scholarly journals In VitroActivity of a Novel Broad-Spectrum Antifungal, E1210, Tested against Aspergillus spp. Determined by CLSI and EUCAST Broth Microdilution Methods

2011 ◽  
Vol 55 (11) ◽  
pp. 5155-5158 ◽  
Author(s):  
Michael A. Pfaller ◽  
Frederick Duncanson ◽  
Shawn A. Messer ◽  
Gary J. Moet ◽  
Ronald N. Jones ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Broad Spectrum ◽  
Antifungal Agents ◽  
Susceptibility Testing ◽  
Hyphal Growth ◽  
Wild Type ◽  
Minimum Effective Concentration ◽  
Content Type ◽  
Excellent Activity

ABSTRACTE1210 is a first-in-class broad-spectrum antifungal that suppresses hyphal growth by inhibiting fungal glycophosphatidylinositol (GPI) biosynthesis. In the present study, we extend these findings by examining the activity of E1210 and comparator antifungal agents againstAspergillusspp. by using the methods of the Clinical and Laboratory Standards Institute (CLSI) and the European Committee for Antimicrobial Susceptibility Testing (EUCAST) to test wild-type (WT) as well as amphotericin B (AMB)-resistant (-R) and azole-R strains (as determined by CLSI methods). Seventy-eight clinical isolates ofAspergilluswere tested including 20 isolates ofAspergillus flavusspecies complex (SC), 22 ofA. fumigatusSC, 13 ofA. nigerSC, and 23 ofA. terreusSC. The collection included 15 AMB-R (MIC, ≥2 μg/ml) isolates ofA. terreusSC and 10 itraconazole-R (MIC, ≥4 μg/ml) isolates ofA. fumigatusSC (7 isolates),A. nigerSC (2 isolates), andA. terreusSC (1 isolate). Comparator antifungal agents included anidulafungin, caspofungin, amphotericin B, itraconazole, posaconzole, and voriconazole. Both CLSI and EUCAST methods were highly concordant for E1210 and all comparators. The essential agreement (EA; ±2 log2dilution steps) was 100% for all comparisons with the exception of posaconazole versusA. terreusSC (EA = 91.3%). The minimum effective concentration (MEC)/MIC90values (μg/ml) for E1210, anidulafungin, caspofungin, itraconazole, posaconazole, and voriconazole, respectively, were as follows for each species: forA. flavusSC, 0.03, ≤0.008, 0.12, 1, 1, and 1; forA. fumigatusSC, 0.06, 0.015, 0.12, >8, 1, and 4; forA. nigerSC, 0.015, 0.03, 0.12, 4, 1, and 2; and forA. terreusSC, 0.06, 0.015, 0.12, 1, 0.5, and 1. E1210 was very active against AMB-R strains ofA. terreusSC (MEC range, 0.015 to 0.06 μg/ml) and itraconazole-R strains ofA. fumigatusSC (MEC range, 0.03 to 0.12 μg/ml),A. nigerSC (MEC, 0.008 μg/ml), andA. terreusSC (MEC, 0.015 μg/ml). In conclusion, E1210 was a very potent and broad-spectrum antifungal agent regardless ofin vitromethod applied, with excellent activity against AMB-R and itraconazole-R strains ofAspergillusspp.

scholarly journals In VitroActivity of ASP2397 against Aspergillus Isolates with or without Acquired Azole Resistance Mechanisms

2015 ◽  
Vol 60 (1) ◽  
pp. 532-536 ◽  
Author(s):  
Maiken Cavling Arendrup ◽  
Rasmus Hare Jensen ◽  
Manuel Cuenca-Estrella
Keyword(s):  
Amphotericin B ◽  
Target Gene ◽  
Antifungal Agents ◽  
Susceptibility Testing ◽  
Resistance Mechanisms ◽  
Azole Resistance ◽  
Wild Type ◽  
Resistance Mutations ◽  
Content Type

