Suspension of Arthroderma and Trichophyton species in RPMI-1640 medium provided long-term viability at room temperature

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Time-Kill Kinetics and In Vitro Antifungal Susceptibility of Non-fumigatus Aspergillus Species Isolated from Patients with Ocular Mycoses

Aspergillus species can cause ocular morbidity and blindness, and thus, appropriate antifungal therapy is needed. We investigated the in vitro activity of itraconazole, voriconazole, posaconazole, caspofungin, anidulafungin, and amphotericin B against 14 Aspergillus isolates obtained from patients with ocular mycoses, using the CLSI reference broth microdilution methodology. In addition, time-kill assays were performed, exposing each isolate separately to 1-, 4-, and 16-fold concentrations above the minimum inhibitory concentration (MIC) of each antifungal agent. A sigmoid maximum-effect (Emax) model was used to fit the time-kill curve data. The drug effect was further evaluated by measuring an increase/decrease in the killing rate of the tested isolates. The MICs of amphotericin B, itraconazole, voriconazole, and posaconazole were 0.5–1.0, 1.0, 0.5–1.0, and 0.25 µg/ml for A. brasiliensis, A. niger, and A. tubingensis isolates, respectively, and 2.0–4.0, 0.5, 1.0 for A. flavus, and 0.12–0.25 µg/ml for A. nomius isolates, respectively. A. calidoustus had the highest MIC range for the azoles (4.0–16.0 µg/ml) among all isolates tested. The minimum effective concentrations of caspofungin and anidulafungin were ≤0.03–0.5 µg/ml and ≤0.03 µg/ml for all isolates, respectively. Posaconazole demonstrated maximal killing rates (Emax = 0.63 h−1, r2 = 0.71) against 14 ocular Aspergillus isolates, followed by amphotericin B (Emax = 0.39 h−1, r2 = 0.87), voriconazole (Emax = 0.35 h−1, r2 = 0.098), and itraconazole (Emax = 0.01 h−1, r2 = 0.98). Overall, the antifungal susceptibility of the non-fumigatusAspergillus isolates tested was species and antifungal agent dependent. Analysis of the kinetic growth assays, along with consideration of the killing rates, revealed that posaconazole was the most effective antifungal against all of the isolates

Worldwide emergence of fluconazole-resistant Candida parapsilosis: current framework and future research roadmap

Candida parapsilosis is one of the most commen causes of life-threatening candidaemia, particularly in premature neonates, individuals with cancer of the haematopoietic system, and recipients of organ transplants. Historically, drug-susceptible strains have been linked to clonal outbreaks. However, worldwide studies started since 2018 have reported severe outbreaks among adults caused by fluconazole-resistant strains. Outbreaks caused by fluconazoleresistant strains are associated with high mortality rates and can persist despite strict infection control strategies. The emergence of resistance threatens the efficacy of azoles, which is the most widely used class of antifungals and the only available oral treatment option for candidaemia. The fact that most patients infected with fluconazole-resistant strains are azole-naive underscores the high potential adaptability of fluconazole-resistant strains to diverse hosts, environmental niches, and reservoirs. Another concern is the multidrug-resistant and echinocandin-tolerant C parapsilosis isolates, which emerged in 2020. Raising awareness, establishing effective clinical interventions, and understanding the biology and pathogenesis of fluconazole-resistant C parapsilosis are urgently needed to improve treatment strategies and outcomes.CJN is a cofounder of BioSynesis, a company developing diagnostics and therapeutics for biofilm infections. MH reports grants and research funding from Astellas Pharma, Gilead Sciences, MSD, Pfizer, Euroimmun, F2G, Pulmocide, IMMY, Mundipharma, and Scynexis, outside the submitted work. TG acknowledges support from the Spanish Ministry of Science and Innovation (PID2021–126067NB-I00), cofounded by European Regional Development Fund, the Catalan Research Agency (AGAUR) SGR423, the European Union's Horizon 2020 research and innovation programme (ERC-2016–724173); the Gordon and Betty Moore Foundation (GBMF9742), the La Caixa foundation (LCF/PR/HR21/00737), and the Instituto de Salud Carlos III (IMPACT Grant IMP/00019, and CIBERINFEC CB21/13/00061- ISCIII-SGEFI/ERDF). BZ acknowledges support from the National Key Research and Development Program of China 2021YFA0911300. All other authors declare no competing interests.Peer Reviewed"Article signat per 15 autors/es: Farnaz Daneshnia, João N de Almeida Júnior, Prof Macit Ilkit, Lisa Lombardi, Austin M Perry, Marilyn Gao, Clarissa J Nobile, Matthias Egger, Prof David S Perlin, Bing Zhai, Prof Tobias M Hohl, Prof Toni Gabaldón, Prof Arnaldo Lopes Colombo, Prof Martin Hoenigl, Amir Arastehfar"Postprint (published version

