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Wednesday, September 12, 2012

Antibiotics, ICAAC and Bronchitis


I am writing this blog on the last day of the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in San Francisco.  As someone whose living depends on the pipeline of new antibiotics coming through, I am depressed.  I always attend the poster review session the first day of the meeting where the 10 best data sets on new products are briefly reviewed.  This year, as in the past few years, there have been precious few gems among the 10 best.  The two most interesting to me were the presentations by Rempex where they are developing a combination (Carbavance) between an old Japanese carbapenem, biapenem, and a new B-lactamase inhibitor, RPX7009 – a boronate.  Although this class of inhibitors has a bad reputation from the past, the data on this molecule and on the combination look encouraging.  Merck – you may get a run for your money! 

The other interesting presentation was from Trius on a topoisomerase inhibitor with a very broad antibacterial spectrum.  It targets Gyrase B and ParE and is a completely novel class.  Its actual binding site is the ATP site.  Unfortunately, many compounds targeting this site have died a toxic death – so the jury is still out – but the data are encouraging so far. The remaining presentations were quinlones or quinolone relatives offering no particular advantage to existing products either marketed or in late stage development.  It seems unlikely that any of these will get off the ground even though at least one has serious investor money behind it.  So – two out of the 10 best . . .I’m depressed.

On a totally separate note, an interesting study of antibiotics in the treatment of exacerbations of bronchitis was recently published. (A caveat – I was unable to get access to the actual article since I would have to pay $$$ – so I am relying on the abstract and news reports for my information).  The investigators in Spain, Dr. Lior and colleagues, studied over 300 patients with diagnosed chronic obstructive lung disease who had acute worsening of their symptoms (exacerbations).  These patients were only moderately ill.  The point of the study is that while it is clear that such patients with severe exacerbations benefit immensely from antibiotics with reduced mortality rates, it is not at all clear that those with milder disease benefit. This study attempted to answer that question.

Half of the patients were treated with an antibiotic, amoxicillin-clavulanate, and the other half received placebo in a blinded fashion.  Those that received antibiotics were 14% more likely to achieve cure of their symptoms within 8 days and showed a longer time to their next episode – 233 days vs. 160 days.  The study provides strong evidence for a treatment effect of antibiotics in moderate exacerbations.  I believe that by altering the design of the study focusing on those most likely to have new bacterial pathogens as the cause of their exacerbation would have led to an even more impressive treatment effect.  This is important because both in Europe and the US, to study a new antibiotic in the treatment of this disease, we would have to run such a placebo controlled trial.  But, as was the case for otitis media in children, equipoise may be lost.  It may no longer be ethical to run such a trial and, it is going to become harder to convince physicians and patients to participate (rightly so!).

I know that I am running up against the pundits who only want us to develop antibiotics for “serious” infections who believe that misuse and abuse in the community breeds resistance.  And I agree with their view in this regard.  But at the same time, new antibiotics for community acquired pneumonia should be developed – most of us agree on that.  So the only thing that will happen is that they will be used “off-label” for "milder" infections like bronchitis.  (By the way - if you are the patient with lung disease experiencing such an exacerbation - I wonder if you would consider the disease to be mild). Further, if antibiotics work, which I think they do for some patients, and I think we can identify those patients, we should be able to develop new antibiotics and get them approved for use in this condition.