C. auris: An urgent threat to US hospitals
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Candida auris is an emerging multidrug-resistant yeast causing nosocomial infections. First identified in 2009 in Japan, C. auris has now also been isolated in North America, South America, Europe, Africa, the Middle East and East Asia.
Researchers from the CDC’s Mycotic Diseases Branch recently reported that cases of C. auris in the United States increased 59% from 2019 to 2020 and 95% from 2020 to 2021, with 17 states reporting their first case between 2019 and 2021.
Four distinct clades have been identified, all of which have been reported in the U.S. In most of these confirmed cases, patients had recently been hospitalized and had been receiving antifungal agents.
C. auris has been deemed a pathogen of concern because of its transmissibility, ability to survive outside a human host longer than other Candida species, the difficulty in identifying it and its growing resistance to antifungals.
Transmission and identification
Patients who have active infection or are colonized can transmit C. auris readily. This may result in direct person-to-person transmission or indirect person-to-person transmission via fomites, especially in the hospital setting.
According to the CDC, live C. auris can be cultured from the beds of colonized patients even after the patient is no longer using the bed. As with other highly transmissible pathogens, infection prevention is a cornerstone in preventing outbreaks. In addition to patient isolation and proper hand hygiene, use of appropriate antimicrobial agents is essential. The EPA’s list of antimicrobial products registered for claims against C. auris provides detailed product information — including contact time — for effectively killing C. auris.
Unfortunately, adequate infection prevention measures in the hospital may be delayed because of limitations in appropriately identifying C. auris in the laboratory. Initially, using diagnostic biochemical tests to identify Candida species often resulted in misidentification of C. auris as other related species, including C. haemulonii, C. duobushaemulonii and C. catenulata. Now, more definitive identification can be made via mass spectrometry MALDI-TOF with an appropriate database. The CDC has compiled guidance for processing swabs to detect C. auris colonization by use of real-time PCR and PCR alternatives. No matter the process used, accurate identification is paramount.
Guidelines
Still, identification of yeast down to the species level takes a significant amount of time, which leaves hospitals vulnerable to outbreaks. While awaiting susceptibilities, empiric treatment with an echinocandin is preferred based on C. auris’ relatively low resistance to the echinocandin class in the U.S.
Assessment of resistance patterns in the U.S. has shown that about 90% of isolates are resistant to fluconazole, about 30% are resistant to amphotericin B and less than 5% are resistant to echinocandins. Because official breakpoints for C. auris have not been established, tentative breakpoints have been published by the CDC as a general guide for clinicians based on available data and expert opinion. The estimated minimum inhibitory concentration (MIC) breakpoint for fluconazole is 32 g/mL or more, amphotericin B is 2 g/mL or more, anidulafungin or micafungin is 4 g/mL or more and caspofungin is 2 g/mL or more. Breakpoints for triazoles have not been established but should generally be considered resistant if the isolate is resistant to fluconazole.
Although most isolates are resistant to two of the three main antifungal classes, there have been rare reports of isolates with elevated MICs for all classes of antifungals. For clinically unresponsive patients, it may be appropriate to transition to — or add — liposomal amphotericin B, pending susceptibilities.
In the rare case that a pediatric patient develops a C. auris infection, treatment recommendations are extrapolated from the 2016 Infectious Diseases Society of America guidelines for the treatment of candidiasis, which recommend caspofungin or micafungin for empiric therapy because both are approved by the FDA for use in children aged at least 2 months. For neonates, amphotericin B deoxycholate is the preferred first-line therapy. If susceptibility reports show elevated MICs to all classes of antifungals, there is evidence to suggest combination therapy with flucytosine plus an echinocandin, amphotericin B or azole sufficiently lowers MICs in vitro. Treatment of asymptomatic, colonized patients is strongly discouraged to prevent the development of resistance.
Treatment pipeline
Slowly, new antifungal agents with retained efficacy against C. auris will become available, with multiple promising agents in the pipeline.
