Antifungal surveillance is an important tool to monitor the prevalence of uncommon fungal species and increasing antifungal resistance throughout the world, but data comparing results across several different Asian countries are scarce. In this study, 372 invasive molds collected in the Asia-Western Pacific region in 2011–2019 were susceptibility tested for mold-active triazoles (isavuconazole, posaconazole, voriconazole, and itraconazole). The collection includes 318 Aspergillus spp. isolates and 53 non- Aspergillus molds. The MIC values using CLSI methods for isavuconazole versus Aspergillus fumigatus ranged from 0.25 to 2 mg l −1 . Isavuconazole, itraconazole, posaconazole, and voriconazole acted similarly against A. fumigatus . The mold-active triazoles exhibited a wildtype phenotype to most of the Aspergillus spp. isolates tested (>94%), but poor activity against Fusarium solani species complex and Lomentospora prolificans . Voriconazole was most active against the Scedosporium spp. and posaconazole was most active against the Mucorales. In summary, isavuconazole displayed excellent activity against most species of Aspergillus and was comparable to other mold-active triazoles against non- Aspergillus molds.

A total of 15 Candida auris 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 C auris clinical isolates that displayed resistance phenotypes.

The epidemiology of invasive filamentous fungal diseases requires monitoring due to changes in susceptibility patterns of new and established antifungal agents that may affect clinical practices. We evaluated the activity of posaconazole against 2,157 invasive moulds collected worldwide from 2010-2017. The isolates included 1,775 Aspergillus spp. and 382 non-Aspergillus moulds, including 81 Fusarium spp., 62 Mucorales group, and 57 Scedosporium spp. Isolates were tested using the CLSI reference broth microdilution method. Posaconazole showed similar activity to itraconazole and voriconazole against A. fumigatus. Applying published ECV, 98.0% of the A. fumigatus and 97.7% to 100.0% of other common Aspergillus species were wildtype to posaconazole. Categorical agreement between posaconazole and the other azoles tested against A. fumigatus was 98.7%. Notably, most of the Aspergillus spp. isolates recovered from this large collection were wildtype to echinocandins and all azoles. Posaconazole non-wildtype rates of A. fumigatus varied across the different geographic regions, with 2.1% in Europe, 2.2% in North America, 1.8% in Latin America, and 0.7% in the Asia-Pacific region. The frequency of azole non-wildtype A. fumigatus isolates from Europe increased steadily from 2010-2017 for all 3 triazoles (0.0%-5.0%). The azole non-wildtype A. fumigatus rates from the other geographic areas were stable over time. Fusarium and/or Scedosporium spp. isolates were highly resistant to azoles and echinocandins. Posaconazole and amphotericin B were the most active agents against the Mucorales. Posaconazole was very active against most species of Aspergillus and was comparable to itraconazole and voriconazole against the less common moulds. Posaconazole should provide a useful addition to the anti-mould grouping of antifungal agents.

Abstract Background Existing antifungal agents are active against many common fungal pathogens; however, breakthrough fungal infections occur and often involve less frequently encountered yeast and mould isolates. These rarer isolates tend to exhibit diminished susceptibility to current agents. Manogepix (MGX, APX001A) is a novel inhibitor of the fungal Gwt1 enzyme. The prodrug (fosmanogepix), is being evaluated in Phase 2 clinical trials for invasive candidiasis/candidemia, Candida auris infections, and invasive aspergillosis. In this study, we evaluated the in vitro activity of MGX and comparators against 2,669 clinical fungal isolates collected worldwide (2018-2019) and stratified by infection type. Methods Fungal isolates were collected from medical centers located in North America (34 sites; 42.3%), Europe (30 sites; 37.9%), Asia-Pacific (11 sites; 12.3%), and Latin America (7 sites; 7.6%). Isolates were collected from bloodstream infections (BSI; 51.7%), pneumonia in hospitalized patients (PIHP; 21.1%), skin and skin structure infections (SSSI; 5.5%), urinary tract infections (UTI; 2.3%), intraabdominal infections (IAI; 1.9%), and other infection types (17.5%). Results MGX demonstrated potent in vitro activity against 1,887 Candida spp. isolates from BSI, PIHP, SSSI, and all infection types (MIC50/90, 0.008/0.03-0.06 mg/L) outperforming all comparator agents (Table). Similarly, MGX was equally active against 578 Aspergillus spp. isolates (MEC50/90, 0.015/0.03 mg/L), regardless of infection type. MGX was active against Cryptococcus neoformans var. grubii isolates from BSI and ALL infection types with MIC50/90 values of 0.5/2 mg/L. Scedosporium spp. isolates from PIHP and all infection types were inhibited by low concentrations of MGX (MEC50/90, 0.03/0.03 mg/L). Table 1 Conclusion MGX demonstrated potent antifungal activity against Candida spp., Aspergillus spp., C. neoformans var. grubii, and non-Aspergillus moulds, including Scedosporium spp. isolates. Notable activity was seen against C. auris, echinocandin-resistant Candida spp., azole-resistant Aspergillus, and Scedosporium spp. isolates. Further clinical development of fosmanogepix in difficult-to-treat resistant fungal infections is warranted. Disclosures Michael A. Pfaller, MD, Amplyx Pharmaceuticals (Research Grant or Support)Basilea Pharmaceutica International, Ltd (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Department of Health and Human Services (Research Grant or Support)Fox Chase Chemical Diversity Center (Research Grant or Support)Paratek Pharma, LLC (Research Grant or Support) Robert K. Flamm, PhD, A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Amplyx Pharmaceuticals (Research Grant or Support)Basilea Pharmaceutica International, Ltd (Research Grant or Support)Department of Health and Human Services (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support) Shawn A. Messer, PhD, Amplyx Pharmaceuticals (Research Grant or Support)Fox Chase Chemical Diversity Center (Research Grant or Support) Beth A. Schaefer, n/a, Amplyx Pharmaceuticals (Research Grant or Support) Paul Bien, MS, Amplyx Pharmaceuticals (Employee) Mariana Castanheira, PhD, 1928 Diagnostics (Research Grant or Support)A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Amplyx Pharmaceuticals (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Fox Chase Chemical Diversity Center (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Merck (Research Grant or Support)Merck (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Paratek Pharma, LLC (Research Grant or Support)Pfizer (Research Grant or Support)Qpex Biopharma (Research Grant or Support)

