In vitro activity of isavuconazole against 140 reference fungal strains and 165 clinically isolated yeasts from Japan

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ABSTRACTSince the separation ofPseudallescheria boydiiandP. apiospermain 2010, limited data on species-specific susceptibility patterns of these and other species ofPseudallescheriaand its anamorphScedosporiumhave been reported. This study presents the antifungal susceptibility patterns of members affiliated with both entities. Clinical and environmental isolates (n= 332) from a wide range of sources and origins were identified down to species level and tested according to CLSI M38-A2 against eight antifungal compounds. WhereasP. apiosperma(geometric mean MIC/minimal effective concentration [MEC] values of 0.9, 2.4, 7.4, 16.2, 0.2, 0.8, 1.5, and 6.8 μg/ml for voriconazole, posaconazole, isavuconazole, itraconazole, micafungin, anidulafungin, caspofungin, and amphotericin B, respectively) andP. boydii(geometric mean MIC/MEC values of 0.7, 1.3, 5.7, 13.8, 0.5, 1.4, 2.3, and 11.8 μg/ml for voriconazole, posaconazole, isavuconazole, itraconazole, micafungin, anidulafungin, caspofungin, and amphotericin B, respectively) had similar susceptibility patterns, those forS. aurantiacum,S. prolificans, andS. dehoogiiwere different from each other. Voriconazole was the only drug with significant activity againstS. aurantiacumisolates. The MIC distributions of all drugs except voriconazole did not show a normal distribution and often showed two subpopulations, making a species-based prediction of antifungal susceptibility difficult. Therefore, antifungal susceptibility testing of all clinical isolates remains essential for targeted antifungal therapy. Voriconazole was the only compound with low MIC values (MIC90of ≤2 μg/ml) forP. apiospermaandP. boydii. Micafungin and posaconazole showed moderate activity against the majority ofScedosporiumstrains.

Section: Discussionmentioning

confidence: 99%

Species-Specific Antifungal Susceptibility Patterns of Scedosporium and Pseudallescheria Species

Lackner

Hoog

Verweij

et al. 2012

257

178

“…resistant to itraconazole, caspofungin, and amphotericin B (21) and to Candida spp. resistant to fluconazole (24). In addition, in in vivo animal models of fungal infections, such as invasive aspergillosis and disseminated candidiasis, isavuconazole showed good therapeutic activity, comparable to that of voriconazole and itraconazole (11,22,23).…”

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confidence: 95%

In Vitro Antifungal Activity of Isavuconazole against Madurella mycetomatis

Kloezen

Meis

Curfs-Breuker

et al. 2012

dCurrently, therapy of black-grain mycetoma caused by Madurella mycetomatis consists of extensive debridement of the infected tissue combined with prolonged antifungal therapy with ketoconazole or itraconazole. In the present study, the in vitro activity of the new triazole isavuconazole toward M. mycetomatis was evaluated. Isavuconazole appeared to have high activity against M. mycetomatis, with MICs ranging from <0.016 to 0.125 g/ml. Due to its favorable pharmacokinetics, isavuconazole could be a promising antifungal agent in the treatment of mycetoma. Madurella mycetomatis is the most common causative agent of eumycetoma. This chronic, granulomatous infection is often found in the lower extremities, but it has been reported in other parts of the body as well (4). The infection starts as a small subcutaneous nodule, which gradually progresses into chronic inflammatory lesions with multiple sinuses that excrete a purulent and seropurulent discharge containing black grains. To date, treatment of eumycetoma in areas where eumycetoma is endemic consists of a combination of extensive mutilating surgery or amputation of the infected tissue or limb and prolonged antifungal therapy with ketoconazole or itraconazole (1). However, eumycetoma is associated with high recurrence rates, even after amputation of the affected limb. For M. mycetomatis, the susceptibility to antifungal agents belonging to the classes of polyenes, azoles, allylamines, and echinocandins has been determined (3,18, 20 Khartoum, Sudan, in 1999 and 2000) in duplicate. The strains were identified previously by morphology, PCRrestriction fragment length polymorphism (RFLP), and internal transcribed spacer (ITS) sequencing (2, 19). MICs were determined by using the 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide (XTT) assay (3). In brief, M. mycetomatis colonies were inoculated in RPMI 1640 medium containing 0.35 g/liter L-glutamine and 1.98 mM 4-morpholinepropanesulfonic acid, sonicated (5 s at 28-m maximum power, Beun de Ronde, The Netherlands), and incubated for 7 days at 37°C. The mycelia were harvested by another sonication step and 5-min centrifugation at 2,628 ϫ g. The pellet was washed and resuspended in sterile saline, and the fungal suspension was adjusted to 70% transmission at 660 nm (Novaspec II; Pharmacia Biotech). The drug concentrations tested ranged from 0.016 g/ml to 16 g/ml isavuconazole. As comparator agents, ketoconazole and itraconazole were tested at the same concentrations. XTT was administered to facilitate endpoint reading. MICs were determined spectrophotometrically and defined as the lowest concentration of antifungal agent where at least an 80% growth reduction was measured. Candida parapsilosis (ATCC 22019) was included in the study as a quality control strain.In concordance with previously published data, M. mycetomatis was strongly inhibited by low concentrations of ketoconazole and itraconazole (18), the antifungal agents currently used to treat mycetoma in the areas where my...

“…In addition, severe side effects, toxicity, primary resistance of fungal species (1,2), and therapeutic failures and/or refractoriness (3) are also considered important issues in the management of these infections (1,4). In agents of severe infections, such as Histoplasma capsulatum (5), Cryptococcus gattii (6), and Coccidioides species (7), reduced susceptibility to antifungals has been detected worldwide.…”

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confidence: 99%

Synthesis and Antifungal Activity In Vitro of Isoniazid Derivatives against Histoplasma capsulatum var. capsulatum

Cordeiro¹,

Marques²,

Cordeiro³

et al. 2014

f Histoplasmosis is a severe infection that affects millions of patients worldwide and is endemic in the Americas. Amphotericin B (AMB) and itraconazole are highly effective for the treatment of severe and milder forms of the disease, but AMB is toxic, and the bioavailability of itraconazole is erratic. Therefore, it is important to investigate new classes of drugs for histoplasmosis treatment. In this study, a series of nine isoniazid hydrazone derivatives were synthesized and evaluated for their antifungal activities in vitro against the dimorphic fungus Histoplasma capsulatum var. capsulatum. The drugs were tested by microdilution in accordance with CLSI guidelines. The compound N=-(1-phenylethylidene)isonicotinohydrazide had the lowest MIC range of all the compounds for the yeast and filamentous forms of H. capsulatum. The in vitro synergy of this compound with AMB against the planktonic and biofilm forms of H. capsulatum cells was assessed by the checkerboard method. The effects of this hydrazone on cellular ergosterol content and membrane integrity were also investigated. The study showed that the compound alone is able to reduce the ergosterol content of planktonic cells and can alter the membrane permeability of the fungus. Furthermore, the compound alone or in combination with AMB showed inhibitory effects against mature biofilms of H. capsulatum. N=-(1-Phenylethylidene)isonicotinohydrazide alone or combined with AMB might be of interest in the management of histoplasmosis.