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Invasive candidiasis is a hospital-acquired infection with a high associated mortality.1 The antifungal drug armamentarium to manage patients with invasive candida infections is quite small and restricted to three drug families: the polyenes, the azoles, and the echinocandins. The Infectious Diseases Society of America and European Society for Clinical Microbiology Diseases international guidelines both support the use of echinocandins as first-line drugs for the treatment of invasive candida infections.2,3 Caspofungin, the first-in-class echinocandin, was approved in 2001 and preceded the marketing of micafungin (launched in 2005) and anidulafungin (launched in 2006). These echinocandins show similar in-vitro activity, pharmacokinetic parameters, and clinical efficacy, and are administered intravenously once a day.4 Rezafungin (formerly SP3025 and CD101) is a next-generation echinocandin derived from anidulafungin. It has echinocandin-expected in-vitro activity against Candida spp and has a chemical modification that confers high stability, a longer half-life, and allows for a once-a-week dosing regimen.5 Rezafungin showed safety and a low potential for drug–drug interactions in a phase 1 study,6 and safety and clinical efficacy in the randomised, controlled, phase 2 STRIVE trial.7

Background Invasive fungal disease (IFD) is a significant cause of morbimortality in children under chemotherapy or hematopoietic stem cell transplant (HSCT). The purpose of this study is to describe the changes in the IFD epidemiology that occurred in a Pediatric Hematology-Oncology Unit (PHOU) with an increasing activity over time. Methods Retrospective revision of the medical records of children (from 6 months to 18 years old) diagnosed with IFD in the PHOU of a tertiary hospital in Madrid (Spain), between 2006 and 2019. IFD definitions were performed according to the EORTC revised criteria. Prevalence, epidemiological, diagnostic and therapeutic parameters were described. Comparative analyses were conducted using Chi-square, Mann-Whitney and Kruskal-Wallis tests, according to three time periods, the type of infection (yeast vs mold infections) and the outcome. Results Twenty-eight episodes of IFD occurred in 27 out of 471 children at risk (50% males; median age of 9.8 years old, [IQR 4.9-15.1]), resulting in an overall global prevalence of 5.9%. Five episodes of candidemia and 23 bronchopulmonary mold diseases were registered. Six (21.4%), eight (28.6%) and 14 (50%) episodes met criteria for proven, probable and possible IFD, respectively. 71.4% of patients had a breakthrough infection, 28.6% required intensive care and 21.4% died during treatment. Over time, bronchopulmonary mold infections and breakthrough IFD increased ( p =0.002 and p =0.012, respectively), occurring in children with more IFD host factors ( p =0.028) and high-risk underlying disorders ( p =0.012). A 64% increase in the number of admissions in the PHOU ( p <0.001) and a 277% increase in the number of HSCT ( p =0.008) were not followed by rising rates of mortality or IFD/1000 admissions ( p =0.674). Conclusions In this study, we found that yeast infections decreased, while mold infections increased over time, being most of them breakthrough infections. These changes are probably related to the rising activity in our PHOU and an increase in the complexity of the baseline pathologies of patients. Fortunately, these facts were not followed by an increase in IFD prevalence or mortality rates.

Background: Candidaemia and invasive candidiasis are typically hospital-acquired. Genotyping isolates from patients admitted to different hospitals may be helpful in tracking clones spreading across hospitals, especially those showing antifungal resistance. Methods: We characterized Candida clusters by studying Candida isolates (C. albicans, n = 1041; C. parapsilosis, n = 354, and C. tropicalis, n = 125) from blood cultures (53.8%) and intra-abdominal samples (46.2%) collected as part of the CANDIMAD (Candida in Madrid) study in Madrid (2019–2021). Species-specific microsatellite markers were used to define the genotypes of Candida spp. found in a single patient (singleton) or several patients (cluster) from a single hospital (intra-hospital cluster) or different hospitals (widespread cluster). Results: We found 83 clusters, of which 20 were intra-hospital, 49 were widespread, and 14 were intra-hospital and widespread. Some intra-hospital clusters were first detected before the onset of the COVID-19 pandemic, but the number of clusters increased during the pandemic, especially for C. parapsilosis. The proportion of widespread clusters was significantly higher for genotypes found in both compartments than those exclusively found in either the blood cultures or intra-abdominal samples. Most C. albicans- and C. tropicalis-resistant genotypes were singleton and presented exclusively in either blood cultures or intra-abdominal samples. Fluconazole-resistant C. parapsilosis isolates belonged to intra-hospital clusters harboring either the Y132F or G458S ERG11p substitutions; the dominant genotype was also widespread. Conclusions: the number of clusters—and patients involved—increased during the COVID-19 pandemic mainly due to the emergence of fluconazole-resistant C. parapsilosis genotypes.

