in ICU (91 %) were the main risk factors. The other risk factors were as follows: surgery (38 %), parenteral nutrition (36 %), yeast colonization (36 %), and diabetes (29 %). Only 9 % of cases received antifungal prophylaxis, and in all cases, the infection was acquired C48 h after hospitalization. Patients were hospitalized in ICU, mostly, for polytraumatism (45.4 %), pneumopathy (9 %), and post-operative complications (7 %). Fever unresponsive to broad-spectrum antibacterial therapy was the predominant sign of infection (83.6 %) followed by respiratory distress (20 %) and septic shock (20 %). Y. lipolytica was isolated in one or several blood cultures (14.5 %) and in the catheter tip culture of nine patients (16.3 %). All epidemiological and clinical characteristics of our patients were summarized in Table 1. The examination of the hands of healthcare workers, intravenous injection samples, other hospital equipment and environment source samples documented colonization by Y. lipolytica in the hands of one worker and in the infusions pumps of three patients. Y. lipolytica was also, isolated in the catheter tip culture of 11 patients who did not have an associated fungemia. On SDA after 3 days at 25 °C, the yeasts formed distinctive cerebriform, convoluted and firm white colonies. Microscopic examination showed ellipsoidal yeasts, single, paired, or single in small clusters. The API ID32C system yielded a 2300011011 code with excellent identification of the genus C. lipolytica.
Mycopathologia Table 1 Epidemiological and clinical characteristics of patients with Y. lipolytica candidemia No.
Age (y)/ sex
Underlying disease
Isolement of Y. lipolytica
Risk factors
Clinical failures
Therapy/ outcome
1
21/M
Polytraumatism
1 blood culture catheter
Antibiotics
Fever
AMB (13 d)
Catheter
Hemoperitonia
FLZ (17 d)
Parenteral nutrition
Pneumoperitoneum
CT removal Remission
Abdominal surgery 2
3
39/M
60/F
Polytraumatism
Diabetes
1 blood culture
1 blood culture
Ischemic cerebrovascular accident 4
5
48/F
32/F
Polytraumatism
Diabetes
1 blood culture
1 blood culture
Status epilepticus 6
15/F
Acute anemia
1 blood culture
Menometrorrhagia
7
8
78/M
50/M
Chronic obstructive pulmonary disease
1 blood culture
Rectosigmoid tumor
1 blood culture
Antibiotics
Fever
CT removal
Catheter Cerebral surgery
Sub-dural hematoma
Remission
Antibiotics
Hypothermia
FLZ (3 d)
Catheter
Pneumonia
AMB (6 d)
Parenteral nutrition
Septic shock
CT removal/dead
Antibiotics
Fever
FLZ (7 d)
Catheter
Pneumonia
CT removal
Cerebral surgery
Meningeal bleeding Fever
Remission
Antibiotics
FLZ (3 d)
Catheter
Respiratory distress
AMB (1 d)/dead
Antibiotics
Fever
FLZ (9 d)
Catheter
Chills
CT removal
Abdominal surgery
Multi visceral failure
Dead
Antibiotics
Fever
FLZ (7 d)
Catheter
Respiratory distress
Remission
Antibiotics
Fever
FLZ (6 d)
Catheter
Abdominal pain
AMB (17 d)
Parenteral nutrition
Peritonitis
Dead
Antibiotics
Hypothermia
AMB (2 d)
Catheter
Septic shock
Dead
Abdominal surgery 9
60/M
Diabetes
1 blood culture
Chronic renal failure
Respiratory distress 10
11
47/M
27/M
Polytraumatism
Thoracic traumatism
1 blood culture
2 blood culture
Antibiotics
Fever
AMB (10 d)
Catheter
Pneumonie
CT removal
Abdominal surgery
Extradural hematoma
Remission
Antibiotics
Fever Hemothorax
FLZ(23 d) CT removal
Catheter Abdominal surgery
Remission
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Mycopathologia Table 1 continued No.
