[Lomentospora prolificans Fungemia in a Patient With T-Cell Large Granular Leukemia: A Rare Pathogen in Türkiye]. / T-hücreli Büyük Granüler Lösemili Bir Hastada Lomentospora prolificans Fungemisi: Türkiye'de Nadir Bir Etken.

Scedosporium/Lomentospora is an opportunistic fungal pathogen found worldwide. While Scedosporium apiospermum and Scedosporium boydii are commonly observed globally, Lomentospora prolificans, which mainly affects immunosuppressed individuals, is rarely encountered and is more prevalent in arid climates, particularly in Australia and Spain. L.prolificans is a fungus commonly found in environmental sources such as contaminated water and soil. This species is known as an opportunistic pathogen that can cause deep-seated fungal infections, especially in immunosuppressed individuals. In this case report, a fatal case of L.prolificans fungemia in a patient with T-cell large granular leukemia during profound neutropenia was presented. The patient admitted to the hospital with prolonged fever, neutropenia, and shortness of breath. Antibiotherapy was administered to the patient for febrile neutropenia, but the fever persisted and his clinical status rapidly deteriorated. L.prolificans was isolated from the blood culture, and considering its antifungal resistance, combination therapy of voriconazole and terbinafine was initiated. However, the patient died of septic shock and multiple organ failure. In conclusion, although L.prolificans infections are rare, they can be life-threatening, especially in immunosuppressed individuals. Diagnosis and treatment of such infections may be difficult, therefore rapid diagnostic methods and appropriate treatment protocols should be developed. Consideration of infections caused by rare fungal pathogens in patients with risk factors may be critical for patient care. The literature review revealed that the first case of L.prolificans fungemia from Türkiye was reported in 2023. This case presentation represents the second reported case. However, in our case, L.prolificans fungemia occurred in 2018, it can be considered that L.prolificans may have been an invasive fungal pathogen of significant concern in Türkiye much earlier than previously documented.

Evaluation of the first Candida auris isolates reported from Türkiye in terms of identification by various methods and susceptibility to antifungal drugs.

PURPOSE: Candida auris is increasingly being isolated from patients all over the world. It has five clades. In this study, it was aimed to compare the results of biochemical tests obtained using different methods and the antifungal susceptibility profiles of C. auris strains isolated from the first seven cases reported in Türkiye, and evaluate whether this information could be useful as preliminary data in determining the clade of strains in centers that lack the opportunity to apply molecular methods. METHODS: Identification test results obtained using API ID 32 C, API 20 C AUX, VITEK-2 YST, and MALDI-TOF MS; colony color and morphology on Chromagar Candida, CHROMagar Candida Plus media, and cornmeal-Tween 80 agar; susceptibility to antifungals were tested and compared. Antifungal susceptibility test was studied using microdilution method according to the recommendations of EUCAST. Additionally, a pilot study was conducted to investigate the value of CHROMagar Candida Plus. RESULTS: All seven strains were identified as Lachancea kluyveri with API ID 32 C, Rhodotorula glutinis; Cryptococcus neoformans with API 20 C AUX, and C. auris with both VITEK-2 YST and MALDI-TOF MS. MIC values for fluconazole were very high (≥64 mg/L) for all seven strains. It was observed that 11 (37.9%) of 29 Candida parapsilosis strains formed colonies with morphology similar to C. auris on CHROMagar Candida Plus medium, leading to false positivity. CONCLUSIONS: Although there have been many isolations of C. auris in our country in recent years, clade distribution of only a small number of strains is known yet. In this study, when the biochemical properties and antifungal susceptibility profiles of the seven strains were evaluated, it was concluded that they exhibited some characteristics compatible with clade I. It was also observed that strains 1 and 2 may belong to a different clade.

Invasive Fungal Diseases in Adult Patients in Intensive Care Unit (FUNDICU): 2024 consensus definitions from ESGCIP, EFISG, ESICM, ECMM, MSGERC, ISAC, and ISHAM.