The increasing prevalence of uncommon fungal species and higher antifungal resistance has turned antifungal susceptibility testing into an important monitoring tool. In response, we evaluated the activity of isavuconazole against 522 clinical mold isolates collected worldwide in 2017-2018, induding 436 Aspergillus spp. isolates and 86 non-Aspergillus molds. The MIC values using Clinical and Laboratory Standards Institute methods for isavuconazole versus Aspergillus ranged from 0.015 mg/L to >8 mg/L. Isavuconazole showed comparable activity to itraconazole, posaconazole, and voriconazole against A. fumigatus species complex. Most of the Aspergillus spp. isolates tested (>90%) were wild type to all azoles and echinocandins. Eleven isolates were non-wild type to isavuconazole and the other 3 azoles, and 10 of those isolates were from Europe. The azoles and echinocandins showed poor activity against Fusarium and Scedosporium spp. Isavuconazole exhibited excellent activity against most species of Aspergillus and was comparable to itraconazole, posaconazole, and voriconazole against the less common molds. (C) 2020 Elsevier Inc. All rights reserved.

We evaluated the activity of rezafungin and comparators, using Clinical and Laboratory Standards Institute (CLSI) broth microdilution methods, against a worldwide collection of 2,205 invasive fungal isolates recovered from 2016 to 2018. Candida (n = 1,904 isolates; 6 species), Cryptococcus neoformans (n = 73), Aspergillus fumigatus (n = 183), and Aspergillus flavus (n = 45) isolates were tested for their susceptibility (5) to rezafungin as well as the comparators caspofungin, anidulafungin, micafungin, and azoles. Interpretive criteria were applied following CLSI published clinical breakpoints (CBPs) and epidemiological cutoff values (ECVs). Isolates displaying non-wild-type (non-WT) echinocandin MIC values were sequenced for hot spot (HS) mutations. Rezafungin inhibited 99.8% of Candida albicans isolates(MIC50/90, 0.03/ 0.06 mu g/ml), 95.7% of Candida glabrata isolates (MIC50/90, 0.06/0.14 mu g/ml), 97.4% of Candida tropicalis isolates (MIC50/90, 0.03/0.06 mu g/ml), 100.0% of Candida krusei isolates (MIC50/90, 0.03/0.06 mu g/ml), and 100.0% of Candida dubliniensis isolates (MIC50/90, 0.06/0.12 mu g/ml) at <= 0.12 mu g/ml. All (329/329 (100.0%)) Candida parapsilosis isolates (MIC50/90, 1/2 mu g/ml) were inhibited by rezafungin at <= 4 mu g/ml. Fluconazole resistance was detected among 8.6% of C. glabrata isolates, 12.5% of C parapsilosis isolates, 3.2% of C. dubliniensis isolates, and 2.6% of C. tropicalis isolates. The activity of rezafungin against these 6 Candida spp. was similar to the activity of the other echinocandins. Detection of the HS mutation was performed by sequencing echinocandin-resistant or non-WT Candida isolates. Good activity against C. neoformans was observed for fluconazole and the other azoles, whereas the echinocandins, including rezafungin, displayed limited activity. Rezafungin displayed activity similar to that of the other echinocandins against A. fumigatus and A. flavus. These in vitro data contribute to accumulating research demonstrating the potential of rezafungin for preventing and treating invasive fungal infections.

