Emergence of the New Menace! Candida Auris and the Rise of MDR Yeasts.

Ear yeast! That is the translation of Candida auris. It was discovered by isolation from an ear infection in an elderly patient in Japan in 2009 and since then it has been isolated in places such as India, southeast Asia and several parts of south America (1-4):

 One of the defining characteristics is its resistance to the azoles such as fluconazole (something that it shares with the notorious KG, C. krusei and C. glabrata), but its defining feature is the possibility of transmission. Most Candida invasive infections are felt to be due to breakdown of natural barriers, such as possible bowel leakage or skin breakdown, however there is concern this organism may lead to nosocomial infections in at-risk populations. In one European report of 620 cases of C. auris infection and colonization found that two countries had experienced four nosocomial outbreaks, accounting for 573 patients in the report (6) with interfacility transmission occurring during these outbreaks.  A CDC report on US cases (7) was able to find epidemiologic links with most, with cases in the northeast being tracked to long-term care facilities and interconnected acute care hospitals. 

Brief Word on Microbiology

I tend to focus on more clinically oriented information, however I think the following points are rather interesting when it comes to C. auris. Unlike other types of pathogenic candida, this one tends to grow at 42C, much higher than most others (1-4). Further, it is closely related to C. haemolumonii complex, and can be confused for those organisms, or others such as C. guilliermondii, C. parapsilosis, Saccharomyces, among others (2). This, of course, depends on the diagnostic method employed, with the following being a small sample:

This can cause some problems when it comes to initiating rapid early therapy, but I do not anticipate this to be much of a problem from a clinical standpoint (see later) but rather an infection control one. Needless to say, it seems that MALDI-TOF is a reasonable and accurate way to diagnose, with one study using it to correctly identify C. auris as well as obtain resistance profiles (8). As noted before with MALDI-TOF, however, a reference organism is needed for accurate diagnosis so many will still run into misidentification issues (1-4, 5). 

The other interesting thing when it comes to C. auris is its ability to tolerate growth at human physiological temperatures and ability to tolerate high salt concentrations when compared to other strains of Candida (4). One study evaluated the ability of a fluconazole-resistant strain of C. auris to resist several physiological stresses when compared to C. glabrata and C. albicans (9). C. auris was able to resist oxidative stresses imposed by H2O2 as well as either sodium chloride or calcium chloride, and was able to grow when exposed to either 10mM H2O2 or 1M NaCl relative to C. albicans. C. auris was also able to grow in the presence of cell-wall damaging agents, however when compared to C. albicans or dublidensis, it was unable to grow in an alkaline environment. Another study evaluating the fungicidal activity of histidine-rich salivary protein histatin 5 (Hst 5, which is found in human saliva) found that those with high fluconazole MICs were susceptible to this salivary protein:

Within the same study, the authors also found that some strains of C. auris demonstrated a high rate of survival within neutrophils. 

All these suggest that C. auris may have a different stress resistance profile compared to other Candida spp that allow it to be an organism that lends itself for more transmissibility and higher ability to survive human physiological stress. Indeed, it has been reported that C. auris can survive on human skin and environmental surfaces for several weeks (4) and while its ability to generate a biofilm is reduced when compared to C. albicans, this is still a virulence factor at play for C. auris (1,3). One review has noted that C. auris has been found on bed sides, windowsills, and monitors.

Resistance Mechanism

I think this is the part of the post most people are curious about. One of the issues that came with the initial reports was the high MIC to first-line agents such as fluconazole. It should be noted, however, that as of writing this there is no agreed upon “breakpoints” for these, however a review on the topic (5) has a nice graphic that puts the problem of C. auris into perspective:

Azoles inhibit the cellular synthesis of ergosterol, while echinocandins inhibit the synthesis of BD glucan within fungi. It stands to reason these two pathways would be mechanisms of resistance and this has been observed in several reviews (4, 5). Lanosterol 14-alpha-demethylase (LD) is responsible for the ergosterol biosynthesis and is encoded by the gene ERG11. Point mutations and overexpression of ERG11 have been found to reduce azole sensitivity to several candida spp, including C. auris. FKS1 and 2 genes encode the enzyme responsible for BD glucan synthesis and this is also the target for possible resistance. Is this important? Perhaps. One study of 24 samples of C. auris obtained from the groin/axilla used asymmetric rtPCR along with allele-specific molecular beacons to identify ERG11 and FKS11 mutations and compared them to standard susceptibility testing (10). In this limited sample, they found concordance with the presence of WT genotype and MIC for echinocandins:

Another cohort of 350 samples of C. auris found that mutations in ERG11, specifically Y132F and K143R, were associated with resistance to fluconazole in 77% of isolates (17). 16 of the 20 samples that harbored that mutation also expressed cross-resistance with voriconazole, isavuconazole, and posaconazole with four of them being pan-azole resistant. Four of 38 isolates from that same study were found to harbor a FKS1 S645S mutation conferring pan-echinocandin resistance. Needless to say, knowledge of these mutations may play a role in molecular diagnostics in the future of not only C. auris but other candida spp.  Given this, what is seen clinically? Unfortunately, high fluconazole MIC is seen. In one of the first reports of candidemia with C. auris (11), the MIC for fluconazole ranged from 2 all the way up to 128 in a case series of 3 patients:

Another case series of 3 patients from the US (12) evaluated similar cases of candidemia with C. auris and found that all cases had developed resistance to amphotericin B, echinocandins, and azoles based on standard CLSI criteria. In one patient with candidemia, 54% of the isolates obtained were resistant to amphotericin B during the duration of therapy while in another patient, 60% of isolates were resistant to amphotericin B. All were resistant to fluconazole. The third patient also had similar resistant rates to amphotericin B and was initially susceptible to echinocandins, however over the course of 2/2017 to late 4/2017, he developed resistance to echinocandins with MIC to caspofungin of 16. More robust data comes from India, with 2 retrospective cohorts evaluating outbreaks of C. auris. In one cohort of 245 isolates, 15 of these (6.1%) were identified as C. auris (13). Seven of these isolates were from blood, with all having prior risk factors such as broad spectrum antibiotic use, neutropenia, immunosuppressive conditions, CKD, and hematologic malignancies. All isolates were resistant to fluconazole, and 73% were resistant to voriconazole, using an MIC >1 as cutoff:

Posaconazole, amphotericin, and the echinocandins retained good activity overall. Another study from an India trauma center evaluated 20 C. auris isolates along with 45 C. tropicalis, 16 C. albicans, and 13 C. parapsilosis (14). Here, 55% of the C. auris strains exhibited high fluconazole MIC (>64), but no resistance to other azoles or echinocandins was seen:

They also evaluated the methods by which the isolates were identified and not surprisingly, C. auris was not picked up by the VITEK 2 system. Notably, C. parapsilosis was identified by MALDI-TOF as other subspecies, but that is a conversation for another day (TL;DR C. parapsilosis is a complex, kind of like M. abscessus):

In South Africa (15), 4 isolates detected in one case series reported high fluconazole MIC in all cases with two being voriconazole resistant:

And another case series of 12 patients (16) also displayed isolates with high fluconazole MIC:

Overall, it seems the vast majority of resistance is to fluconazole, with higher MICs being reported for voriconazole (usually >2). One review (2) recommends initial therapy with an echinocandin with repeat follow up cultures to ensure sterilization. This is due to reported instances of echinocandins. One previously mentioned case was elaborated upon in a case report (18), where a patient with multiple comorbidities had 2 separate episodes of C. auris candidemia. The patient had been treated with micafungin for an extended period for a right hip abscess with C. glabrata prior to his initial C. auris candidemia. His initial isolate was susceptible and was treated with micafungin and then posaconazole. His fevers recurred, however, and repeat cultures after 2 days of micafungin found a C. auris that was resistant to micafungin:

As previously mentioned (17), resistance to all echinocandins has been reported previously with another report that included an additional 102 isolates from India and Columbia finding several isolates that had an elevated MIC for all echinocandins of >4 (19):

Higher MIC to amphotericin have also been reported, with 5 out of 6 evaluated C. auris in one study having an MIC of 2 (20):

Another cohort of 17 samples reported MIC to amphotericin anywhere from 8 to 16 (21). 

