In Vitro Antifungal Activity of Ibrexafungerp (SCY-078) Against Contemporary Blood Isolates From Medically Relevant Species of Candida: A European Study

BackgroundIbrexafungerp (SCY-078) is the newest oral and intravenous antifungal drug with broad activity, currently undergoing clinical trials for invasive candidiasis. ObjectiveThe aim of this study was to assess the in vitro activity of ibrexafungerp and comparators against a collection of 434 European blood isolates of Candida. MethodsIbrexafungerp, caspofungin, fluconazole, and micafungin minimum inhibitory concentrations (MICs) were collected from 12 European laboratories for 434 blood isolates, including 163 Candida albicans, 108 Candida parapsilosis, 60 Candida glabrata, 40 Candida tropicalis, 29 Candida krusei, 20 Candida orthopsilosis, 6 Candida guilliermondii, 2 Candida famata, 2 Candida lusitaniae, and 1 isolate each of Candida bracarensis, Candida catenulata, Candida dubliniensis, and Candida kefyr. MICs were determined by the EUCAST broth microdilution method, and isolates were classified according to recommended clinical breakpoints and epidemiological cutoffs. Additionally, 22 Candida auris from different clinical specimens were evaluated. ResultsIbrexafungerp MICs ranged from 0.016 to >= 8 mg/L. The lowest ibrexafungerp MICs were observed for C. albicans (geometric MIC 0.062 mg/L, MIC range 0.016-0.5 mg/L) and the highest ibrexafungerp MICs were observed for C. tropicalis (geometric MIC 0.517 mg/L, MIC range 0.06->= 8 mg/L). Modal MICs/MIC(50)s (mg/L) against Candida spp. were 0.125/0.06 for C. albicans, 0.5/0.5 for C. parapsilosis, 0.25/0.25 for C. glabrata, 0.5/0.5 for C. tropicalis, 1/1 for C. krusei, 4/2 for C. orthopsilosis, and 0.5/0.5 for C. auris. Ibrexafungerp showed activity against fluconazole- and echinocandin-resistant isolates. If adopting wild-type upper limits, a non-wild-type phenotype for ibrexafungerp was only observed for 16/434 (3.7%) isolates: 11 (4.6%) C. parapsilosis, 4 (5%) C. glabrata, and 1 (2.5%) C. tropicalis. ConclusionIbrexafungerp showed a potent in vitro activity against Candida.This study received funding from SCYNEXIS. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of the article, or the decision to submit it for publication. CM-A is a recipient of a grant from Fundació n ONCE (Oportunidad al Talento). EE, AG, NJ, CM-A, and GQ have received grant support from Consejerı́a de Educación, Universidades e Investigación del Gobierno Vasco (GIC15 IT-990-16), Fondo de Investigación Sanitaria del Gobierno de España (FIS PI11/00203), and UPV/EHU (UFI 11/25). All authors declare no other competing interests

ASPERGILLI MULTIRESISTENTI E DIFFUSIONE AMBIENTALE

Con sempre maggior frequenza viene segnalata la resistenza agli azoli in Aspergillus fumigatus sia in pazienti in trattamento antifungino cronico che in pazienti naive. E\u2019 stato ipotizzato lo sviluppo della resistenza nell\u2019ambiente, a seguito dell\u2019esposizione a fungicidi triazolici in ambito agricolo, confermato dall\u2019isolamento ambientale in Europa. La resistenza \ue8 per lo pi\uf9 associata ad alterazione in cyp51A, gene che codifica l\u2019enzima target degli azoli, ed i codoni 54, 98 e 220 sono quelli pi\uf9 frequentemente coinvolti nella mutazione. La multiresistenza ai triazoli risulta per lo pi\uf9 associata alla mutazione puntiforme T364A (codone 98) nel gene cyp51A e alla presenza di un tandem di 34 paia di basi ripetute nel promotore (TR/L98H) (Snelders 2008 e 2009; Mortensen 2010) Obiettivi dell\u2019attivit\ue0 svolta dal laboratorio di micologia medica del Dipartimento di Scienze Biomediche per la Salute dell\u2019Universit\ue0 degli studi di Milano sono stati quelli di indagare la prevalenza della resistenza agli azoli, studiandone il meccanismo di resistenza, in ceppi clinici di A. fumigatus e ricercare la presenza di ceppi resistenti in prelievi ambientali nell\u2019Italia del nord. Sono stati sottoposti a screening per la resistenza agli azoli 209 ceppi clinici, provenienti da 89 pazienti, nell\u2019ambito dello studio SCARE, e 47 campioni di terra. La resistenza agli azoli dei ceppi clinici ed ambientali \ue8 stata confermata mediante microdiluizione in brodo EUCAST ed E-test. Per i ceppi resistenti \ue8 stato sequenziato il gene \u3b2-tubulina per identificare eventuali specie criptiche, e una parte della regione codificante e del promotore del gene cyp51A per la ricerca del meccanismo di resistenza. Il meccanismo di resistenza \ue8 stato indagato anche in 5 ceppi isolati da pazienti in trattamento cronico con azoli. Sette ceppi clinici, di cui 2 isolati da pazienti naive, sono risultati resistenti a itraconazolo, 4 resistenti anche a posaconazolo, 1 resistente a voriconazolo e due con una ridotta sensibilit\ue0 a voriconazolo. Il meccanismo di resistenza TR/L98H \ue8 stato riscontrato in 5 dei 7 ceppi resistenti. In un ceppo resistente a itraconazolo e posaconazolo \ue8 stata rilevata una mutazione puntiforme nel codone 54, e in un ceppo resistente ai tre azoli una mutazione nel codone 220. Dai 47 campioni di terra esaminati sono stati isolati 9 ceppi resistenti a itraconazolo e posaconazolo, provenienti da campi coltivati a orticole (6), da meleti (1), da compost per rose (2). Tutti i ceppi resistenti sono risultati A. fumigatus sensu stricto all\u2019identificazione molecolare. La mutazione TR/L98H nel gene cyp51A \ue8 stata rilevata in 7 dei 9 ceppi ambientali. Dai risultati di questi studi emerge che anche in Italia sono presenti ceppi sia clinici che ambientali di A. fumigatus resistenti ai triazoli e che, nella maggior parte dei casi, il meccanismo di resistenza \ue8 la mutazione TR/L98H nel gene cyp51A, predominante anche in altri Paesi

