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ABSTRACT: Objectives: Information is scarce on clinical experiences with non-neutropenic patients with invasive fungal infection (IFI) receiving isavuconazole. We aimed to report the safety and effectiveness of this drug as a first-line treatment or rescue in real life. Methods: A retrospective, observational multicentric study of non-neutropenic patients who received isavuconazole as an IFI treatment at 12 different university hospitals (January 2018-2022). All patients met criteria for proven, probable or possible IFI according to EORTC-MSG. Results: A total of 238 IFIs were treated with isavuconazole during the study period. Combination therapy was administered in 27.7% of cases. The primary IFI was aspergillosis (217, 91.2%). Other IFIs treated with isavuconazole were candidemia (n = 10), mucormycosis (n = 8), histoplasmosis (n = 2), cryptococcosis (n = 2), and others (n = 4). Median time of isavuconazole treatment was 29 days. Only 5.9% (n = 14) of cases developed toxicity, mainly hepatic-related (10 patients, 4.2%). Nine patients (3.8%) had treatment withdrawn. Successful clinical response at 12 weeks was documented in 50.5% of patients. Conclusion: Isavuconazole is an adequate treatment for non-neutropenic patients with IFIs. Toxicity rates were low and its effectiveness was comparable to other antifungal therapies previously reported.

Fungemia remains a major threat in intensive care units (ICUs), with high mortality rates despite advances in diagnostics and treatment. Colonisation by yeasts is an independent risk factor for fungemia; however, its predictive utility requires further research. In this 8-year study, we analysed 38,017 samples from 3206 patients and 171 fungemia episodes as part of a weekly fungal surveillance programme. We evaluated species-specific colonisation patterns, the predictive value of the Colonisation Index (CI) and Corrected Colonisation Index (CCI), and candidemia risks associated with different yeast species and anatomical site colonisation. Our results showed that C. auris, N. glabratus, and C. parapsilosis colonisation increased with longer hospital stays (0.8% to 11.55%, 8.13% to 16.8%, and 1.93% to 5.14%, respectively). The CI and CCI had low discriminatory power (AUROC 67% and 66%). Colonisation by any yeast genera demonstrated high sensitivity (98.32%) and negative predictive value (NPV) (95.90%) but low specificity and positive predictive value (PPV) (23.90% and 6.64%). Tracheal and urine cultures had the highest PPV (15.64% and 12.91%), while inguinal cultures had the highest NPV (98.60%). C. auris (12.32%) and C. parapsilosis (5.5%) were associated with a higher fungemia risk (log-rank < 0.001). These findings support the use of weekly surveillance to better stratify the fungemia risk and optimise antifungal use in ICUs.

Introduction: The World Health Organization (WHO)'s Research and Development (R&D) Blueprint for Action to Prevent Epidemics, a plan of action, highlighted several infectious diseases as crucial targets for prevention. These infections were selected based on a thorough assessment of factors such as transmissibility, infectivity, severity, and evolutionary potential. In line with this blueprint, the VACCELERATE Site Network approached infectious disease experts to rank the diseases listed in the WHO R&D Blueprint according to their perceived risk of triggering a pandemic. VACCELERATE is an EU-funded collaborative European network of clinical trial sites, established to respond to emerging pandemics and enhance vaccine development capabilities. Methods: Between February and June 2023, a survey was conducted using an online form to collect data from members of the VACCELERATE Site Network and infectious disease experts worldwide. Participants were asked to rank various pathogens based on their perceived risk of causing a pandemic, including those listed in the WHO R&D Blueprint and additional pathogens. Results: A total of 187 responses were obtained from infectious disease experts representing 57 countries, with Germany, Spain, and Italy providing the highest number of replies. Influenza viruses received the highest rankings among the pathogens, with 79 % of participants including them in their top rankings. Disease X, SARS-CoV-2, SARS-CoV, and Ebola virus were also ranked highly. Hantavirus, Lassa virus, Nipah virus, and henipavirus were among the bottom-ranked pathogens in terms of pandemic potential. Conclusion: Influenza, SARS-CoV, SARS-CoV-2, and Ebola virus were found to be the most concerning pathogens with pandemic potential, characterised by transmissibility through respiratory droplets and a reported history of epidemic or pandemic outbreaks.

