Echinocandin-resistant Strains Research Articles

Evolutionary accumulation of FKS1 mutations from clinical echinocandin-resistant Candida auris

Introduction: Drug resistance to echinocandins, first-line drugs used to treat Candida auris infection, is rapidly emerging. However, the accumulation of mutations in genes other than FKS1 (before an isolate develops to resistance via FKS1 mutations), remains poorly understood. Methods Four clinical cases and 29 isolates associated with the incremental process of echinocandin resistance were collected and analyzed using antifungal drug susceptibility testing and genome sequencing to assess the evolution of echinocandin resistance. Findings: Six echinocandin minimum inhibitory concentration (MIC)-elevated C. auris strains and seven resistant strains were isolated from the urinary system of patients receiving echinocandin treatment. Meanwhile, phylogenetic analyses illustrated that the echinocandin-resistant strains were closely related to other strains in the same patient. Genomic data revealed that the echinocandin-resistant strains had FKS1 mutations. Furthermore, three categories (ECN-S/E/R) of non-synonymous mutant SNP genes (such as RBR3, IFF6, MKC1, MPH1, RAD2, and MYO1) in C. auris appeared to be associated with the three-stage-evolutionary model of echinocandin resistance in C. glabrata: cell wall stress, drug adaptation, and genetic escape (FKS mutation). Interpretation: Echinocandin-resistant C. auris undergoes spatial and temporal phase changes closely related to echinocandin exposure, particularly in the urinary system. These findings suggest that FKS1 mutations mediate an evolutionary accumulation of echinocandin resistance followed by modulation of chromosome remodeling and DNA repair processes that ultimately lead to FKS1 hot spot mutations and the development of drug resistance. This study provides an in-depth exploration of the molecular pathways involved in the evolution of Candida auris echinocandin resistance.

In vitro activity of ibrexafungerp against clinically relevant echinocandin-resistant Candida strains.

Invasive candidiasis is a major hospital-acquired infection. Usually, echinocandins are considered first-line treatment. However, resistant phenotypes have emerged. Ibrexafungerp (IBX) is a new antifungal substance with potent anti-Candida activity. We challenged IBX with a library of 192 pheno-/genotypically echinocandin-resistant Candida isolates, focusing on the substance susceptibility, its activity on certain FKS hotspot (HS) mutated strains, and applying WTULs (wild-type upper limits). Therefore, a 9-year-old strain and patient data collection provided by the German National Reference Center for Invasive Fungal Infections were analyzed. Species identification was confirmed through ITS-sequencing. Molecular susceptibility testing was performed by sequencing HS of the FKS gene. Anidulafungin (AND) and IBX EUCAST-broth-microdilution was conducted. The four most common echinocandin-resistance mediating mutations were found in Candida glabrata [112/192 isolates; F659-(43×) and S663-(48×)] and Candida albicans [63/192 isolates; F641-(15×) and S645-(39×)]. Mutations at the HS-start sequence were associated with higher IBX MIC-values (F659 and F641 (MIC 50/90 mg/L: >4/>4 and 2/4 mg/L) in comparison to AND (F659 and F641 (MIC 50/90: 1/4 and 0.25/1 mg/L). MIC-values in HS-center mutations were almost equal [MIC50/90 in S663: 2/4 (AND and IBX); in S645: 0.5/1 (AND) and 0.25/1 (IBX) mg/L]. In total, 61 vs 78 of 192 echinocandin-resistant isolates may be classified as IBX wild type by applying WTULs, whereas the most prominent effect was seen in C. albicans [48% (30/63) vs 70% (44/63)]. IBX shows in vitro activity against echinocandin-resistant Candida and thus is an addition to the antifungal armory. However, our data suggest that this effect is more pronounced in C. albicans and strains harboring mutations, affecting the HS-center.

Whole genome sequencing analysis demonstrates therapy-induced echinocandin resistance in Candida auris isolates.

Candida auris is an emerging, multidrug-resistant yeast, causing outbreaks in healthcare facilities. Echinocandins are the antifungal drugs of choice to treat candidiasis, as they cause few side effects and resistance is rarely found. Previously, immunocompromised patients from Kuwait with C. auris colonisation or infection were treated with echinocandins, and within days to months, resistance was reported in urine isolates. To determine whether the development of echinocandin resistance was due to independent introductions of resistant strains or resulted from intra-patient resistance development, whole genome sequencing (WGS) single-nucleotide polymorphism (SNP) analysis was performed on susceptible (n = 26) and echinocandin-resistant (n = 6) isolates from seven patients. WGS SNP analysis identified three distinct clusters differing 17-127 SNPs from two patients, and the remaining isolates from five patients, respectively. Sequential isolates within patients had a maximum of 11 SNP differences over a time period of 1-10 months. The majority of isolates with reduced susceptibility displayed unique FKS1 substitutions including a novel FKS1M690V substitution, and nearly all were genetically related, ranging from only three to six SNP differences compared to susceptible isolates from the same patient. Resistant isolates from three patients shared the common FKS1S639F substitution; however, WGS analysis did not suggest a common source. These findings strongly indicate that echinocandin resistance is induced during antifungal treatment. Future studies should determine whether such echinocandin-resistant strains are capable of long-term colonisation, cause subsequent breakthrough candidiasis, have a propensity to cross-infect other patients, or remain viable for longer time periods in the hospital environment.

Candida auris: the new fungal threat.

Candida auris is an emergent fungal pathogen of particular concern. Since its first identification in Japan in 2009, it rapidly spread all over the world, including Italy. The main concern related to the diffusion of this fungus is its antifungal resistance. It is speculated that about 90% of isolates are resistant to fluconazole, 30% to amphotericin B and 5% to echinocandins; furthermore, some cases of pan-antifungal resistance have been described. Critically ill patients are particularly at risk of being colonized by this yeast and person-to-person transmission may generate hospital outbreaks. In fact, C. auris can survive on inanimate surfaces for a long time and commonly used disinfectants are not effective. Additionally, devices such as central venous catheters (CVCs) or urinary catheters are particularly at risk of being colonized, representing a possible source for the development of bloodstream infections caused by C. auris, which carries a high mortality rate. Given its capability to spread in the hospital setting and the limited therapeutic options it is of outmost importance to promptly identify C. auris. However, commonly used biochemical tests frequently misidentify C. auris as other Candida species; currently the best identification techniques are MALDI-TOF and molecular methods, such as PCR of the ITS and D1/D2 regions of the 28s ribosomal DNA. Whole genome sequencing remains the gold standard for the phylogenetic investigation of outbreaks. The majority of cases of colonization by C. albicans will not cause bloodstream infections and contact precautions and surveillance of contacts will be sufficient. When invasive fungal infections occur, echinocandins still represent the first therapeutic choice. A combination therapy or the use of novel antifungals (such as ibrexafungerp or fosmanogepix) would be required for echinocandin resistant strains. In conclusion, C. auris represents a growing threat because of its antifungal resistance characteristics, its difficult identification and its easy spread from person to person. The aim of this mini-review is to summarize the main aspects concerning this pathogen.