ABSTRACTASP2397 is a new compound with a novel and as-yet-unknown target different from that of licensed antifungal agents. It has activity againstAspergillusandCandida glabrata. We compared itsin vitroactivity against wild-type and azole-resistantA. fumigatusandA. terreusisolates with that of amphotericin B, itraconazole, posaconazole, and voriconazole. Thirty-four isolates, including 4 wild-typeA. fumigatusisolates, 24A. fumigatusisolates with alterations in CYP51A TR/L98H (5 isolates), M220 (9 isolates), G54 (9 isolates), and HapE (1 isolate), andA. terreusisolates (2 wild-type isolates and 1 isolate with an M217I CYP51A alteration), were analyzed. EUCAST E.Def 9.2 and CLSI M38-A2 MIC susceptibility testing was performed. ASP2397 MIC50values (in milligrams per liter, with MIC ranges in parentheses) determined by EUCAST and CLSI were 0.5 (0.25 to 1) and 0.25 (0.06 to 0.25) againstA. fumigatusCYP51A wild-type isolates and were similarly 0.5 (0.125 to >4) and 0.125 (0.06 to >4) against azole-resistantA. fumigatusisolates, respectively. These values were comparable to those for amphotericin B, which were 0.25 (0.125 to 0.5) and 0.25 (0.125 to 0.25) against wild-type isolates and 0.25 (0.125 to 1) and 0.25 (0.125 to 1) against isolates with azole resistance mechanisms, respectively. In contrast, MICs for the azole compounds were elevated and highest for itraconazole: >4 (1 to >4) and 4 (0.5 to >4) against isolates with azole resistance mechanisms compared to 0.125 (0.125 to 0.25) and 0.125 (0.06 to 0.25) against wild-type isolates, respectively. ASP2397 was active againstA. terreusCYP51A wild-type isolates (MIC 0.5 to 1), whereas MICs of both azole and ASP2397 were elevated for the mutant isolate. ASP2397 displayedin vitroactivity againstA. fumigatusandA. terreusisolates which was independent of the presence or absence of azole target gene resistance mutations inA. fumigatus. The findings are promising at a time when azole-resistantA. fumigatusis emerging globally.

scholarly journals Antifungal Activity of SCY-078 and Standard Antifungal Agents against 178 Clinical Isolates of Resistant and Susceptible Candida Species

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Wiley A. Schell ◽  
A. M. Jones ◽  
Katyna Borroto-Esoda ◽  
Barbara D. Alexander
Keyword(s):  
Candida Glabrata ◽  
Antifungal Agents ◽  
Candida Parapsilosis ◽  
Candida Krusei ◽  
Wild Type ◽  
Content Type ◽  
Clinical Resistance ◽  
Excellent Activity ◽  
Candida Lusitaniae

ABSTRACT SCY-078 in vitro activity was determined for 178 isolates of resistant or susceptible Candida albicans, Candida dubliniensis, Candida glabrata, Candida krusei, Candida lusitaniae, and Candida parapsilosis, including 44 Candida isolates with known genotypic (FKS1 or FKS2 mutations), phenotypic, or clinical resistance to echinocandins. Results were compared to those for anidulafungin, caspofungin, micafungin, fluconazole, and voriconazole. SCY-078 was shown to have excellent activity against both wild-type isolates and echinocandin- and azole-resistant isolates of Candida species.

scholarly journals Effect of pH onIn VitroSusceptibility of Candida glabrata and Candida albicans to 11 Antifungal Agents and Implications for Clinical Use

2012 ◽  
Vol 56 (3) ◽  
pp. 1403-1406 ◽  
Author(s):  
Claire S. Danby ◽  
Dina Boikov ◽  
Rina Rautemaa-Richardson ◽  
Jack D. Sobel
Keyword(s):  
Amphotericin B ◽  
Candida Glabrata ◽  
Antifungal Agents ◽  
Susceptibility Testing ◽  
Low Ph ◽  
Clinical Use ◽  
Effect Of Ph ◽  
Content Type ◽  
Clinical Observations

