SciCombinator

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Concept: Triazole

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The migrations of different groups to the metal-carbene center of Rh(II) -stabilized iminocarbenes that were derived from N-sulfonyl triazoles are discussed. The reactivity of these Rh-iminocabenes can be tuned easily by variation of substituents in the parent triazole.

Concepts: Fluconazole, Triazole, Triazoles

28

We aim in this study to provide levels of susceptibility of 162 bloodstream isolates of non-Candida albicans and non-C. tropicalis species from a sentinel program conducted in 11 hospitals in Brazil. Additionally, we compared the broth microdilution (BMD) method of the European Committee of Susceptibility Testing (EUCAST) with Clinical Laboratory Standards Institute (CLSI) BMD method for fluconazole, itraconazole, voriconazole, and amphotericin B. The study included 103 C. parapsilosis, 38 C. glabrata, 8 C. orthopsilosis, and 7 C. krusei isolates, and single isolates of Pichia anomala, C. famata, C. lusitaniae, C. kefyr, C. guilliermondii, and C. metapsilosis. Of note, we observed cross-resistance between fluconazole and voriconazole for two isolates being one C. parapsilosis and one C. glabrata. Good essential agreement (EA) was observed between the EUCAST and the CLSI results for C. parapsilosis and for fluconazole, itraconazole, voriconazole, and amphotericin B, respectively: 98%, 99%, 98%, and 97%. Otherwise, for C. glabrata, the EA for fluconazole was 84.2% and for voriconazole 89.4%. Because data from Brazil are scarce, our results contribute to the consolidation of the database of candidemia agents and monitoring of trends in the profile of drug resistance.

Concepts: Laboratory, Amphotericin B, The Europeans, Antifungals, Candidiasis, Ergosterol, Triazole, World Health Organization essential medicines

2

Isavuconazole is a new extended spectrum triazole with activity against yeasts, molds, and dimorphic fungi. It is approved for the treatment of invasive aspergillosis and mucormycosis. Advantages of this triazole include the availability of a water-soluble IV formulation, excellent bioavailability of the oral formulation, and predictable pharmacokinetics in adults. A randomized, double-blind comparison clinical trial for treatment of invasive aspergillosis found that the efficacy of isavuconazole was non-inferior to that of voriconazole. An open-label trial that studied primary, as well as salvage therapy of invasive mucormycosis showed efficacy with isavuconazole that was similar to that reported for amphotericin B and posaconazole. In patients in these studies, as well as in normal volunteers, isavuconazole was well tolerated, appeared to have few serious adverse effects, and had fewer drug-drug interactions than those noted with voriconazole. As clinical experience increases, the role of this new triazole in the treatment of invasive fungal infections will be better defined.

Concepts: Pharmacology, Effectiveness, Aspergillosis, Antifungals, Flucytosine, Ergosterol, Triazole, Itraconazole