Species Distinction in the Trichophyton rubrum Complex

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Antifungal susceptibility, genotyping, resistance mechanism, and clinical profile of <i>Candida tropicalis</i> blood isolates

Candida tropicalis is one of the major candidaemia agents, associated with the highest mortality rates among Candida species, and developing resistance to azoles. Little is known about the molecular mechanisms of azole resistance, genotypic diversity, and the clinical background of C. tropicalis infections. Consequently, this study was designed to address those questions. Sixty-four C. tropicalis bloodstream isolates from 62 patients from three cities in Iran (2014-2019) were analyzed. Strain identification, antifungal susceptibility testing, and genotypic diversity analysis were performed by MALDI-TOF MS, CLSI-M27 A3/S4 protocol, and amplified fragment length polymorphism (AFLP) fingerprinting, respectively. Genes related to drug resistance (ERG11, MRR1, TAC1, UPC2, and FKS1 hotspot9s) were sequenced. The overall mortality rate was 59.6% (37/62). Strains were resistant to micafungin [minimum inhibitory concentration (MIC) ≥1 μg/ml, 2/64], itraconazole (MIC &gt; 0.5 μg/ml, 2/64), fluconazole (FLZ; MIC ≥ 8 μg/ml, 4/64), and voriconazole (MIC ≥ 1 μg/ml, 7/64). Pan-azole and FLZ + VRZ resistance were observed in one and two isolates, respectively, while none of the patients were exposed to azoles. MRR1 (T255P, 647S), TAC1 (N164I, R47Q), and UPC2 (T241A, Q340H, T381S) mutations were exclusively identified in FLZ-resistant isolates. AFLP fingerprinting revealed five major and seven minor genotypes; genotype G4 was predominant in all centers. The increasing number of FLZ-R C. tropicalis blood isolates and acquiring FLZ-R in FLZ-naive patients limit the efficiency of FLZ, especially in developing countries. The high mortality rate warrants reaching a consensus regarding the nosocomial mode of C. tropicalis transmission

Candidemia among iranian patients with severe COVID-19 admitted to ICUs

As a novel risk factor, COVID-19 has led to an increase in the incidence of candidemia and an elevated mortality rate. Despite being of clinical importance, there is a lack of data regarding COVID-19-associated candidemia (CAC) among Iranian patients. Therefore, in this retrospective study, we assessed CAC epidemiology in the intensive care units (ICUs) of two COVID-19 centers in Mashhad, Iran, from early November 2020 to late January 2021. Yeast isolates from patients� blood were identified by 21-plex polymerase chain reaction (PCR) and sequencing, then subjected to antifungal susceptibility testing according to the CLSI M27-A3 protocol. Among 1988 patients with COVID-19 admitted to ICUs, seven had fungemia (7/1988; 0.03), among whom six had CAC. The mortality of the limited CAC cases was high and greatly exceeded that of patients with COVID-19 but without candidemia (100 (6/6) vs. 22.7 (452/1988)). In total, nine yeast isolates were collected from patients with fungemia: five Candida albicans, three C. glabrata, and one Rhodotorula mucilaginosa. Half of the patients infected with C. albicans (2/4) were refractory to both azoles and echinocandins. The high mortality of patients with CAC, despite antifungal therapy, reflects the severity of the disease in these patients and underscores the importance of rapid diagnosis and timely initiation of antifungal treatment. © 2021 by the authors

