David's New Book

Wednesday, January 13, 2016

AstraZeneca Where Are You?

You will all remember that mcr-1 mediated resistance to polymyxin (colistin) emerged on transmissible plasmids last year.  How did it arise? Because Chinese farmers wanted their pigs to grow faster – so they fed them low doses of this antibiotic as a growth promoter.  I pointed out in my previous blog on this that the US allows use of polymyxin as a growth-promoting agent as well. This means that our very last, end of the road, toxic and poorly effective antibiotic for otherwise totally resistant Gram-negative infections is in serious jeopardy.  That means that WE are in serious jeopardy. By the way - since its discovery, the gene has been detected pretty much worldwide. 

These cheerful thoughts lead me to think about Astra-Zeneca?  Why?  Because they (and their partner, Allergan) have an antibiotic in their pipeline that could make a big difference here. Aztreonam-avibactam combines a monobactam (aztreonam) that is resistant to the metallo-beta-lactamases like NDM-1 with a broad spectrum B-lactamase inhibitor that will protect aztreonam from destruction by any other B-lactam hydrolyzing enzymes that might be (and usually are) present in the pathogen in question. This combination has been shown to be active in model systems (hollow fiber) suggesting that it will be highly active in vivo. Way back in 2010, David Livermore, myself and others were pleading with AZ to get aztreonam-avibactam into clinical trials so we could treat highly resistant pathogens like these.

Aztreonam-avibactam did not enter phase I clinical trials until January of 2012. Those phase I trials appear to have been completed according to clinicaltrials.gov. Here we are, four years later and that’s where we are folks. During that time, Astra-zeneca has spun out their antibiotic discovery group into a company called Entasis.  AZ has also turned their antibiotic development group, still within the parent company, into a separate business unit – a move I applauded then and still do. This means that they have their own profits coming in from their sales of ceftaroline and meropenem.  That should be plenty of money to finance the development of aztreonam-avibactam.  Not only that, but they recently received a large grant from BARDA worth up to $220 million and they have funding from the European Union for aztreonam-avibactam as well. So, you might ask, why is this development proceeding at such a tectonic pace?  If this keeps up, the drug won’t be available until my grandchildren reach my age if then.

It strikes me that, for an antibiotic like aztreonam-avibactam, that targets a tiny number of cases (at least today), the data that might be required to get regulatory approval for human use will probably be fairly minimal and could be accomplished quickly – especially in Europe where AZ holds the rights to this drug.

I contacted my friends at AZ to let them know that I was going to be writing this blog.  I asked if they could comment on the development of aztreonam-avibactam.  I asked if at Entasis they were trying to discover even better inhibitors than avibactam that might deal with other resistant strains.  I also asked who it was that was head of the new business unit. No comment, no comment, no comment. Why is the name of the new business unit director a secret???  When I asked that question my friend replied – “you and I both know what its like to work for a large company.”

So – to those of you out there still depending on colistin to treat highly resistant Gram-negative infections, you better hope that mcr-1 does not arrive at your hospital before aztreonam-avibactam does.  Good luck on that.