Fungal infections are becoming more difficult to treat. Will the US Food and Drug Administration approve new drugs?

Fungal infections are becoming more difficult to treat.  Will the US Food and Drug Administration approve new drugs?

Last summer, the Food and Drug Administration rejected an application for a new antifungal drug called Olorofem, sending it back to the company with a request for more data. If approved, it would be the first time since the early 2000s that the FDA has cleared an antifungal that works in an entirely new way.

This could not come at a more important time: In recent years, the potential risk that fungal infections pose to human health has become more apparent, as fungi evolve to evade treatment or spread beyond their typical geographical areas. Doctors around the world are in desperate need of new medicines to combat the growing threat.

“The problem of fungal diseases has reached the point where the World Health Organization has recognized that it represents a widespread threat,” said Dr. Arturo Casadevall, a microbiologist and head of the Department of Molecular Microbiology and Immunology at the Johns Hopkins Bloomberg School of Public Health in the US. Baltimore.

In late 2022, the World Health Organization published its first-ever list of priority fungal pathogens — 19 fungi that the agency said pose a major threat to human health. They include the highly drug-resistant yeast Candida auris, which infects critically ill hospital patients; In 2021 alone, the number of infections in the United States has tripled, according to the Centers for Disease Control and Prevention.

Coccidiosis is also on the WHO list, A fungus causes an infection called valley fever. It has historically been found in the southwestern United States, and scientists have predicted that its range could spread north to the Canadian border and east to the Great Plains by the end of the century.

The situation is complicated by the impact fungi can have on the global food system.

Fungi thrive in soil, and fungal diseases have long been a major problem in agriculture, with up to a quarter of the world’s crops lost to fungal diseases before they are harvested. Another 20% die from the fungus after harvest. Similar to the way doctors use antifungals to treat fungal infections in humans, farmers use fungicides, a type of insecticide, to kill fungal diseases invading crops.

But much-needed fungicides can render important antifungal medications useless.

This is because many fungicides have the same molecular target as antifungal drugs, including existing drugs, as well as some long-awaited new drugs that are in the final stages of clinical trials. If a fungus is regularly exposed to a fungicide intended to kill it — many of the fungi that can infect the human body also thrive in soil and decaying plant matter — they can develop resistance to it. If these mutant fungi infect humans, they will already have the ability to evade the antifungals that target them.

The above scenario is not hypothetical. Scientists have linked commonly used fungicides to increasingly drug-resistant infections of a fungus called Aspergillus fumigatus. In 40 countries, including the United States

Of particular concern is that the fungus has developed resistance to an entire class of antifungals called azoles, the most common type of medication prescribed to treat fungal infections. In addition to treating a wide range of infections, it is also the only antifungal that can be taken at home and the only one that can be taken for more than six months, which is often required to completely clear an infection.

“We have come up with three classes of antifungals, and one of them is azoles,” said Norman van Rijn, a research fellow at the Manchester Fungal Infections Group at the University of Manchester in the UK.

Several new drugs are also hanging in the balance, including Olorofem, part of a new class of drugs that has proven effective against azole-resistant Aspergillus.

“We don’t want to portray this as a clash between medicine and agriculture,” said Leah Quinn, a professor of molecular genetics at the University of Toronto. “It doesn’t mean we need antifungals for one over the other, we need both.” But with different goals.”

The need for new antifungals

Humans are much more closely related to fungi than they are to bacteria and viruses: we share about half of our DNA with fungi, and many of the proteins essential for fungal survival are also essential for human cells.

This makes it very difficult to find a molecular target in a fungal cell that can be attacked without causing serious damage to the human cell, which is why many antifungals have serious side effects, Van Rijn said.

Furthermore, fungi can develop drug resistance very quickly.

Like viruses and bacteria, they have the innate ability to reproduce rapidly and mutate, and these mutations can lead to strains that render drugs ineffective.

This also happens in the world of bacteria and antibiotics – where antibiotic resistance is another major threat to public health – but doctors still have plenty of antibiotics to choose from.

“We only have three main classes of antifungal drugs to treat invasive infections compared to dozens of classes of antibacterials,” Quinn said.

She added that those available are less than perfect as it is. “Some are toxic, some are resistant, and some have a limited range of activity.”

Anna Selecki, an associate professor of microbiology and immunology at the University of Minnesota Medical School, was frank about the urgent need for more drugs that can effectively combat the fungus.

“I am concerned that many patients will die because our current range of antifungal drugs is limited and more fungi are resistant to the few antifungal drugs available,” Celecki said.

Competing goals

Van Rijn said it takes about 25 years to develop a new antifungal drug, and a similarly long time to produce a new fungicide. Scientists have so far identified only a few viable molecular targets in fungal cells, often the same target used in both antifungal drugs and fungicides.

In the case of the new drug Olorofem, it is a fungicide called epflufenoquine – used on fruit and nut trees and in vineyards. The EPA, which reviews and approves pesticides independently of the Food and Drug Administration, cleared epflufenoquine as a fungicide nearly two years ago.

Since the FDA requested more data on Olorofem from British pharmaceutical company F2G, Inc., the new antifungal is in phase III clinical trials. Studies so far have shown that the drug is effective against the fungi that cause valley fever, as well as a rare emerging fungal infection called lomentosporiosis, which is associated with organ transplants.

“Olorofem may be the most promising antifungal,” said Dallas Smith, an epidemiologist in the Mycobacterial Diseases Branch at the Centers for Disease Control and Prevention, noting that the drug has proven effective against “almost every fungal infection.”

Both treatments have the same target: an enzyme called dihydrorotate dehydrogenase.

According to Van Rijn, there are other antifungal drugs in production that follow the same path as Olorofem. He’s concerned that a new antifungal called fosmanogepix, which has not yet been approved by the Food and Drug Administration, may be threatened by an insecticide called aminopyrifen — which is effective against a type of fungus that infests soft fruits like strawberries — that works on the same goal.

Quinn agreed.

She added: “The same story is repeated again.”

Can interagency collaboration save antifungals?

Competition with fungicides is not the only issue leading to resistance to antifungal drugs. Poor diagnostic testing, lack of infection surveillance and misuse of medications – fungal infections are often misdiagnosed – all play a role as well, but more coordinated oversight of new drugs and insecticides and their targets will play an important role in maintaining the effectiveness of antifungals. Move forward. This means that regulatory bodies such as the US Food and Drug Administration (FDA) and Environmental Protection Agency (EPA) will need to work together when approving new drugs and fungicides.

“We need to balance the global food supply with human antifungals, and we need more cooperation in this regard,” Smith said.

With careful planning, he said, there will be room for both olorofim and epflufenoquine, as well as other antifungals and fungicides with similar goals. “We know that not all infections will be inherently resistant to older antifungal drugs.”

In September, the EPA announced it was working with the Department of Health and Human Services and the Department of Agriculture on a potential framework that would better protect antifungals. The agency expects to complete the framework by the end of this year, Remington Belford, EPA press secretary, told NBC News in an emailed statement.

When finalized, the framework will provide guidance for cooperation between agencies dealing with human health and EPA, which approves pesticides, and how pesticides can be evaluated for any potential threats they may pose to antimicrobial resistance.

Even without such a framework, potentially life-saving antifungals should not be dropped because of the risks that newer fungicides pose to antifungal effectiveness, Quinn said.

“We still desperately need this new class of antifungals,” she said. Olorofim has great potential for treating fungal infections for which we currently have no cure.

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