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Clinical Infectious Diseases : An... Dec 2015Invasive fungal infections are an important infection concern for patients with underlying immunosuppression. Antifungal therapy is a critical component of patient care,...
Invasive fungal infections are an important infection concern for patients with underlying immunosuppression. Antifungal therapy is a critical component of patient care, but therapeutic choices are limited due to few drug classes. Antifungal resistance, especially among Candida species, aggravates the problem. The echinocandin drugs (micafungin, anidulafungin, and caspofungin) are the preferred choice to treat a range of candidiasis. They target the fungal-specific enzyme glucan synthase, which is responsible for the biosynthesis of a major cell wall polymer. Therapeutic failure involves acquisition of resistance, although it is a rare event among most Candida species. However, in some settings, higher-level resistance has been reported among Candida glabrata, which is also frequently resistant to azole drugs, resulting in difficult-to-treat multidrug-resistant strains. The mechanism of echinocandin resistance involves amino acid changes in "hot spot" regions of FKS-encoded subunits of glucan synthase, which decreases the sensitivity of enzyme to drug, resulting in higher minimum inhibitory concentration values. The cellular processes promoting the formation of resistant FKS strains involve complex stress response pathways that yield a variety of adaptive compensatory genetic responses. Standardized broth microdilution techniques can be used to distinguish FKS mutant strains from wild type, but testing C. glabrata with caspofungin should be approached cautiously. Finally, clinical factors that promote echinocandin resistance include prophylaxis, host reservoirs including biofilms in the gastrointestinal tract, and intra-abdominal infections. An understanding of clinical and molecular factors that promote echinocandin resistance is critical to develop better diagnostic tools and therapeutic strategies to overcome resistance.
Topics: Anidulafungin; Antifungal Agents; Azoles; Candida; Candida glabrata; Candidiasis; Caspofungin; Drug Resistance, Multiple, Fungal; Echinocandins; Glucosyltransferases; Humans; Intraabdominal Infections; Lipopeptides; Micafungin; Mutation
PubMed: 26567278
DOI: 10.1093/cid/civ791 -
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 -
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 -
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 -
Mycopathologia Aug 2020Echinocandins are recommended for the treatment of invasive candidiasis and candidemia. However, there are few studies comparing anidulafungin and micafungin in terms of...
BACKGROUND
Echinocandins are recommended for the treatment of invasive candidiasis and candidemia. However, there are few studies comparing anidulafungin and micafungin in terms of efficacy and safety. The objective of this study was to evaluate the clinical efficacy and safety between anidulafungin and micafungin treatment for adult patients with candidemia.
METHODS
This retrospective cohort study performed on adult candidemia patients diagnosed from January 2006 through December 2018 at a tertiary medical center. The study subjects included adult patients ≥ 19 years with candidemia who were only treated with anidulafungin or micafungin for ≥ 3 days. Clinical characteristics were collected and analyzed. Hepatotoxicity was assessed according to the Common Terminology Criteria for Adverse Events Version 5.0.
RESULTS
A total of 98 patients with candidemia were treated with anidulafungin (n = 52, 53.1%) or micafungin (n = 46, 46.9%). There were no significant differences in age, sex, source of candidemia, and comorbidities between the anidulafungin and micafungin groups. Although there were more patients with abnormal baseline liver function test (LFT) in the anidulafungin group, the rate of clinical response (51.9% vs. 46.7%), mycological response (76.9% vs. 67.4%), and mortality (30-day mortality 26.9% vs. 21.7% and 90-day mortality 78.8% vs. 73.9%) was similar between the anidulafungin and micafungin groups. Also, there was no significant difference in terms of hepatotoxicity, even among the patients with abnormal baseline LFT between the two groups.
CONCLUSIONS
Our results suggest that clinical efficacy and safety may be similar between anidulafungin and micafungin treatment for adult patients with candidemia.
Topics: Aged; Anidulafungin; Antifungal Agents; Candidemia; Echinocandins; Female; Humans; Lipopeptides; Male; Micafungin; Middle Aged; Retrospective Studies
PubMed: 32705415
DOI: 10.1007/s11046-020-00471-8 -
BMC Oral Health Apr 2023Patients with advanced cancer are prone to develop different opportunistic oral infection due to anti-cancer treatment or the malignancies themselves. Studies of oral... (Observational Study)
Observational Study
BACKGROUND
Patients with advanced cancer are prone to develop different opportunistic oral infection due to anti-cancer treatment or the malignancies themselves. Studies of oral fungal samples show an increased prevalence of non-Candida albicans species in mixed oral infections with Candida albicans. Non-C. albicans and C. albicans are associated with varying degrees of resistance to azoles, which may have implications for treatment. This study aimed to assess the diversity and antifungal susceptibility of Candida species detected in the oral cavity.
