Rare Mould Fungaemia at a Tertiary Academic Hospital in Athens, Greece: A 15-Year Survey and Literature Review
Abstract
1. Introduction
2. Materials and Methods
2.1. Literature Review
2.2. Study Setting
2.3. Identification and AFST
2.4. Statistical Analysis
3. Results
3.1. Literature Review
- (i)
- Patients’ characteristics. Demographic and clinical data were available for 17 of the 22 patients (77%). Among these, 76% (13/17) were male, with a median (range, IQR) age of 60 (0.5–86, 70) years. Haematologic malignancies were reported in 35% (6/17). Most patients had venous catheters (94%, 16/17), either central (n = 12) or peripheral (n = 4), and were receiving antibiotic therapy (88%, 15/17). Concomitant Gram-negative bacteraemia was documented in 24% (4/17). Invasive mould infections typically affect hosts with compromised immune systems, as observed in the majority of patients (53%, 9/17). Notably, however, 8 patients were non-neutropenic or immunocompetent. Among these, 6 cases constituted a cluster following hospital renovation (all elderly individuals aged 63–86 years, admitted with urosepsis, endocarditis, pneumonia or bacteraemia) [16]; 1 case occurred in a critically ill premature neonate [8] and another in an adult without identifiable risk factors for invasive fungal infection [12] (Table 1).
- (ii)
- Species. The causative pathogens belonged to the genera Fusarium (59%, 13/22), Acremonium (27%, 6/22), Exophiala (9%, 2/22) and Scedosporium (5%, 1/22). Among the Fusarium isolates, 7 were identified as F. verticillioides, 5 as Fusarium spp., and 1 as F. musae. The Acremonium isolates included 3 A. kiliense and 3 Acremonium spp., while 2 isolates were identified as E. dermatitidis, and 1 as S. boydii. Identification methods were available for 17/22 isolates and comprised conventional phenotypic techniques (colony morphology and microscopy) in 18% (3/17), and molecular amplification with sequencing of the ITS region or the TEF-1α gene (for Fusarium spp.) in 82% (14/17) (Table 1).
- (iii)
- Antifungal susceptibility. AFST was performed on 13 isolates: 7 F. verticillioides, 3 A. kiliense, 2 E. dermatitidis and 1 F. musae. Standardised CLSI BMD testing of F. verticillioides isolates showed no in vitro activity for the tested antifungals, with MICs > 16 mg/L for all three echinocandins, amphotericin B, 5-flucytosine, itraconazole and posaconazole, and >1 mg/L for voriconazole. For A. kiliense, gradient diffusion strips indicated that voriconazole was the only agent with in vitro activity (MIC 0.5 mg/L). For E. dermatitidis, AFST using both EUCAST BMD and gradient diffusion strips methods showed that azoles (0.06–0.5 mg/L), except fluconazole (8–16 mg/L), and amphotericin B (0.25 mg/L) were active in vitro. The F. musae isolate, tested using the EUCAST BMD method, exhibited high MICs for amphotericin B, 5-flucytosine and all three echinocandins, moderate MICs for itraconazole (4 mg/L) and isavuconazole (1 mg/L), and low MICs for posaconazole and voriconazole (0.5 mg/L each) (Table 1).