2

The in vitro activity of isavuconazole against Mucorales isolates by EUCAST E.Def 9.2 and CLSI M38-A2 methodologies was investigated in comparison with that of amphotericin B, posaconazole and voriconazole.72 isolates were included: Lichtheimia corymbifera 12, Lichtheimia ramosa 5, Mucor circinelloides (Group-I 5, Group-II 9), Rhizomucor pusillus 9, Rhizopus microsporus 26 and Rhizopus oryzae 6. Species identification was confirmed by ITS sequencing. EUCAST MICs were read day 1 (EUCAST-d1) and 2 (EUCAST-d2), CLSI MICs day 2 (CLSI-d2).Isavuconazole MIC50 (range) (mg/L) by EUCAST-d1, CLSI-d2 and EUCAST-d2 were: 1 (0.125-16); 1 (0.125-2); 4 (0.5->16) across all isolates. The similar values for comparator drugs were: posaconazole 0.25 (≤0.03->16); 0.25 (0.06->16); 1 (0.06->16), amphotericin 0.06 (≤0.03-0.5); 0.06 (≤0.03-0.25); 0.125 (≤0.03-1) and voriconazole 16 (2->16); 8 (1->16); >16 (8->16). Isavuconazole activity varied by species. Lichtheimia corymbifera 1 (0.5-2); 1 (1, 2); 2 (1-4), Lichtheimia ramosa 0.25 (0.125-0.5); 1 (0.5-2); 2 (0.5-4), Rhizomucor pusillus 0.5 (0.5-1); 1 (0.125-1); 2 (1, 2), Rhizopus microsporus 1 (0.5-4); 0.5 (0.125-1); 4 (1-8), and Rhizopus oryzae 1 (0.5-4); 1 (0.125-2); 4 (0.5-8) were more susceptible than Mucor circinelloides Group-I 8 (4-8); 4 (2-4) and 16 (2-16) and Group-II 8 (1-16); 8 (1-8); 16 (4->16). This was also observed for posaconazole. The essential agreement was best between EUCAST-d1 and CLSI-d2 (75%-83%).Isavuconazole displayed in vitro activity against Mucorales isolates with exception of Mucor circinelloides. The MICs were in general 1-3 steps higher than those for posaconazole. However, in the clinical setting this may be compensated by the higher exposure at standard dosing.

Concepts: Antifungals, Triazole, Rhizopus, Zygomycota, Rhizopus oryzae, Zygomycosis, Mucoraceae, Mucor

1

Resistance to triazoles in Aspergillus fumigatus has been reported in azole-naive patients in Europe, Asia, Australia and North America. This resistance has been linked to fungicide-driven mutations in the cyp51A gene and its promoter region. We investigated the presence of environmental azole-resistant A. fumigatus strains related to the use of azole fungicides in Colombia. Soil samples were collected from flower beds, flower fields and public gardens from the outskirts, suburbs and city centre of Bogotá. Out of the 86 soil samples taken, 17 (19.8%) grew A. fumigatus of whom eight (9.3%) contained 40 strains able to grow on azole-containing itraconazole and/or voriconazole supplemented media. All but one triazole-resistant strains were isolated from soil samples collected from flower fields and flower beds (39/40). Importantly, the majority had the TR46/Y121F/T289A, TR34/L98H, and TR53 molecular resistance mechanisms and one azole resistant strain had a wild-type cyp51A gene. Soil samples from flower fields and beds contained 4 azole fungicides (penconazole, difenoconazole, tetraconazole and tebuconazole) above the limit of detection. Our findings underline the need for extensive investigations to determine azole-resistant A. fumigatus prevalence in both clinical and environmental samples in other regions of Latin America.

Concepts: DNA, Gene, United States, Antibiotic resistance, Aspergillosis, Aspergillus, Aspergillus fumigatus, Triazole

1

Candida auris is a multidrug resistant yeast that cause wide spectrum of infections, especially in intensive care settings. We investigated C. auris prevalence among 102 clinical isolates previously identified as C. haemulonii or C. famata by VITEK2 system. ITS sequencing confirmed 88.2% of isolates as C. auris and matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF) easily separated all related species viz., C. auris (n=90), C. haemulonii (n=6), C. haemulonii var. vulnera (n=1) and C. duobushaemulonii (n=5). The in vitro antifungal susceptibility was determined using CLSI-BMD, VITEK2 AST card and Etest method. C. auris isolates revealed uniformly elevated fluconazole MICs (MIC50, 64 μg/ml) and an alarming percentage of isolates (37%) exhibited elevated caspofungin MICs by CLSI-BMD. Notably, 34% of C. auris had coexisting elevated MICs (≥2 μg/ml) for both fluconazole and voriconazole and 10% of the isolates had elevated coexisting MICs (≥ 2 μg/ml) to two additional azoles i.e., posaconazole and isavuconazole. In contrast to reduced amphotericin B MICs by CLSI-BMD (MIC50, 1 μg/ml) for C. auris, elevated MICs were noted by VITEK2, (MIC50, 8 μg/ml), which were statistically significant. Candida auris remains an unnoticed pathogen in routine microbiology laboratories as 90% of the isolates characterized by commercial identification systems are misidentified as C. haemulonii. MALDI-TOF proved to be a more robust diagnostic technique for rapid identification of C. auris. Considering that misleading elevated MICs of amphotericin B by VITEK AST-YS07 card may lead to selection of inappropriate therapy, a cautionary approach is recommended for laboratories relying on commercial systems for identification and antifungal susceptibility testing of rare yeasts.

