Antibiotics - The Perfect Storm - The BOOK - NOW AVAILABLE

Tuesday, October 21, 2014

AstraZeneca is Cutting and Running!

For the past two years I have been warning that AstraZeneca would be giving up on antibiotic research and development.  Well, that day is arriving.  It looks like they will continue with their submission for market approval of ceftazidime-avibactam – but what comes after that is still unclear.  I have been able to confirm that AZ has told its antibiotics researchers that they should make efforts to find other jobs in the near future. Even though there has been no official announcement yet that the antibiotics research group will be disbanded, their scientists are starting to head for the hills.  As far as antibiotic discovery and development goes, this has to be the most disappointing news of the entire antibiotic era.  AZ has the strongest antibiotic pipeline in the industry and has an active and successful discovery effort. To jettison all this in spite of everything that has occurred in terms of regulatory reform and everything that is occurring and will occur in terms of improving the antibiotic marketplace, to me, is just the worst kind of hubris no matter what their other financial difficulties might be.

President Barak Obama has just issued a set of executive orders – OK - mostly without any sort of teeth and lacking any new funding – to improve both the regulatory and financial climate for new antibiotics.  David Cameron has ordered the establishment of an advisory panel on the economics of antibiotic development and marketing led by a renowned economist. If nothing else, this should show that the sun is rising on the antibiotic marketplace. But M. Soriot, the CEO of AZ, is not listening and

if he is, he apparently believes that all this will be too little too late for his antibiotic pipeline. To give him credit (not much), he did try and “partner” or sell or spin off his antibiotics unit over the last two years – apparently without success.  My guess is that he wanted more out of such a deal than anyone was willing to offer. So he, like Pfizer, Wyeth, Lilly, BMS, and many others before him, has decided that the solution to AZ’s ills is to jettison their antibiotic research altogether rather than accept something less than what he wanted. 

Given the importance of antibiotic research to society, one must ask where the heads of government are in all this. Did President Obama approach M. Soriot?  Did Prime Minister Cameron speak to Soriot?  I have it on good authority that the answer for the latter question is “no.” Should these government leaders share in the responsibility for the loss of AZ’s antibiotic research unit?  Absolutely!

At the same time and even more frustrating, is the fact that AZ is investing in a large research facility for Alzheimer’s disease and cancer in Cambridge, UK.  This facility will combine academic and industrial research like never before.  This is exactly the kind of endeavor that we need for antibiotic research but that no one is doing.  AZ could have incorporated antibiotic research in Boston into a Cambridge style arrangement – but they have chosen to jettison the whole thing instead.


Once again, we will have an exodus of competent researchers from the field.  I note that the head of the biology group at AZ’s antibiotics research center has already accepted a new job in the Boston area working on a company focusing on therapeutic bacteria of all things.  But he may be the exception.  Many of these folks will go on to other fields or they will retire and be lost to us as a resource for antibiotic discovery and development expertise.  This is a resource we cannot afford to lose. Sanofi, Roche – are you listening?  Hire these people!

Thursday, October 16, 2014

Frontline - The Trouble with Antibiotics

On October 14, PBS Frontline aired the second installment in its series of antibiotic resistance called, “The Trouble with Antibiotics.”  Although I was asked to preview the story for this blog – I found myself without internet access to be able to watch the show because of storms in our area.  It took five days to reacquire access – hence my tardy blog on the subject. 

The show is a fascinating look at the debate on antibiotic use on farms in the US and antibiotic resistance in American patients.  There is also a follow-up on the NIH outbreak of KPC Klebsiella.  But I concentrated on the issue of antibiotic use on farms and the inability of the FDA to regulate this use. There were many talking heads on the show saying that the connection between the use of antibiotics in animals and the appearance of resistant infections have never been clearly linked and that even in the cases where the evidence is strong – the numbers of patients affected are very small.  Wow! To me, this issue was settled back in the 1980s.  Here are some pieces of evidence that I find persuasive.

1.     First there was a study by Wolfgang Witte and his co-workers in the old East Germany.  Wolfgang worked at the East German CDC where all resistant organisms – coming from farms animals and from human infections – were collected from the entire country.  There were some advantages to a strict communist government I guess. These investigators identified resistance to an antibiotic called nourseothricin used in animals as a growth promotant.  The antibiotic was not used in humans – so there would be no particular reason for humans to be colonized or infected with nourseothricin-resistant bacteria unless they had been exposed to resistance coming from farm animals. In their studies, the researchers showed that this gene was carried on a genetic element that also carried another gene causing resistance to trimethoprim – an antibiotic used to treat urinary tract and intestinal infections in humans.  They clearly showed the link between the bacteria isolated from animals on farms and from humans both genetically and epidemiologically.  This remains one of the strongest studies ever done in this regard.  It was not cited in the Frontline report – because it wasn’t a US study?
2.     To me, the avoparcin story and its connection to the rise and spread of VRE is also very persuasive.  Avoparcin is an antibiotic related to vancomycin.  Vancomycin-resistant enterococci were first detected in Europe – specifically in France – in the late 1980s.  They rapidly spread throughout Europe and the US.  In America, they are now responsible for 20,000 infections in US hospitals and 1300 deaths every year according to the CDC.  In order to become resistant to vancomycin, a key antibiotic for treating these infections, enterococci have to acquire the ability to make an entirely different kind of cell wall – requiring a number of new genes. These genes come on a genetic element that is easily transferred – but how did this element end up in enterococci? Its origin – believe it or not – seems to be in the bacteria that produce vancomycin-like antibiotics since they themselves have to be resistant to the antibiotic’s effects in order to survive.  Bacteria in the guts of animals were selected, apparently through use of avoparcin as a growth promotant, and were then spread to humans through food in Europe.  Again – to me – this has been clearly demonstrated.  Further, when avoparcin was removed from the market as a growth promotant in a number of European countries, human colonization with VRE declined substantially.
3.     Highly resistant strains of Salmonella (DT104) have clearly been shown to colonize animals, to contaminate meat during slaughter and subsequently to cause disease in humans.  This organism has been the origin of a number of large recalls of hamburger in the US over the last several decades.