- (iv)
- Antifungal therapy. Breakthrough infections were documented in 35% (6/17) of cases, including 3 patients who had received one of the following regimens: conventional amphotericin B (1 mg/kg/d for 21 days), liposomal amphotericin B (3 mg/kg every 48 h for >5 days, then 5 mg/kg/d for an unspecified number of days) and fluconazole (3 mg/kg/d twice weekly for 40 days). Treatment details were not available for the remaining 3 patients. Voriconazole monotherapy was administered to 59% of patients (10/17), including 6 with F. verticillioides, 3 with A. kiliense and 1 with F. musae. Among them, 5 (50%) died: 3 with F. verticillioides, 1 with A. kiliense and 1 with F. musae. Additionally, one patient with F. verticillioides who received no antifungal therapy, one with S. boydii treated with conventional amphotericin B (100 mg twice daily for 25 days) and one with E. dermatitidis who received liposomal amphotericin B (7 mg/kg/d) in combination with fluconazole (6 mg/kg every 48 h) for 8 days, also succumbed. In contrast, the E. dermatitidis-infected patient who was treated sequentially with caspofungin (50 mg/d for an unspecified number of days) followed by voriconazole (8 mg/kg/d for an unspecified number of days, then 9 mg/kg orally twice daily for 14 days), survived. Another patient with Fusarium spp. survived after sequential therapy with conventional amphotericin B (1 mg/kg/d for 5 days) and caspofungin (50 mg/d for 21 days). Two Acremonium spp.-infected patients received liposomal amphotericin B (1 mg/kg/d for 2–4 days, then 5 mg/kg/d for 26–28 days) followed by fluconazole (5 mg/kg/d orally for 30 days) and survived. The overall crude mortality rate was 47% (8/17) (Table 1).
3.2. Single-Centre Experience from “Attikon” University General Hospital
- (i)
- Incidence. Eight episodes were caused by RM, corresponding to an overall incidence rate of 0.8% (range: 0–3.4%). The estimated incidence density was 0.01 (range: 0–0.04) episodes per 1000 hospital admissions and 0.03 (range: 0–0.10) episodes per 10,000 patient-days. All RM bloodstream infections occurred in patients admitted to internal medicine wards and were sporadically distributed throughout the study period (1 case each in 2011, 2012, 2015, 2016, 2019, and 2020, and 2 cases in 2017 spanning nine months), with no evidence of temporal or spatial clustering (Table 2).
- (ii)
- Patient characteristics. Regarding patient demographics, 75% (6/8) were male, with a median (range, IQR) age of 64 (27–83, 25) years. Haematological malignancies were the most common underlying condition (5/8, 62%). At the time of diagnosis, all patients were febrile, and all but one (88%) were either neutropenic or immunosuppressed. In addition, all patients were receiving antibiotic therapy and had venous catheters (7 central and 1 peripheral). No bacterial bloodstream co-infections were recorded (Table 2).
- (iii)
- Biomarkers. The median (range, IQR) C-reactive protein (CRP) level at the time of RM-positive blood culture sampling, available for all patients, was 113 (15–256, 167) mg/L, while the corresponding procalcitonin level, available for 4/8 patients, was 0.55 (0.40–6.46, 2) ng/mL. 1,3-β-D-glucan (BDG) testing (Fungitell® assay, Associates of Cape Cod, East Falmouth, MA, USA) was performed in two patients within ±1 day of RM-positive blood culture collection, yielding one positive (692 pg/mL; breakthrough N. keratoplastica infection, fatal outcome) and one negative (48 pg/mL; B. dimerum infection, patient survived) result; no follow-up BDG measurements were conducted. The median (range, IQR) time from hospital admission to the diagnosis of RM fungaemia was 29 (4–88, 25) days.
- (iv)
- Species. Overall, the median (range, IQR) time to blood culture positivity was 5 (3–10, 2) days. The predominant etiological agents were Fusarium spp. (including Neocosmospora spp. according to the updated nomenclature; 75%, 6/8), comprising 2 isolates each of Bisifusarium dimerum (formerly F. dimerum), N. keratoplastica (formerly F. keratoplasticum), and F. oxysporum. Single isolates of Lomentospora prolificans and Acremonium spp. were also identified. Mixed fungaemia with N. keratoplastica and C. parapsilosis occurred in one case, while all other episodes involved a single RM species. Molecular identification and AFST were successfully performed for all isolates except the Acremonium spp., which had not been stored (Table 2).