Despite the reported resistances to other azoles, amphotericin, and echinocandins, the newer antifungal ibrexafungerp seems to have in vitro susceptibility. Ibrexafungerp is an antifungal that targets glucan synthase but retains activity against some FKS mutant species and can be given orally. In one analysis of 122 isolates of C.auris, the EUCAST MIC ranged from 0.06 to 2 (MIC50 0.5), which the authors felt suggested uniform susceptibility (22, although given the lack of breakpoints for any fungus-ibrexafungerp combination, I do not know how to interpret these):

Similarly, another study found MICs up to 2 for ibrexafungerp in a sample of 14 isolates (23):

With a dose as small as 0.25mg/L inhibiting growth of an isolate from one patient, suggesting potent activity:

Suffice to say, the risk of C. auris seems to be the high MIC to fluconazole and the possibility of transmission in health care settings. While I did not mention the risk factors for infection with this yeast, they are the same as for all candida infections: immunosuppression, prolonged hospitalization, ICU admission, broad-spectrum antibiotic use, line use, renal/liver disease, etc. The TL;DR for this one

• Watch out if you see C. haemulonii on a standard identification methods (VITEK, BD-phoenix, microscan) as this could be C. auris
• You need some sort of molecular method or MALDI-TOF that has a reference strain for diagnosis
• Either way, you’ll likely start micafungin or another echinocandin, though watch out for developing resistance as well as higher MIC to amphotericin B
• In the future, molecular methods and identification of ERG11 or FKS1 mutations may play a role in diagnostics/therapeutics, as these confer resistance to azoles and echinocandins, respectively
• Ibrexafungerp holds almost universal susceptibility in vitro
• Some review tables below:

References:

1. Spivak ES, Hanson KE. Candida auris: an Emerging Fungal Pathogen. J Clin Microbiol. 2018 Jan 24;56(2):e01588-17. doi: 10.1128/JCM.01588-17. PMID: 29167291; PMCID: PMC5786713.
2. Tsay S, Kallen A, Jackson BR, Chiller TM, Vallabhaneni S. Approach to the Investigation and Management of Patients With Candida auris, an Emerging Multidrug-Resistant Yeast. Clin Infect Dis. 2018 Jan 6;66(2):306-311. doi: 10.1093/cid/cix744. PMID: 29020224; PMCID: PMC5798232.
3. Jeffery-Smith A, Taori SK, Schelenz S, Jeffery K, Johnson EM, Borman A; Candida auris Incident Management Team, Manuel R, Brown CS. Candida auris: a Review of the Literature. Clin Microbiol Rev. 2017 Nov 15;31(1):e00029-17. doi: 10.1128/CMR.00029-17. PMID: 29142078; PMCID: PMC5740969.
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6. Kohlenberg A, Struelens MJ, Monnet DL, Plachouras D; The Candida Auris Survey Collaborative Group. Candida auris: epidemiological situation, laboratory capacity and preparedness in European Union and European Economic Area countries, 2013 to 2017. Euro Surveill. 2018 Mar;23(13):18-00136. doi: 10.2807/1560-7917.ES.2018.23.13.18-00136. PMID: 29616608; PMCID: PMC5883451.
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8. Day AM, McNiff MM, da Silva Dantas A, Gow NAR, Quinn J. Hog1 Regulates Stress Tolerance and Virulence in the Emerging Fungal Pathogen Candida auris. mSphere. 2018 Oct 24;3(5):e00506-18. doi: 10.1128/mSphere.00506-18. PMID: 30355673; PMCID: PMC6200985.
9. Pathirana RU, Friedman J, Norris HL, Salvatori O, McCall AD, Kay J, Edgerton M. Fluconazole-Resistant Candida auris Is Susceptible to Salivary Histatin 5 Killing and to Intrinsic Host Defenses. Antimicrob Agents Chemother. 2018 Jan 25;62(2):e01872-17. doi: 10.1128/AAC.01872-17. PMID: 29158282; PMCID: PMC5786754.
10. Kordalewska M, Lee A, Zhao Y, Perlin DS. Detection of Candida auris antifungal drug resistance markers directly from clinical skin swabs. Antimicrob Agents Chemother. 2019 Oct 7;63(12):e01754-19. doi: 10.1128/AAC.01754-19. Epub ahead of print. PMID: 31591112; PMCID: PMC6879264.
11. Lee WG, Shin JH, Uh Y, Kang MG, Kim SH, Park KH, Jang HC. First three reported cases of nosocomial fungemia caused by Candida auris. J Clin Microbiol. 2011 Sep;49(9):3139-42. doi: 10.1128/JCM.00319-11. Epub 2011 Jun 29. PMID: 21715586; PMCID: PMC3165631.
12. Ostrowsky B, Greenko J, Adams E, Quinn M, O’Brien B, Chaturvedi V, Berkow E, Vallabhaneni S, Forsberg K, Chaturvedi S, Lutterloh E, Blog D; C. auris Investigation Work Group. Candida auris Isolates Resistant to Three Classes of Antifungal Medications – New York, 2019. MMWR Morb Mortal Wkly Rep. 2020 Jan 10;69(1):6-9. doi: 10.15585/mmwr.mm6901a2. PMID: 31917780; PMCID: PMC6973342.
13. Chowdhary A, Anil Kumar V, Sharma C, Prakash A, Agarwal K, Babu R, Dinesh KR, Karim S, Singh SK, Hagen F, Meis JF. Multidrug-resistant endemic clonal strain of Candida auris in India. Eur J Clin Microbiol Infect Dis. 2014 Jun;33(6):919-26. doi: 10.1007/s10096-013-2027-1. Epub 2013 Dec 20. PMID: 24357342.
14. Mathur P, Hasan F, Singh PK, Malhotra R, Walia K, Chowdhary A. Five-year profile of candidaemia at an Indian trauma centre: High rates of Candida auris blood stream infections. Mycoses. 2018 Sep;61(9):674-680. doi: 10.1111/myc.12790. Epub 2018 Jul 5. PMID: 29738604.
15. Magobo RE, Corcoran C, Seetharam S, Govender NP. Candida auris-associated candidemia, South Africa. Emerg Infect Dis. 2014 Jul;20(7):1250-1. doi: 10.3201/eid2007.131765. PMID: 24963796; PMCID: PMC4073876.
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17. Chowdhary A, Prakash A, Sharma C, Kordalewska M, Kumar A, Sarma S, Tarai B, Singh A, Upadhyaya G, Upadhyay S, Yadav P, Singh PK, Khillan V, Sachdeva N, Perlin DS, Meis JF. A multicentre study of antifungal susceptibility patterns among 350 Candida auris isolates (2009-17) in India: role of the ERG11 and FKS1 genes in azole and echinocandin resistance. J Antimicrob Chemother. 2018 Apr 1;73(4):891-899. doi: 10.1093/jac/dkx480. PMID: 29325167.
18. Biagi MJ, Wiederhold NP, Gibas C, Wickes BL, Lozano V, Bleasdale SC, Danziger L. Development of High-Level Echinocandin Resistance in a Patient With Recurrent Candida auris Candidemia Secondary to Chronic Candiduria. Open Forum Infect Dis. 2019 Jun 1;6(7):ofz262. doi: 10.1093/ofid/ofz262. PMID: 31281859; PMCID: PMC6602379.
19. Kordalewska M, Lee A, Park S, Berrio I, Chowdhary A, Zhao Y, Perlin DS. Understanding Echinocandin Resistance in the Emerging Pathogen Candida auris. Antimicrob Agents Chemother. 2018 May 25;62(6):e00238-18. doi: 10.1128/AAC.00238-18. PMID: 29632013; PMCID: PMC5971591.
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21. Morales-López SE, Parra-Giraldo CM, Ceballos-Garzón A, Martínez HP, Rodríguez GJ, Álvarez-Moreno CA, Rodríguez JY. Invasive Infections with Multidrug-Resistant Yeast Candida auris, Colombia. Emerg Infect Dis. 2017 Jan;23(1):162-164. doi: 10.3201/eid2301.161497. PMID: 27983941; PMCID: PMC5176232.
22. Arendrup MC, Jørgensen KM, Hare RK, Chowdhary A. In Vitro Activity of Ibrexafungerp (SCY-078) against Candida auris Isolates as Determined by EUCAST Methodology and Comparison with Activity against C. albicans and C. glabrata and with the Activities of Six Comparator Agents. Antimicrob Agents Chemother. 2020 Feb 21;64(3):e02136-19. doi: 10.1128/AAC.02136-19. PMID: 31844005; PMCID: PMC7038269.
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