Candida auris is an emerging, multidrug-resistant yeast that causes systemic infections, mainly in hospitalized or immunosuppressed patients. This pathogen has a high mortality and morbidity rate. This study aims to evaluate the antifungal potential of micafungin (MICA) encapsulated in a nanoemulsion (NEM) against four clades of C. auris and other non-C. auris species. The antifungal potential of MICA and NEM was evaluated by determining mature biofilm inhibition (0.78–50 µg/mL). The antifungal activities of MICA and NEM (5.92 mg/Kg) were evaluated using an in vivo model of Galleria mellonella. The results showed that NEM intensified the antibiofilm action of MICA, especially in 48 h mature biofilms. In vivo results displayed a higher effectiveness of NEM against all clades of C. auris tested, inhibiting the fungal load in the hemolymph and tissues of G. mellonella with a difference of 3 log10. In addition, C. auris infection caused granulomas surrounded by hemocytes, mainly at the lower and upper ends. Conversely, C. albicans developed pseudohyphae, biofilms, filaments, and chlamydospores. In conclusion, encapsulation of MICA in a nanoemulsion enhances its antifungal activity against mature biofilms of C. auris. This strategy may be considered a therapeutic approach for the control of infections and the dissemination of this new global health threat.

Cetaceans, which are crucial in marine ecosystems, act as sentinels for ecosystem and human–environmental health. However, emerging fungal infections, particularly by Candida spp., pose a growing concern in these marine mammals. This review consolidates current knowledge on the prevalence, clinical manifestations, species distribution, and antifungal resistance of Candida infections in cetaceans. We detail the diverse pathogenic impacts of Candida, including respiratory, dermal, and systemic afflictions, underscoring diagnostic and treatment challenges amid rising antifungal resistance. Our analysis extends beyond health concerns in captive cetaceans, where confinement stress heightens vulnerability, to encompass substantial ecological risks in wild populations. The review emphasizes the One Health perspective, linking cetacean health with broader environmental and human public health issues. We particularly focus on the potential zoonotic transmission of emerging fungal pathogens such as Candida auris and the role of environmental changes in fostering antifungal resistance. The study underscores the need for concerted, interdisciplinary efforts in veterinary, medical, and environmental sciences to enhance understanding and management of Candida infections in cetaceans. We advocate for comprehensive monitoring and collaborative research initiatives to mitigate the rising challenge of these infections. Addressing Candida spp. in cetaceans is not just a conservation priority but a critical step in safeguarding overall marine health and, by extension, human health in the context of evolving infectious diseases.

Candida auris has globally emerged as a multidrug-resistant fungus linked to healthcare-associated outbreaks. There is still limited evidence on its virulence, pathogenicity determinants, and complex host–pathogen interactions. This study analyzes the in vivo fungal behaviour, immune response, and host–pathogen interactions upon C. auris infection compared to C. albicans and C. parapsilosis in G. mellonella. This was performed by immunolabelling fungal structures and larval plasmatocytes and using a quantitative approach incorporating bioinformatic morphometric techniques into the study of microbial pathogenesis. C. auris presents a remarkably higher immunogenic activity than expected at its moderate degree of tissue invasion. It induces a greater inflammatory response than C. albicans and C. parapsilosis at the expense of plasmatocyte nodule formation, especially in non-aggregative strains. It specifically invades the larval respiratory system, in a pattern not previously observed in other Candida species, and presents inter-phenotypic tissue tropism differences. C. auris filaments in vivo less frequently than C. albicans or C. parapsilosis mostly through pseudohyphal growth. Filamentation might not be a major pathogenic determinant in C. auris, as less virulent aggregative phenotypes form pseudohyphae to a greater extent. C. auris has important both interspecific and intraspecific virulence and phenotype heterogeneity, with aggregative phenotypes of C. auris sharing characteristics with low pathogenic species such as C. parapsilosis. Our work suggests that C. auris owns an important morphogenetic plasticity that distinguishes it from other yeasts of the genus. Routine phenotypic identification of aggregative or non-aggregative phenotypes should be performed in the clinical setting as it may impact patient management.

Over 60% of emerging infectious diseases in humans are zoonotic, often originating from wild animals. This long-standing ecological phenomenon has accelerated due to human-induced environmental changes. Recent data show a significant increase in fungal infections, with 6.5 million cases annually leading to 3.7 million deaths, indicating their growing impact on global health. Despite the vast diversity of fungal species, only a few are known to infect humans and marine mammals. Fungal zoonoses, especially those involving marine mammals like cetaceans, are of global public health concern. Increased human–cetacean interactions, in both professional and recreational settings, pose risks for zoonotic disease transmission. This review focuses on the epidemiology, clinical manifestations, and zoonotic potential of major fungal pathogens shared in humans and cetaceans, highlighting their interspecies transmission capability and the challenges posed by antifungal resistance and environmental changes. It underscores the need for enhanced awareness and preventative measures in high-risk settings to protect public health and marine ecosystems.

