image by: HWN

HWN Suggests

Drug-Resistant Fungi: An Emerging Challenge Threatening Our Limited Antifungal Armamentarium

The urgency for new antifungal classes is growing as cases have increased... once-treatable fungi are becoming resistant. Furthermore, only one approved class of antifungal drugs, the azoles, can be taken orally. Due to increasing resistance rates against azoles and echinocandins, invasive Candida infections have become more difficult to treat, given the limited number of classes of antifungals currently available. This limitation in antifungal treatment options was prominently highlighted by the emergence of C. auris, a multidrug-resistant species, which has been associated with outbreaks worldwide and led to clinical alerts to U.S. and European healthcare facilities

read full article

Featured

  The Fungus Among Us: An Antifungal Review

For over two decades, the azole antifungals have been used in clinical practice to treat various fungal infections. They are categorized into two distinctive classes: the imidazoles and the triazoles. The imidazoles include several agents, most notably clotrimazole, ketoconazole, and miconazole. The triazoles include fluconazole, itraconazole, terconazole, voriconazole, and posaconazole.

 A New Type of Antifungal

Let's have some potential good news around here for a moment. There's a paper out today (commentary at Nature here) that seems to be showing us a new type of antifungal, with a natural product molecule that has strong activity against a wide variety of drug-resistant fungi. I've written a number of times over the years about the antifungal field (most recently here), mostly about how hard it is to make headway in it, and how much we need a replacement for drugs-of-last-resort like Amphotericin B. One of the things that's surprising about this new molecule (dubbed mandimycin) is that at first glance, it looks an awful like that last-mentioned drug, which has been with us since the late 1950s.

 Antifungal Medication : Classification, Side effects

An Antifungal medication, also known as an antimycotic medication, is a pharmaceutical fungicide or fungistatic used to treat and prevent mycosis such as athlete’s foot, ringworm, candidiasis (thrush), serious systemic infections such as cryptococcal meningitis, and other.

 Antifungal Pharmacology

Knowledge of fungal cell structure and function is essential for understanding the pharmacology of antifungal agents. Like mammalian cells, fungi are eukaryotes with DNA organized into chromosomes within the cell nucleus and have distinct cytoplasmic organelles including endoplasmic reticulum, Golgi apparatus, mitochondria, and storage vacuoles. This homology to mammalian cells also extends to biosynthetic pathways, where fungi share similar mechanisms for DNA replication and protein synthesis.

 Antifungal resistance – a growing global problem

The spread of antifungal resistance is driven by the widespread use of antifungals in humans and on crops.

 Deadly fungi are becoming drug-resistant. A new compound could beat them

Many of the drugs used to fight off bacterial or fungal infections come from the microbial world themselves: They’re based on compounds that microorganisms have developed to kill each other. Amphotericin B, for example, a so-called polyene, is used by the bacterium Streptomyces nodosus to ward off other fungi. It was discovered in the 1950s in soil samples collected near the Orinoco River in Venezuela. Unlike other polyenes, the team discovered, mandimycin does not attack ergosterol, a compound that, like cholesterol in human cells, makes fungal cell membranes more fluid. Instead, mandimycin attacks phospholipids, the basic building blocks of the cell membrane itself.

 Differentiating 7 Topical Antifungal Medicines

All OTC antifungal products discussed here are products that are applied topically to the skin and/or vaginal area. Topical OTC antifungal products tend to have similar indications, and they commonly can be substituted for one another.

 What the Antifungals Are Really Doing

After that post on bacteria and antibiotics the other day, I thought I might give equal time to the antifungals. It's really hard to say which of those fields is harder to make headway in! As I've mentioned before around here, the continued use of as nasty (and as old) a drug as Amphotericin B really shows how much we need new drugs against fungal infections. I think it's safe to say, though, that the tools available in that research are not as varied and advanced as the ones used in studying bacteria. Some of that is just because of how different fungi are from many other creatures (with the presence of chitin in their cell walls, for example, immediately marking them off from almost every other form of life). Those differences can be exploitable, of course, such as the way that many drugs in this area take advantage the fungal use of ergosterol instead of cholesterol. But they also make it tricky to understand what's going on with them, even though fungal genomes in general are rather small. And to be honest, that part is not really a feature you like in drug discovery, because it means that the number of possible drug targets is also probably limited.