Azole resistance poses a problem for the management of patients with invasive aspergillosis. Former species are in fact groups of closely related species (or complexes); cryptic species frequently show high antifungal resistance. The European Committee on Antimicrobial Susceptibility Testing (EUCAST) Definitive Document (E.Def) 9.3.2 includes guidelines for antifungal susceptibility testing on Aspergillus spp. and clinical breakpoints for amphotericin B, itraconazole, voriconazole, posaconazole, and isavuconazole against A. flavus, A. fumigatus, A. nidulans, A. niger, and A. terreus. New clinical breakpoints were released in February 2020 and one of the most relevant modifications was the definition of the new “susceptible, increased exposure” (formerly “intermediate”) category. Another relevant change was the adoption of the concept of area of technical uncertainty (ATU) that refers to problematic areas which involve uncertainty of susceptibility categorisation (e.g., when minimum inhibitory concentrations (MICs) for susceptible and resistant organisms overlap). To accommodate both the new “susceptible, increased exposure” category and the concept of ATU, MICs of azoles and amphotericin B that fall in the former “intermediate” category have been automatically categorized as either R (amphotericin B) or ATU (triazoles). Finally, EUCAST-AFST (Antifungal Susceptibility Testing) decided to adopt new breakpoints for less common species provided that the epidemiological cut-off value (ECOFF) is below or comparable to the breakpoint for the type species (A. fumigatus).

IntroductionThis study aimed to examine the relationship among adequate dose, serum concentration and clinical outcome in a non-selected group of hospitalized patients receiving antifungals.MethodsProspective cross-sectional study performed between March 2015 and June 2015. Dosage of antifungals was considered adequate according to the IDSA guidelines, whereas trough serum concentrations (determined with HPLC) were considered adequate as follows: fluconazole > 11 µg/ml, echinocandins > 1 µg/ml, voriconazole 1–5.5 µg/ml and posaconazole > 0.7 µg/ml.ResultsDuring the study period, 84 patients (65.4% male, 59.6 years) received antifungals for prophylaxis (40.4%), targeted (31.0%) and empirical therapy (28.6%). The most frequent drug was micafungin (28/84; 33.3%) followed by fluconazole (23/84; 27.4%), voriconazole (15/84; 17.9%), anidulafungin (8/84; 9.5%), posaconazole (7/84; 8.3%) and caspofungin (3/84; 3.6%). Considerable interindividual variability was observed for all antifungals with a large proportion of the patients (64.3%) not attaining adequate trough serum concentrations, despite receiving an adequate antifungal dose. Attaining the on-target serum antifungal level was significantly associated with a favorable clinical outcome (OR = 0.02; 95% CI 0.01–0.64; p = 0.03), whereas the administration of an adequate antifungal dosage was not.ConclusionsWith the standard antifungal dosage, a considerable proportion of patients have low drug concentrations, which are associated with poor clinical outcome.

The objectives of this study were to gain further insight on genotype distribution and percentage of clustered isolates between hospitals and to identify potential clusters involving different hospitals and cities. We aim to genotype spp. isolates causing candidemia in patients admitted to 16 hospitals in Spain, Italy, Denmark, and Brazil. Eight hundred and eighty-four isolates ( = 534; = 282; and = 68) were genotyped using species-specific microsatellite markers. CDC3, EF3, HIS3, CAI, CAIII, and CAVI were used for , Ctrm1, Ctrm10, Ctrm12, Ctrm21, Ctrm24, and Ctrm28 for , and CP1, CP4a, CP6, and B for . 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%; = 45/78) were intra-hospital clusters including intra-ward ones (42.2%; = 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 ( = 21) or in different cities ( = 31). Only one cluster was a widespread genotype found in all four countries. Around 11% of and 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.