Cetaceans, which are integral to marine ecosystems, face escalating anthropogenic threats, including climate change and pollution, positioning them as critical sentinel species for ocean and human health. This review explores the neglected realm of non-Candida yeasts in cetaceans, addressing the gaps in the understanding of their prevalence, pathogenicity, and environmental impacts. By examining identified species such as Cryptococcus spp., Paracoccidioides spp., and several dimorphic fungi, this review emphasizes global prevalence, epidemiology and ecology, pathogenicity, and potential zoonotic implications. It also discusses the fine line between yeast commensalism and pathogenicity by considering environmental influences such as pollution, climate shifts, and immune suppression. Environmental impact discussions delve into how rising ocean temperatures and pollution can modify yeast mycobiota, potentially affecting marine host health and broader ecosystem dynamics. The cetacean’s unique physiology and ecological niches are considered, highlighting potential impacts on behaviors, reproductive success, and survival rates. Identifying crucial knowledge gaps, the review calls for intensified research efforts, employing advanced molecular techniques to unravel the cetacean mycobiome. Systematic studies on yeast diversity, antifungal susceptibility, and their influence on environmental and ecosystem health are proposed, and the balance between commensal and pathogenic species emphasizes the significance of the One Health approach. In conclusion, as marine mammals face unprecedented challenges, unveiling non-Candida yeasts in cetaceans emerges as a critical endeavor with far-reaching implications for the conservation of marine ecosystems and for both animal and human public health.

Candida auris is an emerging yeast of worldwide interest due to its antifungal resistance and mortality rates. The aim of this study was to analyse the in vitro and in vivo antifungal activity of a nanoemulsion loaded with amphotericin B (NEA) against planktonic cells and biofilm of C. auris clinical isolates belonging to four different clades. In vivo assays were performed using the Galleria mellonella model to analyse antifungal activity and histopathological changes. The in vitro results showed that NEA exhibited better antifungal activity than free amphotericin B (AmB) in both planktonic and sessile cells, with >31% inhibition of mature biofilm. In the in vivo assays, NEA demonstrated superior antifungal activity in both haemolymph and tissue. NEA reduced the fungal load in the haemolymph more rapidly and with more activity in the first 24 h after infection. The histological analysis of infected larvae revealed clusters of yeast, immune cells, melanisation, and granulomas. In conclusion, NEA significantly improved the in vitro and in vivo antifungal activity of AmB and could be considered a promising therapy for C. auris infections.

Abstract Incidence of pneumococcal disease has increased worldwide in recent years. Response to pneumococcal vaccine is usually measured using the multiserotype enzyme-linked immunosorbent assay (ELISA) pneumococcal test. However, this approach presents several limitations. Therefore, the introduction of new and more robust analytical approaches able to provide information on the efficacy of the pneumococcal vaccine would be very beneficial for the clinical management of patients. Surface plasmon resonance (SPR) has been shown to offer a valuable understanding of vaccines’ properties over the last years. The aim of this study is to evaluate the reliability of SPR for the anti-pneumococcal capsular polysaccharides (anti-PnPs) IgGs quantification in vaccinated. Fast protein liquid chromatography (FPLC) was used for the isolation of total IgGs from serum samples of vaccinated patients. Binding-SPR assays were performed to study the interaction between anti-PnPs IgGs and PCV13. A robust correlation was found between serum levels of anti-PnPs IgGs, measured by ELISA, and the SPR signal. Moreover, it was possible to correctly classify patients into “non-responder”, “responder” and “high-responder” groups according to their specific SPR PCV13 response profiles. SPR technology provides a valuable tool for reliably characterize the interaction between anti-PnPs IgGs and PCV13 in a very short experimental time.

Candida auris has arisen as an important multidrug-resistant fungus because of several nosocomial outbreaks and elevated rates of mortality. Accurate and rapid diagnosis of C. auris is highly desired; nevertheless, current methods often present severe limitations and produce misidentification. Herein a sensitive, selective, and time-competitive biosensor based on oligonucleotide-gated nanomaterials for effective detection of C. auris is presented. In the proposed design, a nanoporous anodic alumina scaffold is filled with the fluorescent indicator rhodamine B and the pores blocked with different oligonucleotides capable of specifically recognize C. auris genomic DNA. Gate opening modulation and cargo delivery is controlled by successful DNA recognition. C. auris is detected at a concentration as low as 6 CFU/mL allowing obtaining a diagnostic result in clinical samples in one hour with no prior DNA extraction or amplification steps.

