Manogepix (APX001A) In Vitro Activity against Candida auris: Head-to-Head Comparison of EUCAST and CLSI MICs

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ABSTRACT

Fosmanogepix is a novel prodrug in a new class of antifungal agents. Manogepix is the active moiety. We evaluated the CLSI and EUCAST MICs of manogepix and eight comparators against Candida auris. CLSI M27-A3 susceptibility testing of manogepix was performed for 122 C. auris isolates and compared to CLSI and EUCAST MICs for manogepix and eight comparators. Differences and agreement were calculated for each compound. Wild-type upper limits (WT-ULs; the upper MIC where the wild-type distribution ends) for manogepix and correlations with other drugs’ MICs were determined. Manogepix MICs (CLSI/EUCAST [mg/liter]) and WT-ULs were as follows: MIC ₅₀s, 0.008/0.016; MIC ₉₀s, 0.03/0.03; ranges, 0.001 to 0.25/0.001 to 0.125; 97.5% and 99% WT-ULs, 0.03/0.125 and 0.06/0.125, respectively. The manogepix CLSI/EUCAST MIC distributions spanned 9/8 dilutions, respectively. Significant correlation was found for all azoles, particularly fluconazole ( r = 0.22 to 0.74, P < 0.05). Isolates with EUCAST manogepix MICs of ≤0.004 had 7.6-/10.2-fold-lower fluconazole CLSI/EUCAST MICs than the remaining isolates that had higher manogepix MICs. The highest essential agreement between CLSI and EUCAST results was observed for manogepix and fluconazole, with a median difference of −1 to 0 2-fold dilutions, 90th percentile absolute difference of 1, and 90 to 92% and 98 to 100% agreement within ±1 and ±2 dilutions. The lowest agreements within ±1 and ±2 dilutions were found for isavuconazole and anidulafungin (44 to 50% and 69 to 76%). The correlation between CLSI and EUCAST manogepix MICs against C. auris was excellent. Differential MICs were found, and these correlated with fluconazole MICs, suggesting that the C. auris population is a mix of wild-type isolates and non-wild-type isolates with low-grade manogepix MIC elevation, probably involving efflux pump expression. However, manogepix was the most potent agent against C. auris in this in vitro study.

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Simultaneous Emergence of Multidrug-Resistant Candida auris on 3 Continents Confirmed by Whole-Genome Sequencing and Epidemiological Analyses.

Shawn Lockhart, Kizee Etienne, Snigdha Vallabhaneni … (2017)

Candida auris, a multidrug-resistant yeast that causes invasive infections, was first described in 2009 in Japan and has since been reported from several countries.

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Candida auris–Associated Candidemia, South Africa

Rindidzani E. Magobo, Craig Corcoran, Sharona Seetharam … (2014)