ABSTRACTThe treatment of vulvovaginal candidiasis (VVC) due toCandida glabratais challenging, with limited therapeutic options. Unexplained disappointing clinical efficacy has been reported with systemic and topical azole antifungal agents in spite ofin vitrosusceptibility. Given that the vaginal pH of patients with VVC is unchanged at 4 to 4.5, we studied the effect of pH on thein vitroactivity of 11 antifungal agents against 40C. glabrataisolates and compared activity against 15 fluconazole-sensitive and 10 reduced-fluconazole-susceptibilityC. albicansstrains.In vitrosusceptibility to flucytosine, fluconazole, voriconazole, posaconazole, itraconazole, ketoconazole, clotrimazole, miconazole, ciclopirox olamine, amphotericin B, and caspofungin was determined using the CLSI method for yeast susceptibility testing. Test media were buffered to pHs of 7, 6, 5, and 4. Under conditions of reduced pH,C. glabrataisolates remained susceptible to caspofungin and flucytosine; however, there was a dramatic increase in the MIC90for amphotericin B and every azole drug tested. Although susceptible to other azole drugs tested at pH 7,C. albicansstrains with reduced fluconazole susceptibility also demonstrated reduced susceptibility to amphotericin B and all azoles at pH 4. In contrast, fluconazole-sensitiveC. albicansisolates remained susceptible at low pH to azoles, in keeping with clinical observations. In selecting agents for treatment of recurrentC. glabratavaginitis, clinicians should recognize the limitations ofin vitrosusceptibility testing utilizing pH 7.0.

scholarly journals Activities of E1210 and Comparator Agents Tested by CLSI and EUCAST Broth Microdilution Methods against Fusarium and Scedosporium Species Identified Using Molecular Methods

2011 ◽  
Vol 56 (1) ◽  
pp. 352-357 ◽  
Author(s):  
Mariana Castanheira ◽  
Frederick P. Duncanson ◽  
Daniel J. Diekema ◽  
Josep Guarro ◽  
Ronald N. Jones ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Broad Spectrum ◽  
Species Complex ◽  
Molecular Techniques ◽  
Broth Microdilution ◽  
Fungal Cell ◽  
Minimum Effective Concentration ◽  
Content Type ◽  
Highly Active

ABSTRACTFusarium(n= 67) andScedosporium(n= 63) clinical isolates were tested by two reference broth microdilution (BMD) methods against a novel broad-spectrum (active against both yeasts and molds) antifungal, E1210, and comparator agents. E1210 inhibits the inositol acylation step in glycophosphatidylinositol (GPI) biosynthesis, resulting in defects in fungal cell wall biosynthesis. Five species complex organisms/species ofFusarium(4 isolates unspeciated) and 28Scedosporium apiospermum, 7Scedosporium aurantiacum, and 28Scedosporium prolificansspecies were identified by molecular techniques. Comparator antifungal agents included anidulafungin, caspofungin, itraconazole, posaconazole, voriconazole, and amphotericin B. E1210 was highly active against all of the tested isolates, with minimum effective concentration (MEC)/MIC90values (μg/ml) for E1210, anidulafungin, caspofungin, itraconazole, posaconazole, voriconazole, and amphotericin B, respectively, forFusariumof 0.12, >16, >16, >8, >8, 8, and 4 μg/ml. E1210 was very potent against theScedosporiumspp. tested. The E1210 MEC90was 0.12 μg/ml forS. apiospermum, but 1 to >8 μg/ml for other tested agents. AgainstS. aurantiacum, the MEC50for E1210 was 0.06 μg/ml versus 0.5 to >8 μg/ml for the comparators. AgainstS. prolificans, the MEC90for E1210 was only 0.12 μg/ml, compared to >4 μg/ml for amphotericin B and >8 μg/ml for itraconazole, posaconazole, and voriconazole. Both CLSI and EUCAST methods were highly concordant for E1210 and all comparator agents. The essential agreement (EA; ±2 doubling dilutions) was >93% for all comparisons, with the exception of posaconazole andF. oxysporumspecies complex (SC) (60%), posaconazole andS. aurantiacum(85.7%), and voriconazole andS. aurantiacum(85.7%). In conclusion, E1210 exhibited very potent and broad-spectrum antifungal activity against azole- and amphotericin B-resistant strains ofFusariumspp. andScedosporiumspp. Furthermore,in vitrosusceptibility testing of E1210 against isolates ofFusariumandScedosporiummay be accomplished using either of the CLSI or EUCAST BMD methods, each producing very similar results.

