Friday, 31 October 2008

New class of antifungal drug emerging

There are currently several different antifungal drugs available for treatment of aspergillosis - six approved drugs in current use: amphotericin and derivatives, itraconazole, voriconazole, posaconazole, caspofungin and flucytosine (see the Aspergillus Website Treatment section for details here). 
There are currently 6 new drugs relatively close to use on aspergillosis in the clinic; isavuconazole, ravuconazole, micafungin, albaconazole, anidulafungin and SPK-843.

This sounds like a lot of choice for the clinician but unfortunately their usefullness is a little limited as most belong to only three classes of antifungal drug: the polyenes, the triazoles and the echinocandins (details here). In fact there are 6 triazoles, 2 polyenes and 3 echinocandins that are  usefull to treat aspergillus infections.

This is important as all antifungals in a particular class tend to work in the same way, so the fungus can build up resistance to a whole class of antifungal drug once it has become resistant to one drug, or a particular class can be less good at treating some conditions - for example at one time there were only polyene drugs available which tended to be very toxic for some people, so when the triazoles arrived that group of people benefitted greatly as they tended to be much less toxic.

New classes of antifungal drugs are therefore much sought after. This week we saw reports in the media of news of the emergence of a new class of antifungal. f2g (a company based here in Manchester, UK) has announced that it will present research results at a forthcoming major scientific conference (ICAAC 2008). We have few details of the announcement but it looks clear that there is activity against Aspergillus in the laboratory and possibly in animal models. It is also clear that there has been no work carried out on treating patients in the clinic, so all this optimism must be tempered by the knowledge that many drugs look promising at this stage but then prove to be too problematic to use to treat humans, or have little activity against Aspergillus in patients.

If there are any more details to report when we can read the presented research we will do so in a few weeks. Until then we can only hope trials go well and this represents the beginning of the development of a new tool to use against aspergillosis.

Disclosure: f2g has as an advisor Prof David Denning who is also Senior Editor for this website, but no prior knowledge of this announcement was made available to us here at the website. We feature this announcement as an important development in antifungal research and not because any inducement was made by any member of  f2g or its advisors to publish this news.

Monday, 27 October 2008

Bone marrow donor genetics is linked to risk of fungal infection

A bone marrow transplant can be a life-saving treatment for some
patients with leukaemia and some other forms of cancer. But sometimes recipients of bone marrow transplants, come down with invasive aspergillosis - a fungal infection that can be fatal.

Invasive aspergillosis occurs in up to 12% of bone marrow transplant recipients and one-year mortality rates range from 50% to 80%, making it "one of the leading infection-related causes of death," the researchers said.

Toll receptors are found on the surface of cells in the body's innate immune system and help to recognise invading pathogens. Because the toll-like receptors (or TLRs) play a key role in the immune response to fungal pathogens such as aspergillus, the researchers decided to see if genetic variation affected who came down with disease.

This study of bone marrow donors has shown that a particular genetic variation in TLR4, the gene for the toll receptor 4 is associated with a five fold increase of invasive aspergillosis in recipients of bone marrow - when the donor is unrelated. Recipients related to the donor do not appear to be at increased risk which is as yet unexplained, but the relatively small size of the groups in this study may be partially responsible. Further studies will be required to elucidate this. More information.

Read the paper by Buchud here.

Wednesday, 22 October 2008

Genomics to target fungal lung disease

The European Science Foundation has announced the following in this weeks 'Lancet' journal:
The European Science Foundation (ESF) has announced the start of a new pan-European collaboration, FUMINOMICS, to study the opportunistic pathogen Aspergillus fumigatus. This saprophytic filamentous fungus causes severe nosocomial infections that are increasingly problematic for clinicians; invasive aspergillosis is now the leading cause of early death in many transplant centres in Europe.
Jean-Paul Latgé (Institut Pasteur, Paris, France), chair of the new FUMINOMICS steering committee, added, “Our ability to carry out research into this pathogen has only become feasible recently because of the publication of the complete A fumigatus genome and new molecular and biochemical tools that make it possible to genetically modify the fungus in order to undertake large-scale studies including proteomic, transcriptomic analysis and the construction of mutant libraries”.
This collaboration has been made possible by the publicly available genomic sequence of Aspergillus fumigatus, such as that hosted by the Aspergillus Website (for whom Jean-Paul has been an editor for several years). The aims of the project are outlined as:
One of the main clinical objectives will be to investigate how the fungus grows in vivo, to discover the mechanisms that enable it to gain a foothold to establish disease. Another is to develop methods for better early diagnosis—aspergillosis is currently diagnosed very late and drug treatment fails because fungal burden is too high. “We also hope to identify new drug targets to tackle this opportunistic but deadly pathogen more effectively”

Friday, 17 October 2008

PET detects Aspergillosis

Detection of the first positron
Positron Emission Tomography (PET) works by generating a harmless radioactive 'version' of a common metabolic molecule such as glucose (the radioactive version for glucose in this case is known as FDG). The radioactive molecule is injected into the bloodstream of a patient and accumulates in the areas that are most active. In the case of FDG it accumulates in areas where cells have a higher growth rate as in those areas the cells are using more glucose.

Detectors measure where the radioactivity accumulates and thus show up where the actively growing cells are. This is particularly useful when looking for cancer tumours and those cells are rapidly growing and using lots of glucose. It is also useful when needing to tell the difference between benign (slower growing) tumours and malignant (fast growing) tumours.

Unfortunately a recent article states that things aren't quite a simple as they seem for this hugely expensive procedure. Infections such as Aspergillosis also cause an accumulation of FDG causing confusion between what is an infection and what is a tumour. For this reason the article suggests that PET is best used when it is already known that a tumour exists and the PET scans can follow the progress of the tumour during and after treatment, or can differentiate between benign and malignant.
It might be suggested that PET could equally also be used to follow an Aspergillosis (or aspergilloma?) as it is treated, but given the high cost of these scans that seems unlikely in the near future.

NB it is interesting to note that the PET is one of the first practical uses of antimatter as a positron is literally an anti-electron. First postulated in 1928 antimatter has been the subject of many science fiction productions and scientific speculations as to why the known universe is made up almost entirely of matter with virtually no antimatter (given that the two should exist in balance) - perhaps there are entire antimatter galaxies we currently don't know about!

Monday, 13 October 2008

The risk of Aspergillus infection after dental work

Image from Aspergillus mycetoma of the Maxillary Sinus Secondary to Overfilling of a Root Canal by Luciano Giardino, MD, DDS, Francesco Pontieri, MD, Enrico Savoldi, MD, DDS, and Federico Tallarigo, MD
This article mentions that Aspergillus can cause sinusitis. One reason that Aspergillus and other airborne micro-organisms can infect sinuses is that there are air channels leading from the nose directly into the sinuses - partly to provide a natural drainage channel for mucus. Aspergillus spores (seed-like particles) are so small and light they float freely in the least puff of air, so accessing nasal passages and chambers filled with air branching off the nasal passages e.g. the sinus' is quite easy. Taken together with the fact that all of us breathe in Aspergillus spores every day it is not hard to conclude that infection is not prevented by lack of supply of spores!

For the most part our natural defences against infection destroy spores quickly and efficiently - there are movies of precisely that happening in the Educational section of the Aspergillus Website.

Another 'mechanism' of preventing fungal growth in the sinus' that has some speculative merit stems from the observation that there is very little available zinc in the cavity. Fungi such as Aspergillus need zinc to grow, so the absence of zinc prevents fungal growth.
Zinc is plentiful in the material used to fill teeth and a little known fact is that that material can protrude right through a root canal filling into the maxillary sinus. There are two papers (1, 2) which discuss cases of root canal amalgam protruding into the sinus which are covered with fungal growth within the sinus, consistent with the amalgam aiding growth as described above.

We should emphasise that this is an incredibly rare phenomenum - there is no need to question your dentist on his technique just yet, except perhaps to remind him/her not to overfill!

Monday, 6 October 2008

EU go-ahead for paediatric anti-fungal

The European Medicines Agency's paediatric committee last week gave the go-ahead for a paediatric version of Merck Sharp and Dohme's Cancidas, for use in fungal infections - which like the adult version contains the echinocandin, caspofungin acetate, and now only needs to be authorised for marketing by the European Commission. This should happen within two months or so.

The product is already available for paediatric use in the US, where the FDA approved it in August for use in children aged three months and older. In Europe the new indication was submitted for approval under the paediatric regulation, which came into effect in January 2007 and is intended to address the shortage of suitably adapted forms of drugs and the lack of information on paediatric dosing.

Companies have generally been reluctant to develop drugs for use in children, mainly because of the costs involved. Instead, doctors have had to estimate the dose or use drugs off label, which has often led to adverse reactions or denied children access to the latest or most effective treatments.

The EU's new regulations in January 2007 intended to address the shortage of suitably adapted drugs for paediatric use. As well as encouraging trials on new paediatric indications of existing drugs like Cancidas, the regulation also targets new active substances. As of July this year, all new drug applications must include the results of trials conducted in children in accordance with a paediatric investigation plan (unless the company applies for a waiver). View full article.

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