We studied 19 cases of proven/probable mucormycosis diagnosed from 2007 to 2015 in our hospital and assessed the microbiological characteristics of the isolates. We recorded the incidence of mucormycosis and clinical and microbiological data of infected patients. Isolates were identified to molecular level and tested for their antifungal susceptibility to azoles, amphotericin B, and liposomal amphotericin B according to the CLSI M-38 A2 procedure. The incidence of mucormycosis in cases/100,000 hospital admissions during 2007-2015 increased significantly with respect to that reported in 1988-2006 (3.3 vs. 1.2; P<0.05). Patients mainly had hematological malignancies (52.6%) and/or trauma/surgical wounds (52.6%) and had received antifungal agents before the diagnosis of mucormycosis in 68% of cases. Diagnosis was by isolation (n = 17/19) and/or direct staining (n = 17/18) of Mucorales fungi in clinical samples. Identification was by panfungal PCR in patients with negative results in culture and in direct staining. The microorganisms identified were Lichtheimia spp. (42%), Rhizopus spp. (21%), Cunninghamella bertholletiae (16%), and others (21%). Liposomal amphotericin B was always more active than the other drugs against all the microorganisms except C. bertholletiae. All patients received antifungal treatment with 1 or more antifungal agents, mainly liposomal amphotericin B (17/19). Mortality was 47.4%, although this was significantly lower in the 11 patients in whom debridement was performed (18% vs. 87.5%) (P = 0.015). The incidence of mucormycosis has risen in recent years. The proportion of cases with soft tissue involvement was high, and Lichtheimia was the most frequently involved species. The highest antifungal activity was observed with liposomal amphotericin B.

We assessed the performance of Abbott's SARS-CoV-2 IgG assay and the Panbio TM COVID-19 IgG/IgM rapid test device for the diagnosis of either active or cured COVID-19. Three cohorts of patients were chosen. Cohort 1, patients (n = 65) who attended the emergency department on March 30, 2020 with clinical suspicion of active COVID-19 (n = 56 with proven/probable COVID-19). Cohort 2, hospital workers (n = 92) who had either been (n = 40) or not (n = 52) diagnosed with proven/probable COVID-19 and were asymptomatic at the time of the sampling. Cohort 3, patients (n = 38) cared at the hospital before the start of the COVID-19 pandemic. Detection of serum antibodies was done using Abbott´s SARS-CoV-2 IgG assay and the Panbio TM COVID-19 IgG/IgM device. Both methods showed 98% agreement for IgG detection. No antibodies were detected in the 38 samples from hospitalized pre-COVID subjects. The diagnostic performance of IgGs detected by Abbott´s SARS-CoV-2 assay in Cohorts 1/2 was: sensitivity (60.7%/75%) and specificity (100%/84.6%). The diagnostic performance of IgM by Panbio TM COVID-19 in Cohorts 1/2 was: sensitivity (16%/17.5%) and specificity (100%/98.1%). We show that IgG detection alone is insufficient for the diagnosis of active or cured COVID-19. IgM detection has a limited diagnostic value.

Invasive fungal infections (IFIs) are an important cause of morbidity and mortality. Isavuconazole (BAL4815) is a promising novel broad-spectrum triazole in late-stage clinical development that has proven to be active against , and , the most common agents of IFIs. Furthermore, isavuconazole has a pharmacokinetic profile that allows oral and intravenous administration with no severe toxicity. data from animal models are also encouraging. However, very little information on clinical efficacy is available. Four clinical trials are currently in progress to demonstrate the safety and efficacy of isavuconazole for the treatment and prevention of IFIs. In the absence of clinical and cost data, the real possibilities of this agent as a competitor for the treatment and prevention of IFIs in the clinical setting are still unknown.

Since its inception in 2002, the EUCAST Antifungal Susceptibility Testing Subcommittee (AFST) has developed and refined susceptibility testing methods for yeast, moulds and dermatophytes, and established epidemiological cut-off values and breakpoints for antifungals. For yeast, three challenges have been addressed. Interpretation of trailing growth in fluconazole susceptibility testing, which has been proven without impact on efficacy if below the 50% endpoint. Variability in rezafungin MIC testing due to laboratory conditions, which has been solved by the addition of Tween 20 to the growth medium in E.Def 7.4. And third, interpretation of MICs for rare yeast with no breakpoints, where recommendations have been established for MIC-based clinical advice. For moulds, refinements include the validation of spectrophotometer reading for A. fumigatus to facilitate objective MIC determination, and for dermatophytes the establishment of a microdilution method with automated reading and a selective medium to minimise the risk of contaminations. Recent initiatives involve development and validation of agar-based screening assays for detection of potential azole and echinocandin resistance in A. fumigatus and Aspergillus species, respectively, and of terbinafine resistance in Trichophyton species. Moreover, the development of a EUCAST guidance document for molecular resistance testing represents an advancement, particularly for identifying target gene alterations associated with resistance. In summary, EUCAST AFST continues to play a pivotal role in standardizing AFST and facilitating accurate interpretation of susceptibility data for clinical decision-making. Adoption of EUCAST breakpoints for commercial test methods, however, requires thorough validation to ensure concordance with EUCAST reference testing species-specific MIC distributions.