scholarly journals EUCAST Determination of Olorofim (F901318) Susceptibility of Mold Species, Method Validation, and MICs

2018 ◽  
Vol 62 (8) ◽  
Author(s):  
Karin Meinike Jørgensen ◽  
Karen M. T. Astvad ◽  
Rasmus Krøger Hare ◽  
Maiken Cavling Arendrup
Keyword(s):  
Fusarium Solani ◽  
Susceptibility Testing ◽  
Wild Type ◽  
Preparation Methods ◽  
Content Type ◽  
Microtiter Plates ◽  
Upper Limits ◽  
Limited Variation

ABSTRACT Olorofim is a novel antifungal agent with in vitro activity against Aspergillus and some other molds. Here, we addressed technical aspects for EUCAST olorofim testing and generated contemporary MIC data. EUCAST E.Def 9.3.1 testing was performed comparing two plate preparation methods (serial dilution in medium [serial plates] versus predilution in DMSO [ISO plates]), two lots of olorofim, visual (visual-MIC) versus spectrophotometer (spec-MIC) reading, and four polystyrene plates using 34 to 53 Aspergillus isolates from five genera. Subsequently, olorofim MICs were compared to itraconazole, voriconazole, posaconazole, and amphotericin B MICs for 298 clinical mold isolates (2016 to 2017). Wild-type upper limits (WT-UL) were determined following EUCAST principles for epidemiologic cutoff value (ECOFF) setting. Olorofim median MICs comparing serial plates and ISO plates were identical (25/36 [69%]) or one dilution apart (11/36 [31%]). Interperson agreement for visual-MICs was 92% to 94%/100% for ≤1/≤2 dilutions, respectively. The visual-MIC values across tested microtiter plates and olorofim lots revealed only discrete differences (≤1 dilution lower for treated plates). No single spec-MIC criterion was applicable to all species. Olorofim MICs were low against 275 Aspergillus species isolates (modal MIC, 0.06 mg/liter; MIC range, < 0.004 to 0.25 mg/liter) and three dermatophytes (MICs 0.03 to 0.06 mg/liter). MICs against Fusarium were diverse, with full inhibition of F. proliferatum (MIC, 0.016), 50% growth inhibition of Fusarium solani at 1 to 2 mg/liter, and no inhibition of F. dimerum. Olorofim displayed potent in vitro activity against most mold isolates and was associated with limited variation in EUCAST susceptibility testing.

scholarly journals In Vitro Activity of Chlorhexidine Compared with Seven Antifungal Agents against 98 Fusarium Isolates Recovered from Fungal Keratitis Patients

2019 ◽  
Vol 63 (8) ◽  
Author(s):  
Claudy Oliveira dos Santos ◽  
Eva Kolwijck ◽  
Henrich A. van der Lee ◽  
Marlou C. Tehupeiory-Kooreman ◽  
Abdullah M. S. Al-Hatmi ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Antifungal Agents ◽  
Culture Collection ◽  
Fungal Keratitis ◽  
Molecular Techniques ◽  
Temperate Climate ◽  
Eye Drops ◽  
Fungal Culture ◽  
Content Type