METHODS
An observational study with microbiological analysis was conducted. Clinical fungal isolates were collected from patients in a hospice unit in 2014-2016. Isolates were re-grown on chromID® Candida plates in 2020. Single colony of each species was re-cultivated and prepared for biochemical identification with a VITEK2® system and verified by gene sequencing. Etest was performed on RPMI agar, and the antifungals fluconazole, amphotericin B, anidulafungin and nystatin were applied.
RESULTS
Fifty-six isolates from 45 patients were identified. Seven different Candida species and one Saccharomyces species were detected. The results of biochemical identification were confirmed with sequencing analysis. Thirty-six patients had mono infection, and nine out of 45 patients had 2-3 different species detected. Of C. albicans strains, 39 out of 40 were susceptible to fluconazole. Two non-C. albicans species were resistant to fluconazole, one to amphotericin B and three to anidulafungin.
CONCLUSION
C. albicans was the predominant species, with a high susceptibility to antifungal agents. Different Candida species occur in both mono and mixed infections. Identification and susceptibility testing may therefore lead to more effective treatment and may prevent the development of resistance among patients with advanced cancer.
TRAIL REGISTRATION
The study Oral Health in Advanced Cancer was registered at ClinicalTrials.gov (#NCT02067572) in 20/02/2014.
Topics: Humans; Candidiasis, Oral; Fluconazole; Amphotericin B; Anidulafungin; Microbial Sensitivity Tests; Antifungal Agents; Candida; Candida albicans; Neoplasms; Drug Resistance, Fungal
PubMed: 37072843
DOI: 10.1186/s12903-023-02950-y -
Pharmacokinetics of echinocandins in suspected candida peritonitis: A potential risk for resistance.International Journal of Infectious... Dec 2020A possible increase in Candida resistance, especially in Candida glabrata, has been speculated according to poor diffusion of echinocandins to peritoneal fluid.
INTRODUCTION
A possible increase in Candida resistance, especially in Candida glabrata, has been speculated according to poor diffusion of echinocandins to peritoneal fluid.
MATERIALS/METHODS
Peritoneal and serum concentrations of caspofungin, micafungin and anidulafungin were analysed in surgical patients with suspected candida peritonitis. After 4 days of starting therapy, serum and peritoneal samples (through peritoneal drainage) were obtained at baseline, 1, 6, 12 and 24 h of drug administration. Micafungin and anidulafungin concentrations were determined using high-performance liquid chromatography (HPLC/F), whereas caspofungin concentrations were established by bioassay.
RESULTS
Twenty-three critically ill patients with suspected abdominal fungal infection who were receiving an echinocandin were prospectively recruited. No specific criteria were applied to prescribe one specific echinocandin. No special clinical differences were observed among the three groups of patients. All were receiving antibiotic therapy, 80% required inotropic drugs, and fungal peritonitis was confirmed in 74% of them. The AUC (mg × h/L) obtained in serum and peritoneal fluid were: 126.84 and 34.38, 98.52 and 18.83, and 66.9 and 8.78 for anidulafungin, micafungin and caspofungin, respectively. The median concentration in peritoneal fluid ranged from 0.66 to 1.82 μg/mL for anidulafungin, 0.68-0.88 μg/mL for micafungin and 0.21-0.46 μg/mL for caspofungin.
CONCLUSION
The results showed moderate penetration of echinocandins into the peritoneal fluid of these patients. These levels are below the threshold of resistance mutant selection published by other authors. This could justify a potential risk of resistance in patients with prolonged treatment with echinocandins and suboptimal control of abdominal infection.
Topics: Adult; Anidulafungin; Antifungal Agents; Candida glabrata; Candidiasis; Caspofungin; Critical Illness; Echinocandins; Female; Humans; Male; Micafungin; Microbial Sensitivity Tests; Peritonitis; Prospective Studies
PubMed: 32937195
DOI: 10.1016/j.ijid.2020.09.019 -
Antimicrobial Agents and Chemotherapy Mar 2018We report the mutant prevention concentration (MPC) and mutant selection window (MSW) for micafungin and anidulafungin administered to treat We also determine the...