- (v)
- Antifungal susceptibility. Among Fusarium isolates, amphotericin B was the only antifungal agent demonstrating consistent good in vitro activity (MIC 0.5–1 mg/L). Taking into account the EUCAST epidemiological cut-off value of amphotericin B for the Neocosmospora genus (formerly F. solani species complex; 8 mg/L), to which N. keratoplastica belongs, the N. keratoplastica isolates fall within the wild-type population. Voriconazole MICs were elevated, ranging from 2 to 8 mg/L, with N. keratoplastica isolates exhibiting the highest MIC of 8 mg/L, whereas other azoles showed no in vitro activity, with MICs ≥ 8 mg/L. In contrast, none of the antifungal agents tested were active in vitro against L. prolificans (Table 2).
- (vi)
- Antifungal therapy. Half of the patients (4/8) were receiving antifungal therapy at the time of fungaemia onset, including 2 on mould-active prophylaxis. Antifungal treatment for the management of fungaemia was not administered in 3 cases, either due to death prior to blood culture results (n = 2) or discharge before diagnosis, in which case the infection outcome remains unknown. Of the 5 patients who received antifungal therapy, voriconazole monotherapy was used in 2 cases (40%), 1 with L. prolificans (no available information on drug’s dose) and 1 with F. oxysporum (4 mg/kg twice daily for 17 days), both of whom died. One patient infected with N. keratoplastica received a short-course salvage combination of liposomal amphotericin B (5 mg/kg/d) and isavuconazole (200 mg three times a day), which was discontinued after two days due to clinical deterioration and death. On the contrary, a patient infected with B. dimerum survived following 35 days of liposomal amphotericin B monotherapy (5 mg/kg/d). Another patient with F. oxysporum also survived after a sequential therapy with liposomal amphotericin B (5 mg/kg/d for 5 days), followed by combination therapy with the same dose of liposomal amphotericin and voriconazole (4 mg/kg twice a day) for 18 days (Table 2).
- (vii)
- Mortality. The median (range, IQR) length of hospital stay following collection of the RM-positive blood culture was 18 (3–62, 29) days, whereas among patients who succumbed, the median (range, IQR) length of hospital stay from culture collection to death was 4 (3–62, 25) days. The overall crude mortality was 71% (5/7 patients with known outcomes), but when considering only those who received antifungal therapy, the corresponding rate decreased to 60% (3/5) (Table 2).
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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No | Year of Diagnosis (City) | Sex/Age (Years) | Underlying Disease and Risk Factors (Immune Status) | Causative Agent (Identification Method) | Antifungal Susceptibility (Testing Method) | Breakthrough Infection (Previous Antifungal, Duration) | Antifungal Therapy | Outcome | Reference |
---|---|---|---|---|---|---|---|---|---|