ABSTRACT Fungal keratitis is a common but severe eye infection in tropical and subtropical areas of the world. In regions with a temperate climate, the frequency of infection is rising in patients with contact lenses and following trauma. Early and adequate therapy is important to prevent disease progression and loss of vision. The management of Fusarium keratitis is complex, and the optimal treatment is not well defined. We investigated the in vitro activity of chlorhexidine and seven antifungal agents against a well-characterized collection of Fusarium isolates recovered from patients with Fusarium keratitis. The fungus culture collection of the Center of Expertise in Mycology Radboudumc/CWZ was searched for Fusarium isolates that were cultured from cornea scrapings, ocular biopsy specimens, eye swabs, and contact lens fluid containers from patients with suspected keratitis. The Fusarium isolates that were cultured from patients with confirmed keratitis were all identified using conventional and molecular techniques. Antifungal susceptibility testing was performed according to the EUCAST broth microdilution reference method. The antifungal agents tested included amphotericin B, voriconazole, posaconazole, miconazole, natamycin, 5-fluorocytosine, and caspofungin. In addition, the activity of chlorhexidine was determined. The fungal culture collection contained 98 Fusarium isolates of confirmed fungal keratitis cases from 83 Dutch patients and 15 Tanzanian patients. The isolates were collected between 2007 and 2017. Fusarium oxysporum (n = 24, 24.5%) was the most frequently isolated species followed by Fusarium solani sensu stricto (n = 18, 18.4%) and Fusarium petroliphilum (n = 11, 11.2%). Amphotericin B showed the most favorable in vitro inhibition of Fusarium species followed by natamycin, voriconazole, and chlorhexidine, while 5-fluorocytosine, posaconazole, miconazole, and caspofungin showed no relevant inhibiting effect. However, chlorhexidine showed fungicidal activity against 90% of F. oxysporum strains and 100% of the F. solani strains. Our study supports the clinical efficacy of chlorhexidine and therefore warrants its further clinical evaluation for primary therapy of fungal keratitis, particularly in low and middle income countries where fungal keratitis is much more frequent and, currently, antifungal eye drops are often unavailable.

scholarly journals A Revised Species Concept for OpportunisticMucorSpecies Reveals Species-Specific Antifungal Susceptibility Profiles

2019 ◽  
Vol 63 (8) ◽  
Author(s):  
Lysett Wagner ◽  
Sybren de Hoog ◽  
Ana Alastruey-Izquierdo ◽  
Kerstin Voigt ◽  
Oliver Kurzai ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Susceptibility Testing ◽  
Species Concept ◽  
Antifungal Susceptibility ◽  
Content Type ◽  
Mucor Indicus ◽  
Species Specific ◽  
Susceptibility Profiles ◽  
High Mics

ABSTRACTRecently, the species concept of opportunisticMucor circinelloidesand its relatives has been revised, resulting in the recognition of its classical formae as independent species and the description of new species. In this study, we used isolates of all clinically relevantMucorspecies and performed susceptibility testing using the EUCAST reference method to identify potential species-specific susceptibility patterns.In vitrosusceptibility profiles of 101 mucoralean strains belonging to the genusMucor(72), the closely related speciesCokeromyces recurvatus(3),Rhizopus(12),Lichtheimia(10), andRhizomucor(4) to six antifungals (amphotericin B, natamycin, terbinafine, isavuconazole, itraconazole, and posaconazole) were determined. The most active drug for all Mucorales was amphotericin B. Antifungal susceptibility profiles of pathogenicMucorspecies were specific for isavuconazole, itraconazole, and posaconazole. The species formerly united inM. circinelloidesshowed clear differences in their antifungal susceptibilities.Cokeromyces recurvatus,Mucor ardhlaengiktus,Mucor lusitanicus(M. circinelloidesf.lusitanicus), andMucor ramosissimusexhibited high MICs to all azoles tested.Mucor indicuspresented high MICs for isavuconazole and posaconazole, andMucor amphibiorumandMucor irregularisshowed high MICs for isavuconazole. MIC values ofMucorspp. for posaconazole, isavuconazole, and itraconazole were high compared to those forRhizopusand the Lichtheimiaceae (LichtheimiaandRhizomucor). Molecular identification combined within vitrosusceptibility testing is recommended forMucorspecies, especially if azoles are applied in treatment.