466. All-Cause Mortality in Patients with Invasive Candidiasis or Candidemia from an Interim Analysis of a Phase 3 Open-label Study (FURI)

Abstract Background There are limited oral antifungal treatment options for patients with high-mortality fungal infections such as candidemia or invasive candidiasis who fail available antifungals or have infection caused by resistant fungi. Ibrexafungerp is a broad-spectrum glucan synthase inhibitor with activity against Candida spp., including azole- and echinocandin-resistant strains. A Phase 3 open-label study of ibrexafungerp (FURI; NCT03059992) is ongoing for patients intolerant of, or invasive fungal disease refractory to, standard antifungal therapy. We present an interim analysis of all-cause mortality (ACM) through 30 d post-treatment for patients with candidemia or invasive candidiasis (IC) who completed therapy up until Oct 2020. Methods FURI patients are eligible for enrollment with proven/probable severe mucocutaneous candidiasis or IC, or candidemia, with documented evidence of failure, intolerance, or toxicity related to an approved standard-of-care antifungal treatment; or patients who cannot receive oral antifungals (e.g., due to susceptibility), and continued IV antifungal therapy is clinically undesirable/unfeasible. Patients were followed through 30 d post-treatment for ACM. Results Out of the 74 patients who completed therapy in the FURI study through October 2020, 39 (52.7%) had IC or candidemia and received ibrexafungerp. The most common infections in this group were candidemia (28.2%), intra-abdominal infection (28.2%), and bone infection (20.5%). Survival at ≥ 30 d post-treatment was 92.3%. Three patients (7.7%) died within 30 d post ibrexafungerp, a 4th died at 31 d, and a 5th died at 56 d. The mean age of the expired patients was 54 yr. Three patients had candidemia (2 with C. parapsilosis and 1 with C. albicans), and 2 had intra-abdominal candidiasis, (both with C. glabrata). The average time on ibrexafungerp was 16.6 d. The mean time to death post-treatment for these patients was 22 d (median 8 d). In each case, the deaths were due to causes other than the underlying fungal disease. Conclusion Analysis of all-cause mortality in these patients from the FURI study indicates that oral ibrexafungerp provides a favorable therapeutic response in patients with challenging fungal disease and limited treatment options. Disclosures Thomas King, MS MPH, SCYNEXIS, Inc.: employee|SCYNEXIS, Inc.: Stocks/Bonds Nkechi Azie, MD MBA FIDSA, SCYNEXIS, Inc.: employee|SCYNEXIS, Inc.: Stocks/Bonds David A. Angulo, MD, SCYNEXIS, Inc.: employee|SCYNEXIS, Inc.: Stocks/Bonds.

871. Oral Ibrexafungerp Outcomes by Fungal Disease in Patients from an Interim Analysis of a Phase 3 Open-label Study (FURI)

Abstract Background There are limited oral treatment options for patients with fungal infections who fail currently available antifungals or have an infection caused by resistant organisms. Ibrexafungerp is an investigational broad-spectrum glucan synthase inhibitor with activity against Candida and Aspergillus species, including azole- and echinocandin-resistant strains. A Phase 3 open-label, single-arm study of ibrexafungerp (FURI; NCT03059992) is ongoing for the treatment of patients intolerant of, or with fungal disease refractory to, standard antifungal therapy. We present an interim analysis of patient outcomes from the FURI study by fungal disease type. Methods FURI patients are eligible for enrollment if they have proven or probable: severe mucocutaneous candidiasis, invasive candidiasis, chronic or invasive aspergillosis, with documented evidence of failure, intolerance, or toxicity related to a currently approved standard-of-care antifungal treatment; or patients who cannot receive approved oral antifungal options (e.g., due to susceptibility), and continued IV antifungal therapy is clinically undesirable or unfeasible. Results An independent Data Review Committee (DRC) provided an assessment of treatment response for 113 enrolled patients in the FURI study from 27 centers in US, UK and EU treated with ibrexafungerp for mucocutaneous or invasive fungal infections from 2016–2021. Fifty-six patients (49.5%) had invasive candidiasis/candidemia, 32 (28.3%) had mucocutaneous candidiasis, 14 (12.4%) had vulvovaginal candidiasis (VVC), and 11 (9.7%) patients had aspergillosis. Upon DRC review, the percent of patients with complete or partial response, or for VVC, clinical improvement (defined as vulvovaginal signs and symptoms score ≤ 1) was 58.4%; stable disease was 23.9%; and 11.5% had disease progression (including 2 VVC patients not meeting the criteria for clinical improvement). There was 1 death due to underlying causes, and 6 outcomes were indeterminate. The table presents outcomes by disease type. Conclusion Analysis of 113 patients from the FURI study indicates that oral ibrexafungerp provides a favorable therapeutic response in patients with challenging fungal disease and limited treatment options. Disclosures George R. Thompson, III, MD, Amplyx: Advisor/Consultant|Amplyx: Grant/Research Support|Astellas: Advisor/Consultant|Astellas: Grant/Research Support|Cidara: Advisor/Consultant|Cidara: Grant/Research Support|F2G: Advisor/Consultant|F2G: Grant/Research Support|Merck: Grant/Research Support|Pfizer: DSMB|Scynexis: Advisor/Consultant|Scynexis: Grant/Research Support Thomas King, MS MPH, SCYNEXIS, Inc.: employee|SCYNEXIS, Inc.: Stocks/Bonds Nkechi Azie, MD MBA FIDSA, SCYNEXIS, Inc.: employee|SCYNEXIS, Inc.: Stocks/Bonds David A. Angulo, MD, SCYNEXIS, Inc.: employee|SCYNEXIS, Inc.: Stocks/Bonds.

Calcineurin Inhibitor CN585 Exhibits Off-Target Effects in the Human Fungal Pathogen Aspergillus fumigatus.

