Special Report on Candida auris: An Emerging Drug-Resistant Fungal Threat

Candida fungi

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In March of 2023, the CDC issued a warning on Candida auris (C auris), which is spreading at an alarming rate in health care facilities and is now considered an “urgent antimicrobial resistance threat.”¹ This fungal pathogen was first reported in the US in 2016, and cases have increased yearly since then. The CDC states that “The rapid rise and geographic spread of cases is concerning and emphasizes the need for continued surveillance, expanded lab capacity, quicker diagnostic tests, and adherence to proven infection prevention and control.”

Potential Global Threat

C auris has emerged as a potential global health risk due to the bloodstream infections it can cause, resulting in high mortality rates.^2,3,4 It was first identified in 2009 in Japan in the external ear canal of a patient and has been isolated in 35 other countries and on 6 continents to date.^3.4 A recent study screening patients entering New York City health care facilities for C auris has found variable rates of C auris colonization in those patients, with the highest colonization rates for patients of nursing homes. Considering all of the New York City sample sites tested (ranging from hospitals to nursing homes), these researchers found that 6.9% of new patients tested were positive for C auris.⁵

Despite its name (auris being Latin for ear), C auris can affect many regions of the body and cause bloodstream and wound infections. It is most prevalent in hospital settings, thrives in warm temperatures, and is evolving due to the common usage of certain disinfectants and prophylactic antifungal medications, resulting in some isolates having multidrug resistance.^3,6

Risk factors for C auris infection include recent surgery, obesity, immunosuppression, diabetes, use of broad-spectrum antibiotics and antifungals, presence of tracheostomies, PEG tubes, and ventilators.^6,7,8 Long-term usage of broad-spectrum antibiotics can also be a risk factor for acquiring C auris infection.^6,7 Recent studies illustrate that the 30-day mortality of infected patients in an ICU was 31%.⁸

C auris is efficiently transmitted among hosts and typically arises from the host’s microflora.³ It can be spread via direct contact with another person and by shared equipment such as blood pressure cuffs and pulse oximeters.³ In the limited studies conducted on the survivability of C auris on surfaces, one study has suggested that this fungal pathogen can survive on plastic surfaces for up to 14 days under dry conditions.⁹ Another recent study found C auris survived on surfaces including glass, plastic, wood, cotton fabric, and stainless steel for up to 3 weeks.¹⁰ For patients, C auris has been found most consistently to colonize the axilla and groin, which are common locations for swabbing for screening.³ Given its transmissibility, the CDC recommends the usage of proper hand hygiene, isolation of infected patients, contact precautions for health care personnel, daily cleaning, and terminal room disinfection.⁷ Further, expert recommendations also include susceptibility testing, staff education, and long-term surveillance for C auris.¹¹ The CDC does not recommend treatment of C auris identified from noninvasive sites (eg skin colonization) if there is no evidence of infection. However, good infection control and prevention should always be used.

Precautions for COVID-19 Could Have Exacerbated the C auris Situation

Precautions in health care facilities put in place during the COVID-19 pandemic, targeting airborne pathogen spread may have inadvertently shifted focus away from prevention of surface contamination; thus, the rapid expansion in infections due to C auris over the past 5 years may in part be due to somewhat reduced levels of cleaning/disinfection of surfaces in some facilities. Standard techniques encouraged by the CDC for infection prevention in health care facilities that should also apply to the reduction of C auris infections start with the practice of good hand hygiene. Hand washing with soap and warm water should be done frequently, with the liberal use of alcohol-based hand sanitizers at other times. C auris has been found to be readily killed by alcohols in these sanitizers.¹² Infection prevention measures reflecting the most up-to-date information on C auris, established by an infection preventionist (if present), should always be followed.

Isolating and Identifying C auris

Techniques used to isolate and identify C auris in microbiology labs have been slow to develop. Some of the readily available diagnostic kits (eg API ID 32 C system (Biomerieux) have been found to misidentify C auris.¹³ Molecular tools like real-time Polymerase chain reaction test and other more complex systems have been found to accurately identify C auris, but at a steep cost for time and the instruments and reagents required.¹⁴ A relatively new culture-based selective and differential medium, CHROMagar Candida Plus has recently become available. This medium was compared with another cultural-based C auris detection system (dulcitol enrichment broth—requiring later analysis using matrix-assisted laser desorption ionization-time of flight mass spectrometry [MALDI-TOF MS]) using the same swab surveillance samples.¹⁵ Data from the CHROMagar Candida Plus system produced good results after 3 days of incubation and is being considered an excellent "presumptive” test medium for the presence of C auris on surveillance samples.

Eradicating C auris

C auris has been found to survive very harsh conditions, including desiccation and high-saline environments. In addition, C auris produces biofilms which may also interfere with the efficiency of disinfectants.¹⁰ Research on the use of disinfectants and antiseptics on surfaces or sensitive tissues have pointed to some unusual findings with regard to the efficacy of fairly-well known chemical agents.¹⁶ For example, quaternary ammonium compounds (quats), well known to be highly great effective in the control of bacterial pathogens, have generated mixed results when applied to the control of C auris.¹⁷ The use of chlorine-based disinfectants has been found to be much better in controlling C auris on surfaces. As for antiseptics used to control C auris, another example of a quat showing reduced effectiveness is chlorhexidine gluconate, which is often used in soaps for body washes. Chlorhexidine gluconate soaps have shown limited efficacy in the control of C auris for infected patients bathed regularly in these soaps. Alcohols have been found to provide the best antiseptic control of C auris.¹⁷ 

Control of C auris in clinical environments is proving to be problematic. In addition to the development of disinfectant-resistant strains of C auris, inappropriate application of these chemicals can lead to new problems. Strict adherence to manufacturers’ recommendations for contact times may not always be followed. For many disinfectants, the best fungal killing occurs with contact (“wetting”) times of up to 10 minutes. If this contact timing proves difficult in your facility, then your infection preventionist should look for other disinfectants effective against fungi—and C auris in particular—that may have shorter contact times.^18,19

Antifungal Drugs

For patients with C auris infections, antifungal agents should be prescribed sparingly. As with many pathogenic bacteria developing resistance to common antibiotics, resistance to some of the most commonly used antifungal agents against C auris has been observed. Sadly, major problems exist when targeting fungal pathogens when they invade the human body. As originally discussed by Paul Ehrlich more than a century ago, the best chemotherapeutic agents are those that work like a “magic bullet,” targeting the pathogen while leaving the host cells unharmed.⁷ This magic bullet concept worked well when the pathogens are prokaryotic bacteria. The differences in cellular physiology between prokaryotic pathogens and host eukaryotic cells are enough to allow for the development of chemical agents that target bacterial structures and metabolism and not host cells. The issue that comes up when looking for new chemotherapeutic antifungals (eg echinocandins) to target C auris is that this pathogen has a eukaryotic structure and metabolism that is similar to that of human cells. Thus, critical limitations exist with many antifungal drugs against C auris.

Antifungal agents that have been approved for use against C auris have included fluconazole, amphotericin B, and caspofungin. However, strains of C auris resistant to these drugs have been discovered. According to the CDC, C auris resistance to fluconazole and amphotericin B has been found in about 90% and 30% of isolates, with fewer that 5% of C auris isolates showing any resistance to caspofungin.⁴ Of this group of agents, caspofungin is a fungicide that has been approved for internal use by the US Food and Drug Administration.²² This agent works by inhibiting enzymes crucial to synthesizing fungal cell wall components – something that human cells cannot do. However, the newly developed resistance of C auris against caspofungin appears to be due to a mutation in the FKS1 gene that plays a role in C auris cell wall synthesis.²² 

So What Options Do We Have?

With increasing evolution of C auris strains that are resistant to antifungal agents and the rapid spread of this pathogen across continents, are there any other options to control this pathogen? Thankfully, researchers at the Los Angeles Biomedical Research Institute (Lundquist Institute) are working to develop such a vaccine ( https://lundquist.org/news/lundquist-institute-now-working-vaccine-urgent-fungal-threat-candida-auris ).²³ Testing of the efficacy of this vaccine is still in the early stages, with very promising results in rodent models. The next step will be to run human trials of the vaccine. Such a vaccine may prove helpful in limiting the spread of C auris between susceptible humans. Although the use of vaccines will have little direct impact on infection prevention in health care facilities, the development of an effective vaccine may buy time that can then be used to help develop new and better types of disinfectants and cleaning/disinfecting procedures to control this pathogen on surfaces in health care facilities, as well as time to develop new types of antifungals.

References:

1. Centers for Disease Control and Prevention (CDC). 2023. Increasing threat of spread of antimicrobial-resistant fungus in health care facilities. Accessed May 12, 2023. https://www.cdc.gov/media/releases/2023/p0320-cauris.html.

2. Pappas PG, Lionakis MS, Arendrup MC, Ostrosky-Zeichner L, Kullberg BJ. Invasive candidiasis. Nat Rev Dis Primers. 2018;4:18026. Published 2018 May 11. doi:10.1038/nrdp.2018.26

3. Sikora, A., M.F. Hashmi, F. Zahra. 2023. Candida Auris. In: StatPearls. Treasure Island (FL): StatPearls Publishing; February 19, 2023. Accessed May 19, 2023. https://www.ncbi.nlm.nih.gov/books/NBK563297/.