PURPOSE: The aim of this document was to develop standardized research definitions of invasive fungal diseases (IFD) in non-neutropenic, adult patients without classical host factors for IFD, admitted to intensive care units (ICUs). METHODS: After a systematic assessment of the diagnostic performance for IFD in the target population of already existing definitions and laboratory tests, consensus definitions were developed by a panel of experts using the RAND/UCLA appropriateness method. RESULTS: Standardized research definitions were developed for proven invasive candidiasis, probable deep-seated candidiasis, proven invasive aspergillosis, probable invasive pulmonary aspergillosis, and probable tracheobronchial aspergillosis. The limited evidence on the performance of existing definitions and laboratory tests for the diagnosis of IFD other than candidiasis and aspergillosis precluded the development of dedicated definitions, at least pending further data. The standardized definitions provided in the present document are aimed to speed-up the design, and increase the feasibility, of future comparative research studies.

Invasive fungal rhinosinusitis by Fusarium proliferatum/annulatum in a patient with acute myeloid leukemia: A case report and review of the literature.

Antifungal prophylaxis with a mold-effective agent has led to a substantial decrease in invasive infections caused by Aspergillus spp. in the management of patients with acute myeloid leukemia undergoing induction chemotherapy. However, difficult-to-treat infections caused by other molds, such as Fusarium, Lomentospora, and Scedosporium species may still complicate the neutropenic period. Here, we present a case of a 23-year-old woman with acute myeloid leukemia who developed a breakthrough invasive fungal rhinosinusitis caused by Fusarium proliferatum/annulatum on posaconazole prophylaxis. The infection was diagnosed using clinical, microbiological, and radiological criteria and the isolate was identified using Matrix Assisted Lazer Desorption Ionization Time of Flight Mass Spectrometry (MALDI-TOF MS) and sequencing. We searched Pubmed with "Fusarium proliferatum", "Fusarium annulatum", "immunosuppression AND fusariosis", "rhinosinusitis AND Fusarium proliferatum" and summarized the English literature for similar rhinosinusitis cases infected with the same pathogen.

Diagnostic performance and longitudinal analysis of fungal biomarkers in COVID-19 associated pulmonary aspergillosis.

Objectives: Galactomannan lateral flow assay (GM-LFA) is a reliable test for COVID-19 associated pulmonary aspergillosis (CAPA) diagnosis. We aimed to assess the diagnostic performance of GM-LFA with different case definitions, the association between the longitudinal measurements of serum GM-ELISA, GM-LFA, and the risk of death. Methods: Serum and nondirected bronchial lavage (NBL) samples were periodically collected. The sensitivity and specificity analysis for GM-LFA was done in different time periods. Longitudinal analysis was done with the joint model framework. Results: A total of 207 patients were evaluated. On the day of CAPA diagnosis, serum GM-LFA had a sensitivity of 42 % (95 % CI: 23-63) and specificity of 82 % (95 % CI: 78-84), while NBL GM-LFA had a sensitivity of 73 % (95 % CI: 45-92), specificity of 85 % (95 % CI: 76-91) for CAPA. Sensitivity decreased through the following days in both samples. Univariate joint model analysis showed that increasing GM-LFA and GM-ELISA levels were associated with increased mortality, and that effect remained same with serum GM-ELISA in multivariate joint model analysis. Conclusion: GM-LFA, particularly in NBL samples, seems to be a reliable method for CAPA diagnosis. For detecting patients with higher risk of mortality, longitudinal measurement of serum GM-ELISA can be useful.

Necrotizing pneumonia due to Aspergillus and Salmonella after immune checkpoint inhibitor treatment: An unusual case and review of the literature.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are a promising new treatment for different types of cancer. The infectious complications in patients taking ICIs are rare. CASE REPORT: A 58-year-old male who received chemotherapy consisting of pembrolizumab (PD-1 inhibitor) for esophagus squamous cell carcinoma one month before was admitted to the emergency room with shortness of breath soon after fiberoptic bronchoscopy, which was done for the inspection of the lower airway. A computed tomography of the chest revealed a progressive consolidation on the right upper lobe. Salmonella group D was isolated from the bronchoalveolar lavage (BAL) fluid culture. The fungal culture of the same clinical sample yielded Aspergillus niger; furthermore, a high titer (above the cut-off values) of Aspergillus antigen was found both in the BAL fluid and serum of the patient. Despite the effective spectrum and appropriate dose of antimicrobial treatment, the patient died due to disseminated intravascular coagulopathy. CONCLUSIONS: Awareness of unusual pathogens in the etiology of pneumonia after ICI treatment may help to avoid underdiagnosis.

