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Background: Available data on combat wound-related invasive mould infections (IMIs) are limited., Objectives: We aimed to describe the characteristics and outcomes of IMIs in casualties of a recent conflict., Patients/methods: A retrospective study including hospitalised patients with combat-related injuries, fulfilling criteria for wound-related IMI based on Trauma Infectious Disease Outcomes Study definitions. Patient and injury characteristics, management and outcomes are described and compared to previous cohorts. Mould isolates and susceptibility testing results, including the novel agent manogepix, are reported., Results: Overall, 31 patients (69 mould isolates) were included-resulting in an IMI incidence rate of 1.9%. Blast was the most common injury mechanism (71%), with limb amputations and abdominoperineal injuries in 35% and 45%, respectively. Mould cultures, obtained mostly from lower extremities wounds (62%), were positive in all patients. Most (68%) had poly-mould infections, with Aspergillus and Fusarium species predominating. Overall, non-susceptibility rates of > 50% to newer azoles and 38% to amphotericin B reflected the high proportion of Fusarium spp., A. terreus and A. flavus, with the lowest azole minimal inhibitory concentrations demonstrated with posaconazole. Manogepix displayed good in-vitro activity against all isolates, except for Mucorales species. Two patients (6.5%) died of disseminated IMIs and 19% required amputations. Patients with Mucorales had poorer outcomes (40% mortality/amputation vs. 19% for non-Mucorales)., Conclusions: Combat wound-related IMIs are uncommon but carry significant morbidity and mortality. High susceptibility rates to manogepix were observed. Further studies are needed to evaluate optimal surgical approaches and the role of antifungal susceptibility testing in this setting., (© 2025 The Author(s). Mycoses published by Wiley‐VCH GmbH.)

Background: Invasive fungal disease (IFD) is a sinister complication encountered in patients with haematological disorders. When occurring in the central nervous system (CNS), IFDs can have catastrophic outcomes., Objectives: To study the clinical presentation, predisposing etiological factors, and prognosis of a CNS-IFD in a patient with a haematological disorder., Patients and Methods: This is a retrospective study focusing on the clinical profile, diagnosis, treatment strategy and outcomes of 43 patients with an underlying haematological disorder, who were diagnosed with CNS-IFD between 2018 and 2022., Results: Of the 43 patients, 18 were chemotherapy recipients, while 23 were stem cell transplant (SCT) recipients and 2 presented with CNS-IFD at diagnosis. AML/MDS (37.2%) and ALL (18.6%) were the predominant underlying diagnoses. A sudden deterioration in sensorium (53.5%) was the earliest clinical sign, while T2 hyperintensities (26.8%), vascular involvement (26.8%) and ring-enhancing lesions (16.3%) were the commonest radiological findings, with all patients exhibiting diffusion restriction in diffusion-weighted images. Microbiological evidence of infection was obtained in all patients; however, culture positivity was established in only 25 patients. Rhizopus spp (23.2%) and Aspergillus spp (20.9%) were implicated in most cases. Overall survival of the cohort was 27.9% at a median follow-up of 6 months. In patients who succumbed, the median time to death was 4 days (0-46)., Conclusion: CNS-IFD is associated with very poor survival in patients undergoing chemotherapy or an SCT, urging the need for prompt diagnosis and initiation of suitable antifungal therapy., (© 2024 Wiley‐VCH GmbH. Published by John Wiley & Sons Ltd.)

Background: Invasive fungal infections (IFI) are a relevant cause of morbidity and mortality among patients with haematological neoplasms (HMs). Since 2002, a classification of IFI based on host factors, clinical and radiological features and mycological tests was published for research purpose., Objectives: These criteria are widely used in clinical practice to identify patients at risk for IFI. The aim of the study was to evaluate the clinical applicability of EORTC/MSG 2008 criteria for the diagnosis of IFI in daily practice., Patients/methods: This multicentre, non-interventional, observational, prospective study gathered all consecutive inpatients with HMs in which an intravenous antifungal treatment was started. Exclusion criteria were a previous or concomitant transplant procedure, outpatient status and oral antifungal therapy. EORTC/MSG 2008 criteria were used to classify patients at the beginning of antifungal therapy and at 30 days. An independent board reviewed the classification of IFI given by local clinicians at T0 and T30., Results: The highest percentage of agreement was found for possible IFI (96%), while a lower agreement was reported for proven IFI (74%), and the highest variability was observed for probable IFI (56%). At T30, the board re-evaluation confirmed a strict agreement for possible IFI only (98%). Among 306 patients classified as possible, 156 (51%) patients showed non-typical radiological findings and 45 (15%) patients presented host factors only., Conclusions: In real life, the EORTC/MSG criteria can be applicable only for possible IFI. As non-typical radiological findings are reported in possible IFI, introducing a new IFI category should be considered., (© 2024 Wiley‐VCH GmbH. Published by John Wiley & Sons Ltd.)