1 | 1994 (Thessaloniki) | M/2 | Neuroblastoma, CTX, CVC, ABT (neutropenic) | Acremonium spp. (colonial/microscopic morphology) | NA | No | LAMB (30 days; 1 mg/kg/d × 4 days, then 5 mg/kg/d) → FLC (30 days; 5 mg/kg/d po) | Survival (defervescence by day 6 of LAMB, negative cultures by day 10 of LAMB) | [13] |
2 | 1994 (Thessaloniki) | F/4 | ALL, CVC, ABT (neutropenic) | Acremonium spp. (colonial/microscopic morphology) | NA | No | LAMB (30 days; 1 mg/kg/d × 2 days, then 5 mg/kg/d) → FLC (30 days; 5 mg/kg/d po) | Survival (defervescence by day 4 of LAMB, negative cultures by day 8 of LAMB) | [13] |
3 | 2003 (Thessaloniki) | M/67 | AML, CTX, CVC, ABT (neutropenic) | Fusarium spp. (colonial/microscopic morphology) | NA | Yes (AMB, 1 mg/kg/d × 21 days) | AMB (1 mg/kg/d × 5 days) → CAS (50 mg/d × 21 days) | Survival (defervescence and negative cultures by day 7 of CAS) | [11] |
4 | 2009 (Thessaloniki) | F/60 | Possible acute myocardial infarction, 1-month Russian spa treatment 1 month prior (non-neutropenic) | Scedosporium boydii (ITS sequencing) | NA | No | AMB (100 mg bid × 25 days) | Death due to cardiorespiratory arrest | [12] |
5 | 2009–2018 (Athens) | NA | NA | Acremonium spp. (NA) | NA | NA | NA | NA | [14] |
6 | 2009–2018 (Athens) | NA | NA | Fusarium spp. (NA) | NA | NA | NA | NA | [14] |
7 | 2009–2018 (Athens) | NA | NA | Fusarium spp. (NA) | NA | NA | NA | NA | [14] |
8 | 2009–2018 (Athens) | NA | NA | Fusarium spp. (NA) | NA | NA | NA | NA | [14] |
9 | 2009–2018 (Athens) | NA | NA | Fusarium spp. (NA) | NA | NA | NA | NA | [14] |
10 | 2011 (Thessaloniki) | F/39 | Allogeneic HSCT recipient, acute GVHD, CVC, ABT (immunosuppressed) | Acremonium kiliense (ITS sequencing) | FLC > 256 mg/L, AFG/ITC/PSC/CAS/5-FC > 32 mg/L, AMB 32 mg/L, VRC 0.5 mg/L (gradient diffusion strips) | Yes (NA) | VRC (NA) | Survival | [15] |
11 | 2011 (Thessaloniki) | F/33 | Autologous HSCT recipient, relapsed Hodgkin’s disease, CVC, ABT (immunosuppressed) | Acremonium kiliense (ITS sequencing) | FLC > 256 mg/L, AFG/ITC/PSC/CAS/5-FC > 32 mg/L, AMB 32 mg/L, VRC 0.5 mg/L (gradient diffusion strips) | Yes (NA) | VRC (NA) | Survival | [15] |
12 | 2011 (Thessaloniki) | M/23 | Allogeneic HSCT recipient, Gram-negative pneumonia, CVC, ABT (immunosuppressed) | Acremonium kiliense (ITS sequencing) | FLC > 256 mg/L, AFG/ITC/PSC/CAS/5-FC > 32 mg/L, AMB 32 mg/L, VRC 0.5 mg/L (gradient diffusion strips) | Yes (NA) | VRC (NA) | Death due to underlying condition | [15] |
13 | 2012 (Larissa) | M/74 | Gram-negative UTI/BSI, diabetes mellitus, PVC, ABT (non-neutropenic) | Fusarium verticillioides (ITS and TEF-1α sequencing) | AMB/ITC/5-FC > 32 mg/L, PSC 32 mg/L, AFG/CAS/MFG > 16 mg/L, VRC 1 mg/L (CLSI BMD) | No | VRC (4 mg/kg bid × 24 days) | Death | [16] |
14 | 2012 (Larissa) | M/85 | Gram-negative UTI/BSI, CVC, ABT (non-neutropenic) | Fusarium verticillioides (ITS and TEF-1α sequencing) | AMB/ITC/5-FC > 32 mg/L, PSC 32 mg/L, AFG/CAS/MFG > 16 mg/L, VRC 1 mg/L (CLSI BMD) | No | VRC (NA) | Survival | [16] |