Predictors for Prolonged Hospital Stay Solely to Complete Intravenous Antifungal Treatment in Patients with Candidemia: Results from the ECMM Candida III Multinational European Observational Cohort Study.

BACKGROUND: To date, azoles represent the only viable option for oral treatment of invasive Candida infections, while rates of azole resistance among non-albicans Candida spp. continue to increase. The objective of this sub-analysis of the European multicenter observational cohort study Candida III was to describe demographical and clinical characteristics of the cohort requiring prolonged hospitalization solely to complete intravenous (iv) antifungal treatment (AF Tx). METHODS: Each participating hospital (number of eligible hospitals per country determined by population size) included the first ~ 10 blood culture proven adult candidemia cases occurring consecutively after July 1st, 2018, and treating physicians answered the question on whether hospital stay was prolonged only for completion of intravenous antifungal therapy. Descriptive analyses as well as binary logistic regression was used to assess for predictors of prolonged hospitalization solely to complete iv AF Tx. FINDINGS: Hospital stay was prolonged solely for the completion of iv AF Tx in 16% (100/621) of candidemia cases by a median of 16 days (IQR 8 - 28). In the multivariable model, initial echinocandin treatment was a positive predictor for prolonged hospitalization to complete iv AF Tx (aOR 2.87, 95% CI 1.55 - 5.32, p < 0.001), while (i) neutropenia, (ii) intensive care unit admission, (iii) catheter related candidemia, (iv) total parenteral nutrition, and (v) C. parapsilosis as causative pathogen were found to be negative predictors (aOR 0.22 - 0.45; p < 0.03). INTERPRETATION: Hospital stays were prolonged due to need of iv AF Tx in 16% of patients with candidemia. Those patients were more likely to receive echinocandins as initial treatment and were less severely ill and less likely infected with C. parapsilosis.

European candidaemia is characterised by notable differential epidemiology and susceptibility pattern: Results from the ECMM Candida III study.

The objectives of this study were to assess Candida spp. distribution and antifungal resistance of candidaemia across Europe. Isolates were collected as part of the third ECMM Candida European multicentre observational study, conducted from 01 to 07-07-2018 to 31-03-2022. Each centre (maximum number/country determined by population size) included ∼10 consecutive cases. Isolates were referred to central laboratories and identified by morphology and MALDI-TOF, supplemented by ITS-sequencing when needed. EUCAST MICs were determined for five antifungals. fks sequencing was performed for echinocandin resistant isolates. The 399 isolates from 41 centres in 17 countries included C. albicans (47.1%), C. glabrata (22.3%), C. parapsilosis (15.0%), C. tropicalis (6.3%), C. dubliniensis and C. krusei (2.3% each) and other species (4.8%). Austria had the highest C. albicans proportion (77%), Czech Republic, France and UK the highest C. glabrata proportions (25-33%) while Italy and Turkey had the highest C. parapsilosis proportions (24-26%). All isolates were amphotericin B susceptible. Fluconazole resistance was found in 4% C. tropicalis, 12% C. glabrata (from six countries across Europe), 17% C. parapsilosis (from Greece, Italy, and Turkey) and 20% other Candida spp. Four isolates were anidulafungin and micafungin resistant/non-wild-type and five resistant to micafungin only. Three/3 and 2/5 of these were sequenced and harboured fks-alterations including a novel L657W in C. parapsilosis. The epidemiology varied among centres and countries. Acquired echinocandin resistance was rare but included differential susceptibility to anidulafungin and micafungin, and resistant C. parapsilosis. Fluconazole and voriconazole cross-resistance was common in C. glabrata and C. parapsilosis but with different geographical prevalence.

