As rates of antibiotic resistance grow alarmingly among disease-causing bacteria, dangerous fungi also are evolving stronger defenses, with a lot less fanfare.
Every year, infections of molds and yeasts such as Aspergillus and Candida kill more than 1.5 million people globally, more than malaria and on a par with rates for tuberculosis. And new drug-resistant strains are emerging, such as Candida auris, first detected in Japan in 2009 and since then reported on every continent except Antarctica. Between September 1, 2020, and August 31, 2021, the number of reported C. auris cases in the United States has soared to over 1,100 in 21 states, up from 63 cases in four states from 2013 to 2016.
With Covid-19 cases stressing health care systems, changes in hospital infection control have given drug-resistant fungi a leg up, too. In 2019, the Centers for Disease Control and Prevention listed C. auris as an urgent threat; it was the first time the agency had done so for a pathogenic fungus. In December 2020, the CDC reported increased spread of C. auris during the pandemic.
Put simply, "fungal infections are a massive public health problem," says Johanna Rhodes, a genomic epidemiologist of fungal infections at Imperial College London. There are few drugs to fight them, and the pipeline for development of new ones has been frustratingly slow.
Today, though, a few novel antifungals are moving through clinical trials and researchers are developing new approaches to drug discovery that may ultimately strengthen the antifungal arsenal. In the meantime, health care organizations are working on improved practices to help stall the development of resistance in these problematic microbes.
Few weapons, more victims
Fungal pathogens become life-threatening when they get inside the body, infecting the bloodstream and internal organs. Such invasive infections have become more common due to the evolution of drug resistance as well as life-saving medical advancements such as organ transplants and cancer therapies that have created a growing population of immunocompromised people. The armamentarium of drugs to fight them is limited — and dated.
The first antifungal for treating invasive infections, amphotericin B, came out in 1958, and works against a variety of fungi. A member of the antifungal class known as polyenes, amphotericin B binds to key molecules — ergosterols — and extracts them from the fungal cell membrane, thereby damaging the cell's functions. The drug's toxicity to patients limits its use.
Beginning in the late 1970s, doctors also had a new, less toxic class of antifungals to turn to: azoles, which prevent fungal cells from making ergosterol. Then, in the early 2000s, a third class, the echinocandins, was approved by the US Food and Drug Administration for medical use. These drugs act by blocking production of a carbohydrate called beta-D-glucan, a vital part of fungal cell walls.
Resistance to azoles slowly emerged in the 1990s, due in part to agriculture. The industry had begun using azole fungicides to protect crops from fungi such as Aspergillus fumigatus, a common mold, in the 1970s. Later, azole-resistant A. fumigatus infections in people began cropping up, becoming more common after 2003. People with no previous exposure to medical azoles were turning up with resistant infections, a telling sign that they had picked up A. fumigatus from the environment, for example from gardens or soil.
Medical use of antifungals has also pushed pathogens to evolve new defenses. Problems include the failure of patients to finish a course of drugs, as well as improper prescribing — for example starting antifungals in someone with an asymptomatic infection, prescribing the wrong drug or dose, or prescribing too long a course.
Physicians must also strike a delicate balance between preventing deadly infections in immunocompromised patients and trying to limit opportunities for fungi to evolve resistance. They often prescribe antifungals as a preventive measure in such patients which, though protective, also encourages resistant fungi if use is prolonged.
In hospitals, invasive fungal infections featuring drug resistance are increasingly problematic. C. auris infections, almost always acquired in health care facilities, increased by over 100 cases each year from 2017 to 2019, when 469 cases were reported, jumping to 746 cases in 2020, according to the CDC. And in the 12 months from September 2020 through August 2021 there were 1,156 reported cases. Catheters, intravenous lines and ventilators provide ample opportunities for pathogens to enter new hosts. "These are absolute highways for these environmental agents to get into the human body," says Rodney Rohde, a microbiologist at Texas State University.
Covid-19-associated invasive fungal infections have cropped up too — most commonly pulmonary aspergillosis (generally Aspergillus fumigatus), but also black fungus (caused by soil fungi called mucormycetes) and infections with Candida, including C. auris. According to the CDC, overstretched health care facilities have struggled to uphold normal infection control procedures, such as cleaning medical equipment and rooms and screening for C. auris.
Today, 90 percent of C. auris samples from infected patients are resistant to at least one antifungal drug, typically fluconazole, and 30 percent are resistant to at least two. But during the pandemic, C. auris infections that are resistant to all antifungal drugs also have been detected — the first examples of pan-resistant C. auris transmission in US health care facilities.
People with invasive fungal infections "are very sick patients and we don't have very good diagnostic tests. We don't have very good treatment options," says Jose Lopez-Ribot, a medical mycologist at the University of Texas at San Antonio. And this isn't just a risk for people with compromised immunity. "Any of us, even the general public, can go in for a routine surgery and can end up sick in a hospital — that's when you're going to be at risk for these infections," says Tom Chiller, chief of the CDC's mycotic diseases branch. "You want there to be drugs available for you to use."
