C. auris: ‘A nasty bug’ threatening US hospitals

Last June, the CDC issued a clinical alert to health care facilities in the United States about Candida auris, an emerging and often drug-resistant fungus with a high potential to cause hospital outbreaks.

At the time, C. auris infections had been reported in at least a dozen countries around the world, but the CDC was aware of just one U.S. case, from 2013. Five months later, the CDC made what experts characterized as an unsurprising announcement: More than a dozen cases had been reported in the U.S.

C. auris had arrived.

Like many physicians, Cornelius (Neil) J. Clancy, MD, associate professor of medicine at the University of Pittsburgh and chief of the infectious diseases section in the VA Pittsburgh Health Care System, was already aware of C. auris when the CDC issued its alert. He was not surprised that the fungus had reached U.S. soil.

“I suspect eventually it will show up everywhere,” Clancy told Infectious Disease News. “The question is: How big a player is it going to be in the grand scope of invasive candidiasis?”

Among the most worrying aspects of the infection, C. auris is the first Candida spp. to show resistance to all three major classes of antifungals, although no such resistance has been reported so far in the U.S., where the infection still shows susceptibility to front-line echinocandins, according to Tom M. Chiller, MD, MPHTM, chief of the CDC’s Mycotic Disease Branch.

But C. auris is distinct from other Candida spp. in more than one way. For example, rather than being an autoinfection, it spreads from patient to patient or from surface to patient in a health care setting, causing outbreaks.

“This is a nasty bug that sets up shop and spreads differently than the run-of-the-mill Candida,” Chiller said in an interview.

Infectious Disease News spoke with several health experts to better understand C. auris and what its arrival in the U.S. means for clinicians and their patients. Although the infection is still rare in the country, experts have voiced concern about its reported drug resistance and the difficulty of distinguishing it from other invasive Candida infections, which could lead to inappropriate treatment.

“Where we are right now is just waiting to see how extensive this is going to be,” Clancy said.

‘Simultaneous emergence’ of C. auris still a mystery

When it enters the bloodstream, C. auris can spread throughout the body and cause serious invasive infections in hospitalized patients, according to the CDC. It also has been the cause of wound and ear infections.

C. auris was first isolated in 2009 from a Japanese patient’s ear — giving the fungus its name. Although the earliest known strain dates to 1996, researchers believe that C. auris emerged on several continents around the same time in 2008 or 2009 — an idiosyncrasy that has baffled experts.

“I bang my head against the wall all the time,” Chiller said. “And with colleagues. We really wonder about it.”

Using whole-genome sequencing, Chiller and colleagues showed that different clonal populations of C. auris emerged independently in Asia, Africa and South America. Isolates from dozens of patients in Japan, India, Pakistan, South Africa and Venezuela were grouped into unique clades by geographic region, but within each clade, isolates were clonal.

“It suggests that when it sets up shop, it tends to expand clonally. Yet these [clades] are so different that we can’t say, ‘There was a plane flight that introduced it multiple places.’ They’re just too different,” Chiller said.

Experts are working to understand the genomics of C. auris to determine if its emergence can be clarified. According to Chiller and Clancy, possible explanations might involve changes in the environment, use of disinfectants, increased use of antifungals or antibacterials or an ecological or genetic change in the fungus.

“This simultaneous emergence in multiple places in the fungal business is something that’s not been seen before,” Clancy said.

Transmission in health care settings

Most cases of candidemia are caused by a patient’s own Candida reaching the bloodstream from parts of his or her body such as the skin or gut, but C. auris infections are different. According to the best evidence, rather than patients infecting themselves, C. auris acts more like a nosocomial bacterium such as carbapenem-resistant Enterobacteriaceae or Acinetobacter, Chiller said. In other words, the infection is transmitted from patient to patient, or from contaminated machines or other surfaces, an unusual tendency for a Candida spp.

Indeed, the CDC’s clinical alert about C. auris last year came after it received reports that the fungus was causing health care-associated infections with high mortality in other countries.

“On top of that, we’re finding it also really likes to stay on skin and colonize skin and stay on patients for months even after they’ve been completely cured of their more invasive, deeper infection,” Chiller said. “We’re able to culture it from patients for months after that endeavor, and we’re able to culture it in hospital environments, which is not something we generally do with Candida.”

Patients with C. auris infections are typically already sick. In a study published in December, Chiller and colleagues analyzed 41 isolates from 54 patients infected with C. auris between 2012 and 2015. Among them, 61% had bloodstream infections, 41% had diabetes, 51% had had recent surgery, 78% had a central venous catheter, and 41% were receiving systemic antifungal therapy.

“While emerging fungal pathogens are not typically dangerous to a normal person with a healthy immune system, they become extraordinarily dangerous for immunologically suppressed patients, as well as neonates and burn patients,” Elaine G. Cox, MD, pediatric disease specialist and medical director of infection prevention for Riley Hospital for Children at Indiana University Health, said in an interview. “In the event of an Aspergillus infection, or even C. auris, these are the populations at highest risk, compounded by the fact that we do not have the drugs to treat them until their immune system returns, turning these infections fatal.”

In line with reports about deadly outbreaks, 59% of the patients in the study by Chiller and colleagues died. However, although the CDC says C. auris is deadly, determining it as the cause of death is difficult.

“Attributable mortality is very challenging in the medical world,” Chiller said. “Certainly, when you’re dealing with rather sick individuals who have multiple medical problems, it’s often difficult without an autopsy, which is less common these days.”

In interim guidance, the CDC says patients in acute-care settings who have C. auris infection or have been colonized by C. auris should be placed in single rooms on standard and contact precautions. The guidance does not include recommendations on the length of such interventions because the typical duration of C. auris colonization is not known. The CDC says patients might need to be reassessed every 1 to 3 months to determine the duration of their infection. The guidance for nursing home patients is similar.

As for infection control, the CDC says rooms of patients with C. auris should be cleaned and disinfected daily with an EPA–registered hospital-grade disinfectant effective against Clostridium difficile spores (List K).

When it comes to protecting and treating patients, however, Clancy said the most important thing is for health care centers to be aware of C. auris.

“I don’t think we know enough in this country to institute infection control measures. We’ll have to hear details from places that have dealt with outbreaks and what has worked and what hasn’t,” Clancy said. “But the biggest thing is, if you’re not identifying cases, it can get entrenched in your hospital and you may find yourself scrambling to catch up with this infection rather than dealing with it proactively.”

Difficult to diagnose

In addition to its resistance to major antifungal medications and association with transmission in health care settings, C. auris is also challenging to diagnose. According to the CDC, it can be misidentified in biochemical-based tests as other Candida spp. and treated inappropriately. This poses a problem in correctly treating fungal infections in a time-sensitive manner, which threatens patient safety.

Clancy said most tertiary care centers probably have the technology needed to differentiate C. auris from other Candida spp. using methods like matrix-assisted laser desorption ionization time-of-flight mass spectrometry, or MALDI-TOF, provided they have a suitable database of microbes. But C. auris may get missed in small hospitals and other resource-strapped settings.

“Particularly in a number of the settings where it first emerged, the standard technology that’s used may miss it,” Clancy said.

The CDC says C. auris should be suspected when an isolate is identified as any number of Candida spp. or has not been identified at the species level, and that the presence of drug resistance should further raise suspicions. Suspected cases of C. auris — or cases where there is doubt about the species — should be referred to the CDC.

“When we first started to worry about this back with our alert last year, we were concerned that people might not be identifying it or misidentifying it,” Chiller said.

Once diagnosed, the CDC recommends invasive C. auris infections initially be treated with an echinocandin drug at one of these doses:

• 200 mg loading dose, followed by 100 mg daily of anidulafungin;
• 70 mg loading dose, followed by 50 mg daily of caspofungin; and
• 100 mg daily of micafungin.

Although C. auris isolates in the U.S. are still showing susceptibility to these front-line echinocandins, experts are concerned about the potential for the fungus to develop resistance to all three major classes of antifungals.

“The resistance, and the potential for pan-drug resistance, is greater than what we’ve seen with Candida species to this point,” Clancy said.

Unusual phenomenon of multidrug resistance

Chiller and colleagues found that 93% of the 41 isolates in their study were resistant to fluconazole, 35% were resistant to amphotericin B and 7% were resistant to echinocandins. Overall, 41% were resistant to two antifungal classes, while two isolates showed resistance to all three classes.

Among the first seven cases of C. auris identified in the U.S., 71% showed some drug resistance, the CDC said in November.

“As a species, this is something that is unique with auris,” Clancy said. “And I think it’s part of the reason why CDC and Public Health England really wanted to get the word out there so that we don’t end up with a spread of Candida species that’s something like what we’ve seen with the extensively drug-resistant bacteria out there nowadays.”

One theory experts have cited for drug resistance in C. auris is the global overuse of antibiotics. According to Cox, unnecessary antimicrobial use paves the way for fungi to become resistant to antifungals.

“[The antimicrobial] cycle just sets us up to continuing to breed all the types of resistance, including fungal infections,” she said. “I think we could decrease our antibiotic use — that would be one thing; secondly, antifungals have always been more difficult for us to use unlike antibiotics, since in bacteria we have really defined breaking points of what is susceptible, what is not, and the turnaround time on that information is very quick in labs, which is not the case with most fungi.”

In December 2015, a British project titled Review on Antimicrobial Resistance published the first warning about antimicrobial resistance in fungal pathogens. The project was ordered by former British Prime Minister David Cameron to examine the increase of global antibiotic resistance. The investigators found in soil samples that overused agricultural fungicides built up resistance in the environment.

Experts said finding alternatives for pesticides in crops is paramount. However, according to Maurizio Del Poeta, MD, associate professor in the department of molecular genetics and microbiology at Stony Brook University, the development of new antifungal therapies should be at the forefront of discussion in clinical settings to avoid further mortality and the spread of infection.

“It is absolutely essential that in the long term we are not only addressing these emerging fungal infections, but also the current infections: the candidiasis by Candida albicans, aspergillosis by Aspergillus genicanthus and cryptococcosis by Cryptococcus neoformans var gattii,” Del Poeta said in an interview. “These three common infections kill more than 1.3 million people per year.”

There are no clinical trials underway of drugs specifically intended for the treatment of C. auris infection, according to the NIH. However, the National Institute of Allergy and Infectious Diseases is planning to add C. auris screening to its preclinical services program this spring, and there have been other promising announcements recently.

Cidara said its echinocandin antifungal CD101 — a once-weekly, high-exposure therapy for invasive fungal infections that is advancing in phase 2 trials — has shown potent activity against C. auris in vitro. And researchers from Case Western Reserve who tested C. auris isolates against a battery of 11 drugs said low concentrations of the investigational drug SCY-078 (Scynexis), which has shown effectiveness against other Candida spp. that cause catheter-associated infections, distorted C. auris and impaired its growth. The results, which were strain-dependent, suggested that SCY-078 could halt C. auris infections or limit their spread, particularly in catheter-associated infections, according to a news release.

The future of C. auris

On the front lines of the battle against antimicrobial resistance, many infectious disease physicians have adopted a “watch and wait” policy. Until more information about C. auris can be gathered, the CDC has recommended timely reporting; prompt laboratory involvement of suspicious infections; careful adherence to hand hygiene and using contact precautions within health care settings; and most importantly, caution when considering antifungal use.

“The first step in preventing the spread of C. auris and other invasive fungal infections should be consistent antifungal stewardship — monitoring and promoting the effective use and dosages of antifungals,” Peter G. Pappas, MD, FACP, William E. Dismukes Professor of Medicine in the division of infectious disease at the University of Alabama at Birmingham, said in an interview. “I think that the CDC warning on C. auris gives us an opportunity to focus on this even more. The second step is preventing the spread of fungal infection within the hospital setting, because most of these infections are going to occur within the hospital rather than outside.”

The emergence of C. auris has raised more questions than answers. Without knowing why it has emerged or the precise mode of transmission within health care facilities, and without viable defenses against a possible outbreak, infectious disease physicians find themselves wading cautiously into the unknown.