Background: Invasive fungal disease (IFD) is associated with high morbidity and mortality. Data are lacking regarding physicians' perspectives on the diagnosis and management of IFD in China., Objectives: To evaluate physicians' perspectives on the diagnosis and management of IFD., Methods: Based on current guidelines, a questionnaire was designed and administered to 294 physicians working in haematology departments, intensive care units, respiratory departments and infectious diseases departments in 18 hospitals in China., Results: The total score and subsection scores for invasive candidiasis, invasive aspergillosis (IA), cryptococcosis and invasive mucormycosis (IM) were 72.0 ± 12.2 (maximum = 100), 11.1 ± 2.7 (maximum = 19), 43.0 ± 7.8 (maximum = 57), 8.1 ± 2.0 (maximum = 11) and 9.8 ± 2.3 (maximum = 13), respectively. Although the perspectives of the Chinese physicians were in good overall agreement with guideline recommendations, some knowledge gaps were identified. Specific areas in which the physicians' perspectives and guideline recommendations differed included use of the β-D-glucan test to facilitate the diagnosis of IFD, relative utility of the serum galactomannan test and bronchoalveolar lavage fluid galactomannan test in patients with agranulocytosis, use of imaging in the diagnosis of mucormycosis, risk factors for mucormycosis, indications for initiating antifungal therapy in patients with haematological malignancies, when to start empirical therapy in mechanically ventilated patients, first-line drugs for mucormycosis and treatment courses for IA and IM., Conclusion: This study highlights the main areas that could be targeted by training programs to improve the knowledge of physicians treating patients with IFD in China., (© 2023 Wiley-VCH GmbH.)

Background: Invasive fungal diseases (IFD) are life-threatening and demand timely and appropriate treatment. Research showed that isavuconazole treatment positively affects clinical outcome and length of hospital stay (LOS)., Objectives: The aim of this study was to assess the hospital costs of patients diagnosed with IFD and treated with isavuconazole using real-world data from a German cancer centre., Patients/methods: Data and LOS collected from Jan-2016 to Jun-2021 at Department I of Internal Medicine, University Hospital Cologne were retrieved. Case-related resources consumed during the hospital stay across isavuconazole routes of administration (oral, parenteral, and mixed administration) were identified, quantified, valued and compared via a cost analysis that adopted the healthcare payer perspective., Results: In total, 101 cases with isavuconazole treatment were identified (oral: n = 22, 21.8%; parenteral: n = 59, 58.4%; mixed: n = 20, 19.8%). Median total LOS was greater in the mixed group (46.5 days; p = .009). Median ICU LOS and ventilation duration were both longest in the parenteral-only group (16 days, p = .008; 224 h, p = .003). Invasive aspergillosis was the most frequent isavuconazole indication (n = 86, 85.2%). Average hospital costs were highest in the mixed group (€ 101,226). The median overall costs of cases treated with isavuconazole was € 52,050., Conclusions: Treating IFD is resource intensive, often requires intensive care and implies high rates of in-hospital mortality. Our study emphasises the high hospital treatment costs and thus the need for reimbursement systems to enable live-saving costly treatments., (© 2023 The Authors. Mycoses published by Wiley-VCH GmbH.)

Background: Limited data exist to describe end-of-treatment (EOT) parameters of antifungal therapy for invasive mould infections (IMI)., Methods: In a 10-year cohort of consecutive adult allogeneic haematopoietic cell transplant recipients with proven/probable IMI, we describe treatment duration and patient profile at EOT., Results: There were 61 patients with 66 proven/probable IMI identified: 47/66 (71%) invasive aspergillosis (IA), 11/66 (17%) mucormycosis, and 8/66 (12%) other-IMI. Excluding 5 (8%) patients lost to follow-up, treatment was prematurely discontinued due to death or palliative care in 29/56 (51.8%) patients. Antifungal treatment was completed in 27 (48.2%) patients, for a median duration of 280 days (IQR: 110, 809): 258 (IQR: 110, 1905) and 307.5 (99, 809) days in IA and non-IA IMI, respectively. Treatment was continued after 90 and 180 days in 43/56 (76.8%) and 30/56 (53.6%) patients, respectively. At EOT, most patients were not neutropenic (ANC: 2.12 G/L, IQR: 0.04, 5.3), with CD4+ counts at 99 cells/μl (IQR: 0, 759) and immunoglobulins at 5.6 g/L (IQR: 2.3, 10.6). Most patients (16/27, 59.3%) were not receiving steroids at EOT, while 14/27 (53.9%) were on another type of immunosuppression. Amongst 15 patients with imaging at EOT, 12 (80%) had complete/partial radiologic response. Any chart documentation or an infectious disease consultation on treatment discontinuation was observed in 12/56 (21%) and 11/56 (20%) patients, respectively., Conclusions: Long treatment courses are observed in patients with IMI, due to prolonged immunosuppression. Although immune reconstitution and radiological response were frequently observed at EOT, consistent documentation of treatment discontinuation based on well-defined parameters is lacking., (© 2022 The Authors. Mycoses published by Wiley-VCH GmbH.)

Background: Candida bloodstream infections (BSI) became an important invasive disease in the late 20th century, in particular among immunocompromised patients. Although considerable progress has been made in the management of patients with invasive mycoses, Candida BSI are still widespread among hospitalised patients and are associated with relatively high mortality., Objectives: We conducted a retrospective study to evaluate patient characteristics, incidence, species distribution and antifungal susceptibility of BSI isolates of Candida spp. as well as outcomes of Candida BSI from 2001 to 2012, before the widespread use of echinocandins. This is the first epidemiological study of Candida BSI in Slovenia so far., Methods: All documented candidaemia cases from 2001 to 2012 in two major hospitals-University Medical Centre and Institute of Oncology in Ljubljana, Slovenia-were taken into consideration. Candida BSI were identified in 422 patients (250 male, 172 female). Laboratory and clinical data of these patients were retrospectively analysed. Mann-Whitney U test was used to compare continuous variables and Fisher's exact test or chi-squared test for categorical variables., Results and Conclusions: The average incidence of Candida BSI was 0.524/10.000 patient-days (0,317/1000 admissions); 16/422 were younger than 1 year and 251/422 patients were over 60 years old. The most commonly isolated species were Candida albicans and Candida glabrata, followed by Candida parapsilosis. Majority of the patients had a single episode of Candida BSI, multiple episodes of Candida BSI occurred in 18/434 patients (4.1%); in 25/434 patients (5.8%) mixed Candida BSI were observed. Crude 30-day case-fatality rate was 55.4%., (© 2021 Wiley-VCH GmbH.)