Age (y)/ sex
Underlying disease
Isolement of Y. lipolytica
12
43/M
Polytraumatism
3 blood culture
13
52/M
Renal failure
1 blood culture
Cerebrovascular accident
Risk factors
Clinical failures
Therapy/ outcome
Antibiotics
Fever
FLZ
Catheter
Sub-dural hematoma
CT removal/ remission
Antibiotics
Infectious pneumopathy
AMB (7 d)
Catheter
FLZ(2 d) CT removal/dead
14
68/M
Chronic obstructive pulmonary disease
1 blood culture
Antibiotics
Respiratory distress
FLZ
15
36/M
Polytraumatism
1 blood culture
Antibiotics Catheter
Fever Respiratory distress
FLZ AMB Dead
Multiple surgery
Cerebral hemorrhage
Parenteral nutrition 16
17
18
18/M
51/M
46/M
Polytraumatism
Polytraumatism
Polytraumatism
1 blood culture
1 blood culture
1 blood culture catheter
20
62/F
20/M
Acute pancreatitis
Polytraumatism
1 blood culture
1 blood culture
CT removal
Antibiotics
Fever
AMB (8 d)
Catheter
Pneumopathy
CT removal/ remission
Antibiotics
Fever
FLZ (14 d)
Catheter
Septic shock
AMB(6 d) CT removal/ remission
Antibiotics
Fever
AMB (14 d)
Catheter
Extra dural hematoma
CT removal
Parenteral nutrition 19
Remission
Multiple surgery
Infectious pneumopathy
Remission
Antibiotics
Fever
AMB (2 d)
Catheter Parenteral nutrition
Septic shock
Dead
Antibiotics
Fever
FLZ ((25 d)
Catheter
Meningeal hemorrhage
CT removal
Parenteral nutrition
Dead
Pneumothorax
Cerebral surgery 21
73/M
Diabetes
1 blood culture
Renal failure Myocardial infarction 22
74/M
Polytraumatism
3 blood culture
Diabetes
Antibiotics
Fever
ablation
Catheter
Septic shock Pulmonary edema
catheter Dead
Antibiotics
Fever
FLZ (13 d)
Catheter
Septic shock
AMB (2 d) CT removal/dead
23
14/F
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Status epilepticus
2 blood culture
Antibiotics
Fever
FLZ (16 d)
Catheter
Pneumopathy
CT removal
Parenteral nutrition
Epileptic seizure
Remission
Mycopathologia Table 1 continued No.
Age (y)/ sex
24
57/M
Underlying disease
Isolement of Y. lipolytica
Polytraumatism
1 blood culture
26
27
35/F
16/M
58/F
Clinical failures
Therapy/ outcome CT removal
Antibiotics
Fever
Catheter
Pneumopathy
Dead
1 blood culture catheter
Antibiotics
Fever
FLZ
Catheter Surgery(cesarian)
Pneumopathy Hemorrhagic shock
CT removal Remission
1 blood culture
Antibiotics
Fever
FLZ (11 d)
Catheter
Pneumopathy
AMB (16 d)
Multiple surgery
Extra dural hematoma
CT removal/ remission
Antibiotics
Fever
FLZ
Heart failure
Catheter
Pneumopathy
AMB
Cardiomyopathy
Parenteral nutrition
Diabetes 25
Risk factors
Post-operative shock
Polytraumatism
Diabetes
6 blood culture
CT removal Dead
Surgery 28
50/M
Guillain Barre´ syndrome
1 blood culture
Pneumopathy
Antibiotics
Fever
CT removal
Catheter
Respiratory distress
Dead
Parenteral nutrition 29 30
36/M 45/F
Polytraumatism Pneumonia
1 blood culture 1 blood culture catheter
Fever
Catheter
Pneumopathy
Remission
Antibiotics Catheter
Fever Respiratory distress
AMB (6 d) CT removal
Parenteral nutrition 31 32
21/M 61/M
Polytraumatism Polytraumatism
1 blood culture 2 blood culture catheter
Septic shock
Antibiotics
26/M
Polytraumatism
1 blood culture
34
78/M
Polytraumatism
1 blood culture
35
36
27/M
83/M
Polytraumatism
Thoracic trauma Heart failure
1 blood culture
1 blood culture catheter
Dead
Antibiotics
Fever
AMB
Catheter
Pneumopathy
Remission
Antibiotics
Fever
AMB
Catheter
Pneumopathy
CT removal/ remission
Antibiotics Catheter
Fever
CT removal Remission
Parenteral nutrition 33
AMB
Antibiotics
Fever
–
Catheter
Septic shock
Dead
Abdominal surgery
Splenic infarct
Antibiotics
Fever
AMB (14 d)
Catheter
Pneumopathy
CT removal/ remission
Antibiotics Catheter
Fever Pneumothorax
– Dead
Parenteral nutrition
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Mycopathologia Table 1 continued No.