Necrotizing pneumonia due to Aspergillus and Salmonella after immune checkpoint inhibitor treatment: An unusual case and review of the literature / Neumonía necrotizante por Aspergillus y Salmonella tras tratamiento con un inhibidor de puntos de control inmunitario: un caso inusual y revisión de la literatura

Background: Immune checkpoint inhibitors (ICIs) are a promising new treatment for different types of cancer. The infectious complications in patients taking ICIs are rare. Case report: A 58-year-old male who received chemotherapy consisting of pembrolizumab (PD-1 inhibitor) for esophagus squamous cell carcinoma one month before was admitted to the emergency room with shortness of breath soon after fiberoptic bronchoscopy, which was done for the inspection of the lower airway. A computed tomography of the chest revealed a progressive consolidation on the right upper lobe. Salmonella group D was isolated from the bronchoalveolar lavage (BAL) fluid culture. The fungal culture of the same clinical sample yielded Aspergillus niger; furthermore, a high titer (above the cut-off values) of Aspergillus antigen was found both in the BAL fluid and serum of the patient. Despite the effective spectrum and appropriate dose of antimicrobial treatment, the patient died due to disseminated intravascular coagulopathy. Conclusions: Awareness of unusual pathogens in the etiology of pneumonia after ICI treatment may help to avoid underdiagnosis.(AU)

Antecedentes: Los fármacos inhibidores de puntos de control inmunitario (ICI) son una nueva y prometedora opción de tratamiento para diferentes tipos de cáncer. Las complicaciones infecciosas en pacientes que toman ICI son poco frecuentes. Caso clínico: Un varón de 58 años que recibió quimioterapia con pembrolizumab (inhibidor de PD-1) para un carcinoma de células escamosas de esófago hacía un año, ingresó en Urgencias por dificultad respiratoria poco después de realizarse una broncoscopia de fibra óptica para una inspección de las vías aéreas inferiores. La tomografía computarizada de tórax reveló una consolidación progresiva en el lóbulo superior derecho. Se aisló Salmonella grupo D en el cultivo del líquido de lavado broncoalveolar (LBA). En el cultivo de hongos de la misma muestra creció Aspergillus niger; además, se detectó antígeno (por encima de los valores de corte) de Aspergillus tanto en la muestra del LBA como en el suero del paciente. A pesar del espectro eficaz y la dosis adecuada del antifúngico utilizado, el paciente falleció debido a una coagulopatía intravascular diseminada. Conclusiones: El conocimiento de patógenos inusuales en la etiología de la neumonía tras el tratamiento con ICI puede ayudar a evitar el infradiagnóstico.(AU)

Rational Design of New Monoterpene-Containing Azoles and Their Antifungal Activity.

Azole antifungals, including fluconazole, have long been the first-line antifungal agents in the fight against fungal infections. The emergence of drug-resistant strains and the associated increase in mortality from systemic mycoses has prompted the development of new agents based on azoles. We reported a synthesis of novel monoterpene-containing azoles with high antifungal activity and low cytotoxicity. These hybrids demonstrated broad-spectrum activity against all tested fungal strains, with excellent minimum inhibitory concentration (MIC) values against both fluconazole-susceptible and fluconazole-resistant strains of Candida spp. Compounds 10a and 10c with cuminyl and pinenyl fragments demonstrated up to 100 times lower MICs than fluconazole against clinical isolates. The results indicated that the monoterpene-containing azoles had much lower MICs against fluconazole-resistant clinical isolates of Candida parapsilosis than their phenyl-containing counterpart. In addition, the compounds did not exhibit cytotoxicity at active concentrations in the MTT assay, indicating potential for further development as antifungal agents.

Guideline adherence and survival of patients with candidaemia in Europe: results from the ECMM Candida III multinational European observational cohort study.

