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
New antifungal agents are needed to overcome limitations of available ones such as poor pharmacokinetic traits, toxicity, drug-drug interactions, limited clinical efficacy, and emerging antifungal ...resistance. New antifungal drugs belong to well-known families (azoles, polyenes, or beta-d-glucan synthase inhibitors) or to drug families showing completely new mechanisms of action. Some drugs have a head start in terms of potential to reach the clinical setting and are here reviewed.
To describe the epidemiology, strategies for early detection, and clinical management of infections caused by the most commonly found multidrug-resistant (MDR) Candida spp.
Increasing numbers of ...reports describing invasive infections by MDR Candida auris and Candida glabrata has been reported in medical centers worldwide.
We checked all papers published along the last 10 years describing epidemiological, diagnostic, and clinical aspects of infections by MDR Candida spp., with emphasis on C. auris and C. glabrata spp. C. auris has been reported in 15 countries and multidrug resistance rates is usually above 30%. Horizontal transmission is a great concern regarding C. auris. C. glabrata ranks the second most reported Candida spp. in deep-seated infections from United States and some European Centers, although multidrug resistance rates above 10% are restricted to some US centers. Candida haemulonii complex isolates with poor susceptibility to azoles and amphotericin B have been isolated in superficial and deep-seated infections, whereas Candida guilliiermondii complex isolates with poor susceptibility to azoles and echinocandins have been recovered from catheter-related bloodstream infections. Other potential MDR Candida species are Candida krusei, Candida lusitaniae, Candida kefyr, Yarrowia (Candida) lypolitica, and Candida rugosa.
Previous studies show high agreement between MIC spectrophotometric readings and visual inspection of azoles and amphotericin B against Aspergillus fumigatus isolates. Here, we tested and compared ...the
activity of a novel antifungal, olorofim, against Aspergillus spp.,
spp., and Lomentospora prolificans by visual inspection and spectrophotometric readings. Clinical isolates of Aspergillus (
= 686) and
(
= 36) spp. and
(
= 13) were tested. Olorofim MICs were evaluated-following the EUCAST E.Def 9.4 procedure-by visual inspection or spectrophotometric readings (combinations of either ≥90% or ≥95% fungal growth inhibition endpoints compared to drug-free control endpoints and different wavelengths 405 nm, 450 nm, 492 nm, 540 nm, and 620 nm). We observed high
activity of olorofim against all tested Aspergillus spp. (MICs up to 0.06 mg/L), except for A. calidoustus, and against
and
spp. (MICs up to 0.125 mg/L). The combination of ≥90% fungal growth inhibition endpoints at wavelengths of ≥492 nm resulted in high essential agreements with A. fumigatus and lesser agreement with non-
Aspergillus,
spp., and
, although the number of isolates studied was low. This single-center study shows high agreement among olorofim MICs against A. fumigatus by visual inspection and spectrophotometric readings (≥90% fungal growth inhibition endpoints and wavelengths of ≥492 nm) and encouraging results against non-
Aspergillus spp.,
spp., and
.
Abstract Biofilm production in Candida spp. can be studied by measuring the biomass produced after application of crystal violet stain or by measuring metabolic activity with XTT. Our study is the ...first in which crystal violet and XTT are compared to analyze the ability of clinically relevant Candida and non- Candida species to produce biofilm. We studied 577 isolates causing fungemia in 512 patients admitted from January 2007 to July 2013. Based on the biomass production measured by crystal violet and the metabolic activity measured by XTT, strains were divided into terciles to establish tentative cut-offs to classify isolates as being low, moderate, or high biofilm-forming and as having low, moderate, or high metabolic activity. Considerable variability in biofilm production and metabolic activity was found both between species and within species. C. tropicalis showed the highest biomass production, whereas C. glabrata showed the highest metabolic activity, and non- Candida species isolates showed the lowest metabolic activity ( P < 0.0023). The isolates were classified as low metabolic activity, moderate metabolic activity, and high metabolic activity according to their cut-offs by XTT (<0.097, 0.097–0.2, and >0.2) and as low biofilm-forming, moderate biofilm-forming, and high biofilm-forming according to their cut-offs by crystal violet (<0.44, 0.44–1.17, and >1.17). The overall categorical agreement between the procedures was 43.7%, which increased to >50% for C. albicans and C. parapsilosis . XTT and crystal violet are complementary procedures for the study of biofilm production.