Invasive fungal disease (IFD) is frequent in patients with haematologic malignancies and in recipients of haematopoietic cell transplantation (HCT). An epidemiologic study conducted in Brazil reported a high incidence of IFD in haematologic patients, and invasive fusariosis was the leading IFD. A limitation of that study was that galactomannan was not available for at least half of the study period. In order to characterise the epidemiology and burden of IFD in three cohorts, HCT, acute myeloid leukaemia (AML) or myelodysplasia (MDS), and acute lymphoid leukaemia (ALL), we conducted a prospective multicentre cohort study in four haematologic Brazilian centres. From August 2015 to July 2016, all patients receiving induction chemotherapy for newly diagnosed or relapsed AML, MDS or ALL, and all HCT recipients receiving conditioning regimen were followed during the period of neutropenia following chemotherapy or the conditioning regimen. During a 1-year period, 192 patients were enrolled: 122 HCT recipients (71 allogeneic, 51 autologous), 46 with AML, and 24 with ALL. The global incidence of IFD was 13.0% (25 cases, 11 proven and 14 probable). Invasive aspergillosis (14 cases) was the leading IFD, followed by candidemia (6 cases) and fusariosis (3 cases). The incidence of IFD was 26.1% in AML/MDS, 16.7% in ALL, 11.3% in allogeneic HCT, and 2.0% in autologous HCT. The burden of IFD in haematologic patients in Brazil is high, with a higher frequency in AML and ALL. Invasive aspergillosis is the leading IFD, followed by invasive candidiasis and fusariosis., (© 2020 Wiley-VCH GmbH.)

Background: Early diagnosis of invasive fungal diseases (IFDs) remains a major challenge in routine clinical practice., Objectives: The aim of this retrospective cohort study was to evaluate the diagnostic performance of the fungal biomarker (1,3)-ß-d-glucan (BDG) using the β-Glucan test (GT) and the well-established Fungitell assay® (FA) in real-life clinical practice., Patients/methods: We included 109 patients with clinical suspicion of IFD who were treated at Jena University Hospital, Germany, between November 2018 and March 2019. The patients were classified according to the latest update of the EORTC/MSG consensus definitions of IFD. The first serum sample of every patient was analysed for BDG using the FA and the GT, respectively., Results: Fifty-six patients (51.4%) had at least one host factor for IFD. In patients with proven (n = 11) or probable IFDs (n = 20), median BDG concentrations were 145.0 pg/ml for the FA and 5.1 pg/ml for the GT, respectively. A positive test result of both BDG assays at manufacturer's cut-offs predicted 89.5%-98.3% of proven or probable IFD, but the sensitivity of both assays was limited: The FA identified 60.7% of IFDs (cut-off: 80 pg/ml). Reducing the GT cut-off value from 11.0 to 4.1 pg/ml increased the detection rate of IFDs from 35.5% to 54.8%., Conclusions: A positive test result of both BDG assays at manufacturer's cut-off was highly predictive for IFD, but except for Pneumocystis jirovecii pneumonia sensitivities were limited. Adjustment of the GT cut-off value equalised sensitivities of GT and FA., (© 2020 The Authors. Mycoses published by Wiley-VCH GmbH.)

Invasive fungal diseases are associated with significant morbidity and mortality, particularly in immunocompromised individuals. Early and accurate diagnosis is crucial for effective treatment. Despite traditional methods such as microbiological culture, histopathology, radiology and direct microscopy are available, antigen/antibody-based diagnostics are emerging for diagnosis of invasive fungal infections (IFI). Fungal cell wall is a unique structure composed of polysaccharides that are well correlated with fungal burden during fungal infections. Based on this feature, cell wall polysaccharides have been explored as antigens in IFIs diagnostics such as the galactomannan assay, mannan test, β-glucan assay and cryptococcal CrAg test. Herein, we provide an overview on the cell wall polysaccharides from three opportunistic pathogens: Aspergillus fumigatus, Candida albicans and Cryptococcus neoformans, and their applications for IFIs diagnosis. The clinical outcome of newly developed cell wall polysaccharides-based diagnostics is also discussed., (© 2020 Blackwell Verlag GmbH.)