We report the mutant prevention concentration (MPC) and mutant selection window (MSW) for micafungin and anidulafungin administered to treat We also determine the mutation frequency. We studied 20 echinocandin-susceptible, fluconazole-intermediate, and wild-type isolates. Adjusted inocula were stroked directly onto Sabouraud agar plates containing different concentrations of micafungin or anidulafungin and visually inspected daily for up to 5 days of incubation. Individual colonies growing on the plates containing echinocandins at 1 mg/liter were selected for antifungal susceptibility testing. The genes of the resulting individual phenotypically resistant colonies were sequenced, and the MPC, MSW, and mutation frequency were determined. Biofilm was quantified, and the growth kinetics and virulence ( model) of the resulting individual mutant colonies were studied. For micafungin and anidulafungin, we found similar results for the MPC (0.06 to 2 mg/liter and 0.25 to 2 mg/liter, respectively), MSW (0.015 to 2 mg/liter for both echinocandins), and mutation frequency (3.7 × 10 and 2.8 × 10, respectively). A total of 12 isolates were able to grow at 1 mg/liter on echinocandin-containing plates, yielding a total of 32 phenotypically resistant colonies; however, mutations (ΔF658, S663P, W715L, and E655A) were observed only in 21 colonies. We did not find differences in biofilm formation, the kinetic parameters studied, or the median survival of larvae infected by wild-type isolates and the resulting individual mutant colonies. Echinocandin concentrations lower than 2 mg/liter can lead to selection of resistance mutations in isolates .
Topics: Anidulafungin; Antifungal Agents; Candida glabrata; Drug Resistance, Fungal; Echinocandins; Humans; Micafungin; Mutation
PubMed: 29311063
DOI: 10.1128/AAC.01982-17 -
Antimicrobial Agents and Chemotherapy Mar 2021A total of 15 isolates from the SENTRY antimicrobial surveillance program between 2006 and 2019 were combined with 21 isolates from other collections for the evaluation...
Evaluation of Synergistic Activity of Isavuconazole or Voriconazole plus Anidulafungin and the Occurrence and Genetic Characterization of Candida auris Detected in a Surveillance Program.
A total of 15 isolates from the SENTRY antimicrobial surveillance program between 2006 and 2019 were combined with 21 isolates from other collections for the evaluation of antifungal susceptibility and synergy against anidulafungin plus voriconazole or isavuconazole using the checkerboard method. Surveillance isolates were analyzed for genetic relatedness and resistance mechanisms. Applying the tentative statistical epidemiological cutoff values and the Centers for Disease Control tentative breakpoints, 32/36 isolates were resistant to fluconazole, 5/36 were resistant to amphotericin B, 5/36 were non-wild-type (NWT) to anidulafungin, 3/36 were NWT to micafungin, and 1/36 and 10/36 were NWT to isavuconazole and voriconazole, respectively. Of these, 10 isolates were multidrug resistant, which means that these isolates were resistant to 2 antifungal classes. Synergy or partial synergy was noted in 5/36 and 22/36, respectively, of the isolates with the combination of anidulafungin plus voriconazole, and 11/36 and 19/36 isolates, respectively, for the combination of anidulafungin plus isavuconazole. Multilocus sequence type (MLST) analysis of the 15 SENTRY isolates demonstrated that the isolates from the US were genetically related to, but different from, isolates from Latin America (Panama and Colombia) and Germany. Single nucleotide polymorphism (SNP) analysis showed that the 15 SENTRY isolates belonged to the described international clades and had associated Erg11 alterations, including 11 isolates displaying K143R, one displaying F126L, and one displaying Y501H alterations and a fluconazole MIC result of ≥64 mg/liter. Resistance mechanisms were not observed in the two isolates displaying fluconazole MIC values at 4 and 16 mg/liter. Isavuconazole displayed activity and greater synergy when tested with anidulafungin than seen with anidulafungin plus voriconazole against the clinical isolates that displayed resistance phenotypes.
Topics: Anidulafungin; Antifungal Agents; Candida; Colombia; Drug Resistance, Fungal; Drug Synergism; Echinocandins; Germany; Microbial Sensitivity Tests; Multilocus Sequence Typing; Nitriles; Pyridines; Triazoles; Voriconazole
PubMed: 33431416
DOI: 10.1128/AAC.02031-20