New antifungal drugs, such as olorofim, may overcome the problem of resistance in Aspergillus fumigatus. We here report the activity of olorofim against a set of A. fumigatus sensu lato recently ...collected in Spain.
A total of 332 A. fumigatus sensu lato clinical isolates collected in a multicentre study conducted in Spain in 2019 and comprising susceptible and resistant isolates to azoles and/or amphotericin B were tested. Isolates distributed among the following species: A. fumigatus sensu stricto (n = 312), Aspergillus lentulus (n = 6), Aspergillus fumigatiaffinis (n = 5), Neosartorya tsurutae (n = 3), Neosartorya udagawae (n = 3), Aspergillus novofumigatus (n = 2), and Aspergillus thermomutatus (n = 1). Azole resistance was found in 44 A. fumigatus sensu stricto isolates that harboured the following cyp51A gene substitutions: TR34-L98H (n = 24), G54 (n = 5), TR46/Y121F/T289A (n = 1), other mutations (n = 4), and gene wild type (n = 10). Isolates were tested for antifungal susceptibility to olorofim using European Committee on Antimicrobial Susceptibility Testing (EUCAST) E.Def. 9.4 methodology.
Olorofim minimum inhibitory concentrations against A. fumigatus sensu stricto isolates ranged from 0.008 to 0.125 mg/L and in vitro activity of the drug was not impacted by the presence of azole/amphotericin B resistance. Azole resistance and amphotericin B resistance was found in 18 and 13 cryptic species isolates, respectively. Olorofim showed high in vitro activity against cryptic species isolates and minimum inhibitory concentrations ranged from 0.004 to 0.016 mg/L, regardless of the presence of resistance to other drugs.
Olorofim showed in vitro activity against both A. fumigatus sensu stricto and cryptic species clinical isolates and was active against isolates showing resistance to azoles and/or amphotericin B.
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We conducted an updated analysis on yeast isolates causing fungemia in patients admitted to a tertiary hospital in Madrid, Spain, over a 13-year period. We studied 896 isolates associated with 872 ...episodes of fungemia in 857 hospitalized patients between January 2007 and December 2019. Antifungal susceptibility was assessed by EUCAST EDef 7.3.2. Mutations conferring azole and echinocandin resistance were further studied, and genotyping of resistant clones was performed with species-specific microsatellite markers.
(45.8%) was the most frequently identified species, followed by the
complex (26.4%),
(12.3%),
(7.3%),
(2.3%), other
spp. (3.1%), and non-
yeasts (2.8%). The rate of fluconazole resistance in
spp. was 4.7%, ranging from 0% (
) to 9.1% (
). The overall rate of echinocandin resistance was 3.1%. Resistance was highly influenced by the presence of intrinsically resistant species. Although the number of isolates between 2007 and 2013 was almost 2-fold higher than that in the period from 2014 to 2019 (566 versus 330), fluconazole resistance in
spp. was greater in the second period (3.5% versus 6.8%;
0.05), while overall resistance to echinocandins remained stable (3.5% versus 2.4%;
0.05). Resistant clones were collected from different wards and/or time points, suggesting that there were no epidemiological links. The number of fungemia episodes has been decreasing over the last 13 years, with a slight increase in the rate of fluconazole resistance and stable echinocandin resistance. Antifungal resistance is not the cause of the spread of resistant clones.
Objectives
Information on the recently COVID‐19‐associated pulmonary aspergillosis (CAPA) entity is scarce. We describe eight CAPA patients, compare them to colonised ICU patients with coronavirus ...disease 2019 (COVID‐19), and review the published literature from Western countries.
Methods
Prospective study (March to May, 2020) that included all COVID‐19 patients admitted to a tertiary hospital. Modified AspICU and European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria were used.
