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Microbiology Spectrum Dec 2022To understand the changes of resistance in clinically commonly encountered fungi, we used the Antimicrobial Testing Leadership and Surveillance (ATLAS) database to...
Susceptibilities of Worldwide Isolates of Intrapulmonary Species and Important Species in Sterile Body Sites against Important Antifungals: Data from the Antimicrobial Testing Leadership and Surveillance Program, 2017-2020.
To understand the changes of resistance in clinically commonly encountered fungi, we used the Antimicrobial Testing Leadership and Surveillance (ATLAS) database to explore antifungal susceptibilities against clinically important isolates of and species (collected from intrapulmonary and sterile body areas, respectively). We applied the CLSI antifungal 2020 and the EUCAST antifungal 2020 guidelines. From 2017 to 2020, isolates of intrapulmonary Aspergillus fumigatus ( = 660), Aspergillus niger ( = 107), Aspergillus flavus ( = 96), Aspergillus terreus ( = 40), and Aspergillus nidulans species complex ( = 26) and sterile site-originated isolates of Candida albicans ( = 1,810), Candida glabrata ( = 894), Candida krusei ( = 120), Candida dubliniensis ( = 107), Candida lusitaniae ( = 82), Candida guilliermondii ( = 28), and Candida auris ( = 7) were enrolled in this study. Using the EUCAST 2020 breakpoints, it was demonstrated that amphotericin B and posaconazole displayed poor susceptibility rates against A. fumigatus isolates (<50% and 18.9%, respectively). In contrast, isavuconazole and itraconazole showed high potency against most isolates (>92%). Most intrapulmonary isolates exhibited MICs of ≤0.06 μg/mL to anidulafungin. Furthermore, intrapulmonary A. fumigatus isolates collected from Italy and the United Kingdom exhibited lower susceptibility to isavuconazole (72.2% and 69%, respectively) than those in the remaining ATLAS participant countries (>85%). Higher isavuconazole MICs against C. auris and C. guilliermondii (1 and 4 μg/mL, respectively) were observed compared to the other five species. Despite the aforementioned MICs and susceptibilities against fungi, research needs to consider the pharmacokinetic (PK) profiles, pharmacodynamic (PD) parameters, and clinical treatment experience with antifungals against specific species. In addition to monitoring the antifungal susceptibilities of clinically important fungi, reviewing the PK/PD indices and the clinical therapy experience of antifungals under evaluation are important to guide an appropriate antifungal prescription. The efficacies of liposomal amphotericin B complex and anidulafungin for the treatment of pulmonary aspergillosis caused by different species need to be periodically evaluated in the future.
Topics: Anidulafungin; Antifungal Agents; Aspergillus; Candida; Drug Resistance, Fungal; Microbial Sensitivity Tests
PubMed: 36314941
DOI: 10.1128/spectrum.02965-22 -
Antimicrobial Agents and Chemotherapy Aug 2019Echinocandins (caspofungin, micafungin, anidulafungin), targeting β-1,3-glucan synthesis of the cell wall, represent one of the three currently available antifungal... (Review)
Review
Echinocandins (caspofungin, micafungin, anidulafungin), targeting β-1,3-glucan synthesis of the cell wall, represent one of the three currently available antifungal drug classes for the treatment of invasive fungal infections. Despite their limited antifungal activity against spp., echinocandins are considered an alternative option for the treatment of invasive aspergillosis (IA). This drug class exhibits several advantages, such as excellent tolerability and its potential for synergistic interactions with some other antifungals. The objective of this review is to discuss the and clinical efficacy of echinocandins against spp., considering the complex interactions between the drug, the mold, and the host. The antifungal effect of echinocandins is not limited to direct inhibition of hyphal growth but also induces an immunomodulatory effect on the host's response. Moreover, spp. have developed important adaptive mechanisms of tolerance to survive and overcome the action of echinocandins, such as paradoxical growth at increased concentrations. This stress response can be abolished by several compounds that potentiate the activity of echinocandins, such as drugs targeting the heat shock protein 90 (Hsp90)-calcineurin axis, opening perspectives for adjuvant therapies. Finally, the present and future places of echinocandins as prophylaxis, monotherapy, or combination therapy of IA are discussed in view of the emergence of pan-azole resistance among isolates, the occurrence of breakthrough IA, and the advent of new long-lasting echinocandins (rezafungin) or other β-1,3-glucan synthase inhibitors (ibrexafungerp).