BackgroundIbrexafungerp (SCY-078) is the newest oral and intravenous antifungal drug with broad activity, currently undergoing clinical trials for invasive candidiasis.ObjectiveThe aim of this study was to assess the in vitro activity of ibrexafungerp and comparators against a collection of 434 European blood isolates of Candida.MethodsIbrexafungerp, caspofungin, fluconazole, and micafungin minimum inhibitory concentrations (MICs) were collected from 12 European laboratories for 434 blood isolates, including 163 Candida albicans, 108 Candida parapsilosis, 60 Candida glabrata, 40 Candida tropicalis, 29 Candida krusei, 20 Candida orthopsilosis, 6 Candida guilliermondii, 2 Candida famata, 2 Candida lusitaniae, and 1 isolate each of Candida bracarensis, Candida catenulata, Candida dubliniensis, and Candida kefyr. MICs were determined by the EUCAST broth microdilution method, and isolates were classified according to recommended clinical breakpoints and epidemiological cutoffs. Additionally, 22 Candida auris from different clinical specimens were evaluated.ResultsIbrexafungerp MICs ranged from 0.016 to ≥8 mg/L. The lowest ibrexafungerp MICs were observed for C. albicans (geometric MIC 0.062 mg/L, MIC range 0.016–0.5 mg/L) and the highest ibrexafungerp MICs were observed for C. tropicalis (geometric MIC 0.517 mg/L, MIC range 0.06–≥8 mg/L). Modal MICs/MIC50s (mg/L) against Candida spp. were 0.125/0.06 for C. albicans, 0.5/0.5 for C. parapsilosis, 0.25/0.25 for C. glabrata, 0.5/0.5 for C. tropicalis, 1/1 for C. krusei, 4/2 for C. orthopsilosis, and 0.5/0.5 for C. auris. Ibrexafungerp showed activity against fluconazole- and echinocandin-resistant isolates. If adopting wild-type upper limits, a non-wild-type phenotype for ibrexafungerp was only observed for 16/434 (3.7%) isolates: 11 (4.6%) C. parapsilosis, 4 (5%) C. glabrata, and 1 (2.5%) C. tropicalis.ConclusionIbrexafungerp showed a potent in vitro activity against Candida.

Abstract Background Almost one third of the patients with candidemia develop septic shock. The understanding why some patients do and others do not develop septic shock is very limited. The objective of this study was to identify variables associated with septic shock development in a large population of patients with candidemia. Methods A post hoc analysis was performed on two prospective, multicenter cohort of patients with candidemia from 12 hospitals in Spain and Italy. All episodes occurring from September 2016 to February 2018 were analyzed to assess variables associated with septic shock development defined according to The Third International Consensus Definition for Sepsis and Septic Shock (Sepsis-3). Results Of 317 candidemic patients, 99 (31.2%) presented septic shock attributable to candidemia. Multivariate logistic regression analysis identifies the following factors associated with septic shock development: age > 50 years (OR 2.57, 95% CI 1.03–6.41, p = 0.04), abdominal source of the infection (OR 2.18, 95% CI 1.04–4.55, p = 0.04), and admission to a general ward at the time of candidemia onset (OR 0.21, 95% CI, 0.12–0.44, p = 0.001). Septic shock development was independently associated with a greater risk of 30-day mortality (OR 2.14, 95% CI 1.08–4.24, p = 0.02). Conclusions Age and abdominal source of the infection are the most important factors significantly associated with the development of septic shock in patients with candidemia. Our findings suggest that host factors and source of the infection may be more important for development of septic shock than intrinsic virulence factors of organisms.

