Tuesday, 24 February 2009

A New Weapon against Aspergillosis

Wax Moth
People suffering from an aspergillosis infection are treated with drugs designed to stop or kill the invading fungus i.e. antifungal drugs. If the drug stops growth of the fungus but does not eradicate the infection completely (which is what most current antifungal drugs do to Aspergillus) then conditions favour the development of resistance to that drug. Unfortunately there are signs of resistance to the antifungal drugs developing, so alternative antifungal drugs are sometimes needed but of course ultimately resistance could develop to those as well - a different approach is needed.

Researchers in this recent paper have been working on the possibility of finding new targets for attacking the fungus and have described one hopeful candidate - the heat shock protein (hsp), a family of proteins found in most living things. This protein is thought to be involved in how a fungus fights off the stress of attack by an antifungal drug, so if it can be stopped from working then the fungus should be less able to fight off attack. In the study they used inhibitors of hsp90 in combination with antifungals to test if an Aspergillus infection can be completely removed. Antifungal or heat shock protein inhibitor on their own failed to prevent death of the moth larvae, but when used together they had 100% success, which is very good news!

In the words of the author
"Harnessing Hsp90 provides a much-needed strategy for improving the treatment of fungal disease because it enhances the efficacy of existing antifungals, blocks the emergence of drug resistance, and exerts broad- spectrum activity against diverse fungal pathogens."

Unfortunately there is a snag - the heat shock protein inhibitors currently in use will also inhibit human and mouse heat shock proteins, therefore they are toxic for use in either mouse or human. The experiments described above used an insect model (greater wax moth (Galleria mellonella) larvae) to demonstrate the principle as the hsp inhibitors used were not toxic to the moth - presumably because moth hsp90 is different enough from fungal hsp90 to avoid being inhibited!

Further progress requires the development of heat shock protein inhibitors that are specific enough to ignore human heat shock proteins while attacking fungal heat shock proteins. A large grant has been awarded to the researchers to do exactly that.

Tuesday, 17 February 2009

Allergic aspergillosis in people with cystic fibrosis

lung image from cleveland clinic.org
People who suffer with the inherited genetic disease cystic fibrosis (CF) are very vulnerable to lung infection by a number of organisms - of which aspergillus is one and which can be difficult to diagnose and treat. A recent study has looked at a group of CF patients and the occurrence of aspergillus. Patients with cystic fibrosis can be susceptible to colonisation with aspergillus species, to which an allergic reaction can then occur leading to allergic bronchopulmonary aspergillosis (ABPA).
A recent study reported in "Respiratory Care" by Chotirmall et al has addressed the rate of colonisation with aspergillus and ABPA in a group of cystic fibrosis patients (CF) from Ireland.

A group of 50 patients with CF were studied for the presence of aspergillus in sputum and for other signs of ABPA. It was found that 30% of the CF group grew aspergillus from their sputum samples, whilst 12% of patients had ABPA. Subjects with ABPA experienced a sharp, short-term deterioration in lung function, which returned to baseline following at least 4 weeks of treatment. Those positive for aspergillus in sputum showed no difference in forced expiratory lung volume, compared to those who were not aspergillus positive.

The authors concluded that the prevalence of ABPA was 12% but that aspergillus positive sputum on its own was not a poor prognostic sign for lung function, over the 5 year study period. The frequency of aspergillus isolates did not correlate with the occurrence of ABPA, but awareness of ABPA should be considered in any patient who did not improve after taking antibiotics for lung infection.
For more information about cystic fibrosis visit here.

Monday, 9 February 2009

Protection of vulnerable patients from aspergillosis

Thousands of patients every year undergo treatment that severely reduces their ability to fight off infection. Referred to as 'immune-compromised' these people may have had major components of their immune system temporarily removed (e.g. people who are suffering from cancer of one of the components of their immune system - some types of leukemia are caused by this) with the intention of replacing it. These patients are very vulnerable initially and gradually become less vulnerable as their immune systems recover over a period of time - usually a few days/weeks.

At this time these people are kept in an extremely clean environment which is supplied with highly filtered clean air, are often fed with sterilised food and washed in sterile water, all with the intention of preventing contact with fungi or bacteria.

Unfortunately with fungi things are not so simple. The tiny fungal spores are so evasive of attempts to control it a few can get through and every ward has its fungal infections to treat in a small number of patients. This court case attempts to lay the blame at the door of hospitals, presumably in an attempt to get the hospitals to review their protocols for minimising fungal infections, particularly when there are building works in the direct vicinity of the hospital - as was also the case in this instance and in many others.

How to stop these infections? Firstly of course ensure all standard preventative measures common to all hospitals are in place so that risks are reduced. If infections still persist what other ways can fungi get into the patient?
  • The patient's skin & hair and their clothes will be covered in fungal spores from the outside air - do we need to 'sterilise' all patients prior to admittance and remove their clothes & possessions?
  • Water for washing drawn from a showerhead or tap will be non-sterile - do we stop patients cleaning themselves?
  • All staff and the patients' family members entering the ward will also be covered in fungal spores so do we isolate the patient from their caring staff & family?
The patient would need to be kept in a hugely expensive sterile 'bubble' to prevent all sources of infection coming from the outside, but surely once we have done all that we have eliminated all risk?
Not quite: It is possible that fungi may exist for some time growing in a patients lungs prior to being killed by the patients immune system. A patient may thus have active aspergillus spores growing within them when they are admitted to a ward! How do we counter that?

There is an extensive review on this subject on the Aspergillus Website here and many more articles available to search in the Aspergillus Website search engine and in the Aspergillus World search engine.

Hospital acquired infection is referred to as 'nosocomial infection'. Try searching for 'aspergillosis nosocomial'.

Wednesday, 4 February 2009

Old drug learns a new trick

Crystallised Amphotericin B - from Molecular Expressions (click image)
Amphotericin B is one of the oldest antifungal drugs in common use (discovered in 1955)to treat serious fungal infections. It actually kills the fungus (fungicidal) rather than just stop it growing (fungistatic) so remains an important weapon in the fight against Aspergillus to this day.
Conventional formulations of the drug are not absorbed well through the gut and are not easy to dissolve in water, so the drug is delivered via injection into the bloodstream (IV) and must be dissolved using substances that are relatively toxic. This combination inevitably means that its use in this way must be carefully monitored. Patients can suffer severe side effects if not watched closely.

Attempts to reduce toxicity have resulted in several drugs being developed including Amphocil and Abelcet, both of which use less toxic ways to dissolve the drug prior to IV injection - again, lengthy hospital stays are needed.

A recent new paper, featured here features a new way to package up this drug which makes it possible to offer as a pill for oral use. In animal studies it also appears to be less toxic. If clinical trials (in humans) are as positive this could offer a whole new way to offer this important drug to patients, and enable them to take it in their own homes saving time, expense and hopefully improving outcomes for everyone.

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