BACKGROUND: The European Confederation of Medical Mycology (ECMM) collected data on epidemiology, risk factors, treatment, and outcomes of patients with culture-proven candidaemia across Europe to assess how adherence to guideline recommendations is associated with outcomes. METHODS: In this observational cohort study, 64 participating hospitals located in 20 European countries, with the number of eligible hospitals per country determined by population size, included the first ten consecutive adults with culture-proven candidaemia after July 1, 2018, and entered data into the ECMM Candida Registry (FungiScope CandiReg). We assessed ECMM Quality of Clinical Candidaemia Management (EQUAL Candida) scores reflecting adherence to recommendations of the European Society of Clinical Microbiology and Infectious Diseases and the Infectious Diseases Society of America guidelines. FINDINGS: 632 patients with candidaemia were included from 64 institutions. Overall 90-day mortality was 43% (265/617), and increasing age, intensive care unit admission, point increases in the Charlson comorbidity index score, and Candida tropicalis as causative pathogen were independent baseline predictors of mortality in Cox regression analysis. EQUAL Candida score remained an independent predictor of mortality in the multivariable Cox regression analyses after adjusting for the baseline predictors, even after restricting the analysis to patients who survived for more than 7 days after diagnosis (adjusted hazard ratio 1·08 [95% CI 1·04-1·11; p<0·0001] in patients with a central venous catheter and 1·09 [1·05-1·13; p<0·0001] in those without one, per one score point decrease). Median duration of hospital stay was 15 days (IQR 4-30) after diagnosis of candidaemia and was extended specifically for completion of parenteral therapy in 100 (16%) of 621 patients. Initial echinocandin treatment was associated with lower overall mortality and longer duration of hospital stay among survivors than treatment with other antifungals. INTERPRETATION: Although overall mortality in patients with candidaemia was high, our study indicates that adherence to clinical guideline recommendations, reflected by higher EQUAL Candida scores, might increase survival. New antifungals, with similar activity as current echinocandins but with longer half-lives or oral bioavailability, are needed to reduce duration of hospital stay. FUNDING: Scynexis.

A case-control study of the effects of Aspergillus clinical phenotypes on pulmonary functions in patients with cystic fibrosis.

INTRODUCTION: There are no precise data about the effect of Aspergillus infection on lung function other than allergic bronchopulmonary aspergillosis (ABPA) in patients with cystic fibrosis (pwCF). Here, we aimed to determine clinical phenotypes caused by Aspergillus spp. using laboratory and immunologic parameters and to compare Aspergillus phenotypes in terms of pulmonary function tests (PFT) prospectively. METHODS: Twenty-three pwCF who had Aspergillus isolation from respiratory cultures in the last year (case group) and 20 pwCF without Aspergillus isolation in sputum (control group) were included. Aspergillus immunoglobulin (Ig)-G, Aspergillus IgE, Aspergillus polymerase chain reaction (PCR), galactomannan, total IgE from blood samples, and Aspergillus PCR and galactomannan from sputum, and skin prick test reactivity to Aspergillus antigen were used to distinguish different Aspergillus phenotypes. Pulmonary functions and frequency of pulmonary exacerbations were evaluated during a 1-year follow-up. RESULTS: Of 23 pwCF, 11 (47.8%) had Aspergillus colonization, nine (39.1%) had Aspergillus bronchitis, and three (13%) had ABPA. Aspergillus infection was not associated with worse z-scores of forced expiratory volume in the first second (FEV1) (p = 0.612), forced vital capacity  (p = 0.939), and the median FEV 1% decline (0.0%/year vs. -4.7%/year, p = 0.626). The frequency of pulmonary exacerbations in the Aspergillus infected and noninfected groups was similar. CONCLUSION: Although Aspergillus spp. Isolation in pwCF was not associated with decreased lung function, a further decline was seen in the ABPA subgroup, and frequent pulmonary exacerbations during the 1-year follow-up.

The current state of laboratory mycology and access to antifungal treatment in Europe: a European Confederation of Medical Mycology survey.

