Addressing the Growing Problem of Resistant Fungi

Bacteria aren’t the only microorganisms to pose a problem concerning resistance. Fungi, particularly Candida auris, are now looming as serious threats to patient care. A symposium at the annual ID Week meeting being held this year in San Diego, California tackled the problems posed by resistant fungi and steps being taken in response.

C. auris has rocketed onto the scene. Likely a resident of the natural environment, it was first reported clinically as an isolate from the ear of a patient (Auris is Latin for ear) in a Japanese hospital in 2009. The yeast soon spread globally, mainly as a bloodstream infection. Phylogenetic analysis has pegged C. auris as being closely related to other Candida species known for their antifungal resistance.

As C. auris spread geographically, it acquired the genetic wherewithal for drug resistance. Most ominously, C. auris isolates have been reported that display resistance to polyenes (eg, amphotericin B), azoles (eg, fluconazole), and echinocandins.

“C. auris is not easily identified. You need [matrix-assisted laser desorption/ionization-time of flight mass spectrometry] or DNA sequencing. It’s unfortunately easily transmitted. It’s on our skin so it can readily contaminate healthcare environments. It’s difficult to treat because of the multi-drug resistance, and it causes severe infections like invasive candidiasis,” said Tom Chiller, MD, MPH; Chief, Mycotic Diseases Branch, Centers for Disease Control and Prevention (CDC), Atlanta, Georgia.

The convention wisdom holds that infection is due to a host’s own flora, triggered by the stresses of hospital care, with transmission in the hospital not commonly occurring and outbreaks being rare. However, a recent report of a C. auris outbreak in a hospital in the United Kingdom clearly demonstrated patient-to-patient transmission. This spurred an alert in June 2016 from the CDC of the clinical danger posed by multi-drug resistant C. auris.

A 2012 study revealed the surprising news that candidemia—“the other Clostridium difficile”— is the most common healthcare-associated bloodstream infection in the United States, with an incidence of 5-15 per 100,000 persons. These infections result in death 30%-50% of the time, with the mortality rate being about 60% for C. auris. Those most at risk are the elderly with multiple underlying medical conditions who have an indwelling medical device like a tracheostomy or gastrostomy tube, or central venous catheter. Treatment needs to be aggressive, given the mortality rate of 30% within the first 30 days of the infection.

Has C. auris been with us all along, with misidentification as C. haemulonii or other species? Data from state-of-the-art diagnostic methods suggests the answer is no, with virtually no detection prior to 2009, except for 1 case in South Korea in the late 1990s. Whole genome sequencing data indicate that C. auris arose independently in several widely separated regions globally. Isolates from the different geographic regions are vastly different from one another. But, within each region, the isolates are nearly identical genetically. Reflecting the modern era of global air travel, isolates from the United States have come from all the global regions.

“C. auris represents a paradigm shift for Candida infections. Antifungal resistance is the norm. It thrives on skin, contaminates patient rooms, and can spread in the hospital setting,” said Dr. Chiller. His bit of good news is that we are still in a window of opportunity to stop this latest superbug.

One facet of the window of opportunity takes a cue from the bacterial world: stewardship. Emily Spivak, MD, MHS; Internal Medicine, University of Utah Health, Salt Lake City, Utah, discussed antifungal stewardship.

Antifungal stewardship is 1 aspect of the broader antimicrobial stewardship, “a multidisciplinary program of activities that optimizes antimicrobial use in order to improve clinical outcomes and minimize unintended consequences of antimicrobial misuse,” she explained.

The time is now for antifungal stewardship. As has always been the case, diagnosis of invasive fungal diseases is a challenging task. But, the prevalence of these diseases is growing and antifungal resistance is emerging.

“The goals of antifungal stewardship are to preserve the effectiveness of antifungals for patients and society, and to improve patient outcomes in terms of earlier diagnosis, effective therapy or cure, and to minimize toxicities,” said Dr. Spivak.

Antifungal stewardship is not reinventing the wheel. It draws on the multidisciplinary teamwork that drives antibacterial programs, with the addition of fungal-relevant guidelines, markers, and rapid fungal diagnostics. Programs have proven effective in improving care and reducing the costs of care for invasive aspergillosis and candidiasis.

As antifungal stewardship seeks the rational and appropriate use of drugs, new and more effective drugs are still needed. Jeniel Nett, MD, PhD, University of Wisconsin, Madison, Wisconsin, discussed emerging therapeutics for Candida infections.

A compound dubbed SCY-078 disrupts the fungal cell wall by blocking the synthesis of 1,3-β-glucan. The weakened cell wall ruptures under osmotic pressure. SCY-078 is structurally distinct from echinocandin. It can be administered orally or intravenously and has a wide spectrum of activity. Clinical studies have been positive.

Another candidate is CD101, which also inhibits 1,3-β-glucan synthase. It is an echinocandin and a structural analog of anidulafungin. When given intravenously, it has a long half-life of 80-158 hours. It can also be administered topically and vaginally. Clinical studies have been encouraging.

VT-1161 is a next generation azole that specifically targets fungal CYP51. Drug interactions are minimal. It acts on the plasma membrane by inhibiting ergosterol synthesis. Phase 1 and 2 clinical trials have demonstrated the efficacy and safety of VT-1161.

APX001 is a first in class inhibitor of the glycosylphosphatidylinositol (GPI) anchor. As such, it displays a broad spectrum of activity that involves the disruption of cell wall integrity.

Several other drugs are on the horizon, including a repurposed celecoxib derivative and a novel structure comprised of amphotericin B enmeshed in phospholipid bilayers that are arranged in a tube.

The take-home message from the symposium is that we face a challenging problem of antifungal resistance that has been recognized and is being aggressively tackled.

DISCLOSURES

Tom Chiller: None

Emily Spivak: none

Jeniel Nett: none

PRESENTATIONS

Symposium Fungal Resistance: Focus on Candida auris

The Epidemiology of Candida Auris: Rapid Emergence of an MDR Fungus

Tom Chiller, MD, MPH; Mycotic Diseases Branch, Centers for Disease Control and Prevention, Atlanta, GA

Best Practices in Antifungal Stewardship

Emily Spivak, MD, MHS; Internal Medicine, University of Utah Health, Salt Lake City, UT

Emerging Therapeutics for Candida Infections

Jeniel Nett, MD, PhD; Medicine, University of Wisconsin, Madison, Madison, WI

Brian Hoyle, PhD, is a medical and science writer and editor from Halifax, Nova Scotia, Canada. He has been a full-time freelance writer/editor for over 15 years. Prior to that, he was a research microbiologist and lab manager of a provincial government water testing lab. He can be reached at hoyle@square-rainbow.com.