Background: The new Rasamsonia spp. complex can develop invasive infection in immunosuppression or chronic pulmonary disease. It has potential to be misidentified as other genera due to morphological similarities. Nowadays, there is a gap of knowledge on this fungi., Objectives: To provide knowledge base of risk factors and therapeutic decisions in invasive Rasamsonia spp. complex infection., Patients/methods: Cases of invasive infection due to Rasamsonia spp. (formerly Geosmithia/Penicillium spp.) from FungiScope ® registry and all reported cases from a literature were included., Results: We identified 23 invasive infections due to Rasamsonia spp., six (26.1%) in the FungiScope ® registry. Main risk factors were chronic granulomatous disease (n = 12, 52.2%), immunosuppressive treatment (n = 10, 43.5%), haematopoietic stem cell transplantation (n = 7, 30.4%), graft-versus-host disease and major surgery (n = 4, 17.4%, each). Predominantly affected organs were the lungs (n = 21, 91.3%), disease disseminated in seven cases (30.4%). Fungal misidentification occurred in 47.8% (n = 11), and sequencing was used in 69.6% of the patients (n = 16) to diagnose. Breakthrough infection occurred in 13 patients (56.5%). All patients received antifungal treatment, mostly posaconazole (n = 11), caspofungin (n = 10) or voriconazole (n = 9). Combination therapy was administered in 13 patients (56.5%). Susceptibility testing showed high minimum inhibitory concentrations for azoles and amphotericin B, but not for echinocandins. No preferable treatment influencing favourable outcome was identified. Overall mortality was 39% (n = 9)., Conclusion: Rasamsonia spp. are emerging fungi causing life-threatening infections, especially in immunocompromised and critically ill patients. Mortality is high. Treatment is challenging and clinicians dealing with this patient population should become aware of this infection constituting a medical emergency., (© 2019 The Authors. Mycoses published by Blackwell Verlag GmbH.)

Invasive aspergillosis (IA) is a severe complication in immunocompromised patients. Early diagnosis is crucial to decrease its high mortality, yet the diagnostic gold standard (histopathology and culture) is time-consuming and cannot offer early confirmation of IA. Detection of IA by polymerase chain reaction (PCR) shows promising potential. Various studies have analysed its diagnostic performance in different clinical settings, especially addressing optimal specimen selection. However, direct comparison of different types of specimens in individual patients though essential, is rarely reported. We systematically assessed the diagnostic performance of an Aspergillus-specific nested PCR by investigating specimens from the site of infection and comparing it with concurrent blood samples in individual patients (pts) with IA. In a retrospective multicenter analysis PCR was performed on clinical specimens (n = 138) of immunocompromised high-risk pts (n = 133) from the site of infection together with concurrent blood samples. 38 pts were classified as proven/probable, 67 as possible and 28 as no IA according to 2008 European Organization for Research and Treatment of Cancer/Mycoses Study Group consensus definitions. A considerably superior performance of PCR from the site of infection was observed particularly in pts during antifungal prophylaxis (AFP)/antifungal therapy (AFT). Besides a specificity of 85%, sensitivity varied markedly in BAL (64%), CSF (100%), tissue samples (67%) as opposed to concurrent blood samples (8%). Our results further emphasise the need for investigating clinical samples from the site of infection in case of suspected IA to further establish or rule out the diagnosis., (© 2019 The Authors. Mycoses published by Blackwell Verlag GmbH.)

Background: Invasive mucormycosis is a rare but frequently fatal fungal disease. The acute and rapidly progressive evolution causes unfavourable outcome in 22%-59% of patients and its treatment represents a clinical challenge, especially in immunocompromised patients. Current data in paediatric oncological patients are limited., Objectives: The infection Working Group of the Italian Association of Pediatric Hematology and Oncology (AIEOP) analysed the episodes of invasive mucormycosis occurred between 2009 and 2016., Patients: Fifteen cases of proven mucormycosis (male/female 8/7; median age 14.1 years, range 7.7-18.6) were reported after chemotherapy for acute leukaemia and lymphoma (12) and allogeneic stem cell transplantation (3). The aetiology was Rhizopus oryzae 4, Lichtheimia corymbifera 3 and Mucor spp. 8., Results: Paranasal sinus was the primary site of infection in 14/15 patients combined with orbital involvement (9), central nervous system (8), lung (4), thyroid gland and kidney (1). All patients received liposomal Amphotericin B (L-AmB) (3-10 mg/kg), with surgical debridement in 14/15 cases. Eleven patients received maintenance treatment with posaconazole (9) or isavuconazole (2). Eight out of fifteen patients (53.3%) died, after 3-6 months., Conclusions: Mucormycosis involved mainly the sinu-orbital site and affected children >10 years. Despite aggressive treatment with high-dose L-AmB and timely surgical debridement, the mortality rate remains still high., (© 2018 Blackwell Verlag GmbH.)

Invasive fungal diseases (IFD) are a primary cause of morbidity and mortality in patients with haematological malignancies. These infections are mostly life-threatening and an early diagnosis and initiation of appropriate antifungal therapy are essential for the clinical outcome. Most commonly, Aspergillus and Candida species are involved. However, other Non-Aspergillus moulds are increasingly identified in case of documented IFD. For definite diagnosis of IFD, a combination of diagnostic tools have to be applied, including conventional mycological culture and non-conventional microbiological tests such as antibody/antigen and molecular tests, as well as histopathology and radiology. Although varying widely in cancer patients, the risk of invasive fungal infection is highest in those with allogeneic stem cell transplantation and those with acute leukaemia and markedly lower in patients with solid cancer. Since the last edition of Diagnosis of Invasive Fungal Diseases recommendations of the German Society for Hematology and Oncology in 2012, integrated care pathways have been proposed for the management and therapy of IFDs with either a diagnostic driven strategy as opposed to a clinical or empirical driven strategy. This update discusses the impact of this additional evidence and effective revisions., (© 2018 Blackwell Verlag GmbH.)