4. Spivak, E. S., K. E. Hanson. 2018. Candida auris: an emerging fungal pathogen. Journal of Clinical Microbiology, 56:e01588-17. Published 2018 Jan 24. doi:10.1128/JCM.01588-17

5. Rowlands J, Dufort E, Chaturvedi S, et al. Candida auris admission screening pilot in select units of New York City health care facilities, 2017-2019. American Journal of Infection Control. Published online February 2023:S0196655323000482. doi:10.1016/j.ajic.2023.01.012

6. Vinayagamoorthy K, Pentapati KC, Prakash H. Prevalence, risk factors, treatment and outcome of multidrug resistance Candida auris infections in Coronavirus disease (COVID-19) patients: A systematic review. Mycoses. 2022;65(6):613-624. doi:10.1111/myc.13447

7. Al-Rashdi A, Al-Maani A, Al-Wahaibi A, Alqayoudhi A, Al-Jardani A, Al-Abri S. Characteristics, Risk Factors, and Survival Analysis of Candida auris Cases: Results of One-Year National Surveillance Data from Oman. J Fungi (Basel). 2021;7(1):31. Published 2021 Jan 7. doi:10.3390/jof7010031

8. Briano F, Magnasco L, Sepulcri C, et al. Candida auris Candidemia in Critically Ill, Colonized Patients: Cumulative Incidence and Risk Factors. Infect Dis Ther. 2022;11(3):1149-1160. doi:10.1007/s40121-022-00625-9

9. Welsh RM, Bentz ML, Shams A, et al. Survival, persistence, and isolation of the emerging multidrug-resistant pathogenic yeast candida auris on a plastic health care surface. Diekema DJ, ed. J Clin Microbiol. 2017;55(10):2996-3005. doi:10.1128/JCM.00921-17

10. Oremefetse D, Aijaz A, Sanelisiwe D, Mrudula P, 2023. Survival of Candida auris on environmental surface material and low-level resistance to disinfectant. Journal of Hospital Infection. Accessed May 19, 2023 https://doi.org/10.1016/j.jhin.2023.04.007.

380-382. doi:10.1017/ice.2019.1

11. Aldejohann AM, Wiese-Posselt M, Gastmeier P, Kurzai O. Expert recommendations for prevention and management of Candida auris transmission. Mycoses. 2022;65(6):590-598. doi:10.1111/myc.13445.

12. Centers for Disease Control and Prevention (CDC). 2023b. Infection prevention and control for Candida auris. Accessed May 17, 2023. https://cdc.gov/fungal/candida-auris/c-auris-infection-control.html

13. Dennis, EK, Chaturvedi S, Chaturvedi V. 2021. So many diagnostic tests, so little time: Review and preview of Candida auris testing in clinical and public health laboratories. Frontiers in Microbiology, 12:1–13. Accessed May 19, 2023. https://doi.org/10.3389/fmicb.2021.757835.

14. Leach L, Zhu Y, Chaturvedi S. Development and Validation of a Real-Time PCR Assay for Rapid Detection of Candida auris from Surveillance Samples. J Clin Microbiol. 2018;56(2):e01223-17. Published 2018 Jan 24. doi:10.1128/JCM.01223-17

15. Marathe A, Zhu YC, Chaturvedi V, Chaturvedi S. 2022. Utility of CHROMagar Candida Plus for presumptive identification of Candida auris from surveillance samples. Mycopathologia, 187:527-534. Accessed May 19, 2023. https://doi.org/10.1007/s11046-022-00656-3.

16. Rutala WA, Kanamori H, Gergen MF, Sickbert-Bennett EE, Weber DJ. Susceptibility of Candida auris and Candida albicans to 21 germicides used in healthcare facilities. Infect Control Hosp Epidemiol. 2019;40(3):

17. Ku TSN, Walraven CJ, Lee SA. Candida auris: Disinfectants and Implications for Infection Control. Front Microbiol. 2018;9:726. Published 2018 Apr 12. doi:10.3389/fmicb.2018.00726

18. Sexton DJ, Welsh RM, Bentz ML, et al. Evaluation of nine surface disinfectants against Candida auris using a quantitative disk carrier method: EPA SOP-MB-35. Infect Control Hosp Epidemiol. 2020;41(10):1219-1221. doi:10.1017/ice.2020.278

19. U.S. Environmental Protection Agency (EPA). 2023. List P: Antimicrobial products registered with EPA for claims against Candida auris. Accessed May 12, 2023. https://www.epa.gov/pesticide-registration/list-p-antimicrobial-products-registered-epa-claims-against-candida-auris.

20. Chuaire L, and Cediel JF. 2008. Paul Ehrlich: From magic bullets to chemotherapy. Colomtia Medica, 39:296-300. Accessed May 19, 2023. https://www.researchgate.net/profile/LilianChuaire/publication/26549709_Paul_Ehrlich_From_magic_bullets_to_chemotherapy/links/09e415138ed8771610000000/Paul-Ehrlich-From-magic-bullets-to-chemotherapy.pdf.

21. Centers for Disease Control and Prevention (CDC). 2020. Antifungal susceptibility testing and interpretation. Accessed May 12, 2023. https://www.cdc.gov/fungal/candida-auris/c-auris-antifungal.html#:~:text=In%20the%20United%20States%2C%20about,as%20more%20isolates%20are%20tested.

22. Dongmo Fotsing LN, Bajaj T. 2023. Caspofungin. [Updated 2022 Oct 10]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Accessed May 19, 2023. https://www.ncbi.nlm.nih.gov/books/NBK545140/

23. Singh S, Uppuluri P, Mamouei Z, et al. The NDV-3A vaccine protects mice from multidrug resistant Candida auris infection. Gaffen SL, ed. PLoS Pathog. 2019;15(8):e1007460. doi:10.1371/journal.ppat.1007460