Calcineurin (CN) is an attractive antifungal target as it is critical for growth, stress response, drug resistance, and virulence in fungal pathogens. The immunosuppressive drugs, tacrolimus (FK506) and cyclosporin A (CsA), are fungistatic and specifically inhibit CN through binding to their respective immunophilins, FK506-binding protein (FKBP12), and cyclophilin (CypA). We are focused on CN structure-based approaches for the development of non-immunosuppressive FK506 analogs as antifungal therapeutics. Here, we examined the effect of the novel CN inhibitor, CN585, on the growth of the human pathogen Aspergillus fumigatus, the most common cause of invasive aspergillosis. Unexpectedly, in contrast to FK506, CN585 exhibited off-target effect on A. fumigatus wild-type and the azole- and echinocandin-resistant strains. Unlike with FK506 and CsA, the A. fumigatus CN, FKBP12, CypA mutants (ΔcnaA, Δfkbp12, ΔcypA) and various FK506-resistant mutants were all sensitive to CN585. Furthermore, in contrast to FK506 the cytosolic to nuclear translocation of the CN-dependent transcription factor (CrzA-GFP) was not inhibited by CN585. Molecular docking of CN585 onto human and A. fumigatus CN complexes revealed differential potential binding sites between human CN versus A. fumigatus CN. Our results indicate CN585 may be a non-specific inhibitor of CN with a yet undefined antifungal mechanism of activity.

P057 All- cause mortality in patients with invasive Candidiasis or candidemia from an interim analysis of a Phase 3 Open-label Study (FURI)

Poster session 1, September 21, 2022, 12:30 PM - 1:30 PMBackgroundThere are limited oral treatment options for patients with high-mortality fungal infections such as candidemia or invasive candidiasis who fail currently available antifungals or have an infection caused by resistant organisms. Ibrexafungerp is an investigational broad-spectrum glucan synthase inhibitor with activity against Candida species, including azole- and echinocandin-resistant strains. A Phase 3 open-label, single-arm study of ibrexafungerp (FURI; NCT03059992) is ongoing for the treatment of patients intolerant of, or with invasive fungal disease refractory to, standard antifungal therapy. We present an interim analysis of all-cause mortality within 30 days post-treatment from the FURI study by fungal disease type for patients with candidemia or invasive candidiasis, who completed therapy up until October 2021.MethodsFURI patients are eligible for enrolment if they have proven or probable: severe mucocutaneous candidiasis or invasive candidiasis, or candidemia, with documented evidence of failure, intolerance, or toxicity related to a currently approved standard-of-care antifungal treatment; or patients who cannot receive approved oral antifungal options (eg, due to susceptibility), and continued IV antifungal therapy is clinically undesirable or unfeasible. Patients were followed through 30 days post-treatment for all-cause mortality.ResultsOut of the 113 patients who completed therapy in the FURI study through October 2021, 56 (50%) had invasive candidiasis or candidemia and were treated with ibrexafungerp. The most common infections in this group were candidemia (15/56, 26.8%), intra-abdominal infection (13/56, 23.2%), and bone infection (10/56, 17.9%).Overall survival within 30 days post-treatment in this group of 56 patients was 94.6%. Of the 56 patients with candidemia or invasive candidiasis, three (5.3%) died within 30 days after completion of treatment with ibrexafungerp, a fourth died at 31 days, a fifth died at 50 days, and a sixth died at 56 days. The mean age of the expired patients was 56 years. All 4 patients had candidemia (3 with C. parapsilosis and 1 with C. albicans), and 2 had intra-abdominal candidiasis, (both with C. glabrata). The average time on therapy with ibrexafungerp was 15.7 days. The mean time to death post-treatment for these patients was 27 days (median, 21 days). In five cases, the deaths were due to causes other than the underlying fungal disease. For the other case, the cause of death was not disclosed.ConclusionsAnalysis of all-cause mortality in these patients from the FURI study indicates that oral ibrexafungerp provides a favorable therapeutic response in patients with challenging fungal diseases and limited treatment options.

P056 Oral Ibrexafungerp outcomes by fungal disease in patients from an interim analysis of a Phase 3 Open-label Study (FURI)

Poster session 1, September 21, 2022, 12:30 PM - 1:30 PMBackgroundThere are limited oral treatment options for patients with fungal infections who fail currently available antifungals or have an infection caused by resistant organisms. Ibrexafungerp is an investigational broad-spectrum glucan synthase inhibitor with activity against Candida and Aspergillus species, including azole- and echinocandin-resistant strains. A Phase 3 open-label, single-arm study of ibrexafungerp (FURI; NCT03059992) is ongoing for the treatment of patients intolerant of, or with fungal disease refractory to, standard antifungal therapy. We present an interim analysis of patient outcomes from the FURI study by fungal disease type.MethodsFURI patients are eligible for enrollment if they have proven or probable: severe mucocutaneous candidiasis, invasive candidiasis, chronic or invasive aspergillosis, with documented evidence of failure, intolerance, or toxicity related to a currently approved standard-of-care antifungal treatment; or patients who cannot receive approved oral antifungal options (e.g., due to susceptibility), and continued IV antifungal therapy is clinically undesirable or unfeasible.ResultsAn independent Data Review Committee (DRC) provided an assessment of treatment response for 113 enrolled patients in the FURI study from 27 centers in US, UK, and EU treated with ibrexafungerp for mucocutaneous or invasive fungal infections from 2016-2021. A total of 56 patients (49.5%) had invasive candidiasis/candidemia, 32 (28.3%) had mucocutaneous candidiasis, 14 (12.4%) had vulvovaginal candidiasis (VVC), and 11 (9.7%) patients had aspergillosis.Upon DRC review, the percentage of patients with complete or partial response, or for VVC, clinical improvement (defined as vulvovaginal signs and symptoms score ≤ 1) was 58.4%; stable disease was 23.9%; and 11.5% had disease progression (including 2 VVC patients not meeting the criteria for clinical improvement). There was one death due to underlying causes, and six outcomes were indeterminate. Table 1 shows outcomes by disease type.ConclusionsAnalysis of 113 patients from the FURI study indicates that oral ibrexafungerp provides a favorable therapeutic response in patients with challenging fungal disease and limited treatment options.

The Feasibility of Ibrexafungerp for the Treatment of Fungal Infections in Patients with Hematological Malignancies.

Invasive fungal diseases (IFD) remain a major cause of morbidity and mortality in hematological patients, especially those undergoing hematopoietic stem cell transplantation (HSCT). Despite relatively high incidence, diagnosis and treatment remain a challenge due to non-specific manifestation and limited antifungal armamentarium. A first-in-class triterpenoid antifungal ibrexafungerp that acts by inhibiting the glucan synthase enzyme in the fungal cell wall was recently approved by the USA Food and Drug Administration for the treatment of vaginal yeast infections. Preclinical data show activity against numerous fungi species, including azole- and echinocandin-resistant strains. Preliminary data from ongoing phase 3 studies in IFD have been encouraging, but the role of ibrexafungerp in hematological patients who develop fungal infections has not yet been described. Herein, we discuss the feasibility of oral ibrexafungerp-based antifungal therapy for adult patients with hematological malignancies who have either undergone HSCT or received treatment with a novel targeted therapy agent. We present four clinical cases where ibrexafungerp alone or in combination with other antifungal agents was successfully employed for the management of refractory fungal infection. We describe real-life experiences showing the potential clinical implementation of ibrexafungerp for patients with hematological malignancies for the first time, and provoke future discussion.