Abstract Background Leishmaniasis, considered by the World Health Organization as one of the most important tropical diseases, is endemic in the Mediterranean Basin. The aim of this study was to evaluate epidemiological and clinical characteristics of cutaneous (CL) and mucocutaneous leishmaniasis (MCL) in La Fe University Hospital, Valencia, Spain. The particular focus was on diagnosis techniques and clinical differences according to the immunological status of the patients. Methods An eleven-year retrospective observational study of CL and MCL episodes at the hospital was performed. Epidemiological, clinical and therapeutic variables of each case, together with the microbiological and anatomopathological diagnosis, were analyzed. Results A total of 42 patients were included, 30 of them were male and 28 were immunocompetent. Most of the cases (36/42) were diagnosed in the last 5 years (2013–2017). The incidence of CL and MCL increased from 3.6/100,000 (2006–2012) to 13.58/100,000 (2013–2017). The majority of the patients (37/42) exhibited CL, in 30 cases as single lesions (30/37). Ulcerative lesions were more common in immunosuppressed patients (13/14) than in immunocompetent patients (20/28), (P = 0.2302). The length of lesion presence before diagnosis was 7.36 ± 6.72 months in immunocompetent patients and 8.79 ± 6.9 months in immunosuppressed patients (P = 0.1863). Leishmania DNA detection (92.3%) was the most sensitive diagnostic technique followed by Giemsa stain (65%) and histopathological examination (53.8%). Twelve patients (12/42) had close contact with dogs or were living near to kennels, and 10 of them did not present underlying conditions. Intralesional glucantime (21/42) and liposomal amphotericin B (7/42) were the most common treatments administered in monotherapy. All patients evolved successfully and no relapse was reported. Conclusions Some interesting clinical and epidemiological differences were found in our series between immunocompetent and immunosuppressed patients. Future studies can take these results further especially by studying patients with biological therapy. Skin biopsies combining NAAT with histological techniques are the most productive techniques for CL or MCL diagnosis.

Introduction:Candida auris is a major threat to public health. Rapid detection is essential for early treatment and transmission control. The use of chromogenic media allows the presumptive identification of this new species. The aim of this study is to describe the morphological characteristics of C. auris colonies on three commercial chromogenic media. Methods: Nineteen C. auris isolates from different countries/clades and 18 isolates of other species were cultivated in CHROMagarTM Candida Plus, HiCromeTM Candida, CHROMagar-Candida, and fluconazole-supplemented (32 mg/L) CHROMagar-Candida media. Results: On CHROMagarTM Candida Plus and HiCromeTM Candida, C. auris isolates from Colombia, Venezuela, India, Korea, and Japan displayed blue-shaded colonies, while isolates from Spain and Germany exhibited light pink shades with a bluish halo. All isolates showed white to pink colonies on CHROMagar-Candida. On CHROMagar Candida supplemented with fluconazole, whilst C. auris, C. glabrata, or C. krusei showed a similar pink color at 48 h incubation, phenotypic differentiation was possible by the rough, paraffin-like texture or the intense purple color acquired by C. krusei and C. glabrata, respectively. Moreover, in this medium, the presence of C. auris in combination with other species of similar color was not limiting for its early identification, due to this medium selecting only strains resistant to this antifungal. Conclusions: The use of chromogenic media such as CHROMagarTM Candida Plus facilitates a presumptive identification of C. auris. However, this identification can be difficult in the presence of mixed cultures. In these cases, the use of CHROMagarTM Candida medium with 32 mg/L fluconazole offers better performance for the identification of C. auris by inhibiting fluconazole-susceptible strains and selecting rare or high fluconazole MIC (>32 mg/L) isolates.

ABSTRACT Candida auris is an emergent multidrug-resistant fungal pathogen considered a severe global threat due to its capacity to cause nosocomial outbreaks and deep-seated infections with high transmissibility and mortality. However, evidence on its pathogenicity and the complex host-pathogen interactions is still limited. This study used the in vivo invertebrate model in Galleria mellonella to assess its virulence, exploring the mortality kinetics, melanization response, and morphological changes after fungal infection compared to Candida albicans and Candida parapsilosis, with known high and low pathogenicity, respectively. All C. auris isolates presented less virulence than C. albicans strains but higher than that induced by C. parapsilosis isolates. Increased pathogenicity was observed in nonaggregative phenotypes of C. auris, while the melanization response of the larvae to fungal infection was homogeneous and independent of the causing species. C. auris was able to filament in the in vivo animal model G. mellonella, with aggregative and nonaggregative phenotypes presenting various pseudohyphal formation degrees as pathogenicity determinants in a strain-dependent manner. Histological invasiveness of C. auris mimicked that observed for C. albicans, with effective dissemination since the early stages of infection both in yeast and filamented forms, except for a remarkable respiratory tropism not previously observed in other yeasts. These characteristics widely differ between strains and advocate the hypothesis that the morphogenetic variability of C. auris is an indicator of its flexibility and adaptability, contributing to its emergence and rising worldwide prevalence. IMPORTANCE Candida auris is an emergent fungus that has become a global threat due to its multidrug resistance, mortality, and transmissibility. These unique features make it different from other Candida species, but we still do not fully know the degree of virulence and, especially, the host-pathogen interactions. In this in vivo insect model, we found that it presents an intermediate degree of virulence compared to known high- and low-virulence Candida species but with significant variability between aggregative and nonaggregative strains. Although it was previously considered unable to filament, we documented in vivo filamentation as an important pathogenic determinant. We also found that it is able to disseminate early through the host, invading both the circulatory system and many different tissues with a remarkable respiratory tropism not previously described for other yeasts. Our study provides new insights into the pathogenicity of an emergent fungal pathogen and its interaction with the host and supports the hypothesis that its morphogenetic variability contributes to its rising global prevalence.

