Candida auris Is Changing the Paradigm of Antifungal-Resistant Candida

Candida species re one of the most common fungal pathogens, causing invasive infections worldwide and accounting for 600,000 infec­tions each year, and are isolated from approx­imately 25% of all patients in an intensive care unit with central line—associated bloodstream infections in the United States.^1,2

Therapeutic options for the treatment of candidemia and other forms of invasive candidiasis are unfortunately limited, with only 3 classes of antifungal agents currently available to clinicians. Thus, antifungal resistance against clinical isolates, estimated to include 35,000 infections each year and 7% of all cases of candidemia in the United States, is a threat to public health.³ Unlike drug-resistant bacterial pathogens such as methicillin-resistant Staphylococcus aureus and carbapenem-resistant Enterobacteriaceae, infections caused by antifungal drug-resistant Candida are most often reported as individual cases among at-risk patients following previous antifungal exposure, and they are generally not associated with trans­mission in health care settings. The discovery and emergence of Candida auris, however, have significantly changed the way clinicians need to consider antifungal-resistant Candida, and it represents new challenges not previously associated with this genus of fungi.

Shortly after the initial identification of C auris was described in 2009, clinical outbreaks of infections caused by this organism occurred in South Africa, Venezuela, India, and Pakistan.⁴ Less than a decade later, invasive infections caused by C auris have been reported in 40 countries, with approximately 1000 infec­tions and more than 2000 patients colonized in the United States alone.⁵ Furthermore, nearly all clinical C auris isolates are found to be resistant to at least 1 antifungal agent, and a large proportion of isolates are multidrug resistant (defined as resistance to agents from more than 1 class of antifungal agents).^4,6 As a result, C auris has become a fungal pathogen of great clinical concern and is now considered a pathogen of urgent threat level by the US Centers for Disease Control and Prevention (CDC).³ Although considerable research efforts continue to expand the epidemiology and pathogenesis of C auris, 3 factors define its threat to public health: the organ­ism’s ability to rapidly spread among patients and health care environments, challenges in the detection of C auris in the clinical microbiology laboratory, and the prevalence of anti­fungal resistance among clinical isolates.

RAPID SPREAD AMONG PATIENTS AND WITHIN HEALTH CARE

The first clinical specimens of C auris were isolated from patients with ear infections in Japan and South Korea, and this is how the species acquired its name (auris is Latin for “ear”).⁷ Within a few years, C auris was identified as the cause of unrelated outbreaks of invasive infections on 3 continents.⁴ In India and South Africa, where C auris appeared earliest and before widespread recognition, C auris quickly became a leading cause of candidemia in some institutions.^8,9 In fact, the most recently available data from South Africa show that C auris was isolated from 14% of nearly 6000 cases of candi­demia in private sector hospitals.⁹ In health care settings outside these regions, introduction of a single clinical isolate has been reported to cause prolonged outbreaks as a result of the unique ability of C auris to resist commonly employed disinfectants, persist on surfaces for weeks, and colonize patients for months.¹⁰ In the Chicago, Illinois, metropolitan area, where it was first clinically identified in 2016, C auris has now spread across health care facilities, most notably long-term post—acute care facilities with large populations of patients at high risk for infections due to multidrug-resistant organisms. A point prevalence study at one institution reported that 71% of screened patents were colonized with C auris, and 49% of patients were positive for both C auris and carbapenemase-producing bacterial pathogens.¹¹ This high rate of colonization among high-risk patients is partic­ularly concerning considering no established methods exist to effectively decolonize patients; an estimated 5% to 10% of colonized patients develop invasive C auris infections.^11,12

Thus, excellent infection control practices are essential to controlling the spread of C auris colonization and infection. As with other, similar bacterial multidrug-resistant threats, clinicians should report cases of C auris colonization or infec­tions to local and state departments of public health, and they should be aware if C auris has been identified in their region. Clinicians must also evaluate patients for recent travel or direct personal contacts who may have exposed them to C auris, and those who are positive for C auris should be placed under contact precautions. Health care workers should be reminded to employ good hand hygiene, and facilities and equipment should be cleaned and sanitized with agents carrying Environmental Protection Agency claims for C auris or Clostridioides difficile (list K). Further detailed recommen­dations for the prevention and control of C auris in health care settings are available on the CDC’s C auris website.¹³