Candidemia: Evolution of Drug Resistance and Novel Therapeutic Approaches

none5Candidemia and invasive candidiasis are the most common healthcare-associated invasive fungal infections, with a crude mortality rate of 25-50%. Candida albicans remains the most frequent etiology, followed by C. glabrata, C. parapsilosis and C. tropicalis. With the exception of a limited number of species (ie: C. krusei, C. glabrata and rare Candida species), resistance to fluconazole and other triazoles are quite uncommon. However, recently fluconazoleresistant C. parapsilosis, echinocandin-resistant C. glabrata and the multidrug resistant C. auris have emerged. Resistance to amphotericin B is even more rare due to the reduced fitness of resistant isolates. The mechanisms of antifungal resistance in Candida (altered drug-target interactions, reduced cellular drug concentrations, and physical barriers associated with biofilms) are analyzed. The choice of the antifungal therapy for candidemia must take into account several factors such as type of patient, presence of devices, severity of illness, recent exposure to antifungals, local epidemiology, organs involvement, and Candida species. The first-line therapy in nonneutropenic critical patient is an echinocandin switching to fluconazole in clinically stable patients with negative blood cultures and azole susceptible isolate. Similarly, an echinocandin is the drug of choice also in neutropenic patients. The treatment duration is 14 days after the first negative blood culture or longer in cases of organ involvement. An early removal of vascular catheter improves the outcome. The promising results of new antifungal molecules, such as the terpenoid derivative ibrexafungerp, the novel echinocandin with an enhanced half-life rezafungin, oteseconazole and fosmanogepix, representative of new classes of antifungals, are discussed.mixedTortorano, Anna Maria; Prigitano, Anna; Morroni, Gianluca; Brescini, Lucia; Barchiesi, FrancescoTortorano, Anna Maria; Prigitano, Anna; Morroni, Gianluca; Brescini, Lucia; Barchiesi, Francesc

Four-Year Persistence of a Single Candida albicans Genotype Causing Bloodstream Infections in a Surgical Ward Proven by Multilocus Sequence Typing

The present study represents the first application of multilocus sequence typing to retrospectively investigate a suspected outbreak of Candida albicans bloodstream infection cases that occurred in the same hospital ward between July 1987 and October 1991. Results demonstrated that eight bloodstream infections were caused by the same strain, endemic in the ward, over a 4-year period

Antifungal susceptibility profiles of Candida isolates from a prospective survey of invasive fungal infections in Italian intensive care units

The antifungal susceptibility pattern of 302 Candida isolates collected during an Italian survey on invasive fungal infections in an intensive care setting was investigated. The results were correlated with some epidemiological data and compared with the antifungal profiles obtained in a previous survey. No resistance to echinocandins was detected. The overall resistance levels to fluconazole, posaconazole and voriconazole were 12.6, 6.0 and 7.1\u200a%, respectively. Candida tropicalis and Candida parapsilosis accounted for more than half of all the fluconazole resistant isolates. Reduced susceptibility to fluconazole is not uncommon among isolates (12.3\u200a%) and appears to be increasing, particularly among C. parapsilosis isolates, which showed an increase in resistant isolates from 2\u200a% in the 1990s to 25.8\u200a% in the present study. Routine antifungal susceptibility testing of this species is therefore recommended