Benzylic Dehydroxylation of Echinocandin Antifungal Drugs Restores Efficacy against Resistance Conferred by Mutated Glucan Synthase.

Each year, infections caused by fungal pathogens claim the lives of about 1.6 million people and affect the health of over a billion people worldwide. Among the most recently developed antifungal drugs are the echinocandins, which noncompetitively inhibit β-glucan synthase, a membrane-bound protein complex that catalyzes the formation of the main polysaccharide component of the fungal cell wall. Resistance to echinocandins is conferred by mutations in FKS genes, which encode the catalytic subunit of the β-glucan synthase complex. Here, we report that selective removal of the benzylic alcohol of the nonproteinogenic amino acid 3S,4S-dihydroxy-l-homotyrosine of the echinocandins anidulafungin and rezafungin, restored their efficacy against a large panel of echinocandin-resistant Candida strains. The dehydroxylated compounds did not significantly affect the viability of human-derived cell culture lines. An analysis of the efficacy of the dehydroxylated echinocandins against resistant Candida strains, which contain mutations in the FKS1 and/or FKS2 genes of the parental strains, identified amino acids of the Fks proteins that are likely to reside in proximity to the l-homotyrosine residue of the bound drug. This study describes the first example of a chemical modification strategy to restore the efficacy of echinocandin drugs, which have a critical place in the arsenal of antifungal drugs, against resistant fungal pathogens.

123. Oral Ibrexafungerp Outcomes by Fungal Disease in Patients from an Interim Analysis of a Phase 3 Open-label Study (FURI)

Background Candida species are a major cause of invasive and mucocutaneouls infections. There are limited oral treatment options available for patients with Candida infections who are unresponsive to or who are intolerant of currently available antifungals. Oral ibrexafungerp is an investigational broad-spectrum glucan synthase inhibitor antifungal with activity against Candida and Aspergillus species, including azole- and echinocandin-resistant strains. A Phase 3 open-label, single-arm study of ibrexafungerp (FURI; NCT03059992) is ongoing for the treatment of patients intolerant of or with fungal disease refractory to standard antifungal therapy. We present an analysis of patient outcomes from the FURI study by fungal disease type. Table 1: FURI Outcomes by Fungal Disease MethodsFURI patients were eligible for enrollment if they have proven or probable, severe mucocutaneous candidiasis, invasive candidiasis or invasive aspergillosis,other fungal diseases and evidence of failure to, intolerance to, or toxicity related to a currently approved standard-of-care antifungal treatment or can not receive approved oral antifungal options (e.g., susceptibility of the organism) and a continued IV antifungal therapy is clinically undesirable or unfeasible. ResultsAn independent Data Review Committee (DRC) provided an assessment of treatment response for 74 patients enrolled in the FURI study from 22 centers in US, UK and EU treated with ibrexafungerp for mucocutaneous or invasive fungal infections from 2016- 2020. A total of 39 (52.7%) patients had invasive candidiasis, 32 (43.2%) had mucocutaneous candidiasis and 3 (4.5%) patients had invasive aspergillosis. The percent of patients who were determined to have a complete response (CR), partial response (PR), clinical improvement (CI) was 63.5%, stable disease (SD) was 23.0%, patients with progression of disease 6.8% and 4 patients were indeterminate. Additionally, there was 1 death in the FURI study that was not related to fungal disease. Table 1 shows outcomes by fungal disease type as determined by the DRC. ConclusionAnalysis of 74 patients from the FURI study indicates that oral ibrexafungerp provides a favorable therapeutic response in patients with challenging fungal disease and limited treatment options. Disclosures Peter G. Pappas, MD, Astellas (Research Grant or Support)Cidara (Research Grant or Support)F2G (Consultant)Matinas (Consultant, Scientific Research Study Investigator)Mayne Pharma (Research Grant or Support)Scynexis (Research Grant or Support) Oliver Cornely, Prof., Actelion (Consultant, Grant/Research Support)Al-Jazeera Pharmaceuticals (Consultant)Allecra Therapeutics (Consultant)Amplyx (Consultant, Grant/Research Support)Astellas (Consultant, Grant/Research Support)Basilea (Consultant, Grant/Research Support)Biocon (Consultant)Biosys (Consultant)Cidara (Consultant, Grant/Research Support)CoRe Consulting (Consultant)Da Volterra (Consultant, Grant/Research Support)DFG (German Research Foundation) (Grant/Research Support)Entasis (Consultant)F2G (Consultant, Grant/Research Support)German Federal Ministry of Research and Education (Grant/Research Support)Gilead (Consultant, Grant/Research Support)Grupo Biotoscana (Consultant)Immunic (Grant/Research Support)IQVIA (Consultant)Janssen (Grant/Research Support)Matinas (Consultant)Medicines Company (Grant/Research Support)MedPace (Consultant, Grant/Research Support)Melinta Therapeutics (Grant/Research Support)Menarini (Consultant)Merck/MSD (Consultant, Grant/Research Support)Molecular Partners (Consultant)MSG-ERC (Consultant)Mylan (Consultant)Nabriva (Consultant)Noxxon (Consultant)Octapharma (Consultant)Paratek (Consultant)Pfizer (Consultant, Grant/Research Support)PSI (Consultant)Roche Diagnostics (Consultant)Scynexis (Consultant, Grant/Research Support)Seres (Consultant)Shionogi (Consultant)Wiley (Blackwell) (Other Financial or Material Support) Philipp Koehler, MD, Ambu GmbH (Consultant, Speaker's Bureau)Astellas Pharma (Speaker's Bureau)Euopean Confederation of Medical Mycology (Speaker's Bureau)German Federal Ministry of Research and Education (Grant/Research Support)Gilead (Consultant, Speaker's Bureau)MSD (Speaker's Bureau)Noxxon N.V. (Consultant)Pfizer (Speaker's Bureau)State of North Rhine-Westphalia, Germany (Grant/Research Support) Todd P. McCarty, MD, Cidara (Grant/Research Support)GenMark (Grant/Research Support, Other Financial or Material Support, Honoraria for Research Presentation)T2 Biosystems (Consultant) Barbara D. Alexander, MD, MHS, SCYNEXIS, Inc. (Consultant) Rachel Miller, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Caryn Morse, MD, Chimerix (Scientific Research Study Investigator)Covis Pharma (Scientific Research Study Investigator)Gilead Sciences Inc. (Scientific Research Study Investigator)Ridgeback Biotherapeutics (Scientific Research Study Investigator)Roche (Scientific Research Study Investigator)SCYNEXIS, Inc. (Scientific Research Study Investigator)Theratechnologies (Advisor or Review Panel member)Viiv (Advisor or Review Panel member) Luis Ostrosky-Zeichner, MD, Amplyx (Consultant)Cidara (Consultant)F2G (Consultant)Gilead (Grant/Research Support, Speaker's Bureau)Pfizer (Scientific Research Study Investigator, Speaker's Bureau)Scynexis (Grant/Research Support, Scientific Research Study Investigator)Viracor (Consultant) Jürgen Prattes, Dr, AbbVie Inc. (Shareholder)Gilead (Speaker's Bureau)MSD (Grant/Research Support)Novo Nordisk (Shareholder)Pfizer (Advisor or Review Panel member)Stryker (Shareholder) Andrej Spec, MD, MSCI, Mayne Pharma (Grant/Research Support) Riina Rautemaa-Richardson, DDS, PhD, FRCPath, SCYNEXIS, Inc. (Scientific Research Study Investigator) Thomas J. Walsh, MD, PhD (hon), Scynexis (Consultant, Grant/Research Support)Shionogi (Consultant, Grant/Research Support) Francisco M. Marty, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Marisa Miceli, MD, SCYNEXIS, Inc. (Advisor or Review Panel member) Martin Hoenigl, MD, Astellas (Grant/Research Support)Gilead (Grant/Research Support)Pfizer (Grant/Research Support) Martin Hoenigl, MD, Astellas (Individual(s) Involved: Self): Grant/Research Support; F2G (Individual(s) Involved: Self): Grant/Research Support; Gilead (Individual(s) Involved: Self): Grant/Research Support; Pfiyer (Individual(s) Involved: Self): Grant/Research Support; Scýnexis (Individual(s) Involved: Self): Grant/Research Support Thomas F. Patterson, MD, SCYNEXIS, Inc. (Advisor or Review Panel member) Nkechi Azie, MD, SCYNEXIS, Inc. (Employee, Shareholder) David A. Angulo, MD, SCYNEXIS, Inc. (Employee, Shareholder)