Topics: Antifungal Agents; Aspergillosis; Aspergillus fumigatus; Echinocandins; HSP90 Heat-Shock Proteins; Host-Pathogen Interactions; Humans; Invasive Fungal Infections
PubMed: 31138565
DOI: 10.1128/AAC.00399-19 -
Brazilian Journal of Microbiology :... Dec 2022Meyerozyma guilliermondii has been accepted as a complex composed of Meyerozyma guilliermondii, Meyerozyma carpophila, and Meyerozyma caribbica. M. guilliermondii is a... (Review)
Review
Meyerozyma guilliermondii has been accepted as a complex composed of Meyerozyma guilliermondii, Meyerozyma carpophila, and Meyerozyma caribbica. M. guilliermondii is a saprophyte detected on human mucosa and skin. It can lead to serious infections in patients with risk factors like chemotherapy, immunodeficiency, gastrointestinal or cardiovascular surgery, and oncology disorders. Most deaths related to M. guilliermondii infections occur in individuals with malignancy. In recent decades, incidence of M. guilliermondii infections is increased. Sensitivity of this microorganism to conventional antifungals (e.g., amphotericin B, fluconazole, micafungin and anidulafungin) was reduced. Prophylactic and empirical uses of these drugs are linked to elevated minimal inhibitory concentrations (MICs) of M. guilliermondii. Drug resistance has concerned many researchers across the world. They are attempting to discover appropriate solution to combat this challenge. This study reviews the most important mechanisms of resistance to antifungals developed by in M. guilliermondii species complex.
Topics: Humans; Antifungal Agents; Drug Resistance, Fungal; Fluconazole; Amphotericin B; Microbial Sensitivity Tests
PubMed: 36306113
DOI: 10.1007/s42770-022-00813-2 -
A Pragmatic Approach to Susceptibility Classification of Yeasts without EUCAST Clinical Breakpoints.Journal of Fungi (Basel, Switzerland) Jan 2022EUCAST has established clinical breakpoints for the six most common species and but not for less common yeasts because sufficient evidence is lacking. Consequently,... (Review)
Review
EUCAST has established clinical breakpoints for the six most common species and 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.
PubMed: 35205895
DOI: 10.3390/jof8020141 -
Journal of Fungi (Basel, Switzerland) Oct 2021has emerged globally as a multi-drug resistant yeast and is commonly associated with nosocomial outbreaks in ICUs. We conducted a retrospective observational...
has emerged globally as a multi-drug resistant yeast and is commonly associated with nosocomial outbreaks in ICUs. We conducted a retrospective observational multicentre study to determine the epidemiology of infections, its management strategies, patient outcomes, and infection prevention and control practices across 10 centres from five countries. Significant risk factors for infection include the age group of 61-70 years (39%), recent history of ICU admission (63%), diabetes (63%), renal failure (52%), presence of CVC (91%) and previous history of antibiotic treatment (96%). was commonly isolated from blood (76%). Echinocandins were the most sensitive drugs. Most common antifungals used for treatment were caspofungin (40%), anidulafungin (28%) and micafungin (15%). The median duration of treatment was 20 days. Source removal was conductedin 74% patients. All-cause crude mortality rate after 30 days was 37%. Antifungal therapy was associated with a reduction in mortality (OR:0.27) and so was source removal (OR:0.74). Contact isolation precautions were followed in 87% patients. infection carries a high risk for associated mortality. The organism is mainly resistant to most azoles and even amphotericin-B. Targeted antifungal therapy, mainly an echinocandin, and source control are the prominent therapeutic approaches.
PubMed: 34682299
DOI: 10.3390/jof7100878 -
Medical Mycology Jul 2023In vitro interactions between tacrolimus, a calcineurin inhibitor, and fluconazole, itraconazole, caspofungin, or anidulafungin were evaluated against Candida auris, C....