The objectives of this study were to gain further insight on Candida genotype distribution and percentage of clustered isolates between hospitals and to identify potential clusters involving different hospitals and cities. We aim to genotype Candida spp. isolates causing candidemia in patients admitted to 16 hospitals in Spain, Italy, Denmark, and Brazil. Eight hundred and eighty-four isolates (Candida albicans, n = 534; C. parapsilosis, n = 282; and C. tropicalis, n = 68) were genotyped using species-specific microsatellite markers. CDC3, EF3, HIS3, CAI, CAIII, and CAVI were used for C. albicans, Ctrm1, Ctrm10, Ctrm12, Ctrm21, Ctrm24, and Ctrm28 for C. tropicalis, and CP1, CP4a, CP6, and B for C. parapsilosis. Genotypes were classified as singletons (genotype only found once) or clusters (same genotype infecting two or more patients). Clusters were defined as intra-hospital (involving patients admitted to a single hospital), intra-ward (involving patients admitted to the same hospital ward) or widespread (involving patients admitted to different hospitals). The percentage of clusters and the proportion of patients involved in clusters among species, genotypic diversity and distribution of genetic diversity were assessed. Seven hundred and twenty-three genotypes were detected, 78 (11%) being clusters, most of which (57.7%; n = 45/78) were intra-hospital clusters including intra-ward ones (42.2%; n = 19/45). The proportion of clusters was not statistically different between species, but the percentage of patients in clusters varied among hospitals.A number of genotypes (7.2%; 52/723) were widespread (found at different hospitals), comprising 66.7% (52/78) of clusters, and involved patients at hospitals in the same city (n = 21) or in different cities (n = 31). Only one C. parapsilosis cluster was a widespread genotype found in all four countries. Around 11% of C. albicans and C. parapsilosis isolates causing candidemia are clusters that may result from patient-to-patient transmission, widespread genotypes commonly found in unrelated patients, or insufficient microsatellite typing genetic discrimination.

Epidemiological trends show a dramatic increase in the prevalence of fungal infections, and in the isolation of multidrug-resistant species, such as Candida auris. CHROMagarTM Candida (CC; CHROMagar, Paris, France) and other chromogenic media, which are widely used in the clinical laboratory because they allow a rapid identification of most Candida species. Recently, CHROMagarTM Candida Plus (CC-Plus; CHROMagar, Paris, France) was developed to detect and differentiate C. auris in addition to other major clinical Candida species, such as C. albicans, C. tropicalis, C. glabrata, or C. krusei. C. auris colonies display a differential light blue color with a blue halo. A multicentric study was designed to evaluate the performance of the CC-Plus medium in the detection of Candida species in patients’ surveillance and environmental samples from three Spanish hospitals with active C. auris outbreaks. A total of 364 patients’ surveillance samples and 212 environmental samples were tested. Samples were inoculated in CC and CC-Plus in parallel, and the plates were read at 24 and 48 h. All recovered colonies were presumptively identified according to colony color described by manufacturer, and the definitive identification was performed by mass spectrometry at 48 h. A total of 134 C. auris isolates were obtained (101 from patients’ surveillance samples, and 33 from environmental samples). Sensitivity, specificity, and predictive positive and negative values were 99.5%, 100%, 100%, and 99.1%, respectively, for the main clinical Candida species, showing that CC-Plus is comparable to CC, with the advantage of being able to differentiate C. auris from C. parapsilosis. Furthermore, CC-Plus was able to detect one C. albicans, one C. glabrata, and eight C. auris that did not grow in CC. Additionally, the yeast colonies were generally larger, suggesting that this novel medium could be a richer medium, and suitable for surveillance and environmental cultures of C. auris and other clinically relevant Candida species.