983. Outcomes of Candida Bone and Joint Infections in Eight Patients from a Phase 3 Open-label Study (FURI)

Abstract Background Candida osteoarticular infections are often preceded by candidemia with the intervertebral discs and knee joints the most common area for candidemic seeding. Candida osteomyelitis has significant morbidity and diagnosis is often delayed difficult to treat. Treatment courses are usually long and there are limited oral options available for patients who have an azole-resistant infection. Oral ibrexafungerp is an investigational broad-spectrum glucan synthase inhibitor antifungal with activity against Candida and Aspergillus species, including azole- and echinocandin-resistant strains. A Phase 3 open-label, single-arm study of ibrexafungerp (FURI; NCT03059992) is ongoing for the treatment of patients with fungal disease refractory or who intolerant of to standard of care antifungal therapy. Table 1. FURI Bone and Joint Infection Outcomes Methods FURI subjects were eligible for enrollment if they have proven or probable, severe mucocutaneous candidiasis, invasive candidiasis or invasive aspergillosis and documented evidence of failure to, intolerance to, or toxicity related to a currently approved standard-of-care antifungal treatment or can not receive approved oral antifungal options (e.g., susceptibility of the organism) or a continued IV antifungal therapy is clinically undesirable or unfeasible. Results An independent Data Review Committee (DRC) provided an assessment of treatment response for a total 74 subjects enrolled in the FURI study from 22 centers in US, UK and EU treated with ibrexafungerp for mucocutaneous or invasive fungal infections from 2016- 2020. There were 8 subjects out of the 74 subjects who were diagnosed with various bone and joint infections, 5 subjects with spondylodiscitis, 1 subject with a knee/prosthetic joint infection and 2 subjects with bone infections, one of the tibia and one of the zygomatic arch. Table 1 shows outcomes for this patient group, five (75%) patients had a clinical benefit (complete or partial response and stable response), one (12.5%) had progression of disease and one patient was indeterminate. The median days of therapy for this group was 210.5 days. Conclusion Analysis of 8 subjects from the FURI study indicates that oral ibrexafungerp provides a promising therapeutic response in option for patients with bone and/or joint infections. Disclosures Caryn Morse, MD, Chimerix (Scientific Research Study Investigator)Covis Pharma (Scientific Research Study Investigator)Gilead Sciences Inc. (Scientific Research Study Investigator)Ridgeback Biotherapeutics (Scientific Research Study Investigator)Roche (Scientific Research Study Investigator)SCYNEXIS, Inc. (Scientific Research Study Investigator)Theratechnologies (Advisor or Review Panel member)Viiv (Advisor or Review Panel member) Oliver Cornely, Prof., Actelion (Consultant, Grant/Research Support)Al-Jazeera Pharmaceuticals (Consultant)Allecra Therapeutics (Consultant)Amplyx (Consultant, Grant/Research Support)Astellas (Consultant, Grant/Research Support)Basilea (Consultant, Grant/Research Support)Biocon (Consultant)Biosys (Consultant)Cidara (Consultant, Grant/Research Support)CoRe Consulting (Consultant)Da Volterra (Consultant, Grant/Research Support)DFG (German Research Foundation) (Grant/Research Support)Entasis (Consultant)F2G (Consultant, Grant/Research Support)German Federal Ministry of Research and Education (Grant/Research Support)Gilead (Consultant, Grant/Research Support)Grupo Biotoscana (Consultant)Immunic (Grant/Research Support)IQVIA (Consultant)Janssen (Grant/Research Support)Matinas (Consultant)Medicines Company (Grant/Research Support)MedPace (Consultant, Grant/Research Support)Melinta Therapeutics (Grant/Research Support)Menarini (Consultant)Merck/MSD (Consultant, Grant/Research Support)Molecular Partners (Consultant)MSG-ERC (Consultant)Mylan (Consultant)Nabriva (Consultant)Noxxon (Consultant)Octapharma (Consultant)Paratek (Consultant)Pfizer (Consultant, Grant/Research Support)PSI (Consultant)Roche Diagnostics (Consultant)Scynexis (Consultant, Grant/Research Support)Seres (Consultant)Shionogi (Consultant)Wiley (Blackwell) (Other Financial or Material Support) Philipp Koehler, MD, Ambu GmbH (Consultant, Speaker’s Bureau)Astellas Pharma (Speaker’s Bureau)Euopean Confederation of Medical Mycology (Speaker’s Bureau)German Federal Ministry of Research and Education (Grant/Research Support)Gilead (Consultant, Speaker’s Bureau)MSD (Speaker’s Bureau)Noxxon N.V. (Consultant)Pfizer (Speaker’s Bureau)State of North Rhine-Westphalia, Germany (Grant/Research Support) Jürgen Prattes, Dr, AbbVie Inc. (Shareholder)Gilead (Speaker’s Bureau)MSD (Grant/Research Support)Novo Nordisk (Shareholder)Pfizer (Advisor or Review Panel member)Stryker (Shareholder) Guenter Weiss, MD, MSD (Speaker’s Bureau)Novartis (Speaker’s Bureau)Pfizer (Speaker’s Bureau)Pharmacosmos (Speaker’s Bureau)Scynexis (Scientific Research Study Investigator)Vifor (Speaker’s Bureau) Nkechi Azie, MD, SCYNEXIS, Inc. (Employee, Shareholder) David A. Angulo, MD, SCYNEXIS, Inc. (Employee, Shareholder)