Treatment outcomes in patients with proven/probable vs possible invasive mould disease (IMD; 2008 European Organisation for Research and Treatment of Cancer/Mycoses Study Group [EORTC/MSG] criteria) needed further assessment. The Phase III SECURE trial compared isavuconazole vs voriconazole for treatment of IMD. This post hoc analysis assessed all-cause mortality (ACM) through day 42 (primary endpoint) and day 84, overall and clinical success at end of treatment (EOT), and drug-related treatment-emergent adverse events (TEAEs) in subgroups with proven/probable or possible IMD. Of 516 randomised patients, 304 (58.9%) had proven/probable IMD and 164 (31.8%) had possible IMD as per EORTC/MSG criteria; 48 did not have IMD. Across treatment groups, day 42 and day 84 ACM were numerically lower for possible vs proven/probable IMD (day 42: 17.1% vs 21.1%; P = 0.3, day 84: 26.2% vs 32.6%; P = 0.15). Overall and clinical success at EOT were significantly higher for possible IMD compared with proven/probable IMD (48.2% vs 36.2%; P = 0.01, 75.0% vs 63.1%; P = 0.01 respectively). Fewer drug-related TEAEs were reported with isavuconazole compared with voriconazole in patients with either proven/probable or possible IMD. Compared with patients with proven/probable IMD, those with possible IMD demonstrated higher overall and clinical success rates, supporting early initiation of antifungal treatment., (© 2018 Blackwell Verlag GmbH.)

The optimal approach to treat invasive fungal disease (IFD) caused by more than one fungal species is unknown. We documented the efficacy and safety of isavuconazole for treatment of IFDs caused by more than one fungal species. VITAL was a single-arm, international, open-label study evaluating the efficacy and safety of isavuconazole (200 mg orally or intravenously every 8 hours for 48 hours, then once daily) for treatment of rare IFDs. The primary outcome was the overall response at Day 42; key secondary outcomes were overall responses at Day 84 and end of treatment (EOT), mortality at Days 42 and 84, and safety. This analysis includes patients with IFD caused by multiple fungal species. Fifteen patients were included in this analysis (including Aspergillus spp., n = 11; without Aspergillus spp., n = 4); median treatment duration was 97 days [range, 6-544] days). Overall treatment success was observed in 2/15 patients (13.3%) at Days 42 and 84, and 2/14 (14.3%) at EOT. All-cause mortality was 2/15 (13.3%) at Day 42 and 4/15 (26.7%) at Day 84. All patients had ≥1 treatment-emergent adverse event (TEAE); 12 patients (80.0%) had serious TEAEs; TEAEs led to discontinuation of isavuconazole in two patients (13.3%). Isavuconazole may be useful to treat some IFDs caused by multiple fungal species., (© 2018 The Authors. Mycoses Published by Blackwell Verlag GmbH.)

A clear link between mating type and virulence has been demonstrated for some fungal pathogens, but not for Aspergillus fumigatus as of yet. An association between mating type and invasiveness has recently been established. The mating type proportion (MAT1-1:MAT1-2) of 213 A. fumigatus strains was determined (48.5%:51.5%) and results were in agreement with previous studies. However, these percentages changed when the strain collection was divided into azole-susceptible and -resistant strains. The 163 susceptible strains kept these proportions, but among the 50 azole-resistant strains 60.0% MAT1-1 and 40% MAT1-2 were found. Moreover, looking at the clinical outcome associated to 27 azole-resistant strains, we found that MAT1-1 was linked to a high mortality rate (64%), whereas the rate associated to MAT1-2 genotype was markedly lower (15%). The pathogenicity linked to the Mat type was tested in a Galleria mellonella model of infection, showing that MAT1-1 strains were consistently more pathogenic than MAT1-2, independently of their susceptibility phenotype. This data would suggest that A. fumigatus mating type determination at the time of diagnosis could have a prognostic value in invasive aspergillosis., (© 2017 Blackwell Verlag GmbH.)

This is an observational-retrospective study comparing the real-world outcomes associated with posaconazole vs itraconazole as prophylaxis treatments. Two hundred and ninety-three patient admissions attributable to 174 patients were included in the study. Patients were treated with itraconazole (n = 114 admissions; 39%) or posaconazole (n = 179; 61%). Antifungal prophylaxis failure (APF) due to treatment-related adverse events (in 34 out of 293 patient admissions; 11.6%) was more frequent in the posaconazole group (6.1% vs 15.1%; P = .024). There were 9 patient admissions for episodes of APF due to probable/proven breakthrough fungal infection (primary endpoint): 6 and 3 in the itraconazole and posaconazole group respectively (5.3% vs 1.7%; P = .095). All of them were associated with invasive pulmonary aspergillosis (IPA). APF was more frequent with itraconazole (65% vs 30%; P < .001), along with failure due to possible/probable/proven IPA (25% vs 10%; P = .002) and overall failure by any of the 3 different causes of prophylaxis failure (70% vs 38%; P < .001). In agreement with clinical trial data, this real-world evidence supports the use of posaconazole over itraconazole in AML or MDS patients undergoing intensive chemotherapy., (© 2017 Blackwell Verlag GmbH.)

Plasma 1,3-β-D-glucan (BDG) is indicated as a tool for early diagnosis of invasive fungal diseases (IFD). However, data on its diagnostic value are scarce in children. Therefore, definition of BDG test performance in paediatrics is needed. BDG was evaluated in children admitted to "Istituto Giannina Gaslini," Genoa, Italy, who developed clinical conditions at risk for IFD. Results were analysed for sensitivity, specificity, predictive values, likelihood ratios, accuracy, informedness and probability of missing one case by a negative test. A total of 1577 BDG determinations were performed on 255 patients (49% males, median age 5.4 years). Overall 46 IFD were diagnosed, 72% proven/probable. The test performance was evaluated for 80 pg/mL, 120 pg/mL, 200 pg/mL, 350 pg/mL, 400 pg/mL cut offs. Sensitivity was always <0.80 and specificity > 0.90 only for cut offs ≥200 pg/mL. Negative predictive value was ≥0.90 for all the cut offs evaluated, while positive predictive value resulted barely 0.50 (8% IFD prevalence). Accuracy was never >0.90, and informedness was at best 0.50. The risk of missing one IFD by a negative result was < 10%. Analyses in haemato-oncological or newborn patients did not show major differences. Detection of serum BDG does not appear a valuable adjunctive diagnostic tool for IFD in paediatrics., (© 2017 Blackwell Verlag GmbH.)