15 | 2012 (Larissa) | M/86 | Endocarditis, CVC, ABT (non-neutropenic) | Fusarium verticillioides (ITS and TEF-1α sequencing) | AMB/ITC/5-FC > 32 mg/L, PSC 32 mg/L, AFG/CAS/MFG > 16 mg/L, VRC 1 mg/L (CLSI BMD) | No | No | Death | [16] |
16 | 2012 (Larissa) | M/70 | ITP, PVC, corticosteroid therapy (immunosuppressed) | Fusarium verticillioides (ITS and TEF-1α sequencing) | AMB/ITC/5-FC > 32 mg/L, PSC 32 mg/L, AFG/CAS/MFG > 16 mg/L, VRC 1 mg/L (CLSI BMD) | No | VRC (NA) | Death | [16] |
17 | 2012 (Larissa) | M/63 | Gram-negative pneumonia, PVC, ABT (non-neutropenic) | Fusarium verticillioides (ITS and TEF-1α sequencing) | AMB/ITC/5-FC > 32 mg/L, PSC 32 mg/L, AFG/CAS/MFG > 16 mg/L, VRC 1 mg/L (CLSI BMD) | No | VRC (NA) | Death | [16] |
18 | 2012 (Larissa) | M/82 | Gram-negative pneumonia, PVC, ABT (non-neutropenic) | Fusarium verticillioides (ITS and TEF-1α sequencing) | AMB/ITC/5-FC > 32 mg/L, PSC 32 mg/L, AFG/CAS/MFG > 16 mg/L, VRC 1 mg/L (CLSI BMD) | No | VRC (NA) | Survival | [16] |
19 | 2012 (Larissa) | M/80 | Gram-negative BSI, CVC, ABT (non-neutropenic) | Fusarium verticillioides (ITS and TEF-1α sequencing) | AMB/ITC/5-FC > 32 mg/L, PSC 32 mg/L, AFG/CAS/MFG > 16 mg/L, VRC 1 mg/L (CLSI BMD) | No | VRC (NA) | Survival | [16] |
20 | 2021 (Athens) | M/0.5 | ELBW, Gram-negative BSI, abdominal surgery, PN, CVC, ABT, (non-neutropenic) | Exophiala dermatitidis (ITS sequencing) | FLC 16 mg/L, AFG/MFG 4 mg/L, CAS 2 mg/L, ISA 0.5 mg/L, AMB 0.25 mg/L, VRC/ITC 0.125 mg/L, PSC 0.06 mg/L (EUCAST BMD) | Yes (FLC, 3 mg/kg/d biw × 40 days) | LAMB (7 mg/kg/d) + FLC (6 mg/kg q48h) × 8 days | Death | [8] |
21 | 2022 (Crete) | M/4.5 | Ewing’s sarcoma, 1 month post-CTX, CVC, ABT (immunosuppressed) | Exophiala dermatitidis (ITS sequencing) | AFG/MFG/CAS/5-FC > 32 mg/L, FLC 8 mg/L, AMB 0.25 mg/L, VRC 0.06 mg/L (gradient diffusion strips) | No | CAS (NA; 50 mg/d) → VRC (NA; 8 mg/kg/d × NA days, then 9 mg/kg bid po × 14 days) | Survival | [10] |
22 | 2024 (Athens) | M/1.2 | Refractory KMT2A-rearranged infant B-ALL, CTX, CVC, ABT (neutropenic) | Fusarium musae (ITS sequencing) | AMB/5-FC 32 mg/L, ITC 4 mg/L, ISA 1 mg/L, PSC/VRC 0.5 mg/L, AFG/CAS/MFG 8 mg/L (EUCAST BMD; ISA by gradient diffusion strips) | Yes (LAMB 3 mg/kg q48h × >5 days, then 5 mg/kg/d × NA days) | VRC (18 weeks; increased from 4 mg/kg bid to 15 mg/kg bid based on TDM) | Gradual resolution of symptoms/signs shortly after dose increase to 15 mg/kg bid—Death due to underlying disease | [9] |
No | Year of Diagnosis | Sex/Age (Years) | Underlying Disease and Risk Factors (Immune Status) | Causative Agent (Identification Method) | Antifungal Susceptibility Based on EUCAST BMD | Breakthrough Infection (Previous Antifungal, Duration) | Antifungal Therapy | Outcome |
---|---|---|---|---|---|---|---|---|
1 | 2011 | M/27 | HSCT recipient, invasive rhinosinusitis, CVC, ABT (immunosuppressed) | Lomentospora prolificans (ITS and β-tubulin sequencing) | AFG/CAS/MFG > 8 mg/L, PSC/VRC/ITC/ISA > 8 mg/L, AMB 4 mg/L | Yes (FLC 400 mg/d × 25 days) | VRC (NA) | Death |