992. Oral Ibrexafungerp Outcomes in Patients with Oropharyngeal and Esophageal Candidiasis from an Interim Analysis of a Phase 3 Open-label Study (FURI)

Abstract Background Candida albicans is the predominant organism causing esophageal candidiasis (EC) and oropharyngel candidiasis (OPC). These infections may arise from subjects colonized with Candida who are predisposed due to illness, debility or a local reduction in host resistance to an overgrowth of their own indigenous flora. Patients with mucocutaneous Candida infections can be treated in the outpatient setting, yet there are limited oral treatment options available for patients who are unresponsive to or who are intolerant to currently available antifungals. Oral ibrexafungerp is an investigational broad-spectrum glucan synthase inhibitor antifungal with activity against Candida species, including azole- and echinocandin-resistant strains. A Phase 3 open-label, single-arm study of ibrexafungerp (FURI; NCT03059992) is ongoing for the treatment of patients intolerant of or with fungal disease refractory to standard antifungal therapy. Table 1. FURI Outcomes in OPC and EC Methods FURI subjects were eligible for enrollment if they had proven or probable severe mucocutaneous candidiasis, invasive candidiasis, invasive aspergillosis, or other fungal diseases with evidence of treatment failure, intolerance, or toxicity related to a currently approved standard-of-care antifungal treatment or if they were unable to receive an approved oral antifungal option (e.g., susceptibility of the organism) and a continued IV antifungal therapy was clinically undesirable or unfeasible. Results An independent Data Review Committee (DRC) provided an assessment of treatment response for 74 subjects enrolled in the FURI study from 22 centers in US, UK and EU treated with ibrexafungerp for mucocutaneous or invasive fungal infections from 2016- 2020. A total 32 subjects (43.2%) had mucocutaneous candidiasis and 24 subjects were diagnosed with OPC or EC. The percent of patients who were determined to have a complete response (CR) or partial response (PR) was 62.5%, stable disease (SD), 20.8%, and progression of disease, 16.7%. Table 1 shows outcomes by EC and OPC as determined by the DRC. Conclusion Analysis of 24 EC and OPC patients from the FURI study indicates that oral ibrexafungerp provides a favorable therapeutic response in patients with challenging mucocutaneous fungal disease and limited treatment options. Disclosures Oliver Cornely, Prof., Actelion (Consultant, Grant/Research Support)Al-Jazeera Pharmaceuticals (Consultant)Allecra Therapeutics (Consultant)Amplyx (Consultant, Grant/Research Support)Astellas (Consultant, Grant/Research Support)Basilea (Consultant, Grant/Research Support)Biocon (Consultant)Biosys (Consultant)Cidara (Consultant, Grant/Research Support)CoRe Consulting (Consultant)Da Volterra (Consultant, Grant/Research Support)DFG (German Research Foundation) (Grant/Research Support)Entasis (Consultant)F2G (Consultant, Grant/Research Support)German Federal Ministry of Research and Education (Grant/Research Support)Gilead (Consultant, Grant/Research Support)Grupo Biotoscana (Consultant)Immunic (Grant/Research Support)IQVIA (Consultant)Janssen (Grant/Research Support)Matinas (Consultant)Medicines Company (Grant/Research Support)MedPace (Consultant, Grant/Research Support)Melinta Therapeutics (Grant/Research Support)Menarini (Consultant)Merck/MSD (Consultant, Grant/Research Support)Molecular Partners (Consultant)MSG-ERC (Consultant)Mylan (Consultant)Nabriva (Consultant)Noxxon (Consultant)Octapharma (Consultant)Paratek (Consultant)Pfizer (Consultant, Grant/Research Support)PSI (Consultant)Roche Diagnostics (Consultant)Scynexis (Consultant, Grant/Research Support)Seres (Consultant)Shionogi (Consultant)Wiley (Blackwell) (Other Financial or Material Support) Philipp Koehler, MD, Ambu GmbH (Consultant, Speaker’s Bureau)Astellas Pharma (Speaker’s Bureau)Euopean Confederation of Medical Mycology (Speaker’s Bureau)German Federal Ministry of Research and Education (Grant/Research Support)Gilead (Consultant, Speaker’s Bureau)MSD (Speaker’s Bureau)Noxxon N.V. (Consultant)Pfizer (Speaker’s Bureau)State of North Rhine-Westphalia, Germany (Grant/Research Support) Riina Rautemaa-Richardson, DDS, PhD, FRCPath, SCYNEXIS, Inc. (Scientific Research Study Investigator) G. Marshall Lyon, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Francisco M. Marty, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Rachel Miller, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Thomas J. Walsh, MD, PhD (hon), Scynexis (Consultant, Grant/Research Support)Shionogi (Consultant, Grant/Research Support) Peter Pappas, MD, Astellas (Grant/Research Support)Cidara (Grant/Research Support, Advisor or Review Panel member)Mayne (Grant/Research Support, Advisor or Review Panel member)Merck (Grant/Research Support)SCYNEXIS, Inc. (Consultant, Grant/Research Support) Todd P. McCarty, MD, Cidara (Grant/Research Support)GenMark (Grant/Research Support, Other Financial or Material Support, Honoraria for Research Presentation)T2 Biosystems (Consultant) Caryn Morse, MD, Chimerix (Scientific Research Study Investigator)Covis Pharma (Scientific Research Study Investigator)Gilead Sciences Inc. (Scientific Research Study Investigator)Ridgeback Biotherapeutics (Scientific Research Study Investigator)Roche (Scientific Research Study Investigator)SCYNEXIS, Inc. (Scientific Research Study Investigator)Theratechnologies (Advisor or Review Panel member)Viiv (Advisor or Review Panel member) Luis Ostrosky-Zeichner, MD, Amplyx (Consultant)Cidara (Consultant)F2G (Consultant)Gilead (Grant/Research Support, Speaker’s Bureau)Pfizer (Scientific Research Study Investigator, Speaker’s Bureau)Scynexis (Grant/Research Support, Scientific Research Study Investigator)Viracor (Consultant) Jürgen Prattes, Dr, AbbVie Inc. (Shareholder)Gilead (Speaker’s Bureau)MSD (Grant/Research Support)Novo Nordisk (Shareholder)Pfizer (Advisor or Review Panel member)Stryker (Shareholder) Andrej Spec, MD, MSCI, SCYNEXIS, Inc. (Consultant, Scientific Research Study Investigator) David Andes, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Oliver Witzke, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Nkechi Azie, MD, SCYNEXIS, Inc. (Employee, Shareholder) David A. Angulo, MD, SCYNEXIS, Inc. (Employee, Shareholder)