New triazoles or tetrazoles appear to maintain efficacy for azole-resistant C. auris strains. VT-1598 recently completed phase 1 human studies for safety and pharmacokinetics as of December 2021. A new echinocandin, rezafungin, which was recently approved by the FDA, was found to be at least as active as other echinocandins in vitro. Ibrexafungerp, a novel drug of the triterpenoid class, which is approved for vulvovaginal candidiasis and is being investigated for invasive candidiasis, has also shown in vitro activity against C. auris. Similarly, fosmanogepix, the first member of a new therapeutic class targeting the Gwt1 protein, is undergoing phase 3 studies for invasive candidiasis and/or candidemia and has also shown in vitro efficacy against C. auris.
A recent review of a C. auris outbreak in the Chicago metropolitan area from May 2018 to April 2019 identified 28 patients with at least one positive culture for C. auris in eight hospitals. Four of the isolates were resistant to fluconazole, one was resistant to amphotericin B, and one was resistant to echinocandins.
The median age of the patients was 70 years old, and 93% were admitted from a skilled nursing facility. Of these, 12 patients were treated for C. auris infection. Untreated patients were either discharged back to their skilled nursing facility in stable condition (n = 2), died before cultures were available (n = 3) or were determined to be colonized (n = 11).
Among those who received treatment, 92% received empiric micafungin. Once susceptibilities were available, nine received definitive micafungin therapy, two received fluconazole therapy and one received itraconazole therapy. The average treatment duration was 14 days, with 10 patients achieving clinical success. The other two patients died within 30 days of the first positive blood culture, and both had a central line-associated bloodstream infection.
The overall mortality rate was 17%, which is much lower than other reports ranging from 30% to 72%. Despite the promising resistance patterns and prognosis of the patients in this outbreak, there is continued concern that C. auris poses an urgent threat. With increasing data and judicious use of antifungals, this threat may be diminished as C. auris infections continue to spread globally.
References:
- Arensman K, et al. Emerg Infect Dis. 2020; doi:10.3201/eid2605.191588.
- CDC. Candida auris. https://www.cdc.gov/fungal/candida-auris/index.html. Published Dec. 27, 2022. Accessed March 10, 2023.
- CDC. Identification of Candida auris. https://www.cdc.gov/fungal/candida-auris/identification.html. Last reviewed Dec. 14, 2022. Accessed March 27, 2023.
- CDC. Treatment and management of C. auris infections and colonization. https://www.cdc.gov/fungal/candida-auris/c-auris-treatment.html. Last reviewed Dec. 14, 2022. Accessed March 27, 2023.
- Chowdhary A, et al. J Hosp Infect. 2016;doi:10.1016/j.jhin.2016.08.004.
- EPA. List P: Antimicrobial products registered with EPA for claims against Candida Auris. https://www.epa.gov/pesticide-registration/list-p-antimicrobial-products-registered-epa-claims-against-candida-auris. Published Feb. 2, 2023. Accessed March 10, 2023.
- Lone SA, et al. Mycoses. 2019;doi:10.1111/myc.12904.
- Lyman M, et al. Ann Intern Med. 2023;doi:10.7326/M22-3469.
- O'Brien B, et al. Antimicrob Agents Chemother. 2020;doi:10.1128/AAC.02195-19.
- O'Brien B, et al. Lancet Microbe. 2020;doi:10.1016/S2666-5247(20)30090-2.
- Pappas PG, et al. Clin Infect Dis. 2016;doi:10.1093/cid/civ933.
- Sanyaolu A. Infect Chemother. 2022;doi:10.3947/ic.2022.0008.
- Spivak ES, Hanson KE. J Clin Microbiol. 2018;doi:10.1128/JCM.01588-17.
- Tóth Z, et al. J Antimicrob Chemother. 2019;doi:10.1093/jac/dkz390.
- Tsay S, et al. Clin Infect Dis. 2018;doi:10.1093/cid/cix744.
- Understanding C. auris transmission with the healthcare environment. https://asm.org/Press-Releases/2019/June/Understanding-C-auris-Transmission-with-the-He-1. Published June 23, 2019. Accessed March 10, 2023.
For more information:
Elisa Worledge, PharmD, is a PGY1 pharmacy practice resident at Denver Health Medical Center.
Kati Shihadeh, PharmD, BCIDP, is a clinical pharmacy specialist in infectious diseases at Denver Health Medical Center. Shihadeh can be reached at katherine.shihadeh@dhha.org.
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