In vitro interactions between tacrolimus, a calcineurin inhibitor, and fluconazole, itraconazole, caspofungin, or anidulafungin were evaluated against Candida auris, C. albicans, C. parapsilosis, and C. glabrata (each five strains). Tacrolimus-itraconazole, tacrolimus-caspofungin, and tacrolimus-fluconazole combinations resulted in synergistic interactions against 95%, 90%, and 60% of Candida isolates, respectively. However, tacrolimus-anidulafungin resulted in only a 35% synergistic effect. A combination of tacrolimus and itraconazole was most potent with synergy against 100% of C. auris, C. parapsilosis, and C. glabrata isolates. Of note, no antagonistic interaction was found.
Topics: Animals; Antifungal Agents; Candida; Tacrolimus; Fluconazole; Candida auris; Caspofungin; Anidulafungin; Itraconazole; Echinocandins; Candida glabrata; Candida parapsilosis; Microbial Sensitivity Tests
PubMed: 37437917
DOI: 10.1093/mmy/myad069 -
Medizinische Klinik, Intensivmedizin... Sep 2023Invasive fungal infections caused by Candida or Aspergillus are associated with a high mortality. Knowledge about the risk factors, diagnosis and treatment management... (Review)
Review
BACKGROUND
Invasive fungal infections caused by Candida or Aspergillus are associated with a high mortality. Knowledge about the risk factors, diagnosis and treatment management is crucial for improving the survival of those affected.
OBJECTIVE
To give a practical overview about risk factors and treatment management of Candida and Aspergillus infections as well as providing an outlook on new antifungal agents.
MATERIAL AND METHODS
Summary of the relevant literature and recommendations on candidemia and invasive candidiasis as well as invasive and chronic pulmonary aspergillosis.
RESULTS
The first line treatment of candidemia and invasive candidiasis are echinocandins including caspofungin, anidulafungin and micafungin. Regular blood cultures have to be taken to determine the duration of treatment. After the first negative control blood culture treatment should be continued for another 14 days. The first line treatment of invasive pulmonary aspergillosis is azoles including voriconazole and isavuconazole. The duration of treatment depends on disease severity and is recommended for 6-12 weeks. The duration of treatment for chronic pulmonary aspergillosis is 6-12 months. Therapeutic drug monitoring is recommended for voriconazole and for posaconazole. New antifungal agents including olorofim, fosmanogepix, opelconazole, rezafungin or ibrexafungerp will broaden the therapeutic spectrum in the foreseeable future.
CONCLUSION
Knowledge about risk factors and the correct treatment management is crucial for the survival of patients with invasive fungal infections.
Topics: Humans; Antifungal Agents; Candida; Voriconazole; Candidemia; Aspergillus; Invasive Fungal Infections; Pulmonary Aspergillosis; Candidiasis, Invasive
PubMed: 37644243
DOI: 10.1007/s00063-023-01051-6 -
Microbial Biotechnology Jan 2024Invasive fungal infections have increased remarkably, which have become unprecedented concern to human health. However, the effectiveness of current antifungal drugs is... (Review)
Review
Invasive fungal infections have increased remarkably, which have become unprecedented concern to human health. However, the effectiveness of current antifungal drugs is limited due to drug resistance and toxic side-effects. It is urgently required to establish the effective biosynthetic strategy for developing novel and safe antifungal molecules economically. Echinocandins become a promising option as a mainstay family of antifungals, due to specifically targeting the fungal specific cell wall. To date, three kinds of echinocandins for caspofungin, anidulafungin, and micafungin, which derived from pneumocandin B , echinocandin B, and FR901379, are commercially available in clinic and have shown potential in managing invasive fungal infections in a cost-effective manner. However, current echinocandins-derived precursors all are produced by environmental fungal isolates with long fermentation cycle and low yields, which challenge the production efficacy of these precursors in industry. Therefore, understanding their biosynthetic machinery is of great importance for improving antifungal titres and creating new echinocandins-derived products. With the development of genome-wide sequencing and establishment of gene-editing technology, there are a growing number of reports on echinocandins-derived products and their biosynthetic gene clusters. This review briefly summarizes the discovery and development history of echinocandins, compares their structural characteristics and biosynthetic processes, and sums up existed strategies for improving their production. Moreover, the genomic analysis of related biosynthetic gene clusters of echinocandins is discussed, highlighting the similarities and differences among the clusters. Last, the biosynthetic processes of echinocandins are compared, focusing on the activation and attachment of side-chains and the formation of the hexapeptide core. This review aims to provide insights into the development and production of new echinocandin drugs by modifying the structure of echinocandin-derived precursors and/or optimizing the fermentation processes; and achieve a new microbial chassis for efficient production of echinocandins in heterologous hosts.