Age (y)/ sex
37
42/M
Underlying disease
Isolement of Y. lipolytica
Polytraumatism
1 blood culture
Diabetes 38
30/M
Polytraumatism Diabetes
1 blood culture catheter
Risk factors
Clinical failures
Therapy/ outcome
Antibiotics
Fever
AMB
Catheter
Pneumonia
CT removal
Pneumothorax
Remission
Antibiotics
Fever
CT removal
Catheter
Pneumopathy
Remission
Parenteral nutrition 39
45/M
Polytraumatism
1 blood culture
Antibiotics
Fever
FLZ
40
50/M
Diabetes Pharyngeal cancer
2 blood culture
Catheter Antibiotics
Pneumonia Fever
AMB/dead AMB (2 d)
41
61/M
Diabetes
1 blood culture
Acute colitis
Surgery
Pneumopathy
Dead
Antibiotics
Hypothermia
FLZ (7 d)
Catheter
Severe sepsis
Remission
Hypothermia Thrombophlebitis
AMB (1 d) Dead
CT removal
Parenteral nutrition Abdominal surgery 42
52/M
Hemorrhagic rectocolitis
1 blood culture
Antibiotics Catheter Parenteral nutrition Abdominal surgery
43
36/F
Diabetes
1 blood culture
Chronic renal failure 44
25/F
Diabetes
1 blood culture
Epilepsy Caustic oesophagitis 45
38/M
Thoracic and abdominal trauma
1 blood culture
diabetes 46
29/M
Abdominal trauma
Antibiotics
Hypothermia
Catheter
Septic shock
Remission
Antibiotics
Fever
AMB (4 d)
Catheter Parenteral nutrition
Pneumonia Respiratory distress
CT removal Dead
Antibiotics
Pneumopathy
AMB
Catheter
Renal failure
CT removal
Parenteral nutrition 1 blood culture
Dead
Antibiotics
Fever
AMB
Catheter
Pneumonia
FLZ
Parenteral nutrition
Septic shock
Dead
Abdominal surgery 47
48
30/M
46/M
Thoracic trauma
Diabetes Bronchopneumopathy
123
1 blood culture
Antibiotics
Fever
CT removal
Catheter
Catheter
Dead
Surgery
Hemorrhagic shock Pulmonary abscess
Antibiotics
Septic shock
FLZ
Catheter
Respiratory distress
Dead
1 blood culture
Mycopathologia Table 1 continued No.
Age (y)/ sex
Underlying disease
Isolement of Y. lipolytica
49
32/M
Nosocomial pneumopathy
1 blood culture
50
34/M
Polytraumatism
1 blood culture
51
64/M
Hemorrhagic
1 blood culture
Cerebrovascular accident
52
60/M
53
4/M
Diabetes Acute pulmonary edema
1 blood culture
Soda intoxication
1 blood culture
Caustic oesophagitis 54
40/M
Polytraumatism
1 blood culture
55
18/M
Polytraumatism
1 blood culture
Risk factors
Clinical failures
Therapy/ outcome AMB
Antibiotics
Fever
Catheter
Septic shock
CT removal
Antibiotics
Fever
FLZ
Catheter
Pneumopathy
Remission
Antibiotics
Fever
AMB
Catheter
Pneumonia
FLZ
Cerebral surgery
Cerebral edema
CT removal/ Dead
Antibiotics Catheter
Fever Pneumopathy
FLZ CT removal/ remission CT removal
Antibiotics
Fever
Catheter
Septic shock
Dead
Antibiotics
Fever
CT removal
Catheter
Pneumopathy
Dead
Antibiotics
Fever
AMB
Catheter
Pneumonia
CT removal/ remission
Y year, M male, F female, AMB amphotericin B, FLZ fluconazole, d day, CT catheter
The isolates were confirmed to be Y. lipolytica using a sequence analysis (GenBank accession no. KC254114.1) of the amplified ITS region using the BLAST program 9. The length of the query sequence was 358 bp. A 99 % identity with Y. lipolytica genes was obtained. Treatment was based on intravenous amphotericin B (1 mg/kg/day) (58.2 %), fluconazole (400 mg/day) (45.4 %) and/or the removal catheter (69 %). Apyrexia or blood cultures sterilization was obtained for 34 patients (61.8 %). In vitro susceptibility testing of the strains showed that: the MICs of amphotericin B was B1 lg/ml for 94.5 % of strains; the MICs of fluconazole was \8 lg/ml for 87.2 % of strains; the MICs of VRZ was B1 lg/ml for 98 % of strains; the MICs of caspofungin was B28 lg/ml for 96.3 % of strains and the MICs of 5-flucytosine was B4 lg/ml for 20 % of strains.