scholarly journals Implications of the EUCAST Trailing Phenomenon inCandida tropicalisfor theIn VivoSusceptibility in Invertebrate and Murine Models

2018 ◽  
Vol 62 (12) ◽  
Author(s):  
K. M. T. Astvad ◽  
D. Sanglard ◽  
E. Delarze ◽  
R. K. Hare ◽  
M. C. Arendrup
Keyword(s):  
Susceptibility Testing ◽  
Galleria Mellonella ◽  
Growth Control ◽  
Resistant Isolate ◽  
Murine Models ◽  
Wild Type ◽  
Content Type ◽  
Gradual Loss

ABSTRACTCandida tropicalisisolates often display reduced but persistent growth (trailing) over a broad fluconazole concentration range during EUCAST susceptibility testing. Whereas weak trailing (<25% of the positive growth control) is common and found not to impair fluconazole efficacy, we investigated if more pronounced trailing impacted treatment efficacy. Fluconazole efficacy against two weakly (≤25% growth), two moderately (26% to 50% growth), and one heavily (>70% growth) trailing resistant isolate and one resistant (100% growth) isolate were investigatedin vitroandin vivo(in aGalleria mellonellasurvival model and two nonlethal murine models).CDR1expression levels andERG11sequences were characterized. The survival in fluconazole-treatedG. mellonellawas inversely correlated with the degree of trailing (71% to 9% survival in treatment groups). In mice, resistant and heavily trailing isolates responded poorly to fluconazole treatment.CDR1expression was significantly higher in trailing and resistant isolates than in wild-type isolates (1.4-fold to 10-fold higher). All isolates exhibitedERG11wild-type alleles. Heavily trailing isolates were less responsive to fluconazole in allin vivomodels, indicating an impact on fluconazole efficacy.CDR1upregulation may have contributed to the observed differences. Moderately trailing isolates responded less well to fluconazole in larvae only. This confirms clinical data suggesting fluconazole is effective against infections with such isolates in less severely ill patients and supports the current 50% growth endpoint for susceptibility testing. However, it is still unclear if the gradual loss of efficacy observed for moderately trailing isolates in the larva model may be a reason for concern in selected vulnerable patient populations.

scholarly journals APX001A In Vitro Activity against Contemporary Blood Isolates and Candida auris Determined by the EUCAST Reference Method

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
Maiken Cavling Arendrup ◽  
Anuradha Chowdhary ◽  
Karen M. T. Astvad ◽  
Karin Meinike Jørgensen
Keyword(s):  
Susceptibility Testing ◽  
Yeast Species ◽  
Reference Method ◽  
Common Species ◽  
Drug Candidate ◽  
Its Sequencing ◽  
Wild Type ◽  
Candida Auris ◽  
Content Type