Abstract Background Fox Chase Chemical Diversity Center (FCC) is developing non-peptide analogs of host defense proteins for the treatment of invasive fungal infections mainly caused by Candida (CAN) and Aspergillus (ASP). We evaluated the activity of 6 novel compounds and 2 comparators against 150 isolates from 15 fungal groups. Methods Susceptibility testing was performed per CLSI broth microdilution methods for investigational compounds and comparators against 70 CAN and 40 ASP isolates in addition to 10 Cryptococcus spp. (CRYP), 10 Fusarium spp. (FUS), 10 Mucorales, and 10 Scedosporium spp. (SCED) isolates from recent (2017-2019) clinical infections. MIC results were determined as ≥ 50% reduction at 24 and 72 hours for CAN and CRYP respectively, and 100% reduction at 24, 72, and 48 hours for Mucorales, SCED, and other moulds, respectively. CLSI clinical breakpoint (CBP) and epidemiological cutoff value (ECV) interpretive criteria were applied for comparators. Results Compounds FC10790, FC11083, FC11212, and FC11275 had MIC50 results at ≤ 0.015 mg/L and MIC90 results at ≤ 0.015 to 0.12 mg/L against CRYP, ASP, and FUS isolates. Compounds FC5096 and FC11022 were 2- to 4-fold less active while demonstrating MIC50 and MIC90 results of 0.03 to 0.5 mg/L against CAN, CRYP, ASP, and FUS isolates. The Mucorales isolate set showed the widest range of MIC results for FC compounds. FC10790 exhibited the greatest potency with a MIC50/90 at 0.5/2 mg/L. FC compounds showed potent activity against SCED with MIC90 results of 0.03 to 0.25 mg/L. Fluconazole showed a wide range of MIC results, from 0.06 to >64 mg/L, but the highest results observed were for Candida auris (MIC50/90, 64/ > 64 mg/L) and Candida krusei (MIC50/90; 16/32 mg/L). Itraconazole was active against all ASP (MIC50/90, 1/1 mg/L), but showed poor activity against FUS (MIC50/90, > 8/ > 8 mg/L). Amphotericin B showed a narrow range of MIC results (0.5 to 2 mg/L) for all isolates except 1 ASP and most SCED. Conclusion Novel FCC compounds showed equal or greater activity than comparators against most CAN, ASP, SCED, and FUS. FC10790, FC11212, and FC11275 showed the greatest activity against all tested fungal isolates. development of this series of compounds for clinical studies. Table 1 Disclosures Paul R. Rhomberg, n/a, Cidara Therapeutics (Research Grant or Support)Fox Chase Chemical Diversity Center (Research Grant or Support)Merck (Research Grant or Support) Shawn A. Messer, PhD, Amplyx Pharmaceuticals (Research Grant or Support)Fox Chase Chemical Diversity Center (Research Grant or Support) Richard W. Scott, PhD, Fox Chase Chemical Diversity Center (Employee) Simon DP Baugh, PhD, Fox Chase Chemical Diversity Center (Employee) Michael A. Pfaller, MD, Amplyx Pharmaceuticals (Research Grant or Support)Basilea Pharmaceutica International, Ltd (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Department of Health and Human Services (Research Grant or Support)Fox Chase Chemical Diversity Center (Research Grant or Support)Paratek Pharma, LLC (Research Grant or Support) Mariana Castanheira, PhD, 1928 Diagnostics (Research Grant or Support)A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Allergan (Research Grant or Support)Amplyx Pharmaceuticals (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Fox Chase Chemical Diversity Center (Research Grant or Support)GlaxoSmithKline (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Merck (Research Grant or Support)Merck (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Paratek Pharma, LLC (Research Grant or Support)Pfizer (Research Grant or Support)Qpex Biopharma (Research Grant or Support) Cecilia G. Carvalhaes, MD, PhD, A. Menarini Industrie Farmaceutiche Riunite S.R.L. (Research Grant or Support)Allergan (Research Grant or Support)Cidara Therapeutics (Research Grant or Support)Cipla Ltd. (Research Grant or Support)Fox Chase Chemical Diversity Center (Research Grant or Support)Melinta Therapeutics, Inc. (Research Grant or Support)Merck (Research Grant or Support)Merck (Research Grant or Support)Merck & Co, Inc. (Research Grant or Support)Pfizer (Research Grant or Support)

Life-threatening infections can be caused by a fungus called Candida auris (shortened to C. auris) that is found in the hospital environment. This study looked at how well different drugs could treat C. auris infection. Samples were collected from 36 people who had C. auris infection. The samples were treated with single drugs and in combination. We found that the main drug types did not work on most samples. Genetic differences we found in the C. auris samples could explain why the main drugs did not work. However, a drug called isavuconazole worked on almost all samples. We also found that a drug called anidulafungin worked better against C. auris when it was combined with either isavuconazole or another drug called voriconazole. To read the full Plain Language Summary of this article, click on the View Article button above and download the PDF.