Access to the appropriate tools is crucial for early diagnosis and clinical management of invasive fungal infections. This Review aims to describe the invasive fungal infection diagnostic capacity of Europe to better understand the status and the most pressing aspects that need improvement. To our knowledge, this is the first time that the mycological diagnostic capability and access to antifungal treatments of institutions has been evaluated at a pan-European level. Between Nov 1, 2021, and Jan 31, 2022, 388 institutions in Europe self-assessed their invasive fungal infection management capability. Of the 388 participating institutions from 45 countries, 383 (99%) had access to cultures, 375 (97%) to microscopy, 363 (94%) to antigen-detection assays, 329 (85%) to molecular tests (mostly PCR), and 324 (84%) to antibody tests for diagnosis and management. With the exception of microscopy, there were considerable differences in access to techniques among countries according to their gross domestic product. At least one triazole was available in 363 (94%) of the institutions, one echinocandin in 346 (89%), and liposomal amphotericin B in 301 (78%), with country gross domestic product-based differences. Differences were also observed in the access to therapeutic drug monitoring. Although Europe is well prepared to manage invasive fungal infections, some institutions do not have access to certain diagnostic tools and antifungal drugs, despite most being considered essential by WHO. These limitations need to be overcome to ensure that all patients receive the best diagnostic and therapeutic management.

Multicentre validation of a modified EUCAST MIC testing method and development of associated epidemiologic cut-off (ECOFF) values for rezafungin.

OBJECTIVES: Rezafungin EUCAST MIC testing has been associated with notable inter-laboratory variation, which prevented ECOFF setting for C. albicans. We assessed in vitro susceptibility and reproducibility for a modified EUCAST methodology and established associated wild-type upper limits (WT-ULs). METHODS: MICs against 150 clinical Candida isolates (six species), molecularly characterized fks mutants (n = 13), and QC strains (n = 6) were determined at six laboratories according to E.Def 7.3 but using Tween 20 supplemented medium. WT-ULs were determined using the derivatization method, the ECOFFinder programme and visual inspection. Consensus WT-ULs were determined. RESULTS: The laboratory- and species-specific MIC distributions were Gaussian with >99.5% MICs within four 2-fold dilutions except for C. parapsilosis (92.8%). The following consensus WT-UL were determined: C. albicans 0.008 mg/L; C. dubliniensis and C. glabrata 0.016 mg/L; C. krusei and C. tropicalis 0.03 mg/L; and C. parapsilosis 4 mg/L. Adopting these WT-UL, six clinical isolates were non-wild-type, five of which harboured Fks alterations. For 11/13 mutants, all 670 MICs were categorized as non-wild-type whereas MICs for C. glabrata Fks2 D666Y and C. tropicalis Fks1 R656R/G overlapped with the corresponding wild-type distributions. Repeat testing of six reference strains yielded 98.3%-100% of MICs within three 2-fold dilutions except for C. albicans CNM-CL-F8555 (96%) and C. parapsilosis ATCC 22019 (93.3%). CONCLUSIONS: The modified EUCAST method significantly improved inter-laboratory variation, identified wild-type populations and allowed perfect separation of wild-type and fks mutants except for two isolates harbouring weak mutations. These consensus WT-UL have been accepted as ECOFFs and will be used for rezafungin breakpoint setting.

A screening study for COVID-19-associated pulmonary aspergillosis in critically ill patients during the third wave of the pandemic.

BACKGROUND: COVID-19-associated pulmonary aspergillosis (CAPA) has been reported as an important cause of mortality in critically ill patients with an incidence rate ranging from 5% to 35% during the first and second pandemic waves. OBJECTIVES: We aimed to evaluate the incidence, risk factors for CAPA by a screening protocol and outcome in the critically ill patients during the third wave of the pandemic. PATIENTS/METHODS: This prospective cohort study was conducted in two intensive care units (ICU) designated for patients with COVID-19 in a tertiary care university hospital between 18 November 2020 and 24 April 2021. SARS-CoV-2 PCR-positive adult patients admitted to the ICU with respiratory failure were included in the study. Serum and respiratory samples were collected periodically from ICU admission up to CAPA diagnosis, patient discharge or death. ECMM/ISHAM consensus criteria were used to diagnose and classify CAPA cases. RESULTS: A total of 302 patients were admitted to the two ICUs during the study period, and 213 were included in the study. CAPA was diagnosed in 43 (20.1%) patients (12.2% probable, 7.9% possible). In regression analysis, male sex, higher SOFA scores at ICU admission, invasive mechanical ventilation and longer ICU stay were significantly associated with CAPA development. Overall ICU mortality rate was higher significantly in CAPA group compared to those with no CAPA (67.4% vs 29.4%, p < .001). CONCLUSIONS: One fifth of critically ill patients in COVID-19 ICUs developed CAPA, and this was associated with a high mortality.