2 | 2012 | M/73 | AML, CTX, CVC, ABT (neutropenic) | Fusarium oxysporum (ITS and TEF-1α sequencing) | AFG/CAS/MFG/ITC > 8 mg/L, ISA 8 mg/L, PSC/VRC 2 mg/L, AMB 0.5 mg/L | Yes (VRC 4 mg/kg bid × 10 days) | VRC (4 mg/kg bid × 17 days) | Death |
3 | 2015 | M/83 | Decreased level of consciousness, aspiration pneumonia, PVC, ABT (non-neutropenic) | Acremonium spp. (colonial/microscopic morphology) | NA | No | No | Death * |
4 | 2016 | M/58 | NHL, corticosteroid therapy, CVC, ABT (neutropenic) | Neocosmospora keratoplastica (ITS and TEF-1α sequencing) | AFG/CAS/MFG > 8 mg/L, PSC/ITC/ISA > 8 mg/L, VRC 8 mg/L, AMB 1 mg/L | No | No | Death * |
5 | 2017 | F/75 | Pulmonary malignancy with cerebral metastases, CTX, CVC, ABT (neutropenic) | Bisifusarium dimerum (ITS and TEF-1α sequencing) | AFG/CAS/MFG > 8 mg/L, PSC/ITC/ISA > 8 mg/L, VRC 8 mg/L, AMB 1 mg/L | No | No | NA # |
6 | 2017 | F/42 | SLE, tuberculosis, corticosteroid therapy, CVC, ABT (immunosuppressed) | Bisifusarium dimerum (ITS and TEF-1α sequencing) | AFG/CAS/MFG > 8 mg/L, PSC/ITC/ISA > 8 mg/L, VRC 4 mg/L, AMB 0.5 mg/L | No | LAMB (5 mg/kg/d × 35 days) | Survival |
7 | 2019 | M/70 | NHL, corticosteroid therapy, CVC, ABT (neutropenic) | Neocosmospora keratoplastica (ITS and TEF-1α sequencing) ^ | AFG/CAS/MFG > 8 mg/L, PSC/ITC/ISA > 8 mg/L, VRC 8 mg/L, AMB 1 mg/L | Yes (AFG 100 mg/d × 3 days → CAS 50 mg/d × 7 days → LAMB 5 mg/kg/d × 4 days) | LAMB (5 mg/kg/d) + ISA (200 mg tid) × 2 days | Death |
8 | 2020 | M/51 | AML, corticosteroid therapy, CVC, ABT (neutropenic) | Fusarium oxysporum (ITS and TEF-1α sequencing) | AFG/CAS/MFG/ITC/ISA > 8 mg/L, PSC/VRC 4 mg/L, AMB 1 mg/L | Yes (ISA 200 mg/d × 12 days) | LAMB (5 mg/kg/d × 5 days) → LAMB (5 mg/kg/d) + VRC (4 mg/kg bid) × 18 days | Survival |
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Siopi, M.; Alevra, A.; Mitsopoulos, D.; Pournaras, S.; Meletiadis, J. Rare Mould Fungaemia at a Tertiary Academic Hospital in Athens, Greece: A 15-Year Survey and Literature Review. J. Fungi 2025, 11, 644. https://doi.org/10.3390/jof11090644
Siopi M, Alevra A, Mitsopoulos D, Pournaras S, Meletiadis J. Rare Mould Fungaemia at a Tertiary Academic Hospital in Athens, Greece: A 15-Year Survey and Literature Review. Journal of Fungi. 2025; 11(9):644. https://doi.org/10.3390/jof11090644
Chicago/Turabian StyleSiopi, Maria, Angeliki Alevra, Dimitrios Mitsopoulos, Spyros Pournaras, and Joseph Meletiadis. 2025. "Rare Mould Fungaemia at a Tertiary Academic Hospital in Athens, Greece: A 15-Year Survey and Literature Review" Journal of Fungi 11, no. 9: 644. https://doi.org/10.3390/jof11090644
APA StyleSiopi, M., Alevra, A., Mitsopoulos, D., Pournaras, S., & Meletiadis, J. (2025). Rare Mould Fungaemia at a Tertiary Academic Hospital in Athens, Greece: A 15-Year Survey and Literature Review. Journal of Fungi, 11(9), 644. https://doi.org/10.3390/jof11090644