DIFFICULT IDENTIFICATION IN THE CLINICAL MICROBIOLOGY LABORATORY

Reliable and timely identification of C auris in the clin­ical setting is imperative to the prevention of its spread in health care environments. Unfortunately, many clin­ical microbiology laboratories are unable to provide definitive species-level identification of Candida isolates in-house. Among those that can, standard pheno­typic methods often misidentify C auris (platform-specific examples are available on the CDC’s C auris website), and in some cases, misidentification occurs even after imple­menting updated testing panels.^14-16 Taken together, the most reliable methods of identifying C auris from clinical specimens are matrix-assisted laser desorption ionization—time of flight platforms with C auris spectral libraries, the T2 magnetic resonance platform with the updated T2Cauris panel, and molecular techniques such as sequencing of ribosomal DNA markers.^14,15,17,18 However, these methods require costly equip­ment or advanced technical skills that may not be feasible in every clinical setting. Thus, clinicians must be aware of resources available at their own institutions for the identifica­tion of C auris, and if limitations exist, clinicians should also carefully consider them when caring for patients in whom C auris is suspected. Clinical isolates exhibiting multidrug antifungal resistance should also be carefully identified to the species level by methods capable of identifying C auris. Clinicians can send clinical isolates in question to the CDC’s Antibiotic Resistance Laboratory Network for confirmatory identification and susceptibility testing.¹⁴

HIGH RESISTANCE TO ANTIFUNGALS

Further contributing to the clinical significance of this emerging fungal pathogen, C auris demonstrates higher-level resistance to most antifungal drug classes than do other Candida species. Although clinical experience and epidemi­ologic data relating to C auris are currently insufficient to support the establishment of true clinical breakpoints at this time, in an effort to provide provisional guidance for clinicians, the CDC has put forth tentative antifungal breakpoints for the treatment of C auris infections.⁶ These breakpoints are based on available in vitro susceptibility data, limited in vivo pharmacodynamics studies, and the distribution of mutations in genes associated with antifungal resistance in other species of Candida. The specific breakpoints and comments relating to their appropriate application are avail­able on the CDC’s C auris website.⁶

Approximately 90%, 30%, and 5% of clinical C auris isolates from the United States are resis­tant to fluconazole, amphoter­icin B, and the echinocandins, respectively, when applying these tentative breakpoints.¹⁵ Moreover, one-third of isolates are resistant to agents from more than 1 class of antifun­gals, and isolates resistant to all available therapies have repeat­edly been identified. The CDC currently recommends empiric therapy with echinocandins (using labeled dosing) for the treatment of infections in which C auris is suspected in patients at least 2 months of age.¹⁹ Furthermore, fungal cultures with species-level identification and antifungal susceptibility testing are recommended, as is the consul­tation of an infectious disease specialist. Clinicians should obtain repeat cultures and antifungal susceptibilities and monitor patients carefully for signs of clinical response, as cases of patients developing antifungal-resistant C auris infections on therapy have been reported. Most of these instances of acquired antifungal resistance have occurred following prolonged courses of treatment with echinocan­dins.^20,21 However, the rate at which C auris may develop resistance to echinocandins or other classes of antifungals is unknown. In the event of insufficient patient response or the development of echinocandin-resistant disease, clini­cians should consider switching to liposomal amphotericin B. However, clinicians need to consider specific patient-, pathogen-, and infection-related factors on a case-by-case basis in collaboration with infectious disease specialists.¹⁹

CONCLUSIONS

Although much research is needed on C auris and its long-term impact on invasive candidiasis as a whole, ultimately the best strategies to overcome the challenges posed by C auris focus on not only therapeutics but also infection control and mitigation. Clinicians must be aware of any cases of C auris in their local area, monitor new patients for travel or contacts with risk of C auris exposure, and practice good antimicrobial stewardship and infection control when C auris is suspected or identified. Finally, clinicians should regularly check the CDC’s C auris website for the latest information and recommendations.

Rybak is a postdoctoral research associate at The University of Tennessee College of Pharmacy in Memphis. His research focuses on the identification and characterization of antifungal resistance mechanisms in fungal pathogens such as Aspergillus fumigatus and Candida auris. *He is an active member of both the Society of Infectious Diseases Pharmacists and Making a Difference in Infectious Diseases (MAD-ID).

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