Results
COVID‐19‐associated pulmonary aspergillosis was diagnosed in eight patients (3.3% of 239 ICU patients), mostly affected non‐immunocompromised patients (75%) with severe acute respiratory distress syndrome (ARDS) receiving corticosteroids. Diagnosis was established after a median of 15 days under mechanical ventilation. Bronchoalveolar lavage was performed in two patients with positive Aspergillus fumigatus cultures and galactomannan (GM) index. Serum GM was positive in 4/8 (50%). Thoracic CT scan findings fulfilled EORTC/MSG criteria in one case. Isavuconazole was used in 4/8 cases. CAPA‐related mortality was 100% (8/8). Compared with colonised patients, CAPA subjects were administered tocilizumab more often (100% vs. 40%, p = .04), underwent longer courses of antibacterial therapy (13 vs. 5 days, p = .008), and had a higher all‐cause mortality (100% vs. 40%, p = .04). We reviewed 96 similar cases from recent publications: 59 probable CAPA (also putative according modified AspICU), 56 putative cases and 13 colonisations according AspICU algorithm; according EORTC/MSG six proven and two probable. Overall, mortality in the reviewed series was 56.3%.
Conclusions
COVID‐19‐associated pulmonary aspergillosis must be considered a serious and potentially life‐threatening complication in patients with severe COVID‐19 receiving immunosuppressive treatment.
Abstract
We compared the antifungal susceptibility of 92 Mucorales isolates obtained by visual inspection and spectrophotometric readings following EUCAST (European Committee on Antimicrobial ...Susceptibility Testing) testing. Amphotericin B minimum inhibitory concentrations (MICs) were up to 1 mg/l against most isolates and variable among species, except for Cunninghamella bertholletiae. Posaconazole MICs against most isolates were up to 1 mg/l and high against Mucor circinelloides, some Rhizopus arrhizus, and Rhizopus microsporus. Isavuconazole MICs ranged between 1 and 8 mg/l but were invariably >8 mg/l against M. circinelloides and C. bertholletiae. The agreement between MICs obtained by visual endpoint or spectrophotometric readings was moderate and higher when using the ≥90% fungal growth inhibition endpoint.
Lay Summary
The agreement between minimum inhibitory concentration (MIC) values obtained by visual inspection or spectrophotometric readings was moderate and higher when the ≥90% fungal growth inhibition endpoint was chosen. Isavuconazole presented higher MICs than posaconazole, regardless of the inhibition endpoint used.
Ibrexafungerp is a new oral glucan synthase inhibitor with in vivo and in vitro activity against Candida spp., including echinocandin- and azole-resistant isolates. We studied the in vitro activity ...of ibrexafungerp against Candida species isolated from blood cultures and assessed wild-type upper limits against the five Candida species most frequently associated to candidaemia.
Isolates (n = 958) causing incident episodes of candidaemia in patients admitted to Gregorio Marañón hospital (Madrid, Spain) between January 2007 and April 2021 were studied. Antifungal susceptibility to ibrexafungerp, fluconazole, micafungin and anidulafungin was tested (EUCAST E.Def 7.3.2) and wild-type upper limits determined against C. albicans (n = 462), C. glabrata (n = 120), C. parapsilosis (n = 249), C. tropicalis (n = 73) and C. krusei (n = 24). fksgene sequencing was carried out in non-wild-type isolates.
Ibrexafungerp showed antifungal in vitro activity against the studied isolates. Wild-type upper limits for ibrexafungerp were >0.25 mg/L against C. albicans, >1 mg/L against C. parapsilosis, C. glabrata, and C. tropicalis, and >2 mg/L against C. krusei. Percentages of ibrexafungerp non-wild-type isolates were low (C. parapsilosis and C. krusei, 0%; C. albicans, 0.22% (1/462); C. glabrata, 0.83% (1/120); and C. tropicalis, 1.37% (1/73)). Ibrexafungerp proved in vitro activity against fluconazole- or echinocandin-resistant isolates.
We show in vitro activity of ibrexafungerp against the tested Candida species. Furthermore, we provide ibrexafungerp wild-type upper limits, which allows defining the wild-type populations of the five most relevant Candida species.
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