Concepts: Mass spectrometry, Yeast, Antifungals, Flucytosine, Candidiasis, Ergosterol, Triazole, World Health Organization essential medicines

0

Candida spp. is a common cause of invasive fungal disease. The aim of this study was to examine the susceptibility of Candida spp. to fluconazole, itraconazole and voriconazole and explore the correlation between triazoles susceptibility. The antifungal susceptibility in the present study was measured by ATB Fungus 3 method, and the potential relationship was examined by obtaining the correlation of measured minimal inhibitory concentrations (MICs) of Candida spp. isolates. A total of 2099 clinical isolates of Candida spp. from 1441 patients were analyzed. The organisms included 1435 isolates of Candida albicans, 207 isolates of Candida glabrata, 65 isolates of Candida parapsilosis, 31 isolates of Candida krusei, 268 isolates of Candida tropicalis. Voriconazole and itraconazole were more active than fluconazole and against Candida spp. in vitro. The fluconazole, itraconazole and voriconazole MIC90 (MIC for 90% of the isolates) for all Candida spp. isolates was 4mg/L, 1mg/L and 0.25mg/L, respectively. There was a moderate correlation between the fluconazole MICs for Candida spp. isolates and this for voriconazole (R2=0.475; P<0.01) and itraconazole (R2=0.431; P<0.01). Voriconazole MICs for the Candida spp. isolates also correlated with those for itraconazole (R2=0.401; P<0.01). These observations suggest that the in vitro susceptibility of Candida spp. to fluconazole, itraconazole and voriconazole exhibits a moderate correlation.

Concepts: Fungus, In vitro, Antifungals, Candidiasis, Fluconazole, Triazole, Triazoles, Itraconazole

0

Posaconazole is superior to fluconazole or itraconazole in preventing invasive fungal diseases (IFDs) in patients with haematological malignancies; however, there have been reports of the comparing posaconazole and voriconazole.

Concepts: Triazole, Itraconazole

0

0

Isavuconazole, the active moiety of its prodrug isavuconazonium, is a new extended-spectrum triazole whose activity against yeasts, molds, including Aspergillus and mucorales, and dimorphic fungi has been shown in vitro and in preclinical models. The most relevant pharmacokinetics features are water-solubility of the prodrug, rapid cleavage of the prodrug into active moiety and cleavage product by plasmatic esterases, high oral bioavailability of isavuconazole with an extensive penetration into most tissues and a good safety profile even in case of renal impairment. The results of two main clinical studies have led to an approval by FDA and EMA in the treatment of invasive aspergillosis and invasive mucormycosis. Isavuconazole is non-inferior to voriconazole in terms of response and survival in invasive aspergillosis and has shown improved safety and tolerability. Importantly, less hepatobiliary, skin and eye disorders have been reported in isavuconazole-treated patients. Isavuconazole has therefore been granted a grade A-I recommendation by the European Conference on Infections in Leukemia (ECIL) for the treatment of invasive aspergillosis. Efficacy has also been demonstrated in mucormycosis in an open-label study. Survival was similar to the survival of matched patients from the international Fungiscope registry and treated with an amphotericin B formulation. Isavuconazole failed to show non-inferiority to caspofungin in a large double-blind candidemia trial. The aim of this review is to give the reader an overview of the data available so far to support inclusion of isavuconazole in the anti-mold therapeutic arsenal.

Concepts: Pharmacology, Pharmacokinetics, Biopharmaceutics Classification System, Aspergillosis, Aspergillus, Antifungals, Bioavailability, Triazole