Frequency of azole resistance in clinical and environmental strains of Aspergillus fumigatus in Turkey: a multicentre study.

OBJECTIVES: Aspergillus fumigatus causes several diseases in humans and azole resistance in A. fumigatus strains is an important issue. The aim of this multicentre epidemiological study was to investigate the prevalence of azole resistance in clinical and environmental A. fumigatus isolates in Turkey. METHODS: Twenty-one centres participated in this study from 1 May 2018 to 1 October 2019. One participant from each centre was asked to collect environmental and clinical A. fumigatus isolates. Azole resistance was screened for using EUCAST agar screening methodology (EUCAST E.DEF 10.1) and was confirmed by the EUCAST E.DEF 9.3 reference microdilution method. Isolates with a phenotypic resistance pattern were sequenced for the cyp51A gene and microsatellite genotyping was used to determine the genetic relationships between the resistant strains. RESULTS: In total, resistance was found in 1.3% of the strains that were isolated from environmental samples and 3.3% of the strains that were isolated from clinical samples. Mutations in the cyp51A gene were detected in 9 (47.4%) of the 19 azole-resistant isolates, all of which were found to be TR34/L98H mutations. Microsatellite genotyping clearly differentiated the strains with the TR34/L98H mutation in the cyp51A gene from the strains with no mutation in this gene. CONCLUSIONS: The rate of observed azole resistance of A. fumigatus isolates was low in this study, but the fact that more than half of the examined strains had the wild-type cyp51A gene supports the idea that other mechanisms of resistance are gradually increasing.

A Pragmatic Approach to Susceptibility Classification of Yeasts without EUCAST Clinical Breakpoints.

EUCAST has established clinical breakpoints for the six most common Candida species and Cryptococcus neoformans but not for less common yeasts because sufficient evidence is lacking. Consequently, the question "How to interpret the MIC?" for other yeasts often arises. We propose a pragmatic classification for amphotericin B, anidulafungin, fluconazole, and voriconazole MICs against 30 different rare yeasts. This classification takes advantage of MIC data for more than 4000 isolates generated in the EUCAST Development Laboratory for Fungi validated by alignment to published EUCAST MIC data. The classification relies on the following two important assumptions: first, that when isolates are genetically related, pathogenicity and intrinsic susceptibility patterns may be similar; and second, that even if species are not phylogenetically related, the rare yeasts will likely respond to therapy, provided the MIC is comparable to that against wild-type isolates of more prevalent susceptible species because rare yeasts are most likely "rare" due to a lower pathogenicity. In addition, the treatment recommendations available in the current guidelines based on the in vivo efficacy data and clinical experience are taken into consideration. Needless to say, it is of utmost importance (a) to ascertain that the species identification is correct (using MALDI-TOF or sequencing), and (b) to re-test the isolate once or twice to confirm that the MIC is representative for the isolate (because of the inherent variability in MIC determinations). We hope this pragmatic guidance is helpful until evidence-based EUCAST breakpoints can be formally established.

The Emergence of Echinocandin-Resistant Candida glabrata Exhibiting High MICs and Related FKS Mutations in Turkey.

