First trial for new antifungal begins

It has been mentioned elsewhere in this blog that the search for new antifungals is important and ongoing. Particularly important are antifungals that have different modes of action when compared to existing antifungals so it is encouraging that a local company here in Manchester, UK have announced the first tests are under way of their new antifungal which has a novel target of activity:

F2G Limited, the Manchester UK based antifungal drug discovery and development company, today announced the initiation of a Phase I clinical study of FG3622, the company’s lead antifungal drug candidate.

The Phase 1 trial is a randomised, placebo-controlled study designed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of FG3622. 100 healthy volunteers will be enrolled in the trial which will evaluate single as well as multiple ascending doses of FG3622 which will be administered orally. This clinical trial is the first-in-human study in the global development of FG3622 and will be conducted in the UK.

FG3622 is the first of a new generation of novel class systemic antifungal agents active by both oral and intravenous administration to enter the clinic. The mechanism of action, discovered by scientists at F2G, involves the selective inhibition of a fungal enzyme and is completely distinct from any other class of marketed antifungal agent. The compound displays highly potent activity against a wide range of clinically significant moulds including the common pathogen Aspergillus fumigatus which is the leading cause of Invasive Aspergillosis, a serious, debilitating disease associated with very high mortality rates despite current therapy options.

Plenty of work to do yet before this is proven to be useful but this is another example of a growing list of new options becoming available to treat fungal infection.

FDA revise guidelines for rheumatoid arthritis drug Leflunomide

The Food and Drug Administration (FDA) in the United States has issued a safety update for a drug used to treat active rheumatoid arthritis. They now recommend that all patients must be screened for tuberculosis and other pulmonary infections such as aspergillosis prior to taking Leflunomide due to the risk that the drug will increase the chances that these infections will get worse.

Medications with immunosuppressive potential, such as leflunomide, may increase patient susceptibility to opportunistic infections, particularly tuberculosis (including extrapulmonary disease), Pneumocystis jiroveci pneumonia, and aspergillosis.

The FDA notes that leflunomide has not been studied in patients with a positive tuberculin screen result, and the safety of leflunomide in those with latent infection remains unknown. Patients with a positive test result should be treated by standard medical practice before starting leflunomide therapy.

Leflunomide is indicated to reduce signs and symptoms of disease, inhibit structural damage, and improve physical function in patients with active rheumatoid arthritis.

Composting 'scaremongering'??

Industrial scale composting is expanding quickly in the UK and across europe as alternatives to disposing of waste via landfill are explored more vigorously.

Composting is mainly done via open 'windrows' where piles of rotting vegetable matter are left in the open air and turned mechanically at regular intervals. Each turning releases vast clouds of fungals spores, principally Aspergillus fumigatus, an important human pathogen and allergen. Those clouds are rapidly dispersed into the air and diluted such that a safe distance from the composting site should be achievable.

How safe is this practice to both the workers at the composting site and to people living close by? Newspaper articles contend that composting is not yet carried out under completely safe conditions, a story based on a recent paper by Drew et.al. which found that risk analyses at most UK locations where composting is carried out were inadequate.
A rebuttal was issued by pro-composting groups here calling the newspaper stories 'scaremongering' and suggesting that living close to a composting site is no more a risk to health than a walk in the woods:

anyone who walks through a wood especially in the autumn will be exposed to higher levels of these spores than living near a compost site.

I would suggest that it is impossible or impractical to identify individuals who's health is at risk from breathing in fungal spores. Those individuals can include those with poor immune systems & asthmatics. That risk is probably increased if increased number of spores are breathed in therefore until it is possible to warn all people at risk a large margin for safety should be used when setting boundaries for minimising health risks. Risk analyses need to be of a consistently high standard.

Darwins' fungi

Charles Darwin was born two hundred years ago this year (1809). His contributions to how we understand the natural world were many and varied, culminating in the publication of his book 'On the Origin of Species by Means of Natural Selection' published in 1859.

Darwin was an avid collector and contributed many thousands of species to the British Museum, perhaps most famously during his voyages to the Galapagos Islands. Some of these specimens show the multitude of small differences that Darwin hypothesised constituted adaptions to the local environments of particular islands within the archipelago, caused by natural selection - the driving force of evolution.

Some of the specimens Darwin collected were fungi (mainly fruiting bodies which at that time were thoughtby many to be simple plants) and these are now stored at the Royal Botanic Gardens at Kew, London, UK along with a vast collection of 1.2 million species of fungi including every species of Aspergillus.

This massively important collection, originating 20 years after Darwin published his most famous book, is one of the worlds most complete collections of fungi and forms a resource available to all scientists around the world.

Taxanomic advances lead to better diagnosis & treatment

Invasive aspergillosis is by far most commonly caused by Aspergillus fumigatus. This is an infection that is notoriously difficult to diagnose and it is important to get the diagnosis right as quickly as possible.

Modern techniques to precisely identify different species and strains have started to reveal that different isolates from what was previously thought to be a single species can actually belong to a different groups within that species definition.

What we thought was one fungal species seems to be several different 'species'. To some extent this conclusion might be academic - the differences can seem quite small. This begs the question Are these differences important?

Aspergillus fumigatus is one of the species that have been shown to actually be several slightly different 'subspecies' so it should be possible to look for clinical differences between those subspecies.

A recent paper does precisely that - it looks at a series of 36 isolates (taken from infected patients) that were formerly identified as A. fumigatus and found that they were in fact a group of fungi now named Aspergillus subsection fumigati subgenus fumigati. 4 of the isolates were identified as Neosartorya udagawae (NB Neosartorya is simply the name for the sexual state of Aspergillus).
Furthermore the research paper shows that infections by N. udagawae behaved quite differently to A. fumigatus. The infections were much longer lasting - 35 weeks compared with 5 weeks for A. fumigatus and tended to need a higher dose of antifungal medication.

We thus have an example of how having a much more refined method of identifying the infecting Aspergillus strain could help make the treatment of that infection more effective, improving medical care to the patient.