“We do not know much about the mechanisms of multidrug resistance development among Candida species, its molecular basis, or the potential contribution of factors other than exposure to antifungals,” Dimitrios Farmakiotis, MD, the transplant-oncology infectious diseases attending physician at Rhode Island Hospital, told Infectious Disease News. “We do not even know if the use of more than one antifungal drug against multidrug-resistant Candida and other pathogens is beneficial or harmful.”

Pappas said the main obstacle in developing new antifungals is that not enough is known about them.

“It takes something drastic like C. auris to get you to start doing the right things sometimes,” Pappas said. “The truth is that we are dealing with several multidrug-resistant fungi, both yeasts and molds, that really require our attention, and we need to respond in a similar way, especially as it relates to unnecessary use of antifungal agents.”

‘Think auris’

As of Feb. 16, 35 cases of C. auris had been reported to the CDC from U.S. health care facilities, including 28 in the state of New York. According to Chiller, “a combination of factors” — including aggressive case finding — probably explains why New York has seen so many cases compared with other states. (Illinois has reported three cases, New Jersey has reported two and Maryland and Massachusetts have each reported one.)

Chiller said the CDC has been working with state health departments and hospitals to control and contain the infections when they are found.

“The good news is that it’s exceedingly rare in the U.S.,” he said. “We need hospitals and health care providers to remain aware that it exists, to look for it in their patients, to make sure if they have a Candida species that their hospital can’t identify, they work with their state or work with us to help identify what that species is, and to stay alert for more news from us and the health care community.”

Clancy said the CDC deserves credit for issuing its clinical alert about C. auris last June. He was struck by the agency’s proactive rather than reactive response to the emerging pathogen and its potential to harm patients.

“If it turns out to be not that big of a deal, it may prove that their vigilance made a difference,” he said.

Compared with other Candida species such as C. glabrata, which has caused thousands of infections in the U.S. and has shown higher resistance to echinocandins, Chiller said C. auris is less of a threat. Nevertheless, he hopes physicians and health care centers are vigilant when they come across an atypical Candida infection that could end up being C. auris.

“There are probably a lot of those cases occurring in the U.S.,” Chiller said. “I’d love to get people to ‘think auris’ and just reaffirm with the lab.” – by Gerard Gallagher and Kate Sherrer

Editor’s note: This article has been updated with the correct doses of echinocandin agents recommended by the CDC for the treatment of invasive C. auris infections. The editors regret the error.

 

• References:
• CDC. Candida auris. 2017. https://www.cdc.gov/fungal/diseases/candidiasis/candida-auris.html. Accessed February 10, 2017.
• CDC. Clinical alert to U.S. healthcare facilities – June 2016. https://www.cdc.gov/fungal/diseases/candidiasis/candida-auris-alert.html. Accessed February 10, 2017.
• CDC. First cases of Candida auris reported in United States. 2016. https://www.cdc.gov/media/releases/2016/p1104-candida-auris.html. Accessed February 10, 2017.
• Clancy CJ, Nguyen MH. Clin Infect Dis. 2016;doi:10.1093/cid/ciw696.
• Lockhart SR, et al. Clin Infect Dis. 2016;doi:10.1093/cid/ciw691.
• Vallabhaneni S, et al. MMWR Morb Mortal Wkly Rep. 2016;doi:10.15585/mmwr.mm6544e1.

• For more information:
• Tom M. Chiller, MD, MPHTM, can be reached at media@cdc.gov.
• Cornelius (Neil) J. Clancy, MD, can be reached at cjc76@pitt.edu.
• Elaine G. Cox, MD, can be reached at Riley Children’s Health, 705 Riley Hospital Dr #5837, Indianapolis, IN 46202.
• Maurizio Del Poeta, MD, can be reached at 150 Life Science Building, Stony Brook, NY 11794.
• Dimitrios Farmakiotis, MD, can be reached at dimitrios.farmakiotis@lifespan.org.
• Peter G. Pappas, MD, FACP, can be reached at the University of Alabama at Birmingham, 1900 University Blvd, 229 THT, Birmingham, AL 35294-0006.

Disclosures: Chiller, Clancy, Cox, Del Poeta, Farmakiotis and Pappas report no relevant financial disclosures.