Topics: Humans; Antifungal Agents; Echinocandins; Fermentation; Invasive Fungal Infections; Microbial Sensitivity Tests; Lipopeptides
PubMed: 37885073
DOI: 10.1111/1751-7915.14359 -
Mycoses Jan 2023The gradual increase in caspofungin usage in Pakistan raises a concern of emergence of echinocandin resistance in local Candida glabrata strains. We sequenced and...
INTRODUCTION
The gradual increase in caspofungin usage in Pakistan raises a concern of emergence of echinocandin resistance in local Candida glabrata strains. We sequenced and determined mutations in fks1 and fks2 genes in invasive Candida glabrata strains from Pakistan.
MATERIAL AND METHODS
Thirty-six invasive C. glabrata strains were selected with median (min-max) minimum inhibitory concentrations (MICs) of 0.06 (0.015-0.25) mg/L for caspofungin, 0.015 (0.008-0.06) mg/L for micafungin and 0.06 (0.015-0.12) mg/L for anidulafungin. fks1 and fks2 gene fragments were sequenced using Sanger methodology. Sequences were analysed with MEGA-6 software to identify specific single-nucleotide polymorphisms (SNP) against wild-type sequences of C. glabrata.
RESULTS
In fks1 gene, non-synonymous mutation D632H was observed in one isolate with caspofungin MIC of 0.25 mg/L. Synonymous mutation at position A742 was observed in 26/36 (72%) of the isolates. 34/36 (94.5%) isolates analysed for fks2 gene were observed as wild type. A novel non-synonymous mutation at I661T was observed in fks2 gene in one isolate with caspofungin MIC of 0.12 mg/L and anidulafungin and micafungin MIC of 0.06 and 0.015 mg/L, respectively. Novel fks2 synonymous mutations at position T647, K652 and I706 were observed in 16/36 (44%), 25/36 (69%) and 23/36 (63%) isolates, respectively.
CONCLUSION
Low frequencies of both non-synonymous and synonymous polymorphisms were observed in invasive C. glabrata strains. Since S663P in fks2 gene is associated with caspofungin resistance, a novel mutation at 661 codon identified in our study needs correlation with treatment outcome data and mandates periodic genomic surveillance.
Topics: Humans; Candida glabrata; Micafungin; Anidulafungin; Caspofungin; Pakistan; Antifungal Agents; Glucosyltransferases; Fungal Proteins; Echinocandins; Microbial Sensitivity Tests; Mutation; Drug Resistance, Fungal
PubMed: 36106428
DOI: 10.1111/myc.13527 -
Journal of Fungi (Basel, Switzerland) Nov 2020Rezafungin (formerly CD101) is a new β-glucan synthase inhibitor that is chemically related with anidulafungin. It is considered the first molecule of the new... (Review)
Review
Rezafungin (formerly CD101) is a new β-glucan synthase inhibitor that is chemically related with anidulafungin. It is considered the first molecule of the new generation of long-acting echinocandins. It has several advantages over the already approved by the Food and Drug Administration (FDA) echinocandins as it has better tissue penetration, better pharmacokinetic/phamacodynamic (PK/PD) pharmacometrics, and a good safety profile. It is much more stable in solution than the older echinocandins, making it more flexible in terms of dosing, storage, and manufacturing. These properties would allow rezafungin to be administered once-weekly (intravenous) and to be potentially administered topically and subcutaneously. In addition, higher dose regimens were tested with no evidence of toxic effect. This will eventually prevent (or reduce) the selection of resistant strains. Rezafungin also has several similarities with older echinocandins as they share the same in vitro behavior (very similar Minimum Inhibitory Concentration required to inhibit the growth of 50% of the isolates (MIC) and half enzyme maximal inhibitory concentration 50% (IC)) and spectrum, the same target, and the same mechanisms of resistance. The selection of mutants occurred at similar frequency for rezafungin than for anidulafungin and caspofungin. In this review, rezafungin mechanism of action, target, mechanism of resistance, and in vitro data are described in a comparative manner with the already approved echinocandins.
PubMed: 33139650
DOI: 10.3390/jof6040262