Candida Auris: Scary and difficult to treat

There is something inherently creepy about yeast and fungus. At least that will probably be your assessment if you watched both seasons of The Last of Us. (Highly recommended, unless you like to sleep at night.) While the show is based on a fictional human-adapted Cordyceps fungus, the real-world pathogen Candida auris is causing plenty of concern of its own.

Yeast can be scary. Resistant Candida auris even more so.

Candida auris is a species of yeast [1] that is emerging as an important cause of infections in hospitals and long-term care facilities worldwide.  The US is no exception. The concern is justified. Bloodstream infections caused by C. auris are fatal in 30-70% of cases, and our treatment options are very limited because the pathogen is resistant to many of our most commonly used antifungal drugs.

C. auris tends to live harmlessly on human skin.  It was originally identified in 2009 from a swab of a Japanese patient’s ear. It is also very happy on surfaces like handrails, floors, and stethoscopes. For reasons unknown, it is very hard to eliminate C. auris from the skin, so these sites all serve as environmental reservoirs for infection. 

Serious C. auris infections occur primarily in patients who are already critically ill. They tend to be older, be on mechanical ventilation, and have intravenous or urinary catheters.  IV catheters (as if they're so much fun) are the source of most of the C. auris bloodstream infections.  Lung infections are almost always related to mechanical ventilation.  All are deadly. 

The CDC recently provided an update on its ongoing surveillance of C. auris infections. The good news is that the CDC has managed to maintain its hospital infections group, despite a difficult environment. . 

According to the CDC, there have been just over 13,000 C. auris infections in US health facilities during these years.  But over 40% occurred in 2024, indicating an increasing frequency of these resistant infections. 

Our most commonly used antifungal drugs, such as fluconazole, are ineffective against C. auris. In the US, amphotericin (highly toxic but it works) and echinocandin – both only available in intravenous formulations – are usually effective. But even there, amphotericin resistance is occurring in the US, especially in the western region. Outside the US, for example in certain Middle Eastern and Asian countries, resistance to all three top-line drugs approaches levels of 25%. For those patients, the WHO recommends treatment with either still experimental antifungal agents or those approved for treatment of other fungal infections but which have good activity in test tubes against C auris. How many of these last-line agents exist? About three.

Why antifungal drugs are so difficult to develop

At first glance, fungi seem as though they should be easy to kill. After all, we routinely eliminate bacteria with antibiotics. But fungi pose a fundamentally different challenge because, biologically speaking, they are much more like us than bacteria are.

Bacteria are prokaryotes—simple cells that differ dramatically from human cells. These differences provide numerous drug targets that antibiotics can attack without causing excessive damage to the patient. Penicillin, for example, blocks synthesis of the bacterial cell wall, a structure that human cells lack entirely. 

Fungi, by contrast, are eukaryotes. Like our own cells, they possess a nucleus, mitochondria, and many of the same metabolic pathways. This similarity leaves drug developers with far fewer opportunities to selectively kill the fungus without harming the patient. As a result, modern medicine has dozens of major classes of antibacterial drugs but only a handful of major classes of antifungal drugs.

Our Antifungal Pipeline

Our antifungal pipeline is woefully unprepared for the emergence of a pathogen like C. auris. Antifungal research is hobbled by the absence of investment, especially in this era of US government pullback from research funding in general. The commercial opportunities for such therapies are very limited given the still relatively low numbers of highly resistant C. auris infections and the reluctance of the healthcare community and governments to pay sufficiently high prices for lifesaving therapy of infections as opposed to, say, cancer. For those patients experiencing such infections, present-day options are very limited – and they may be even more limited in the future if pipeline drugs fail to be approved, or, as is more likely, their sponsors go bankrupt for lack of sufficient sales. 

Why catheters provide such an inviting home

One reason Candida auris causes so many bloodstream infections is its remarkable ability to form biofilms on the surfaces of intravenous catheters and other medical devices.

A biofilm is not merely a collection of fungal cells. It is an organized community embedded within a sticky, self-produced matrix of sugars, proteins, and DNA that functions as a protective fortress. Once established, the organisms become much more difficult for both antifungal drugs and the immune system to eliminate.

Biofilms also serve as a launching pad for infection. Cells can continually break away from the community, enter the bloodstream, and spread throughout the body. Simply treating the patient with antifungal drugs may not be enough; removing the infected catheter is often essential to curing the infection.

Amphotericin B: effective, but nasty

When C. auris resists more commonly used antifungal drugs, physicians often turn to amphotericin B, a medication that has been saving lives for more than half a century. Unfortunately, it has also earned a reputation for causing serious side effects.

The drug works by binding to ergosterol in the fungal cell membrane. Once attached, amphotericin molecules form tiny pores that perforate the membrane, allowing ions and other cellular contents to leak out until the fungal cell dies.

The not-so-good news is that the most recent surveillance covers 2021-2024, so it is already somewhat out of date. That imperfect selectivity explains many of the drug's toxic effects, particularly kidney damage, as well as the fever and chills that often accompany its infusion. Physicians have long joked that the drug should be called "Amphoterrible"—a reflection of its toxicity rather than its effectiveness.

Despite these drawbacks, amphotericin B remains one of the few dependable options for patients with multidrug-resistant fungal infections. That reality underscores a sobering fact: our limited arsenal of antifungal drugs leaves little room for resistance to emerge before we begin running out of effective treatments.

Like antibacterial drugs, antifungal drugs require new approaches to assure their ultimate commercial success.  Without this, we can look forward to increasing infections for which efficacious treatments will not really exist. 

NOTES:

[1] A yeast is a type of fungus. The main difference is that yeasts, such as Candida auris, usually exist as single cells, while many other fungi grow as long branching threads or as familiar forms like molds and mushrooms. In other words, all yeasts are fungi, but not all fungi are yeasts.