Candida auris has unprecedently emerged as a multidrug resistant fungal pathogen, considered a serious global threat due to its potential to cause nosocomial outbreaks and deep-seated infections with staggering transmissibility and mortality, that has put health authorities and institutions worldwide in check for more than a decade now. Due to its unique features not observed in other yeasts, it has been categorised as an urgent threat by the Centers for Disease Control and Prevention and other international agencies. Moreover, epidemiological alerts have been released in view of the increase of healthcare-associated C. auris outbreaks in the context of the COVID-19 pandemic. This review summarises the current evidence on C. auris since its first description, from virulence to treatment and outbreak control, and highlights the knowledge gaps and future directions for research efforts.

The aims of this study were to characterize the antifungal activity of amphotericin B against Candida auris in a static in vitro system and to evaluate different dosing schedules and MIC scenarios by means of semi-mechanistic pharmacokinetic/pharmacodynamic (PK/PD) modelling and simulation. A two-compartment model consisting of a drug-susceptible and a drug-resistant subpopulation successfully characterized the time-kill data and a modified Emax sigmoidal model best described the effect of the drug. The model incorporated growth rate constants for both subpopulations, a death rate constant and a transfer constant between both compartments. Additionally, the model included a parameter to account for the delay in growth in the absence or presence of the drug. Amphotericin B displayed a concentration-dependent fungicidal activity. The developed PK/PD model was able to characterize properly the antifungal activity of amphotericin B against C. auris. Finally, simulation analysis revealed that none of the simulated standard dosing scenarios of 0.6, 1 and 1.5 mg/kg/day over a week treatment showed successful activity against C. auris infection. Simulations also pointed out that an MIC of 1 mg/L would be linked to treatment failure for C. auris invasive infections and therefore, the resistance rate to amphotericin B may be higher than previously reported.

A case of 1-year- old male multivisceral transplant recipient with candidemia diagnosed by the T2Candida® test is presented. Optimal management of the candidemia complemented the treatment of the global clinical episode. Duration of treatment might be established much more precisely with the T2Candida® test than with blood cultures. Keywords: Candidemia, T2Candida, Multivisceral transplant recipient

Candida auris is an emerging fungal pathogen of great concern among the scientific community because it is causing an increasing number of hospital outbreaks of difficult management worldwide. In addition, isolates from this species frequently present reduced susceptibility to azole and echinocandin drugs. For this reason, it is necessary to develop new antifungal strategies to better control the disease caused by this yeast. In this work, we screened drugs from the Prestwick chemical library, which contains 1,280 off-patent compounds that are already approved by the Food and Drug Administration, with the aim of identifying molecules with antifungal activity against C. auris. In an initial screening, we looked for drugs that inhibited the growth of three different C. auris strains and found 27 of them which it did so. Ten active compounds were selected to test the susceptibility profile by using the EUCAST protocol. Antifungal activity was confirmed for seven drugs with MICs ranging from 0.5 to 64 mg/L. Some of these drugs were also tested in combination with voriconazole and anidulafungin at sub-inhibitory concentrations. Our results suggest synergistic interactions between suloctidil and voriconazole with fractional inhibitory concentration index (FICI) values of 0.11 to 0.5 and between ebselen and anidulafungin (FICI, 0.12 to 0.44). Our findings indicate that drug repurposing could be a viable alternative to managing infections by C. auris.

Fungal diseases and antifungal resistance continue to increase, including those caused by rare or emerging species. However, the majority of the published in vitro susceptibility data are for the most common fungal species. We reviewed the literature in order to pool reference minimal inhibitory concentration (MIC) data (Clinical and Laboratory Standards Institute—CLSI and European Committee on Antimicrobial Susceptibility—EUCAST) for rare/non-prevalent Candida and other yeast species. MIC results were compared with those for Candida albicans, C. glabrata, and C. krusei. Data were listed for twenty rare and emerging Candida spp., including C. auris, as well as two Cryptococcus spp., two Trichosporon spp., Saccharomyces cerevisiae and five Malassezia spp. The best detectors of antimicrobial resistance are the breakpoints, which are not available for the less common Candida species. However, epidemiological cutoff values (ECVs/ECOFFs) have been calculated using merely in vitro data for both reference methods for various non-prevalent yeasts and recently the CLSI has established ECVs for other Candida species. The ECV could identify the non-wild type (NWT or mutants) isolates with known resistance mechanisms. Utilizing these ECVs, we were able to report additional percentages of NWT, especially for non-prevalent species, by analyzing the MIC distributions in the literature. In addition, since several antifungal drugs are under development, we are listing MIC data for some of these agents.

Pneumocystis pneumonia (PcP) is a disease produced by the opportunistic infection of the fungus Pneumocystis jirovecii. As delayed or unsuitable treatments increase the risk of mortality, the development of rapid and accurate diagnostic tools for PcP are of great importance. Unfortunately, current standard methods present severe limitations and are far from adequate. In this work, a time-competitive, sensitive and selective biosensor based on DNA-gated nanomaterials for the identification of P. jirovecii is presented. The biosensor consists of a nanoporous anodic alumina (NAA) scaffold which pores are filled with a dye reporter and capped with specific DNA oligonucleotides. In the presence of P. jirovecii genomic DNA, the gated biosensor is open, and the cargo is delivered to the solution where it is monitored through fluorescence spectroscopy. The use of capping oligonucleotides able to form duplex or triplex with P. jirovecii DNA is studied. The final diagnostic tool shows a limit of detection (LOD) of 1 nM of target complementary DNA and does not require previous amplification steps. The method was applied to identify DNA from P. jirovecii in unmodified bronchoalveolar lavage, nasopharyngeal aspirates, and sputum samples in 60 min. This is a promising alternative method for the routinely diagnosis of Pneumocystis pneumonia.

Parasitic infections are rarely documented in hematopoietic stem cell transplant recipients. However, they may be responsible for fatal complications that are only diagnosed at autopsy. Increased awareness of the possibility of parasitic diseases both in autologous and allogeneic stem cell transplant patients is relevant not only for implementing preventive measures but also for performing an early diagnosis and starting appropriate therapy for these unrecognized but fatal infectious complications in hematopoietic transplant recipients. In this review, we will focus on parasitic diseases occurring in this population especially those with major clinical relevance including toxoplasmosis, American trypanosomiasis, leishmaniasis, malaria, and strongyloidiasis, among others, highlighting the diagnosis and management in hematopoietic transplant recipients.

Rafael Zaragoza1, Javier Pemán2, Miguel Salavert3, Ángel Viudes2, Amparo Solé4, Isidro Jarque5, Emilio Monte6, Eva Romá6, Emilia Cantón71Servicio de Medicina Intensiva, Hospital Universitario Dr Peset, Valencia, Spain; 2Servicio de Microbiología; 3Unidad de Enfermedades Infecciosas; 4Unidad de Trasplante Pulmonar; 5Servicio de Hematología; 6Servicio de Farmacia; 7Unidad de Microbiología Experimental, Centro de Investigación, Hospital Universitario La Fe Valencia, SpainAbstract: The high morbidity, mortality, and health care costs associated with invasive fungal infections, especially in the critical care setting and immunocompromised host, have made it an excellent target for prophylactic, empiric, and preemptive therapy interventions principally based on early identification of risk factors. Early diagnosis and treatment are associated with a better prognosis. In the last years there have been important developments in antifungal pharmacotherapy. An approach to the new diagnosis tools in the clinical mycology laboratory and an analysis of the use new antifungal agents and its application in different clinical situations has been made. Furthermore, an attempt of developing a state of the art in each clinical scenario (critically ill, hematological, and solid organ transplant patients) has been performed, trying to choose the best strategy for each clinical situation (prophylaxis, pre-emptive, empirical, or targeted therapy). The high mortality rates in these settings make mandatory the application of early de-escalation therapy in critically ill patients with fungal infection. In addition, the possibility of antifungal combination therapy might be considered in solid organ transplant and hematological patients.Keywords: invasive fungal infections, prophylaxis, empirical therapy, preemptive treatment, targeted therapy

BACKGROUND:Statins have immunomodulatory properties and hinder Candida growth. However, it is unknown whether they may improve prognosis in patients with candidemia. We sought to determine the effect of prior statin use on the clinical outcomes of patients suffering candidemia. METHODS AND FINDINGS:Multicenter cohort study of hospitalized adults with candidemia between 2005 and 2011 in six hospitals in Spain, Brazil and Argentina. Of 326 candidemias, 44 (13.5%) occurred in statin users and 282 (86.5%) in statin non-users. The median value of APACHE II at candidemia diagnosis was similar between groups (18 vs. 16; p=.36). Candida albicans was the most commonly isolated species, followed by C. parapsilosis, C. tropicalis, C. glabrata, and C. krusei. There were no differences regarding appropriate empirical antifungal treatment. Statin users had a lower early (5 d) case-fatality rate than non-users (4.5 vs. 17%; p=.031). This effect was not observed with other cardiovascular drugs (aspirin, beta blockers and ACE inhibitors). Independent factor related to early case-fatality rate was APACHE II score (AOR, 1.08; 95% CI, 1.03-1.14; p=.002). An appropriate empirical antifungal therapy (AOR, 0.11; 95% CI, 0.04-0.26; p=