The frequency of invasive fungal infections shows a rising trend as well as a high morbidity and mortality. Among the causative agents, a shift toward the non-albicans Candida species including Candida glabrata species complex is being observed in several centers. Echinocandin resistance is increasingly published; however, isolates presenting with an in vitro resistance have not yet been reported from Turkey. We, herein, report the first FKS mutant and phenotypically echinocandin-resistant C. glabrata clinical strains from a single center in Turkey. In a 43-year-old female patient, several enterocutaneous fistulae developed after a long term hospitalization period and several complicated surgeries. She eventually required parenteral nutrition via a tunneled central venous catheter (CVC). Following a number of bacteremic and fungemic episodes as well as intensive antimicrobial interventions (including fluconazole, caspofungin and anidulafungin), a CVC-related candidemia caused by C. glabrata was detected. The isolated strain yielded high minimum inhibitory concentration (MIC) values for echinocandins and was categorized as resistant. A resistance-related mutation was detected in FKS2 HS1 (D666V). Blood cultures remained negative after the removal of the CVC and treatment with caspofungin and high-dose fluconazole. Following this first case, two additional C. glabrata strains with high echinocandin MICs were isolated from the urine cultures of two unrelated patients from different wards with different mutations in FKS2 HS1 (S663P and delF659). Our findings indicate that routine antifungal susceptibility testing is crucial and underlines the need for attention for the increasing trend of acquired echinocandin resistance in C. glabrata.

Global guideline for the diagnosis and management of rare yeast infections: an initiative of the ECMM in cooperation with ISHAM and ASM.

Uncommon, or rare, yeast infections are on the rise given increasing numbers of patients who are immunocompromised or seriously ill. The major pathogens include those of the genera Geotrichum, Saprochaete, Magnusiomyces, and Trichosporon (ie, basidiomycetes) and Kodamaea, Malassezia, Pseudozyma (ie, now Moesziomyces or Dirkmeia), Rhodotorula, Saccharomyces, and Sporobolomyces (ie, ascomycetes). A considered approach to the complex, multidisciplinary management of infections that are caused by these pathogens is essential to optimising patient outcomes; however, management guidelines are either region-specific or require updating. In alignment with the One World-One Guideline initiative to incorporate regional differences, experts from diverse geographical regions analysed publications describing the epidemiology and management of the previously mentioned rare yeasts. This guideline summarises the consensus recommendations with regards to the diagnostic and therapeutic options for patients with these rare yeast infections, with the intent of providing practical assistance in clinical decision making. Because there is less clinical experience of patients with rare yeast infections and studies on these patients were not randomised, nor were groups compared, most recommendations are not robust in their validation but represent insights by use of expert opinions and in-vitro susceptibility results. In this Review, we report the key features of the epidemiology, diagnosis, antifungal susceptibility, and treatment outcomes of patients with Geotrichum, Saprochaete, Magnusiomyces, and Trichosporon spp infections.

Implementation of Pharmacist-Driven Antifungal Stewardship Program in a Tertiary Care Hospital.

Antifungal stewardship (AFS) is recommended to reduce the inappropriate use of antifungal drugs. In this study, the role of AFS in providing appropriate antifungal therapy was evaluated. This study included three periods, consisting of observation, feedback/education, and daily AFS activities. In the observation period, the use of systemic antifungals was evaluated for a baseline measurement of appropriateness. In the second period, monthly meetings were organized to provide feedback and education to physicians regarding antifungal therapy and the rate of adherence to the clinical guidelines. In the final period, a clinical pharmacist participated in daily ward rounds to evaluate the appropriateness of the antifungal therapy. A scoring system for appropriateness was used for comparison between the three periods. Four hundred eighteen episodes of antifungal therapy were evaluated. Baseline demographics of patients were similar in all three periods for age, gender, and the number of comorbidities. The indications for antifungal use were for prophylaxis in 22.7%, Candida infections in 58.6%, and invasive mold infections in 18.7%. During the third period, 157 (78.9%) recommendations were made and 151 (96.2%) were accepted. The overall appropriateness of antifungal use increased significantly for prophylaxis (30.8%, 17.9%, and 46.3%; P = 0.046) and treatment of fungal diseases (27.8%, 32.4%, and 71.9%; P < 0.001) between the first, second, and third periods, respectively. The 30-day mortality was not significantly changed between the three periods (19%, 15.6%, and 27.5%; P = 0.050). Appropriateness in antifungal therapy can be augmented by the integration of an AFS program. A team-based evaluation of fungal infections and assessment of patients by a clinical pharmacist with a therapeutic perspective may help to increase the quality of antifungal therapy.