Multifactorial Role of Mitochondria in Echinocandin Tolerance Revealed by Transcriptome Analysis of Drug-Tolerant Cells

ABSTRACTFungal infections cause significant mortality and morbidity worldwide, and the limited existing antifungal reservoir is further weakened by the emergence of strains resistant to echinocandins, a first line of antifungal therapy. Candida glabrata is an opportunistic fungal pathogen that rapidly develops mutations in the echinocandin drug target β-1,3-glucan synthase (GS), which are associated with drug resistance and clinical failure. Although echinocandins are considered fungicidal in Candida sp., a subset of C. glabrata cells survive echinocandin exposure, forming a drug-tolerant cell reservoir, from which resistant mutations are thought to emerge. Despite their importance, the physiology of rare drug-tolerant cells is poorly understood. We used fluorescence-activated cell sorting to enrich for echinocandin-tolerant cells, followed by modified single-cell RNA sequencing to examine their transcriptional landscape. This analysis identified a transcriptional signature distinct from the stereotypical yeast environmental stress response and characterized by upregulation of pathways involved in chromosome structure and DNA topology and downregulation of oxidative stress responses, of which the latter was observed despite increased levels of reactive oxygen species. Further analyses implicated mitochondria in echinocandin tolerance, wherein inhibitors of mitochondrial complexes I and IV reduced echinocandin-mediated cell killing, but mutants lacking various mitochondrial components all showed an echinocandin hypotolerant phenotype. Finally, GS enzyme complexes purified from mitochondrial mutants exhibited normal in vitro inhibition kinetics, indicating that mitochondrial defects influence cell survival downstream of the drug-target interaction. Together, these results provide new insights into the C. glabrata response to echinocandins and reveal a multifactorial role of mitochondria in echinocandin tolerance.

Emergence of resistant Candida glabrata in Germany.

Background Candida glabrata is the second leading fungal pathogen causing candidaemia and invasive candidiasis in Europe. This yeast is recognized for its rapid ability to acquire antifungal drug resistance.ObjectivesWe systematically evaluated 176 C. glabrata isolates submitted to the German National Reference Center for Invasive Fungal Infections (NRZMyk) between 2015 and 2019 with regard to echinocandin and fluconazole susceptibility.MethodsSusceptibility testing was performed using a reference protocol (EUCAST) and a range of commercial assays. Hot spot regions of the echinocandin target FKS genes were sequenced using Sanger sequencing.ResultsIn total, 84 of 176 isolates were initially classified as anidulafungin-resistant based on EUCAST testing. Of those, 71 harboured mutations in the glucan synthase encoding FKS genes (13% in FKS1, 87% in FKS2). Significant differences in anidulafungin MICs were found between distinct mutation sites. 11 FKS wild-type (WT) isolates initially classified as resistant exhibited anidulafungin MICs fluctuating around the interpretation breakpoint upon re-testing with multiple assays. Two FKS WT isolates consistently showed high anidulafungin MICs and thus must be considered resistant despite the absence of target gene mutations. Over one-third of echinocandin-resistant strains displayed concomitant fluconazole resistance. Of those, isolates linked to bloodstream infection carrying a change at Ser-663 were associated with adverse clinical outcome.ConclusionsResistant C. glabrata strains are emerging in Germany. Phenotypic echinocandin testing can result in misclassification of susceptible strains. FKS genotyping aids in detecting these strains, however, echinocandin resistance may occur despite a wild-type FKS genotype.

1248. Efficacy and Safety of Oral Ibrexafungerp in 41 Patients with Refractory Fungal Diseases, Interim Analysis of a Phase 3 Open-label Study (FURI)