This study evaluated the activity of echinocandins, azoles and amphotericin B against Candida spp. isolates and other yeasts and characterised azole resistance mechanisms in Candida parapsilosis and Candida tropicalis. Invasive Candida spp. isolates (n = 2936) collected in 60 hospitals worldwide during 20162017 underwent antifungal susceptibility testing by broth microdilution. Azole-resistant C. parapsilosis and C. tropicalis were submitted to qPCR for ERG11, CDR1 and MDR1, and the whole genome sequence was analysed. Results of non-susceptibility to echinocandins ranged from 0.0-2.3%, being highest in Candida glabrata. More than 99.0% of the Candida albicans isolates were susceptible to both fluconazole and voriconazole. Fluconazole resistance in C. glabrata was 6.5% overall, being highest in the USA (13.0%). Resistance to voriconazole in Candida krusei was only noted in the USA (5.0%). Azoles inhibited 89.1-91.6% of C. parapsilosis isolates, with most resistant isolates noted in Europe (15.1%), including 36 isolates from Italy (three hospitals), of which 34 harboured Erg11 Y132F mutations and overexpressed MDR1. Azole non-wild-type C. tropicalis (7/227) were found in five countries: 3 isolates from Thailand had the same Erg11 Y132F alteration. Fluconazole non-wild-type isolates were noted among 3/77 (3.9%) Candida dubliniensis, 4/17 (23.5%) Candida guilliermondii, 4/47 (8.5%) Candida lusitaniae and other less common yeast species. Echinocandin use has been recommended over fluconazole for invasive Candida infections. However, azoles are still active against the most common Candida spp. and resistance appears to be restricted to certain geographic regions and associated with Erg11 Y132 alterations in C. parapsilosis and C. tropicalis. (C) 2019 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

Abstract Background Echinocandins are the first-line treatment of candidemia. We evaluated the activity of rezafungin (RZF), a novel long-acting echinocandin with front-loaded drug exposure and extensive distribution to sites of infection, and comparators using CLSI broth microdilution methods against 709 invasive fungal isolates collected worldwide during 2018. Methods Susceptibility (S) tests on 663 Candida spp. (6 species), 21 C. neoformans (CNEO), and 25 A. fumigatus (ASF) were conducted for RZF, anidulafungin (ANF), caspofungin (CSF), micafungin (MCF), and azoles. CLSI clinical breakpoint (CBP) and epidemiological cutoff value (ECV) interpretive criteria were applied. Isolates displaying echinocandin MIC>ECV were sequenced for fks hot spot (HS) mutations. Results RZF inhibited 99.7% of C. albicans (CA) isolates (MIC50/90, 0.015/0.06 mg/L), 100.0% of C. tropicalis (CT) (MIC50/90, 0.03/0.06 mg/L), 98.9% of C. glabrata (CG) (MIC50/90, 0.03/0.06 mg/L), 100.0% of C. krusei (CK) (MIC50/90, 0.015/0.12 mg/L), and 100.0% of C. dubliniensis (CD) (MIC50/90, 0.03/0.06 mg/L) at ≤0.12 mg/L. All (104/104 [100.0%]) C. parapsilosis (CP) isolates (MIC50/90,1/2 mg/L) were inhibited by RZF at ≤2 mg/L. Fluconazole resistance was detected among 9.0% of CG, 17.3% of CP, and 1.6% of CT. The activity of RZF against these 6 Candida spp. was similar to that of the other echinocandins, the vast majority of which were susceptible/wild type (WT) using CBP/ECV. A total of 5 isolates (3 CG, 1 CA, and 1 CT) displayed 1 or more non-WT or-resistant MIC values and were sequenced for fks HS mutations. Fluconazole and other azoles displayed good activity against CNEO whereas echinocandins including RZF displayed limited activity against CNEO isolates. Echinocandins displayed good activity against ASF, and RZF activity was similar to that of anidulafungin, caspofungin, and micafungin. All but 1 isolate (non-WT MIC for itraconazole, 2 mg/L) displayed WT MIC values for the mould-active azoles. Conclusion Rezafungin was as active as other echinocandins against common organisms recovered from invasive fungal infections. These in vitro data contribute to accumulating research demonstrating rezafungin potential for prevention and treatment of invasive fungal infection. Disclosures All authors: No reported disclosures.

Echinocandins are important agents for treating invasive fungal infections. We evaluated the activity of rezafungin (RZF; previously CD101), an echinocandin with extended half-life, and comparators using CLSI broth microdilution methods against 719 invasive fungal isolates collected worldwide during 2017. Susceptibility tests were conducted on 616 Candida spp. (6 species), 25 C. neoformans (CNEO), 18 A. flavus (AFL), and 60 A. fumigatus (AFU) for RZF, anidulafungin, caspofungin, micafungin, and azoles. CLSI clinical breakpoint (CBP) and epidemiological cutoff value (ECV) interpretive criteria were applied. RZF inhibited 100.0% of C. albicans (CA) isolates, 96.3% of C. tropicalis (CT), 93.4% of C. glabrata (CG), 100.0% of C. krusei, and 100.0% of C. dubliniensis at ≤0.12 µg/mL. All but 2 (116/118 [98.3%]) C. parapsilosis (CP) isolates were inhibited by RZF at ≤2 µg/mL. Resistance to fluconazole was detected among 10.7% of CG, 10.2% of CP, 1.9% of CT, and 0.7% of CA. The activity of RZF against these 6 Candida spp. was similar to that of the other echinocandins, the vast majority of which were susceptible/wild type (WT) using CBP/ECV. Fluconazole and other triazoles displayed good activity against CNEO whereas echinocandins, including RZF, displayed limited activity against CNEO isolates (MIC90 >8 µg/mL). Echinocandins displayed good activity against ASF and AFL, and RZF activity was similar to that of anidulafungin, caspofungin, and micafungin. All isolates displayed WT MIC values for the mold-active azoles. Rezafungin was as active as other echinocandins against common fungal organisms recovered from invasive fungal infections. The extended half-life and stability of rezafungin is very desirable for prevention and treatment, especially in patients who could be discharged on outpatient therapy. M. A. Pfaller, Cidara Pharmaceuticals: Research Contractor, Research support. S. A. Messer, Cidara Pharmaceuticals: Research Contractor, Research support. P. R. Rhomberg, Cidara Pharmaceuticals: Research Contractor, Research support. B. A. Schaefer, Cidara Pharmaceuticals: Research Contractor, Research support. M. Castanheira, Cidara Pharmaceuticals: Research Contractor, Research support.