To the Editor: We noted the report by Chowdhary et al. ( 1 ) and report Candida auris as a causative agent of candidemia in South Africa, with an estimated prevalence of 0.3% (N.P. Govender et al., unpub. data). First isolated in 2009, C. auris is an emerging species associated with clinical disease ( 2 – 6 ). We analyzed 4 isolates submitted to the National Institute for Communicable Diseases (Johannesburg, South Africa) from 4 patients with candidemia who had been admitted to different public- and private-sector hospitals from October 2012 through October 2013. Identification of the isolates was undertaken by using ChromAgar Candida medium (Mast Diagnostics, Merseyside, UK), Vitek-2 YST (bioMérieux, Marcy ľEtoile, France), API 20C AUX (bioMérieux), and sequencing of internal transcribed spacer (ITS) and D1/D2 domains of the ribosomal RNA gene ( 7 ), followed by microbroth dilution susceptibility testing ( 8 ). All isolates were misidentified as C. haemulonii and Rhodotorula glutinis by Vitek-2 YST and API 20C AUX assays, respectively (Table). Table Identification and antifungal susceptibility results of 4 Candida auris isolates from 4 male patients with candidemia, South Africa, October 2012–October 2013* Isolate ID Patient age, y Hospital unit Vitek-2 YST† API 20C AUX† DNA sequence analysis‡ MIC AMB FLX VRC POS ITC 5FC CAS MFG AFG 208 85 High-care C. haemulonii Rhodotorula glutinis C. auris 1 >256 0.5 0.03 0.12 0.12 0.25 0.06 0.25 209 60 Medical ICU C. haemulonii R. glutinis C. auris 0.5 >256 1 0.06 0.12 0.12 0.12 0.06 0.12 224 73 Burn C. haemulonii R. glutinis C. auris 1 >256 2 0.06 0.25 0.12 0.25 0.12 0.25 293 27 Trauma ICU C. haemulonii R. glutinis C. auris 1 64 0.25 0.015 0.06 0.06 0.03 0.06 0.06 *AMB, amphotericin B; FLX, fluconazole; VRC, voriconazole; POS, posaconazole; ITC, itraconazole; 5FC, flucytosine; CAS, caspofungin; MFG, micafungin; AFG, anidulafungin. †bioMérieux, Marcy ľEtoile, France. ‡Sequence data for the 4 isolates have been deposited in GenBank, accession nos. KJ1236762–KJ126765 and KJ126758–KJ126761 for the internal transcribed spacer and D1/D2 regions, respectively. Similar to the findings of Chowdhary et al., all isolates assimilated N-acetyl-glucosamine ( 1 ). With the use of the CBS-KNAW database, pairwise sequence alignment of ITS region showed 99% sequence homology to Kuwait isolates, and alignment of D1/D2 domain showed 98% homology to the Kuwait/India isolates ( 9 ). In a neighbor-joining phylogenetic tree based on ITS sequences, South Africa isolates formed a cluster with India and Kuwait isolates (Technical Appendix Figure). Fluconazole MICs were high for all isolates (Table). Isolates 209 and 224 showed reduced voriconazole susceptibility with MICs of 1 μg/mL and 2 μg/mL, respectively, which is above the epidemiologic cutoff value for 11 Candida species ( 10 ). Isolates were susceptible to amphotericin B and echinocandins at low MICs Clinical data were available for 1 patient (Technical Appendix Table). Two C. haemulonii isolates were identified during laboratory-based sentinel surveillance for candidemia in South Africa; the ITS region of one isolate was sequenced and the isolate identified as C. auris (N.P. Govender, pers. comm.). In this study, C. auris was misidentified by routinely used tests and was accurately identified by sequencing, in keeping with previous findings ( 1 , 3 , 4 , 6 ). Technical Appendix Phylogenetic relatedness of internal transcribed spacer region of the ribosomal RNA gene of Candida auris with closely related Candida species and clinical characteristics of a patient with candidemia caused by C. auris, South Africa.

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Comparison of EUCAST and CLSI Reference Microdilution MICs of Eight Antifungal Compounds for Candida auris and Associated Tentative Epidemiological Cutoff Values.

M C Arendrup, Anupam Prakash, Joseph Meletiadis … (2017)

Candida auris is an emerging multidrug-resistant yeast. So far, all but two susceptibility testing studies have examined ≤50 isolates, mostly with the CLSI method. We investigated CLSI and EUCAST MICs for 123 C. auris isolates and eight antifungals and evaluated various methods for epidemiological cutoff (ECOFF) determinations. MICs (in milligrams per liter) were determined using CLSI method M27-A3, and the EUCAST E.Def 7.3. ANOVA analysis of variance with Bonferroni's multiple-comparison test and Pearson analysis were used on log2 MICs (significance at P values of 2). The ECOFFs (in milligrams per liter) were similar across the three different methods for itraconazole (ranges for CLSI/EUCAST, 0.25 to 0.5/0.5 to 1), posaconazole (0.125/0.125 to 0.25), amphotericin B (0.25 to 0.5/1 to 2), micafungin (0.25 to 0.5), and anidulafungin (0.25 to 0.5/0.25 to 1). In contrast, the estimated ECOFFs were dependent on the method applied for voriconazole (1 to 32) and isavuconazole (0.125 to 4). CLSI and EUCAST MICs were remarkably similar and confirmed uniform fluconazole resistance and variable acquired resistance to the other agents.