The Frontline show clearly described the FDA's attempt to regulate antibiotic use in animals in the 1970s and their utter failure to persuade congress to go along.  Apparently, four decades later, the FDA is still feeling the effects of their interaction with congress.  As I noted previously, we do not have a congress right now that is capable of acting in any sort of positive way - they only act by inaction. 


In their exhaustive and excellent review on this topic, Marshall and Levy state that the gaps in data do not justify our failure to restrict antibiotic use in animals in the US in ways similar to regulations implemented by European authorities.  To my mind, once gain, Europe is leading the way!  This is amazing to me since Europe in many ways is so much more dysfunctional than the US - but there it is. 

Monday, September 29, 2014

New Antibiotics = New Targets?

I am about to go to a meeting in Europe where one of the topics of discussion will be where Europe should spend its money on antibiotic discovery research. Of course, geographically – in Europe – sorry Americans.  But what kinds of discovery research should they support with their Euros? I’ve had this conversation so many times now that I am starting to sound like a broken record even to myself.  Every time this topic is raised (with academicians) the first two words out of their mouths are “New” and “Targets.” In theory – this is a great idea.  If the antibiotic hits something entirely new and different than what is hit by existing antibiotics, at least the resistant strains that exist today won’t be resistant (at least mostly) to the new product – until they become resistant that is. And every time I hear these arguments,  I get a little less tactful in my response.  But who cares?  I’m retired – right?  I can say what I want (mostly) – right?

My thoughts run as follows.

Every pharmaceutical company in the world already investigated a very large number of new targets during the 1990s and early 2000s. Just read David Payne’s wonderful exposition of GSK’s efforts in this regard (assuming you have a subscription to Nature or you want to pay). We certainly went through the same trauma at Wyeth and so did Schering and many many others.  Unfortunately, much of the billions of pages of resulting data were never published because the results were, almost 100%, negative! And those of you in the academic world know how hard it is to publish negative data. There were some interesting scientific observations that were published based on this research – but little of the kind of data noted by David Payne and colleagues made it to press. So what will the academic community bring to this table?

First on my wish list would be a way to understand how we can make small molecules enter Gram-negative cells and avoid efflux. This is a basic science research effort that can be separated to a large extent from drug discovery per se. Hans Moser has already published some fascinating work on this topic and additional research is already being funded to some extent by IMI. 
 

Then, even if we identify a novel target – what makes us think we can find a drug that will work against that target?  Academic researchers in general are not trained to carry out drug discovery research. And when they try to enter the area without adequate training, the results are not good.

So – what do I say to people who ask me if they should spend money on research into novel targets for antibacterial drug discovery in academia?

1.     First – get academics trained in antibiotic discovery research.  They must understand many aspects of translational research that they currently have not even considered. This includes everything from biophysical properties of small molecules to PK/PD to toxicology to chemical manufacturing. This seems like the highest priority to me.
2.     Get people to think about new approaches to existing antibiotic classes.  This is less risky and might well provide more bang for the buck.  How about some additional B-lactamase inhibitors targeting the class D carbapenemases.  Lots of people (Merck and AstraZeneca among others) have worked on this class of inhibitors known fondly as DABCO.  Why not focus efforts on a set of enzymes where there is high medical need?  Are other companies working on this?  Of course.  Have they gotten anywhere? – not to the stage of clinical trials at least according to clinicaltrials.gov.
3.     Encourage research on known targets using new approaches.  Look at all the binding sites in ribosomes that have not yet been explored.
4.     Finally, if you plan to spend taxpayer money on research in novel antibacterial targets, require researchers to provide a chemically tractable ligand that binds the target and gets into bacterial cells and avoids efflux before you throw too much money at the project. Seed money OK.  Small projects with high risk – OK.  But that’s it.

For more on this topic, my blog contains a number of articles on writing grants for antibiotic discovery (1, 2, 3, 4, 5).  I have also previously discussed the issue of training for academics in antibiotic drug discovery.