Monday, 20 December 2010

Are We Going to Run Out of Antibiotics??

Antibiotics have been the mainstay of treatment for bacterial infections for 60 years, a time before which it was routine to have to have a hospital stay to treat a bacterial infection. We have several generations of patients and doctors who have grown up assuming that bacterial infections are trivial as there will always be a cheap, safe, accessible packet of capsules that cause few side effects and have very low toxicity which will quickly bring the infection under control & eradicate it.

But this is gradually changing. Bacteria are fighting back, becoming resistant to antibiotics in larger numbers every year. Many old antibiotics are now useless and the usefulness of enough of the more modern drugs is threatened by the rise of resistance. There are several reasons for this trend but the outcome is clear - we must reserve the most recently developed antibiotics for only the most necessary applications to try to delay the development of resistance to them as long as possible.

In addition we need to develop new antibacterial drugs and keep on developing them to prevent the supply of effective antibiotics running dry. But there is a snag - antibiotics are cheap so there is minimal profit to be made out of them. Secondly in the last paragraph we have just discussed why new antibiotics must be used minimally, at least at first. As far as drug companies are concerned this is a 'double whammy' as they can neither charge enough money or sell enough product to raise enough to pay back the investment it needs to make to develop a new drug. In its latest newsletter the Infectious Diseases Society of America (IDSA) mentions that only five of the 13 largest drug development companies are still searching for new antibiotics, suggesting that they prefer to invest in the development of more lucrative drugs.

This situation has now got so serious the US government are introducing new legislation to try to increase financial incentives for antibiotic development (Generating Antibiotic Incentives Now Act of 2010) by extending the time a company has rights to stop any other company reproducing a new drug (and thus reducing the profit) by 5 years. In practice this could mean a 40-50% increase in the time the company that made the original investment in the new antibiotic has to make money out of it. Hopefully this will make a substantial difference, however IDSA and partners are pushing the government to go further, lobbying for the need for 10 new antifungal drugs by 2020

Detailed article

Tuesday, 14 December 2010

Deaths caused by Tragic Error in Dosage of an Antifungal

Paul Richards was undergoing treatment for a fungal infection at Birmingham Heartlands Hospital in UK and was receiving one of the more recent formulations of Amphotericin, an antifungal that has been in use for many years. The new formulations (Ambisome and Abelcet) are much less toxic than the original formulation (Fungizone) and as such are often given in much higher doses, 3-5mg per kg of patient weight. Fungizone has a maximum dose of 1.25mg per kg.

In this incident an inexperienced doctor who was new to the hospital had apparently been instructed to administer the patient his antifungal medication. The information presented on the patient's chart led the doctor to understand that they were to give Fungizone when in fact the intended drug was one of the more modern formulations. Presumably the chart gave the dose as 5mg/kg.
More established staff members understood what was required but this doctor was new and did not come to the same conclusion. The confusion led to Paul Richards and another patient being given Fungizone at 5mg/kg, both of whom subsequently died.

This tragic story illustrates the consequence of a series of small errors and contributing factors adding up to a huge error: including:
  1. The doctor was new and was not familiar with the convention on that ward
  2. Senior nursing staff failed to notice the error or inform the doctor of the convention
  3. The doctor failed to read the notes supplied with the drug that warned of the maximum safe dose
  4. Labelling of the chart was inaccurate
 The article in the British Medical Journal made the following points:
In a report on patient safety alerts published last August, the charity Action against Medical Accidents (AvMA), said an alert in March 2007, Promoting Safer Use of Injectable Medicines, might have saved Mr Richards’s life but 104 trusts had still not implemented it nearly two years after the deadline set.
After his death the National Patient Safety Agency issued a rapid response alert on the safer use of amphotericin to all NHS trusts in September 2007. But AvMA research published in February 2010 found that 10 NHS trusts had still not implemented it.

Monday, 13 December 2010

Abby Beats Serious Acute Aspergillosis and Leads a Normal Life

In 1999 leukemia patient Abby Rosen received news that was difficult to take, she had developed an invasive aspergillus infection that had spread to her brain. The infection was so serious that she had to endure the removal of part of her skull (craniectomy) to prevent damage caused by swelling of her brain - it essentially gives the swollen tissue somewhere to go to and prevents the brain tissue being crushed by the buildup of pressure.
Treatment for leukemia causes a severe reduction in the effectiveness of the patients' immune system until it recovers from the first stage of chemotherapy treatment. This gives infectious agents including aspergillus fungi a 'window of opportunity' that they are more than happy to climb through.
Bacterial infections are common in this situation but antibiotic treatments are so effective and plentiful these do not normally cause too much of a problem. Fungal infections such as aspergillus are a different story.

Fungal infections have to be treated using one of a limited number of antifungal drugs. Some of these are quite toxic and cannot be used for some patients e.g. those with impaired kidney or liver function. This cuts the choice down further. More modern antifungals tend to be very expensive which can make then unattractive to use! On top of all this there is difficulty getting antifungals into the brain as there is a blood/brain barrier that prevents easy passage of drugs into the brain. How do fungi cross this barrier? It isn't really known for sure but one possibility is that it simply grows across it using the ability of its hyphae to 'push' through tissue.

All of this sounds like there is no hope, surely any patient faced with these odds might as well give up?! The happy answer is NO not at all. 12 years after suffering from cancer and this major infection Abby is back at work as an accountant and has been for the last 6 years. Thanks to the treatment she received she  recovered, regaining so much of what was lost that on November 21st 2010 Abby was married to Andy and has spent the last few weeks on honeymoon in Hawaii.

Abby's mum Sandra commented:
When my husband first contacted Dr. Denning in 1999 and he told him about a five year old boy that had survived aspergillus that was a great deal of encouragement for me. I hope Abby's story of hope and success will help other families who are in need of that encouragement. It is an amazing story to be told.
I have to say that it was a long journey to get to where she is today. One can't imagine how delighted we all are that she is with us and how much progress she has made after her brain injury.  She is still improving daily. There definitely is a life after cancer and a brain injury.
I don't think there is anything to add to that!

Wednesday, 8 December 2010

Clinical trial examines intravenous micafungin versus voriconazole for chronic pulmonary aspergillosis

The chronic form of aspergillosis is a slowly progressive lung illness caused by Aspergillus infection. There have been many clinical case reports on the treatment of CPA and also a few retrospective studies.
The Infectious Diseases Society of America recommends oral azoles as primary therapy for CPA, but data from large scale clinical trials have not been available.
The use of intravenous antifungal treatment as induction therapy, followed by oral antifungals as a maintenance therapy, have now been trialed in a larger group of CPA patients in Japan (Kohno et al 2010) as reported in the Journal of Infection.
In this drug trial, intravenous micafungin was compared with intravenous voriconazole as induction therapy for 2 weeks in CPA patients needing immediate treatment. A total of 107 patients were studied.
Clinical effectiveness was defined by clinical, mycological, radiological and serological responses.
The study indicated no difference in efficacy between the two IV drugs but fewer adverse effects occurred in the micafungin group than with IV voriconazole. The overall treatment success rate for both drugs was around 60%.

The take home message is that there was not much difference between the efficacy of micafungin and voriconazole intravenously - but the side effects of micafungin were less severe and less frequent - meaning that more patients could be successfully treated with micafungin (IV) as a primary therapy for CPA.

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