CD101 is a novel echinocandin with exceptional chemical stability and long-acting pharmacokinetics. The activity of CD101 and comparators was evaluated using CLSI broth microdilution methods against 713 invasive fungal isolates, including 589 Candida spp. (6 species), 14 C. neoformans, 97 A. furnigatus and 13 A. fluvus species complex collected worldwide during 2015. All C tropicalis, C. krusei and C dubliniensis, 99.7% of C albicans and 98.3% of C glabrata were inhibited by <= 0.12 mu g/mL of CD101, and these isolates were susceptible/wild type to other echinocandins using CLSI clinical breakpoint and epidemiological cutoff value (ECV) interpretive criteria. C. parapsilosis displayed higher MIC values (range 0.25-2 mu g/mL), but similar results were observed for other echinocandins. One C. glabrata and one C. albicans with CD101 MIC value at 1 and 0.25 mu g/mL possessed F6255 and S645P alterations on FKS1, respectively. These isolates also displayed elevated MIC values for at least one clinically available echinocandin. Fluconazole resistance was noted for 6.6% of C. glabrata and 3.6% C parapsilosis. Echinocandins had limited activity against C neoformaus. CD101 activity against A. fumigatus and A. flavus (MEC <= 0.03 ug/mL) was comparable to other echinocandins (MEC <= 0.03 mu g/mL). These moulds had MIC values below ECVs for the mould-active azoles. CD101 was as active as other echinocandins against common fungal organisms recovered from invasive fungal infections. The extended half-life profile is very desirable as less frequent dosing of this agent should facilitate shorter and more cost-effective hospital stays, improve compliance for outpatients, and provide more convenient outpatient prophylaxis. (C) 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

ABSTRACT SCY-078 (formerly MK-3118) is a novel orally active inhibitor of fungal β-(1,3)-glucan synthase (GS). SCY-078 is a derivative of enfumafungin and is structurally distinct from the echinocandin class of antifungal agents. We evaluated the in vitro activity of this compound against wild-type (WT) and echinocandin-resistant isolates containing mutations in the FKS genes of Candida spp. Against 36 Candida spp. FKS mutants tested, 30 (83.3%) were non-WT to 1 or more echinocandins, and only 9 (25.0%) were non-WT (MIC, >WT-upper limit) to SCY-078. Among C. glabrata isolates carrying FKS alterations, 84.0% were non-WT to the echinocandins versus only 24.0% for SCY-078. In contrast to the echinocandin comparators, the activity of SCY-078 was minimally affected by the presence of FKS mutations, suggesting that this agent is useful in the treatment of Candida infections due to echinocandin-resistant strains.

ABSTRACT The activity of CD101 and comparator antifungal agents against 606 invasive fungal isolates collected worldwide during 2014 was evaluated using the Clinical and Laboratory Standards Institute (CLSI) method. All Candida albicans ( n = 251), Candida tropicalis ( n = 51), Candida krusei ( n = 16), and Candida dubliniensis ( n = 11) isolates were inhibited by ≤0.12 μg/ml of CD101 and were susceptible or showed wild-type susceptibility to the other echinocandins tested. Five C. glabrata isolates ( n = 100) displayed CD101 MIC values of 1 to 4 μg/ml, had elevated MICs of caspofungin (2 to >8 μg/ml), anidulafungin (2 to 4 μg/ml), and micafungin (2 to 4 μg/ml), and carried mutations on fks1 and fks2 . Candida parapsilosis ( n = 92) and Candida orthopsilosis ( n = 10) displayed higher CD101 MIC values (ranges, 0.5 to 4 μg/ml and 0.12 to 2 μg/ml, respectively), and similar results were observed for the other echinocandins tested. Fluconazole resistance was noted among 11.0% of Candida glabrata isolates, 4.3% of C. parapsilosis isolates, and 2.0% of C. albicans and C. tropicalis isolates. The activity of CD101 against Aspergillus fumigatus ( n = 56) was similar to that of micafungin and 2-fold greater than that of caspofungin but less than that of anidulafungin. These isolates had wild-type susceptibility to itraconazole, voriconazole, and posaconazole. The echinocandins had limited activity against Cryptococcus neoformans ( n = 19). CD101 was as active as the other echinocandins against common fungal organisms recovered from patients with invasive fungal infections. The long half-life profile is very desirable for the prevention and treatment of serious fungal infections, especially in patients who can then be discharged from the hospital to complete antifungal therapy on an outpatient basis.