Pneumocystis jirovecii is the causative agent of Pneumocystis pneumonia (PcP), a common and often life-threatening opportunistic infection in HIV-infected patients. However, non-HIV, immunocompromised patients are at risk of PcP as well, whereas the mortality appears to be higher among these patients. Pneumocystis co-infections with other microorganisms are less frequent and only sparse reports of combined PcP and invasive pulmonary fungal infections exist in the literature, especially in the non-HIV patients. Two cases of pulmonary co-infections by P. jirovecii and Aspergillus fumigatus are presented. Both patients were non-HIV infected, the first one was suffering from crescentic IgA nephropathy under immunosuppressive treatment and the second from resistant non-Hodgkin lymphoma under chemotherapy. Both patients were treated with intravenous trimethoprim/sulphamethoxazole (TMP/SMX) combined with voriconazole. The first patient showed gradual clinical improvement while the outcome for the second patient was unfavourable. In addition, a literature review of the previous published cases of co-infection by P. jirovecii and other fungi in non-HIV patients was performed. Our target was to provide comprehensive information on this kind of infections, highlighting the importance of clinical suspicion., (© 2017 Blackwell Verlag GmbH.)

Invasive aspergillosis(IA) is a potentially lethal complication of Aspergillus infection affecting mainly immunocompromised hosts; however, during the last two decades its incidence was increasingly observed in critically ill immunocompetent patients. The objective of this study is to describe the clinical characteristics of histologically proven endomyocardial and pericardial invasion, in the context of IA, in critically ill patients. Eight critically ill patients with histopathological confirmation of endomyocardial/pericardial aspergillosis were evaluated. Risk factors, clinical and laboratory characteristics, treatment, histopathological characteristics and mortality were recorded. Signs and symptoms of cardiac dysfunction were not observed in any of the patients. Therapy was administered to six of them shortly after the first positive culture. The observed histopathological lesions included haemorrhagic lesions, small vessels with central thrombosis and surrounding consolidated tissue with necrosis. Voriconazole, caspofungin, lipid amphotericin B and itraconazole were the used antifungals. The mortality rate was high (87.5%). Endomyocardial and pericardial aspergillosis are devastating complications of invasive aspergillosis. Clinical suspicion is low making the diagnosis difficult, therefore histopathological examination of tissues are required. The mortality is high., (© 2017 Blackwell Verlag GmbH.)

A novel dimorphic fungus, Emergomyces orientalis sp. nov. a close relative of systemic pathogens in the family Ajellomycetaceae (Blastomyces, Histoplasma). The fungus is reported in a 64-year-old male from Shanxi, China. The patient developed disseminated skin lesions, productive cough with fever and showed nodular opacities in his left lung on chest radiography. The patient had no identified cause of immunodeficiency apart from type-2 diabetes mellitus. Clinical, histopathological and mycological characteristics of the agent are given, and its phylogenetic position is determined with multilocus sequence data., (© 2017 The Authors. Mycoses Published by Blackwell Verlag GmbH.)

Limited specific data and investigations are available for the diagnosis of Invasive Fungal Infection (IFI) in paediatrics cancer patients. Three non-invasive tests; Platelia Aspergillus EIA for galactomannan (GM), β-D-glucan (BDG) assay and pan-fungal real-time PCR for fungal DNA in blood were evaluated. One hundred twenty-five paediatrics cancer patients at the high risk of IFI were enrolled. Single blood and serum samples were evaluated by all the three methods. Patients were classified into 10 proven, 52 probable and 63 no IFI cases in accordance with EORTC MSG 2008 revised guidelines. The sensitivity, specificity, PPV and NPV of all the three tests in proven, probable and no IFIs cases were analysed singly and in combination. The sensitivity, specificity, PPV and NPV of GM, BDG and pan-fungal real-time PCR were: 87%, 61%, 81%, 69.5% for GM, 88%, 59.5%, 81%, 71.4% for BDG and 89%, 69.2%, 85%, 67.5% for PCR (95% CI). Among different combinations, best combination was found to be GM and PCR with sensitivity, specificity, PPV and NPV of 98.2%, 89.3%, 97.1% and 90% respectively. Single samples must be evaluated by combination of tests., (© 2016 Blackwell Verlag GmbH.)