Discussion Despite the fact that Candida albicans remained the most common species causing invasive candidiasis
worldwide (overall, 66 % of all Candida spp.), we noted a decreasing trend in the isolation of C. albicans, proportionately, due to widespread prophylactic use of fluconazole. Non-albicans Candida species are being reported more commonly as these are resistant to fluconazole [3, 9]. Y. lipolytica candidemia is a rare but an emerging pathogenic yeast infection in humans [2, 3, 10]. It was not included in the long list in Hazen’s [11] careful 1995 review of emerging yeast pathogens. Y. lipolytica infection was first reported by Wehrspann and Fu¨llbrandt [4] in 1985. Since then, Y. lipolytica candidemia has been increasingly reported and strongly associated with intravascular catheterization. In the multicenter study of Pfaller and Diekema [12], his incidence crossed from 0 % in 1997 to 0.8 % in 2003. In the literature, 55 cases of human infections due to Y. lipolytica have been described [2–5, 13–21]. Recently, Liu et al. [10] found 16 cases by reviewing relevant studies in English from PubMed. This first report documents 55 cases of Y. lipolytica fungemia that occurred in the same department (ICU). No previous isolate of Y. lipolytica from clinical, surveillance, or environmental samples has been
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reported at our hospital. The isolation of several cases of such an uncommon species in a hospital ward suggested an outbreak. The 55 patients involved were hospitalized in adjacent units and cared sometimes for by the same healthcare workers. Although the source of the outbreak was not, certainly, identified, positive cultures of vascular catheters tips from some patients in the absence of other potential sources of infection were very suggestive of vascular catheter-associated candidemia. In the literature, contaminated infusions or the hands of healthcare workers are considered potential exogenous sources of Candida spp, such as Candida parapsilosis [22]. Shin et al. have reported the ability of this fungus to cause epidemic transmission but deep visceral infections and mortality have not been documented [3, 14]. It seems that the virulence of Y. lipolytica is weak. Neither deep visceral infections nor profound febrile reactions developed in the experimental cases. In almost cases, the patients were immunocompromised and received parenteral nutrition or antibiotic treatment via a catheter [23]. Documented infections of candidemia due to Y. lipolytica have been described in persons with hematological disorders such as leukemias, bone marrow transplant recipients, traumatic ocular infections, chronic sinusitis, and vascular catheter-related infections [6]. Indwelling catheter devices, especially central venous catheters, were strongly correlated in almost all cases of Y. lipolytica candidemia. In addition, D’Antonio et al. [6] claimed that Y. lipolytica produced large amounts of viscous slime materials, which are responsible for its capacity to adhere to and to colonize the central catheter. These catheters could introduce the yeast pathogen into the blood stream easily. Therefore, C. lipolytica might be considered one of the causative agents of catheter-related candidemia. In the present case, fever unresponsive to broadspectrum antibacterial therapy was the predominant sign of infection. In line with other studies, the clinical feature of Y. lipolytica septicemia is often non specific and frequently resembles those of invasive candidiasis. Appropriate management of Y. lipolytica candidemia is still controversial. Some suggest a stand back or a wait-and-watch approach without catheter removal or antifungal therapy [6]. Others suggest that although the yeast may colonize in the catheter and be seeded
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into the bloodstream, removal of catheter alone resolves fungemia [2, 14]. Consistent with the current guideline for the management of candidiasis, most studies suggest systemic antifungal therapy as well as the removal of the potentially infected vascular catheter as the best treatment [24]. Importantly, almost all infections due to Y. lipolytica were catheter related. Removal of the catheter or its replacement, in some cases combined with antifungal therapy, resulted invariably in clearance of the pathogen [15, 17, 18]. Our results showed that most Y. lipolytica isolates are susceptible to fluconazole and amphotericin B. In vitro susceptibility tests revealed that Y. lipolytica is susceptible to amphotericin B, ketoconazole, fluconazole, itraconazole, voriconazole, and caspofungin [2, 6, 18, 21], whereas in some isolates resistance has been reported to 5-flucytosine (5FC) and itraconazole [21]. Decreased susceptibilities of Y. lipolytica isolates to fluconazole, the triazoles posaconazole and voriconazole were also observed [23].
Conclusion Though Y. lipolytica is an environmental contaminant, the increasing evidence of catheter-related Y. lipolytica infections suggests that Y. lipolytica should be included in any list of emerging yeast pathogens and also poses the problem of defining the best strategy of patient management, given the current controversy on the most appropriate approach.
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