The Endgame

For background to this blog, see - http://amr-review.org/sites/default/files/Antimicrobials%20in%20agriculture%20and%20the%20environment%20-%20Reducing%20unnecessary%20use%20and%20waste.pdf, http://www.theguardian.com/society/2015/dec/08/antibiotic-use-food-fuels-humans-resistance-vital-drugs-report, and http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(15)00424-7/abstract.

 

Is this how it will end for us? We use our absolutely last line antibiotic to attempt to put fat on a pig more quickly and select for a plasmid-mediated resistance gene capable of spreading worldwide? Even more galling is that China is not the only country to do this – count the US in as well.

I guess I should start at the beginning of this story. We are now living in an era where, according to Jim O’Neill in the UK, 700,000 people globally die of resistant infections every year. The most resistant bacterial pathogens we deal with today are the Gram-negative bacteria like those resistant to our next-to-last line antibiotics, the carbapenems (CRE). Currently, we can treat CRE with tigecycline (sometimes) and most often, with colistin.  Colistin is an old antibiotic discovered around 1947  and marketed in the 1950s.  It was almost never used systemically since it is  neurotoxic and nephrotoxic (causes nerve and kidney damage).  Given that colistin, at least until the emergence of CRE, was never used – no one knew how to use it or even if it actually was effective when given systemically. Since physicians are having to use colistin more and more frequently to treat CRE infections, we are now learning that it can be effective and that there are a few things we can do to lessen its toxic effects. But, no matter what, it is still not a very effective treatment and it remains toxic. On the other hand, until now, we have had nothing else to offer.

Luckily, for some CRE, we now have a new antibiotic, ceftazidime-avibactam, that should work.  The antibiotic was approved last year in the US and will be approved (I presume) in Europe very soon. But it does not cover all CRE – only some of them. Another antibiotic, wending its way through clinical trials at a tectonic pace is aztreonam-avibactam.  This will address another group of CRE. Finally, there is eravacycline – a tetracycline similar to tigecycline with fewer side-effects and the potential for oral use.  But it recently failed a key phase III trial in urinary tract infection and its future is in doubt. Further, most tigecycline-resistant bacteria will also be resistant to eravacycline. Is there resistance to these new antibiotics? Yes.  Will we still need other options including colistin?  Probably.

This brings us back to fattening pigs. A month or so ago, the Lancet reported the emergence of colistin-resistance caused by a gene, mcr-1, found in samples from animals and some human patients in hospitals in China.  This gene is carried on plasmids and can readily spread from one bacterium to another.  It has already been reported outside of China- in Malaysia and now in Europe. The origin of the gene?  Feeding colistin to pigs to promote growth. Who besides China allows this practice?  The United States – that’s who.

Do we even need to use antibiotics to cause more rapid growth of animals?  Probably not.  A raft of studies has shown that with more advanced farming techniques, antibiotics as growth promoters add little (less than 5%) to the value of meat produced. True – that with poor technique like overcrowding and unsanitary conditions, antibiotics seem to be more important – but why don’t we work on bettering conditions for raising animals rather than relying on antibiotics.  Also – if we have to rely on antibiotics to promote growth of animals, it is the height of stupidity to use the one that is our absolute last hope for highly resistant human pathogens.

Unfortunately, even if we could do better in the US – and if we had an effective FDA we could – we also need to address this problem globally, including in China and other Asian countries with whom we have signed a new trade agreement. If we don’t address this now, at home and abroad, we will lose our ability to stay ahead of bacterial resistance altogether.

– and this might just be how it all ends.

Big News - FDA Delays Again

Well, here we are again talking about the FDA and the use of antibiotics in animals. The FDA just finalized its long-awaited rule requiring industry to report how the antibiotics marketed for use in animals are actually used (see the report by STAT).  The FDA will now have actual data about how much and which antibiotics are used for growth promotion, prevention of infection and for therapy. Of course, one could ask how long it will take for them to collect all this information and then decide whether to act on the data or not.

 

To me, as those of you who follow my blog already know, this is nothing more than a delaying tactic.  In my view, as I have expressed on multiple occasions, the argument as to whether antibiotic use in animals leads to resistance in pathogens that infect humans was settled back in the 1980s. Once again, I think the FDA is maneuvering to avoid congressional pressure.  They also have received cover in this regard from none other than the President’s Council of Advisors on Science and Technology who stated in their report that the data showing the link between use of antibiotics in animals and resistance in humans has not yet been convincingly shown.  This is a view I could not disagree with more strongly.

All the FDA need do is look at data from Europe where halting the use of antibiotics as growth promoters in animals has clearly led to decreasing levels of resistance in human pathogens. Europe leads the way once again!

While there is nothing wrong with collecting more data – the time for the FDA to act has long passed.  But what else is new?

Obama's Plan to Combat Antibiotic Resistance

There has been much press lately about President Obama’s plan to address the growing crisis of antibiotic-resistant bacterial pathogens. And I agree with many that there is much to like in the plan.  But I also find a number of key deficiencies that will lead us nowhere.

The goals of the plan are all laudable –

1. Slow the emergence of resistant bacteria and prevent the spread of resistant infections;

2. Strengthen national One-Health surveillance efforts to combat resistance;

3. Advance development and use of rapid and innovative diagnostic tests for identification and characterization of resistant bacteria;

4. Accelerate basic and applied research and development for new antibiotics, other therapeutics, and vaccines; and

5. Improve international collaboration and capacities for antibiotic-resistance prevention, surveillance, control, and antibiotic research and development.

Who can argue with that?

To achieve the first goal, the plan contains a number of key elements.  Among them are strengthening of antibiotic stewardship in both inpatient and outpatient settings including long term care. Surveillance is to be strengthened by providing regional reference centers to detect resistant strains in clinical and veterinary settings. Importantly, there is a plan to streamline the regulatory process for approving susceptibility-testing devices such that they are available when a new antibiotic is marketed instead of the one to two year delay that now occurs.  I like that one especially. Another piece of this plan is to establish a national database on antibiotic use.  That’s another one I like, but man, will that be hard to implement.

An obvious goal is to eliminate the use of medically important antibiotics as growth promoters in animal feed.  Wow.  What a surprise.  But the plan does not include an outright ban. Rather, it supports the FDA’s efforts, which could ultimately succeed, I suppose, to get the industry to back off. But why is there such consternation around an outright ban? I don’t know.

One piece of the plan calls for establishing a susceptibility-testing network for animal pathogens.  It seems like this is aimed at providing better and more focused therapy for infected animals. Good idea. What this will require is an entirely new approach to animal pathogens including setting breakpoints for what is considered resistant or susceptible in different animal species.  Right now, the assumption is that animals are humans – which I can tell you - physiologically, they’re not. Who is going to do all the sophisticated PK/PD experiments in the different species to establish these breakpoints? Is there going to be funding for this piece?  Or is there no one but me who sees this as a possible pitfall?

The there is the section on establishing rapid diagnostic testing.  See my blog on this.  I say again.  It has to be bedside and idiot-proof.  This could take a while, folks.

Finally, there is the part on accelerating both basic and applied research aimed at finding new antibiotics, vaccines and other therapeutic approaches. But the way this is worded sounds like a way to let the NIH off the hook.  For the last 50 years, the NIH has been shortchanging antibiotic research and funneling money into the study of vaccines and pathogenesis of infections.  I don’t argue that these are not worthy of study.  I just will state that antibiotic research has always gotten the short end of this stick.  And, if I read the plan correctly, this is unlikely to change in the future.

What is glaringly absent from the plan is what was recommended by PCAST in terms of providing for a return on investment for companies who pursue the research and development of new antibiotics for resistant infections. Of course, that was the most expensive part of the PCAST report.  That report would augment funding for BARDA in its effort to support applied research in academia and industry. It would also provide for various pull incentives such as an upfront purchase or so-called patent voucher system. Without this, as far as the development of new antibiotics is concerned, the plan is another piece of paper in a long line of such.  Show me the money!!!

So here we are. There is much good here.  But it is clear that the much-touted “doubling of funding” that the press is so excited about is less than it seems. Not only that, but what makes anyone think that the President’s budget, where this plan is enshrined, will pass? If it does, will it have to do so on the back of Medicare, Medicaid or food stamps? I’m sorry – but my eyes are on Jim O’Neill and the UK for now.