Saprochaete and Geotrichum spp. are rare emerging fungi causing invasive fungal diseases in immunosuppressed patients and scarce evidence is available for treatment decisions. Among 505 cases of rare IFD from the FungiScope ™ registry, we identified 23 cases of invasive infections caused by these fungi reported from 10 countries over a 12-year period. All cases were adults and previous chemotherapy with associated neutropenia was the most common co-morbidity. Fungaemia was confirmed in 14 (61%) cases and deep organ involvement included lungs, liver, spleen, central nervous system and kidneys. Fungi were S. capitata (n=14), S. clavata (n=5), G. candidum (n=2) and Geotrichum spp. (n=2). Susceptibility was tested in 16 (70%) isolates. All S. capitata and S. clavata isolates with the exception of one S. capitata (MIC 4 mg/L) isolate had MICs>32 mg/L for caspofungin. For micafungin and anidulafungin, MICs varied between 0.25 and >32 mg/L. One case was diagnosed postmortem, 22 patients received targeted treatment, with voriconazole as the most frequent first line drug. Overall mortality was 65% (n=15). Initial echinocandin treatment was associated with worse outcome at day 30 when compared to treatment with other antifungals (amphotericin B ± flucytosine, voriconazole, fluconazole and itraconazole) (P=.036). Echinocandins are not an option for these infections., (© 2017 Blackwell Verlag GmbH.)

Macromolecular immunosuppressive monoclonal antibodies and fusion proteins directed against molecules or cells involved in inflammation and immunity represent a recent and important addition to our therapeutic armamentarium. Tumor necrosis alpha (TNFα) is a cytokine involved in systemic inflammation and clinical utilization of its antagonists has revolutionized treatment of juvenile rheumatoid and psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, and plaque psoriasis. Clinical utility has also been demonstrated for use against steroid-refractory graft-vs-host disease and other immune-mediated conditions. Currently, five anti-TNFα agents are approved by the European Medicines Agency (EMA), including the monoclonal anti-TNF antibodies infliximab, adalimumab, golimumab and certolizumab pegol along with etanercept, a TNFα-receptor/IgG-Fc fusion protein. Theoretical considerations related to their mode of action and clinical observations suggest that opportunistic infectious complications should be seriously considered as possible adverse events of macromolecular immunosuppressants. The purpose of this review is to critically analyze the literature on invasive fungal infections (IFIs) occurring in association with TNFα inhibitors alone or in combination with other immunosuppressive agents, with a focus on pediatric patients, and to provide a framework of evaluating the risk for IFIs in this population., (© 2016 Blackwell Verlag GmbH.)

Aspergillus spp. are a leading cause of mortality in chronic granulomatous disease (CGD), but other fungi have emerged in the era of mould prophylaxis. Of these, Phellinus spp. are an under-recognised cause of invasive fungal infections (IFIs) in CGD, and data on their presentation and management are scarce. We present a patient with CGD who developed disseminated IFI involving the lungs and brain. Surgical specimens grew a basidiomycete which was disregarded as a contaminant. After three months of progressive disease despite antifungals, he was diagnosed with Phellinus tropicalis by internal transcribed spacer (ITS) sequencing. He improved with amphotericin B and isavuconazole but required haematopoietic stem cell transplantation (HSCT). We review the literature on Phellinus infections in CGD and conclude that: (i) these infections emerge on mould-active prophylaxis and are indolent; (ii) they typically cause locally destructive disease but can disseminate; (iii) diagnosis is delayed and requires molecular methods; (iv) amphotericin B is most active in vitro; and (v) treatment is protracted and requires surgery and possibly HSCT. In conclusion, Phellinus spp. are emerging pathogens in CGD. Every effort should be made to establish the diagnosis of non-Aspergillus IFIs in patients with CGD by sending tissue specimens for molecular diagnostics., (© 2016 The Authors. Mycoses Published by Blackwell Verlag GmbH.)

Invasive fungal infections, an important cause of mortality, are primarily treated using amphotericin B, which is available in different formulations, both conventional and lipid-based (liposomal, lipid complex, colloidal dispersion and Intralipid ® infusion). The aim of our study was to determine the efficacy and safety of conventional amphotericin B vs its lipid-based formulations. A systematic review followed by pairwise meta-analysis was performed, including randomised controlled trials (RCTs) that evaluated the use of lipid-based amphotericin B in patients with any degree of immunosuppression and susceptibility to invasive fungal infection. An electronic search was conducted using PubMed, Scopus, Web of Science and Scielo databases. Extracted outcomes were related to efficacy (cure) and safety (incidence of adverse events). Results were evaluated and meta-analyses were performed. Twenty-three RCTs were identified (n=2677 participants) for meta-analysis. No significant differences between conventional amphotericin B and any of the five formulations evaluated were observed, with regard to the efficacy analysis. With respect to the adverse events of nephrotoxicity, fever, chills and vomiting, all lipid formulations presented better profiles than the conventional formulation. The present systematic review and meta-analysis showed that conventional amphotericin B presents the same efficacy profile as lipid-based formulations, although the latter were associated with a safer profile., (© 2016 Blackwell Verlag GmbH.)

Patients undergoing allogeneic haematopoietic stem cell transplantation (alloHSCT) are at risk of developing invasive fungal infections (IFIs). Even with introduction of oral triazole antifungal agents (fluconazole, itraconazole, posaconazole and voriconazole) IFI-associated morbidity and mortality rates and economic burden remain high. Despite their proven efficacy, it is currently unknown which is the most cost-effective antifungal prophylaxis (AFP) agent. To determine the costs and outcomes associated with AFP, a decision-analytic model was used to simulate treatment in a hypothetical cohort of 1000 patients undergoing alloHSCT from the perspective of the Spanish National Health System. Generic itraconazole was the least costly AFP (€162) relative to fluconazole (€500), posaconazole oral suspension (€8628) or voriconazole (€6850). Compared with posaconazole, voriconazole was associated with the lowest number of breakthrough IFIs (36 vs 60); thus, the model predicted fewer deaths from breakthrough IFI for voriconazole (24) than posaconazole (33), and the lowest predicted costs associated with other licensed antifungal treatment and IFI treatment in a cohort of 1000. Voriconazole resulted in cost savings of €4707 per patient compared with posaconazole. Itraconazole demonstrated a high probability of being cost-effective. As primary AFP in alloHSCT patients 180 days posttransplant, voriconazole was more likely to be cost-effective than posaconazole regarding cost per additional IFI and additional death avoided., (© 2016 The Authors. Mycoses Published by Blackwell Verlag GmbH.)

Posaconazole may be useful for salvage treatment (ST) for invasive fungal infections (IFIs). The aim of this study was to evaluate the efficacy of posaconazole ST with either posaconazole oral suspension (SUS) or delayed-released tablet (TAB) in patients with IFI. A retrospective review of patients who received posaconazole ST for IFI at the University of Utah Health Sciences Center between December 2007 and March 2014 was conducted. A total of 14 episodes of posaconazole ST for proven (9 episodes) and probable (5 episodes) IFI were identified in 14 patients. The median age was 54 years and the majority of patients (64.3%) had underlying haematological diseases. Posaconazole SUS and TAB were used in 11 episodes and 3 episodes respectively. The duration of posaconazole ST ranged from 28 to 370 days with a median of 65 days. Posaconazole ST with TAB achieved favourable serum posaconazole trough concentrations (median 1.4 μg mL -1 ) compared to posaconazole SUS (median 1.0 μg mL -1 ). The overall clinical success rate with posaconazole ST was 71.4% (10 of 14 episodes). One patient died of progression of IFI. Adverse events were noted in two patients. Posaconazole SUS or TAB may be used effectively for IFI ST., (© 2016 Blackwell Verlag GmbH.)

Invasive fungal infections, usually Aspergillus and Candida, represent a major cause of morbidity and mortality in patients with malignant haematological diseases, but in the last years rare fungal infections have more frequently been reported. Here, we report the clinical history of three patients affected with haematological malignancies who developed an infection caused by Geotrichum (G.) clavatum. Two out of three patients were affected by acute myeloid leukaemia (AML), and one by mantle cell lymphoma (MCL). All patients received cytarabine-based chemotherapeutic regimens and developed G. clavatum infection within 3 weeks from therapy initiation. In all cases, G. clavatum was isolated from central venous catheter and peripheral blood cultures. In vitro susceptibility test confirmed an intrinsic resistance to echinocandins and, in all cases, visceral localisations (spleen, liver and lung) were documented by total body computed tomography (CT) scan. A prolonged antifungal therapy with high doses liposomal amphotericin-B was necessary to obtain fever resolution. Only the patient with MCL died while the other two AML recovered, and one of them after received an allogeneic stem cell transplantation. We consecutively reviewed all published cases of infection caused by G. clavatum. Our experience and literature review indicate that G. clavatum can cause invasive infection in haematological patients, mainly in those with acute leukaemia., (© 2016 Blackwell Verlag GmbH.)

In 2001, caspofungin received market authorisation by the FDA and EMA and is globally licensed for several indications, including candidiasis, empirical antifungal therapy in patients with neutropenic fever of unknown origin and treatment of invasive aspergillosis in patients refractory to or intolerant of amphotericin B, lipid formulations of amphotericin B or itraconazole. Despite the lack of phase III data in first-line treatment of invasive aspergillosis, increasing evidence supports the use of first-line therapy. Here, we analyse the evidence of therapeutic activity, represented by favourable response rates, of caspofungin for invasive aspergillosis. A systematic literature search was conducted to identify international presentations and papers reporting monotherapy with caspofungin. Efficacy data are summarised separately for first-line and salvage therapy. Thirty-one papers and published abstracts reported caspofungin therapy for aspergillosis. Fifteen full papers and two abstracts fulfilled the criteria of reporting significant outcome data for caspofungin monotherapy for invasive aspergillosis. Consistent with other analyses and the known safety profile, few adverse events and associated terminations of caspofungin medication have been reported. Although a randomised, comparative, prospective study using caspofungin in this indication is still lacking, growing evidence supports the efficacy of this echinocandin not only for salvage but also for first-line therapy., (© 2016 Blackwell Verlag GmbH.)

Fungi in the order Mucorales cause acute, invasive and frequently fatal infections in susceptible patients. This study aimed to perform a systematic review of all reported mucormycosis cases during the last 25 years in Iran. After a comprehensive literature search, we identified 98 cases in Iran from 1990-2015. The mean patient age was 39.8 ± 19.2 years. Diabetes was the most common underlying condition (47.9%), and 22.4% of the patients underwent solid organ or bone marrow transplantation. The most common clinical forms of mucormycosis were rhinocerebral (48.9%), pulmonary (9.2%) and cutaneous (9.2%). Eight cases of disseminated disease were identified. Overall mortality in the identified cases was 40.8%, with the highest mortality rate in patients diagnosed with disseminated infection (75%). The mortality rate in rhinocerebral infection patients was significantly lower (45.8%). Rhinocerebral infection was the most common clinical manifestation in diabetes patients (72.9%). Patients were diagnosed using various methods including histopathology (85.7%), microscopy (12.3%) and culture (2.0%). Rhizopus species were the most prevalent (51.7%), followed by Mucor species (17.2%). Sixty-nine patients were treated with a combination of surgery and antifungal therapy (resulting survival rate, 66.7%). Owing to the high mortality rate of advanced mucormycosis, early diagnosis and treatment may significantly improve survival rates. Therefore, increased monitoring and awareness of this life-threatening disease is critical., (© 2016 Blackwell Verlag GmbH.)