Objectives The objective of this study was to evaluate the in vitro activity of CD101, a novel echinocandin with a long serum elimination half-life, and comparator (anidulafungin and caspofungin) antifungal agents against a collection of Candida and Aspergillus spp. isolates. Methods CD101 and comparator agents were tested against 106 Candida spp. and 67 Aspergillus spp. isolates, including 27 isolates of Candida harbouring fks hotspot mutations and 12 itraconazole non-WT Aspergillus, using CLSI and EUCAST reference susceptibility broth microdilution (BMD) methods. Results Against WT and fks mutant Candida albicans, Candida glabrata and Candida tropicalis, the activity of CD101 [MIC90 = 0.06, 0.12 and 0.03 mg/L, respectively (CLSI method values)] was comparable to that of anidulafungin (MIC90 = 0.03, 0.12 and 0.03 mg/L, respectively) and caspofungin (MIC90 = 0.12, 0.25 and 0.12 mg/L, respectively). WT Candida krusei isolates were very susceptible to CD101 (MIC = 0.06 mg/L). CD101 activity (MIC50/90 = 1/2 mg/L) was comparable to that of anidulafungin (MIC50/90 = 2/2 mg/L) against Candida parapsilosis. CD101 (MIC mode = 0.06 mg/L for C. glabrata) was 2- to 4-fold more active against fks hotspot mutants than caspofungin (MIC mode = 0.5 mg/L). CD101 was active against Aspergillus fumigatus, Aspergillus terreus, Aspergillus niger and Aspergillus flavus (MEC90 range = ≤0.008–0.03 mg/L). The essential agreement between CLSI and EUCAST methods for CD101 was 92.0%–100.0% among Candida spp. and 95.0%–100.0% among Aspergillus spp. Conclusions The activity of CD101 is comparable to that of other members of the echinocandin class for the prevention and treatment of serious fungal infections. Similar results for CD101 activity versus Candida and Aspergillus spp. may be obtained with either CLSI or EUCAST BMD methods.

Among 1846 fungal clinical isolates from 31 countries, echinocandin resistance in Candida spp. ranged from 0.0% to 2.8% (highest for anidulafungin versus Candida glabrata), and fluconazole resistance was noted among 11.9% and 11.6% of the C. glabrata and Candida tropicalis, respectively. Two isolates of Aspergillus fumigatus displayed elevated MICs for itraconazole and carried cyp51a mutations encoding TR34 L98H. All Cryptococcus neoformans had azole MIC values below epidemiological cutoff values. The increasing resistance among certain species and more frequent reports of breakthrough infections in patients undergoing antifungal therapy highlights the importance of antifungal surveillance to guide therapy for patients with invasive fungal infections.

Background: Echinocandins are important agents for treatment of invasive fungal infections. We evaluated the activity of CD101, a once-weekly echinocandin with extended half-life, and comparators against 606 invasive fungal isolates collected worldwide during 2014 using CLSI broth microdilution methods. Methods: 531 Candida spp. (7 species), 19 C. neoformans (CNEO) and 56 A. fumigatus (ASF) were susceptibility (S) tested for CD101, anidulafungin (ANF), caspofungin (CSF), micafungin (MCF) and azoles. CLSI clinical breakpoint (CBP) and epidemiological cutoff value (ECV) interpretive criteria were applied. Isolates displaying echinocandin MIC>ECV were sequenced for fks hot spot (HS) mutations. Results: The activity of CD101 was similar to that of other echinocandins (Table). All C. albicans (CA), C. tropicalis (CTRO), C. krusei and C. dubliniensis (n=11) were inhibited by ≤0.12 μg/ml of CD101 and were S/wild-type to other echinocandins using CBP/ECV. Five C. glabrata (CGLA) displayed CD101 MIC >0.12 μg/ml (MIC, 1-4 μg/ml), elevated CSF (2->8 μg/ml), ANF (2-4 μg/ml) and MCF (2-4 μg/ml) results and carried mutations on fks1 HS1 S629P (3 isolates/2 also had HS2 S663P), HS2 F659S (1) or S663P (3 isolates). C. parapsilosis (CPRP; n=92) and C. orthopsilosis (n=10) displayed higher MIC values (ranges 0.5-4 and 0.12-2 μg/ml, respectively), but similar results were observed for other echinocandins. Fluconazole resistance was noted among 11.0% of CGLA, 4.3% CPRP and 2.0% CA and CTRO. Echinocandins had limited activity against CNEO. CD101 activity against ASF was similar to that of MCF, two-fold greater than CSF, but less than ANF. These moulds displayed MIC values below ECVs for the mould-active azoles (itraconazole, voriconazole and posaconazole). Conclusions: CD101 was as active as other echinocandins against common fungal organisms recovered from invasive fungal infections. The extended half-life profile is very desirable for prevention and treatment of serious fungal infections, especially in patients that can then be discharged. INTRODUCTION Despite the broad utilization of echinocandins to treat invasive candidiasis (IC) in critically ill hospitalized patients, clinical resistance to these agents remains uncommon, although both breakthrough infections and acquired resistance mutations in some species of Candida have been noted. Whereas the currently available echinocandins are highly efficacious and relatively easy to use in the treatment of IC and other invasive fungal infections (IFI), they must be administered daily by intravenous infusion, potentially prolonging the hospitalization of patients undergoing therapy and limiting their use to the inpatient setting. The availability of an echinocandin with activity that is comparable to those presently in use but with a pharmacokinetic (PK) profile that allows for less frequent administration, would alter the standard-of-care therapy (e.g., echinocandin therapy) to be more easily administered in both inpatient and outpatient settings. CD101 IV is a novel echinocandin antifungal agent that displays chemical stability in plasma, aqueous solution, and at elevated temperature as well as possessing a long-acting PK. CD101 IV is being developed for once-weekly IV administration for the treatment and prevention of serious fungal infections. Less frequent administration while maintaining high exposure would alter hospital stays, improve compliance for outpatients and provide more convenient outpatient prophylaxis or maintenance treatment regimens. In the presented study, we determined the activity and potency of CD101 and comparator antifungal agents tested against 606 clinical fungal isolates collected worldwide from IFI (2014). MATERIALS AND METHODS Fungal organisms. A total of 606 non-duplicate prospectively collected fungal isolates from 38 medical centers located in North America (161 isolates; 10 sites), Europe (294; 17), the Asia-Pacific Region (82; 6) and Latin America (69; 5) were evaluated. Isolates selected were from the following sources: bloodstream, (379 strains), normally sterile body fluids, tissues or abscesses (22 strains), respiratory tract specimens (96 strains) and 109 were collected from other or non-specified body sites. Species identification. Yeast isolates were subcultured and screened using CHROMagar Candida (Becton Dickinson, Sparks, Maryland USA) to ensure purity and to differentiate Candida albicans/Candida dubliniensis, Candida tropicalis and Candida krusei. Isolates suspected to be either C. albicans or C. dubliniensis (green colonies on CHROMagar) were incubated at 45°C. All other yeast isolates were submitted to Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS) using the MALDI Biotyper according to the manufacturer’s instructions (Bruker Daltonics, Billerica, Massachusetts USA). Isolates that were not identified by either phenotypic or proteomic methods were identified using sequencing-based methods as previously described. Antifungal susceptibility testing. All isolates were tested by broth microdilution according to Clinical and Laboratory Standards Institute (CLSI) methods outlined in documents M27-A3 and M38-A2. Frozen-form panels used RPMI 1640 broth supplemented with MOPS (morpholinepropane sulfonic acid) buffer and 0.2% glucose and inoculated with 0.5 to 2.5 X 103 cells/ml suspensions. MIC/MEC values were determined visually, after 24, 48 or 72 hours of incubation at 35oC, as the lowest concentration of drug that resulted in ≥50% inhibition of growth relative to the growth control or complete (100%) inhibition. CLSI clinical breakpoints were used for the five most common species of Candida (C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, and C. krusei) for echinocandins, fluconazole and voriconazole. Epidemiological cutoff values (ECV) were applied when available. Quality control was performed as recommended in CLSI documents M27-A3 and M38-A2 using strains C. krusei ATCC 6258, C. parapsilosis ATCC 22019, A. flavus ATCC 204304 and A. fumigatus MYA-3626. RESULTS • CD101 (MIC50/90, 0.03/0.06 μg/ml) inhibited all 251 C. albicans isolates at ≤0.12 μg/ml (Table 1). This compound displayed activity most similar to that of caspofungin (MIC50/90, 0.03/0.06 μg/ml). • CD101 (MIC50 and MIC90, 0.03 and 0.06 μg/ml) inhibited 95 (95.0%) of the C. glabrata isolates at ≤0.12 μg/ml (Table 1). The activity of this investigational echinocandin was two-fold greater when compared to anidulafungin or caspofungin (MIC50 and MIC90, 0.06 and 0.12 μg/ml for both compounds) and two-fold less than the activity of micafungin (MIC50 and MIC90, 0.015 and 0.03 μg/ml; Table 1). • All C. parapsilosis isolates were inhibited by CD101 (MIC50 and MIC90, 1 and 2 μg/ml) at ≤4 μg/ml (Table 1). CD101 displayed similar activity to that of micafungin (MIC50/90, 1/2 μg/ml), slightly greater activity when compared to anidulafungin (MIC50/90, 2/4 μg/ml) and was two-fold less active than caspofungin (MIC50/90, 0.5/1 μg/ml; Table 1). • C. tropicalis isolates (n=51) were considered susceptible to the clinically available echinocandins and CD101 (MIC50/90, 0.015/0.06 μg/ml) inhibited all isolates at ≤0.06 μg/ml (Table 1). • CD101 (MIC50 and MIC90, 0.03 and 0.06 μg/ml) was very active against 16 C. krusei and all isolates were inhibited at ≤0.06 μg/ml (Table 1). • The activity of CD101 (MIC50 and MIC90, 0.03 and 0.06 μg/ml; Table 1) against C. dubliniensis isolates was comparable to that of caspofungin (MIC50 and MIC90, 0.03 and 0.06 μg/ml). • CD101 (MIC50 and MIC90, 0.5 and 1 μg/ml) activity against C. orthopsilosis was similar to the activity of anidulafungin and micafungin (MIC50/90, 0.5/1 μg/ml for both). Caspofungin was two-fold more active against C. orthopsilosis isolates (MIC50 and MIC90, 0.25 and 0.5 μg/ml; Table 1) when compared to other echinocandins. • The echinocandins, including CD101, had limited activity against C. neoformans var. grubii isolates (n=19; Table 1); all isolates had MIC values at ≥8 μg/ml for these compounds. • Echinocandins displayed good activity against A. fumigatus; CD101 (MEC50 and MEC90, 0.015 and 0.015 μg/ml) activity was two-fold greater than that of caspofungin (MEC50/90, 0.03/0.03 μg/ml) and similar to that of micafungin. Anidulafungin (MEC50/90, ≤0.008/0.015 μg/ml; Table 1) was slightly more active than the other compounds from the same class. • Among the five C. glabrata isolates displaying resistant MIC results for clinically available echinocandins, one harbored a mutation on fks1 HS1 encoding alteration S629P and another two carried alterations on fks2 HS1 F659S or S663P. The two remaining isolates were collected from the same patient in Edmonton, Canada and both strains carried alterations on fks1 HS1 S629P and fks2 HS1 S663P conferring elevated caspofungin MIC results (>8 μg/ml) and MIC results of 2-4 μg/ml for CD101, anidulafungin and micafungin (Table 2). • The activity of comparator agents tested against organisms/organism groups is displayed in Figure 1. Fluconazole resistance was noted among 2.0% of C. albicans and C. tropicalis, 11.0% of C. glabrata and 4.3% of C. parapsilosis. All C. neoformans var. grubii and A. fumigatus isolates were considered wild-type for the azoles. CONCLUSIONS • The activity of CD101 tested by reference methods against common fungal species isolated from invasive infections worldwide during 2014 was comparable to currently available echinocandins. • Further evaluation of CD101 against less common species is recommended, and expanded clinical development of this long-acting echinocandin is warranted.

The SENTRY Antifungal Surveillance Program monitors global susceptibility rates of newer and established antifungal agents. We report the in vitro activity of seven antifungal agents against 496 contemporary clinical isolates of yeasts and molds. The isolates were obtained from 20 laboratories in the Asia-Western Pacific (APAC) region during 2010 through 2012. Anidulafungin, caspofungin, micafungin, fluconazole, itraconazole, posaconazole and voriconazole were susceptibility tested using CLSI methods and species-specific interpretive criteria. Sequencing of fks hot spots was performed for echinocandin-resistant strains. Isolates included 13 species of Candida (n=460), 5 species of non-Candida yeasts (21), 5 species of Aspergillus (11) and 4 other molds. Echinocandin resistance was uncommon among eight species of Candida and was only detected in three isolates of Candida glabrata, two from Australia harboring mutations in fks1 (F625S) and fks2 (S663P). Resistance to the azoles was much more common and was observed among all species with the exception of Candida dubliniensis. Fluconazole resistance rates observed with C. glabrata (6.8%) was comparable to that seen with Candida parapsilosis (5.7%) and Candida tropicalis (3.6%). Cross resistance among the triazoles was seen with each of these three species. The mold-active azoles and the echinocandins were all active against isolates of Aspergillus fumigatus. Azole resistance was not detected among the isolates of Cryptococcus neoformans. Antifungal resistance is uncommon among isolates of fungi causing invasive fungal infections in the APAC region. As in other regions of the world, emerging resistance to the echinocandins among invasive isolates of C. glabrata bears close monitoring.

SummaryWe report the in vitro activity of nine systemically active antifungal agents against 237 contemporary clinical isolates of yeast and moulds obtained from 13 laboratories in China during 2010 through 2012. Susceptibility testing was performed using CLSI methods. Sequencing of fks hot spots was performed for echinocandin non‐wild‐type (WT) strains. Isolates included 220 from eight species of Candida, 15 from four species of Aspergillus and one isolate each of Rhodotorula mucilaginosa and Trichosporon asahii. Resistance to amphotericin B (0.0%), flucytosine (0.0–1.7%) and the echinocandins (0.0–3.4%) was distinctly uncommon among C. albicans, C. parapsilosis, C. tropicalis, C. glabrata and C. pelliculosa. Three C. albicans isolates showed resistance to echinocandins and one harboured a mutation in HS1 of fks1. Resistance to the azoles was much more common with resistance to fluconazole, voriconazole and posaconazole detected among isolates of C. glabrata and C. tropicalis. Both C. parapsilosis and C. pelliculosa exhibited decreased susceptibility to fluconazole. Amphotericin B, the mould‐active azoles and the echinocandins were all quite active against isolates of A. fumigatus and A. flavus. Consistent with previous studies from China, resistance to fluconazole is prominent among Candida spp. isolates in this country.