ABSTRACT APX001A is the active moiety of the first-in-class drug candidate APX001. So far, most susceptibility testing studies have examined ≤30 isolates/species, and only one used the EUCAST method. Here, we investigated the in vitro activity of APX001A and five comparators against 540 candidemia and 122 C. auris isolates. Isolates (17 Candida and 3 yeast species) were identified using CHROMagar, matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF) and, when needed, internal transcribed space (ITS) sequencing. EUCAST E.Def 7.3.1 susceptibility testing included APX001A, amphotericin B, anidulafungin, micafungin, fluconazole, and voriconazole. Wild-type upper limits (WT-UL) were established following the EUCAST principles for epidemiological cutoff value setting for APX001A, allowing classification as wild type (WT) or non-WT. APX001A MIC50 values (mg/liter) were as follows: Candida albicans, Candida dubliniensis, and Candida tropicalis, 0.004 to 0.008; Candida parapsilosis and Candida auris, 0.016; Candida glabrata, 0.06; and Candida krusei, >0.5. APX001A MICs against the rare species varied from ≤0.0005 (C. pelliculosa) to >0.5 (Candida norvegensis). APX001A was equally or more active in vitro than the comparators against all species except C. krusei and C. norvegensis. Four isolates were APX001A non-WT; all were fluconazole resistant. A correlation was observed between APX001A and fluconazole MICs across all species except Candida guilliermondii and C. auris, and when comparing high and low fluconazole MIC isolates of C. albicans, C. dubliniensis, C. glabrata, C. tropicalis, and C. auris. APX001A showed promising in vitro activity against most Candida and other yeast species, including C. auris, compared to five comparators. WT-UL were suggested for the common species, and a new and unexplained correlation to fluconazole susceptibility was observed.

scholarly journals Manogepix (APX001A) Displays Potent In Vitro Activity against Human Pathogenic Yeast, but with an Unexpected Correlation to Fluconazole MICs

2020 ◽  
Vol 64 (7) ◽  
Author(s):  
Maiken Cavling Arendrup ◽  
Karin Meinike Jørgensen
Keyword(s):  
Amphotericin B ◽  
Broad Spectrum ◽  
Hot Spot ◽  
Its Sequencing ◽  
Wild Type ◽  
Pathogenic Yeast ◽  
Fluconazole Resistance ◽  
Content Type ◽  
Spectrum Activity ◽  
Broad Spectrum Activity

ABSTRACT Manogepix (APX001A) is the active moiety of the novel drug candidate fosmanogepix (APX001). We previously reported the broad-spectrum activity of manogepix but also observed a correlation between increased manogepix and fluconazole MICs. Here, we extended this study and included isolates with acquired fluconazole resistance. Isolates (n = 835) were identified using CHROMagar, matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS), and, when needed, internal transcribed spacer (ITS) sequencing. EUCAST E.Def 7.3.1 susceptibility testing included manogepix, amphotericin B, anidulafungin, micafungin, fluconazole, and voriconazole. Manogepix wild-type-upper-limit (WT-UL) values were established following EUCAST principles for the epidemiological cutoff value (ECOFF) setting allowing wild-type/non-wild-type classification. Drug-specific MIC correlations were investigated using Pearson’s correlation. Manogepix modal MICs were low (range, 0.004 to 0.06 mg/liter against 16/20 included species). Exceptions were Candida krusei and Candida inconspicua and, to a lesser extent, Candida kefyr and Pichia kluyveri. The activity was independent of Fks echinocandin hot spot alterations (n = 17). Adopting the WT-UL established for Candida albicans, Candida dubliniensis, Candida glabrata, Candida parapsilosis, and Candida tropicalis, 14/724 (1.9%) isolates were non-wild type for manogepix. Twelve of these (85.7%) were also non-wild type for fluconazole. A statistically significant correlation was observed between manogepix and fluconazole MICs for C. albicans, C. dubliniensis, C. glabrata, C. parapsilosis, and C. tropicalis (Pearson’s r = 0.401 to 0.575) but not between manogepix and micafungin or amphotericin B MICs for any species except C. tropicalis (r = 0.519 for manogepix versus micafungin). Broad-spectrum activity was confirmed for manogepix against contemporary yeast. However, a 1 to 4 2-fold dilutions increase in manogepix MICs is observed in a subset of isolates with acquired fluconazole resistance. Further studies on the potential underlying mechanism and implication for optimal dosing are warranted.

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