Hospitals can help to prevent drug resistance
To keep existing drugs useful for as long as possible, hospitals need to adopt careful practices. "All hospitals have antimicrobial stewardship programs where usually an infectious-disease doctor, often with an infectious-disease pharmacist, will try to limit antibiotic use to situations where it's strictly necessary," says Stuart Levitz, an infectious-disease physician at UMass Memorial Medical Center, who wrote about fungal infections and immunity in the 2018 Annual Review of Immunology.
Such programs require early and accurate diagnoses and tracking of fungal infections, reports of antifungal use and feedback to physicians on their prescribing habits. Levitz, for example, helps to inform antifungal prescribing policies as part of his hospital's stewardship efforts, determining which patients should receive them. His hospital's microbiology lab is on the lookout for drug resistance and tracks its patterns within the hospital, while the clinical pharmacists track antifungal prescriptions — including patient numbers, dosages and drug costs.
Such stewardship attention to fungi has generally taken second place to bacteria in hospitals — but that is changing, Rhodes says: "We're starting to see more antifungal stewardship programs avoid inappropriate use of antifungals, especially in immunocompromised patients."
But though antifungal stewardship programs can cut costs and decrease antifungal use — which is crucial for preventing resistance — according to a review of stewardship programs at several hospitals, they don't in and of themselves decrease deaths and thus don't erase the need for better drugs.
Antifungal drugs lag behind
Even as rates of fungal infections and drug resistance are increasing, the speed of drug development is not. "We're basically limited to three classes, and the spectrum of activity of each of the classes doesn't cover the whole gamut of fungal infection," says Lopez-Ribot. The business incentive is lacking, despite the fact that globally, about 13.5 million people develop life-threatening fungal infections each year, because physicians use the drugs for relatively few patients.
The pandemic has also drawn pharmaceutical companies toward vaccine and antiviral development, away from other work, Rhodes says. "Even prior to Covid, a lot of the big pharmaceutical companies had basically abandoned their antifungal drug discovery pipelines…. It's a sorry state of affairs."
Scientific challenges also hamper drug development. Fungi are eukaryotes — they have cells with nuclei — and so are biochemically far more similar to humans than bacteria are. This makes it harder to design drugs that won't also harm a patient. Until recently, only one antifungal drug, and no new antifungal drug class, had been approved by the Food and Drug Administration in the last two decades.
But today, researchers are testing a few new types of antifungal drugs that act in novel ways, and the FDA is prioritizing their approval process. "There were some smaller companies that have taken some of these drugs into clinical trials, and they're looking very promising," Chiller says.
For example, fosmanogepix from Amplyx Pharmaceuticals (recently acquired by Pfizer) showed some success in a small, Phase 2 clinical trial of 20 patients with Candida blood infections — 16 tested negative for Candida after two weeks and survived the infection. The drug acts by blocking a key fungal enzyme and so impedes the pathogen's ability to stick to tissue surfaces in the body. Researchers are now recruiting 50 patients with invasive infections of Aspergillus and other molds to test the effectiveness of fosmanogepix in a Phase 2 trial.
Another company, F2G, has developed the antifungal olorofim, which targets an enzyme that fungi need to make some of the building blocks of DNA and RNA. Researchers are recruiting 200 participants with invasive fungal infections that aren't responding to other treatments for a Phase 2 trial of the drug.
And in June 2021, the FDA approved an antifungal drug in a new class for vaginal yeast infections caused by Candida. There is hope that the drug will treat invasive infections, too. The drug, ibrexafungerp from Scynexis, targets the same cell wall component as echinocandins do — beta-D-glucan — but it binds to a different site.
In a Phase 3 trial — a larger clinical trial with controls that is the final step before the FDA approves a drug — researchers are recruiting 200 participants to test how well ibrexafungerp performs against severe invasive fungal infections that haven't responded to other medications.
And researchers are still looking for new drugs. Lopez-Ribot, for example, is scouring libraries of chemical compounds that don't kill fungi or stop their growth but disarm them so they can't harm the human host. He works with Candida albicans, whose cells assemble into microbial mats — biofilms — that adhere firmly to surfaces, making them difficult to clear. In the body, they can also grow string-like filaments, a growth pattern associated with infection severity. His group is searching for molecules that rob C. albicans of biofilm- or filament-forming abilities, or both. One plus to this approach, he says, is that it doesn't exert the same degree of evolutionary pressure for resistance as traditional antifungals.
Of the drugs in clinical trials, Lopez-Ribot says that the most advanced are not those with novel mechanisms but ones within existing classes. Pathogens may soon evolve resistance to these new iterations, but something is better than nothing.
"My philosophy is very simple," he says. "We have so few, that any type of addition to the antifungal armamentarium should be welcome."
Jackie Rocheleau is a freelance journalist covering health and science. Her work has appeared in Forbes, Knowable, Scientific American, and other publications.
This article originally appeared in Knowable Magazine on January 18, 2022. Knowable Magazine is an independent journalistic endeavor from Annual Reviews, a nonprofit publisher dedicated to synthesizing and integrating knowledge for the progress of science and the benefit of society. Sign up for Knowable Magazine's newsletter.
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