Background Candida infections resistant to currently available antifungals are an emerging global threat. Ibrexafungerp is an investigational broad-spectrum glucan synthase inhibitor antifungal with activity against Candida and Aspergillus species, including azole- and echinocandin-resistant strains. A Phase 3 open-label, single-arm study of oral ibrexafungerp (FURI) (Clinicaltrials.gov NCT03059992) is ongoing for the treatment of patients (≥18 years) with fungal diseases who are intolerant of or refractory to standard antifungal therapies.MethodsAn independent Data Review Committee (DRC) provided an assessment of treatment response for 41 patients. Patients were enrolled in 22 centers from 6 countries. Patients were eligible for enrollment if they had proven or probable, invasive or severe mucocutaneous candidiasis and documented evidence of failure of, intolerance to, or toxicity related to a currently approved standard-of-care antifungal treatment or could not receive approved oral antifungal options (e.g., susceptibility of the organism) and a continued IV antifungal therapy was undesirable or unfeasible.ResultsThe 41 patients assessed had the following infection types: intra-abdominal abscesses, oropharyngeal candidiasis, esophageal candidiasis, candidemia, and others. The DRC adjudicated 23 patients (56%) as achieving complete or partial response, 11 patients (27%) maintaining stable disease, 6 patients (15%) with progression of disease and one case was considered as indeterminate. The efficacy of oral ibrexafungerp by pathogen is shown in Table 1. Ibrexafungerp was well-tolerated with the most common treatment-related adverse events being of gastrointestinal origin. No deaths due to progression of fungal disease were reported.Table 1: Ibrexafungerp Outcomes by Pathogen ConclusionPreliminary analysis of these 41 cases indicate that oral ibrexafungerp provides a favorable therapeutic response in the majority of patients with difficult to treat Candida spp. infections, including those caused by non-albicans Candida species.Disclosures Barbara D. Alexander, MD, MHS, SCYNEXIS, Inc. (Employee, Scientific Research Study Investigator, Research Grant or Support) Oliver Cornely, Prof., Actelion (Grant/Research Support)Actelion (Other Financial or Material Support, Personal fees)Al Jazeera Pharmaceuticals (Consultant)Allecra Therapeutics (Other Financial or Material Support, Personal fees)Amplyx (Other Financial or Material Support, Personal fees)Amplyx (Grant/Research Support)Astellas (Grant/Research Support)Astellas (Other Financial or Material Support, Personal fees)Basilea (Other Financial or Material Support, Personal fees)Basilea (Grant/Research Support)Biosys UK Limited (Other Financial or Material Support, Personal fees)Cidara (Other Financial or Material Support, Personal fees)Cidara (Grant/Research Support)Da Volterra (Grant/Research Support)Da Volterra (Other Financial or Material Support, Personal fees)Entasis (Other Financial or Material Support, Personal fees)F2G (Other Financial or Material Support)F2G (Grant/Research Support)Gilead (Grant/Research Support)Gilead (Other Financial or Material Support, Personal fees)Grupo Biotoscana (Other Financial or Material Support, Personal fees)Janssen Pharmaceuticals (Grant/Research Support)Matinas (Other Financial or Material Support, Personal fees)Medicines Company (Grant/Research Support)MedPace (Grant/Research Support)MedPace (Other Financial or Material Support, Personal fees)Melinta Therapeutics (Grant/Research Support)Menarini Ricerche (Other Financial or Material Support, Personal fees)Merck/MSD (Other Financial or Material Support, Personal fees)Merck/MSD (Grant/Research Support)Mylan Pharmaceuticals (Consultant)Nabriva Therapeutics (Other Financial or Material Support, Personal fees)Octapharma (Other Financial or Material Support, Personal fees)Paratek Pharmaceuticals (Other Financial or Material Support, Personal fees)Pfizer (Other Financial or Material Support, Personal fees)Pfizer (Grant/Research Support)PSI (Other Financial or Material Support, Personal fees)Rempex (Other Financial or Material Support, Personal fees)Roche Diagnostics (Other Financial or Material Support, Personal fees)Scynexis (Other Financial or Material Support, Personal fees)Scynexis (Grant/Research Support)Seres Therapeutics (Other Financial or Material Support, Personal fees)Tetraphase (Other Financial or Material Support, Personal fees) Peter Pappas, MD, SCYNEXIS, Inc. (Consultant, Advisor or Review Panel member, Research Grant or Support) Rachel Miller, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Luis Ostrosky-Zeichner, MD, Amplyx (Scientific Research Study Investigator)Astellas (Consultant, Scientific Research Study Investigator, Other Financial or Material Support, Non-branded educational speaking)Biotoscana (Consultant, Other Financial or Material Support, Non-branded educational speaking)Cidara (Consultant, Scientific Research Study Investigator)F2G (Consultant)Gilead (Consultant)Mayne (Consultant)Octapharma (Consultant)Pfizer (Other Financial or Material Support, Non-branded educational speaking)Scynexis (Consultant, Grant/Research Support, Scientific Research Study Investigator)Stendhal (Consultant)Viracor (Consultant) Andrej Spec, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator, Advisor or Review Panel member) Riina Rautemaa-Richardson, DDS, PhD, FRCPath, SCYNEXIS, Inc. (Scientific Research Study Investigator) Robert Krause, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Caryn Morse, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) John W. Sanders, III, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) David Andes, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator, Advisor or Review Panel member) George Lyon, MD, SCYNEXIS, Inc. (Scientific Research Study Investigator) Francisco M. Marty, MD, Allovir (Consultant)Amplyx (Consultant)Ansun (Scientific Research Study Investigator)Avir (Consultant)Cidara (Scientific Research Study Investigator)F2G (Consultant, Scientific Research Study Investigator)Kyorin (Consultant)Merck (Consultant, Grant/Research Support, Scientific Research Study Investigator)New England Journal of Medicine (Other Financial or Material Support, Honorarium for Video)Regeneron (Consultant, Scientific Research Study Investigator)ReViral (Consultant)Scynexis (Scientific Research Study Investigator)Symbio (Consultant)Takeda (Scientific Research Study Investigator)United Medical (Consultant)WHISCON (Scientific Research Study Investigator) Marisa H. Miceli, MD, FIDSA, SCYNEXIS, Inc. (Advisor or Review Panel member) Thomas F. Patterson, MD, SCYNEXIS, Inc. (Advisor or Review Panel member) Martin Hoenigl, MD, SCYNEXIS, Inc. (Grant/Research Support, Scientific Research Study Investigator, Advisor or Review Panel member) Nkechi Azie, MD, SCYNEXIS, Inc. (Employee, Shareholder) David A. Angulo, MD, SCYNEXIS, Inc. (Employee, Shareholder)

Activity of a novel 1,3-beta-D-glucan Synthase Inhibitor, Ibrexafungerp (formerly SCY-078), Against Candida glabrata.

Ibrexafungerp (formerly SCY-078), a novel glucan synthase inhibitor with oral availability, was evaluated for activity against Candida glabrata Susceptibility of clinical strains to Ibrexafungerp was determined by microdilution and time kill assays. The MIC range against wild type strains was 1-2 μg/mL. IBX was also active against the majority of echinocandin-resistant strains. Time kill studies showed a 4 to 6-log reduction in growth at concentrations of 0.25 to 4 μg/ml at 24 and 48 hr.

Ibrexafungerp: A novel oral glucan synthase inhibitor.

Ibrexafungerp is a novel glucan synthase inhibitor currently undergoing phase II and phase III clinical trials. This compound has demonstrated in vitro activity against clinically important fungal pathogens including Candida spp. and Aspergillus spp. It is able to retain activity against many echinocandin-resistant strains of Candida due to differential avidity for the target site compared to echinocandins. In vivo animal models have demonstrated efficacy in murine models of invasive candidiasis, aspergillosis, and pneumocystis. Due to high bioavailability, it can be administered both orally and intravenously. A favorable drug interaction and tolerability profile is observed with this compound. This review summarizes existing data that have either been published or presented at international symposia.

Clinical and Laboratory Development of Echinocandin Resistance in Candida glabrata: Molecular Characterization.

The pathogenic yeast Candida glabrata has become a public health issue due to the increasing number of echinocandin resistant clinical strains reported. In this study, acquisition and development of resistance to this antifungal class were studied in serial C. glabrata isolates from five patients admitted in two Spanish hospitals with a resistant profile against echinocandins associated with different mutations in hot-spot 1 of FKS2 gene. For two of these patients susceptible FKS wild-type isolates obtained prior to resistant ones were also investigated. Isolates were genotyped using multilocus sequence typing and microsatellite length polymorphism techniques, which yielded comparable results. Susceptible and resistant isolates from the same patient had the same genotype, being sequence type (ST) 3 the most prevalent among them. Isolates with different FKS mutations but the same ST were present in the same patient. MSH2 gene alterations were also studied to investigate their correlation with antifungal resistance acquisition but no association was found with antifungal resistance nor with specific genotypes. In vitro exposure to increasing concentrations of micafungin to susceptible isolates developed colonies carrying FKS mutations in agar plates containing a minimum concentration of 0.06 mg/L of micafungin after less than 48 h of exposure. We investigated the correlation between development of resistance and genotype in a set of susceptible strains after being in vitro exposed to micafungin and anidulafungin but no correlation was found. Mutant prevention concentration values and spontaneous growth frequencies after selection with both echinocandins were statistically similar, although FKS mutant colonies were more abundant after micafungin exposure (p < 0.001). Mutation S663P and F659 deletion were the most common ones found after selection with both echinocandins.