Articles of Interest

A New Multidrug-Resistant Fungus Emerges

Three main classes of antifungal medications are available for treating invasive yeast infections: azoles (such as fluconazole), polyenes (namely amphotericin B) and echinocandins (i.e., caspofungin). In the United States, approximately 85% of C. auris isolates are resistant to azoles, 33% are resistant to amphotericin B, and 1% to echinocandins; pan-resistant isolates are resistant to all three classes of drugs.

Adverse Effects Associated With Currently Commonly Used Antifungal Agents...

We found that echinocandins are the most tolerated antifungal agents with high safety. The AEs of triazole drugs are mainly concentrated on the increase in liver enzymes, nervous system disorders, especially visual disorders, gastrointestinal disorders, and cardiac diseases. LAmB is the least tolerated and has the most abundant AEs.

Antifungal Agents

There are essentially five workhorse antifungal agents commonly used in critically ill patients.

Antifungal agents for common outpatient paediatric infections

The most common fungal infections in infants and children are mucocutaneous candidiasis, pityriasis versicolor, tinea corporis, tinea pedis, and tinea capitis]. The objective of the present update is to inform clinicians on options for treatment of these symptomatic but non-life-threatening fungal infections in immune-competent hosts, given the wide variety of topical, usually over-the-counter (OTC), and oral prescription drugs available.

Antifungal agents: mechanisms of action

The massive emergence of fungal diseases associated with AIDS in the 1980s and the rising frequency of fatal mycoses associated with increasing use of immunosuppressive medical therapies since the 1970s stimulated research directed towards the discovery of novel antifungal agents.

Antifungal Agents: Mode of Action, Mechanisms of Resistance, and Correlation of These Mechanisms with Bacterial Resistance

The increased use of antibacterial and antifungal agents in recent years has resulted in the development of resistance to these drugs. The significant clinical implication of resistance has led to heightened interest in the study of antimicrobial resistance from different angles.

Antifungal Drug Repurposing

Control of fungal pathogens is increasingly problematic due to the limited number of effective drugs available for antifungal therapy. Conventional antifungal drugs could also trigger human cytotoxicity associated with the kidneys and liver, including the generation of reactive oxygen species. Moreover, increased incidences of fungal resistance to the classes of azoles, such as fluconazole, itraconazole, voriconazole, or posaconazole, or echinocandins, including caspofungin, anidulafungin, or micafungin, have been documented..

Antifungal drug resistance: an update

The number of antifungal classes is small, and resistance is becoming a much more frequent problem.

Antimicrobial Resistance Series Part 2: Antifungal Resistance

First identified in 2009 in Japan from a man’s earwax, the fungus, Candida auris, has quickly spread around the globe and become one of the most multidrug-resistant and deadliest fungi known.

Fungi and Anti-fungal Agents

There are five main classes of antifungal agents...

Tackling Human Fungal Infections

Fungi infect billions of people every year, yet their contribution to the global burden of disease is largely unrecognized. Most are “relatively” minor infections, but millions contract diseases that kill at least as many people as tuberculosis or malaria. Although true mortality rates are unknown because of a lack of good epidemiological data, the incidence of invasive fungal infections is rising as a result of modern medical interventions and immunosuppressive diseases, such as AIDS. Despite the high mortality rates of invasive fungal infections, they remain understudied and underdiagnosed as compared with other infectious diseases.

The EMPIRICUS trial—the final nail in the coffin of empirical antifungal therapy in the intensive care unit?

Recent randomized controlled trials of prophylactic, pre-emptive or empiric antifungal treatment in high-risk ICU patients have failed to demonstrate a survival benefit.

Tinea Capitis & Kerions

Tinea capitis requires systemic antifungal Rx...

Worldwide emergence of resistance to antifungal drugs challenges human health and food security

The recent rate of emergence of pathogenic fungi that are resistant to the limited number of commonly used antifungal agents is unprecedented. The azoles, for example, are used not only for human and animal health care and crop protection but also in antifouling coatings and timber preservation. The ubiquity and multiple uses of azoles have hastened the independent evolution of resistance in many environments. One consequence is an increasing risk in human health care from naturally occurring opportunistic fungal pathogens that have acquired resistance to this broad class of chemicals.

Resources

StatPearls

Antifungal drugs represent a pharmacologically diverse group of drugs that are crucial components in the modern medical management of mycoses. While antimycotic pharmacology has advanced significantly, particularly in the last three decades, common invasive fungal infections still carry a high mortality rate: