There has been a good deal of discussion in the news lately
– especially from the UK and Europe – on the increasing danger of antibiotic
resistance. In a statement towards the end of last year
and again more recently,
Dame Sally Davies, the Chief Medical Officer for England, said that the coming
apocalypse is the lack of effective antibiotics. She said that this could make routine medical
care like surgery untenable for a large number of patients. A recent paper
from the CDC seems to underline this point demonstrating a clear increase in
incidence of carbapenem-resistant Klebsiella (CRKP) infections over the last
decade. On the other hand, I think talk of a coming apocalypse is probably
hyperbole that makes good news but not necessarily good sense. A better way to look at this is that
antibiotic resistance is becoming more and more of a public health threat that
we ignore at our peril. In the case of
CRKP, the rate has increased from about 5 to 11%. This is a doubling and should make us all
quake in our boots – but it is not 100%. Further, there are antibiotics in our late
stage pipeline today that will address this threat. They include various antibiotics combined
with avibactam or MK7655, both novel Beta-lactamase inhibitors that inhibit the
resistance making the organisms susceptible once again.
But most authorities agree that in spite of the promise of
our late stage pipeline, the threat is that this pipeline is not nearly as
robust as it needs to be. Some of these
pipeline products may yet fail during development. Many resistant organisms are still left
out. So what can be done to supplement
our faltering antibiotic armamentarium for our future and that of our children?
Antibiotics are special.
They are jewels that we must preserve.
They are the only drug class (with a very few exceptions) that actually
cures disease in a matter of days. We must value them as such. Society, and I mean the global society, has
to see this as it applies to new drugs to treat highly resistant infections.
Since these new products will only be used by relatively small numbers of patients,
they will have to be priced such that companies can still recoup their return
on investment and maybe even, excuse my French, make a profit. Prices from $2000 to $30,000 per course have
been considered. One problem with this
approach is that of empiric therapy. 80%
of antibiotics are started in hospitals without knowledge of the infecting
organism and sometimes without knowledge of the site of infection. But obviously, with such expensive drugs,
empiric use will have to somehow be very controlled and well justified. This is all good because with limited use,
these new jewels will be preserved and protected to some extent from the
inevitable emergence of resistance. How will this play out in the emerging
economies like India, Indonesia, Singapore, Malaysia, China and others? This is
a commercial question that must be answered at some point soon.
Another possibility would be to have the government(s)
guarantee the market for such products by purchasing and distributing them as
necessary and alleviating the need for companies to actually “market” their
products. At risk of sounding heretical
– in this I think the market ought to be allowed to choose. In fact, there are a number of products in
the pipeline with overlapping utility.
Which should be chosen? Each
hospital ought to be able to make this choice depending on its own needs. I’m not sure the government can fulfill this
market function without essentially providing guaranteed markets for all these
products. Having worked for the Veterans Administration for sixteen years, I
think I can remember 3 years when we had a budget on time. This does not bode well for government being
the sole market for needed new antibiotics.
Secondly, we as a global society have to provide a
regulatory pathway for the development of such products recognizing that their
limited use will require limited studies and therefore some higher risk on the
safety side. Less data equals more risk.
So, which would you choose – limited numbers of effective antibiotics for your
next bout of pneumonia acquired in the hospital or limited safety data on an
antibiotic that is likely to cure your infection? Such an approach is already
being considered and even applied both in the EU and the US. The LPAD (Limited
Population Antibiotic Development) proposal of IDSA is one example. Another is NEWDIGS. NEWDIGS focuses on adaptive approvals and
release to market. It is very
reminiscent of a proposal made by the Manhattan Institute to FDA a number of years
ago. Here, a drug would first be
developed for a limited population with high unmet need (sound familiar?) and
would be approved for such based on small trials and limited data. More trials and more data would allow
approval for larger more general populations.
I would anticipate that pricing would reflect this evolution. NEWDIGS is
not yet focusing on antibiotics – but of course it should do so.
So – let’s try and get what we pay for!
Thank you for the piece, interesting to learn about NEWDIGS and the international parallels to LPAD. I follow your blog with interest.
ReplyDeleteTwo corrections on the CRKP study you reference: 1) it should be attributed to the Center for Disease Dynamics, Economics & Policy (CDDEP), not the CDC. 2) the 5% to 11% jump was for presumed ESBL producers (ceftazidime resistant Klebsiella), not CRKP http://tinyurl.com/c2dyl46
Thank you for your comments and corrections - much appreciated. I can reveal that our own data suggest that carbapenem resistance rates are also increasing in the US.
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