Antifungal Activity of a Novel Triazole, Efinaconazole and Nine Comparators against 354 Molecularly Identified Aspergillus Isolates

Management of superficial aspergillosis is a major challenge owing to the frequent relapses and treatment failure, which may pose a potential risk, thereby gradually developing resistant species. Therefore, necessitating the development of new antifungals with higher potency should be considered as alternative strategies for efficient management of infections. We aimed to investigate the susceptibility of Aspergillus isolates toward a novel triazole, efinaconazole, in comparison with various classes of antifungal drugs. Antifungal susceptibility testing was performed according to the Clinical and Laboratory Standards Institute M38-A2 guidelines. Efinaconazole exhibited poor activity against mutant A. fumigatus strains, A. niger sensu stricto, and A. tubingensis with GM MIC values of 3.62, 1.62, and 2 mu g/ml, respectively; however, surprisingly, it efficiently inhibited the growth of A. terreus sensu stricto, followed by wild-type A. fumigatus and A. flavus with GM MIC values of 0.29, 0.42, and 0.52 mu g/ml, respectively. Presumably, efinaconazole is inefficient in aspergillosis treatment due to the low susceptibility of A. niger sensu stricto, A. tubingensis, and mutant A. fumigatus; however, it may be effective in treating superficial aspergillosis caused by wild-type A. fumigatus, A. terreus sensu stricto, and A. flavus. Further studies are needed to determine how these findings may translate into in vivo efficacy

Aspergillus fumigatus and aspergillosis: From basics to clinics

The airborne fungus Aspergillus fumigatus poses a serious health threat to humans by causing numerous invasive infections and a notable mortality in humans, especially in immunocompromised patients. Mould-active azoles are the frontline therapeutics employed to treat aspergillosis. The global emergence of azole-resistant A. fumigatus isolates in clinic and environment, however, notoriously limits the therapeutic options of mould-active antifungals and potentially can be attributed to a mortality rate reaching up to 100 %. Although specific mutations in CYP51A are the main cause of azole resistance, there is a new wave of azole-resistant isolates with wild-type CYP51A genotype challenging the efficacy of the current diagnostic tools. Therefore, applications of whole-genome sequencing are increasingly gaining popularity to overcome such challenges. Prominent echinocandin tolerance, as well as liver and kidney toxicity posed by amphotericin B, necessitate a continuous quest for novel antifungal drugs to combat emerging azole-resistant A. fumigatus isolates. Animal models and the tools used for genetic engineering require further refinement to facilitate a better understanding about the resistance mechanisms, virulence, and immune reactions orchestrated against A. fumigatus. This review paper comprehensively discusses the current clinical challenges caused by A. fumigatus and provides insights on how to address them.AA, RGR, and DSP were supported by NIH AI 109025. MH was supported by NIH UL1TR001442. AC was supported by the Fundação para a Ciência e a Tecnologia (FCT) (CEECIND/03628/2017 and PTDC/MED GEN/28778/2017). Additional support was provided by FCT (UIDB/50026/2020 and UIDP/50026/2020), the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (ERDF) (NORTE-01-0145-FEDER-000013 and NORTE-01-0145-FEDER-000023), the European Union's Horizon 2020 Research and Innovation programme under grant agreement no. 847507, and the “la Caixa” Foundation (ID 100010434) and FCT under the agreement LCF/PR/HP17/52190003. DJA was supported by CF Trust Strategic Research Centre TrIFIC (SRC015), Wellcome Trust Collaborative Award 219551/Z/19/Z and the NIHR Centre for Antimicrobial Optimisation.S