Last week, I sketched out the increasing danger and a few of the responses to the spiraling problem of microbial resistance to our outdated and shrinking array of effective antibiotics. The new reports from the Pew Charitable Trust and the Wellcome Trust contributed to the alarm bells I am already hearing.
Then, last week, something happened—something not particularly good, almost as if there were an urgent need to prove that what we are discussing in this edition of bLogPhase is really serious. A paper published in ASM’s Antimicrobial Agents and Chemotherapy (AAC) journal described, for the first time, an E. coli strain resistant to the last-resort antibiotic colistin. The news was all over the press, TV, and social media, and ASM was at the center of it. However, it is important to note that this described strain of E. coli that harbors the mcr-1 plasmid, which confers resistance to colistin, remained susceptible to the antibiotics carbapenem and nitrofurantoin. So, while the detection of colistin resistance in our backyard is really scary, it is important to notice that this was not a “superbug” resistant to everything; it had its susceptibility and the patient was treated. Yet, reasons to be alarmed abound.
As I was describing last week, the world medicine cabinet is looking barer while the bugs are getting stronger. It is clear that we have a big problem in fundamental research and commercial development of new antibiotics. The Pew report in particular points to the need to discover new antimicrobial agents. All of the antibiotics in current use are derived from basic discoveries made 30 or more years ago. Last week, I compared antibiotics to telephones, asking you to imagine your current physician strolling into the examination room dragging a rotary dial phone on a long copper wire cord. The research undergirding that expensive antibiotic your doctor is writing up this minute is of the same vintage as rotary phones. In addition, the Pew report calls for new incentives for industry to enter the antimicrobial market, which is currently not sexy, unstable, and not very promising.
Chronic Diseases and Chronic Profits
With so many agents—doctors, patients, basic researchers, pharma executives—involved and with so many misaligned incentives driving them, I believe in the urgent need for global coordination to rebuild our antibiotic arsenal. The Pew report calls for the establishment of a full-time core scientific leadership group, which would set priorities and direct milestone-driven research to find new chemical matter for antibiotic discovery. But there’s also a big need for industry to have the correct incentives to develop new antimicrobials. As we know, the cost of developing a new drug is largely buried in R&D operations. These costs are further weighed down by the cost of failed drugs that could not be taken to market. While the marginal cost of producing each additional pill may be trivial, the cost of creating the first effective one can be mammoth. The strongest incentives for a drug company to enter a market are in treatments for chronic diseases (perfect examples are statins for hypercholesterolemia). Drugs for chronic diseases are taken by large swaths of the population, often daily and often forever. Unfortunately, the market for antimicrobials is the exact opposite. Antimicrobials are taken by a relatively small number of people (those correctly diagnosed with the correct bacterial infection) and for a short time. The length of patent protection for antimicrobials is the same as for other drugs, which creates another disincentive to enter a less-profitable market.
To address this issue, 85 pharmaceutical companies attending the 2016 World Economic Forum in Davos signed a declaration committing themselves to increased R&D in antimicrobials, if governments offered better incentives. In its report last week, the Wellcome Trust floated an interesting proposal for governments to put up large cash prizes to incentivize market entry for certain drugs such as antimicrobials.
There Are No DIY Lighthouses
Many quibble with the appropriateness of these sorts of government interventions. True, such efforts can skew markets and deliver taxpayer money to private companies who will ultimately keep the long-term revenues. Yet I am convinced that government intervention is appropriate in this case because of the public good of an effective response to infectious diseases. A public good is a benefit that is provided or consumed in common. It needs to satisfy both the condition of nonexclusivity and non-rivalry. The best example I know of a public good is the lighthouse. No ship captain would ever pay to build a personal light tower to signal perilous shoals for navigation. After all, other ships would benefit from the lighthouse—why should I pay to solve the problem, while others will benefit? The fact that one captain can use the signals from the lighthouse does not exclude other captains from reaping its safety benefits. This is why it is governments that build lighthouses and not individual sea captains. I believe that the worsening problem of infectious diseases that are increasingly resistant to our aging antibiotics is a problem requiring a public good solution. The very nature of spreading antimicrobial resistance is an illustration of the tragedy of the commons, as I explained last week. Without a public good response, the problem will get much, much worse.
Another Challenge: An Environmental One, This Time
As if all of this were not complicated enough, we are also confronted with an environmental challenge. In the U.S. and in China, it is common practice to feed livestock low doses of antibiotics to promote faster growth. In the U.S., over 70% (by weight) of the antibiotics defined as medically important for humans by the U.S. Food and Drug Administration (FDA) are sold for use in animals. The European Union is banning this practice, and the U.S. and China should as well. The introduction of such large quantities of antibiotics in the environment has severe consequences in the development of resistance in organisms in soil and water. The genes that drive microbial resistance are easily passed within and between species of bacteria. The great danger here is that loosed in the general environment, these genes could be transferred to human pathogens that currently lack them. There was a report last year from China of bacteria resistant to colistin, and the evidence points to agricultural use as the way that this particular resistance was developed. Both the Pew and Wellcome reports correctly call for a ban of this practice, offering data that show how better hygiene in animal husbandry can replace antibiotic use without significant effects on the economics of farming.
Enter the Resistome
On this front, a paper in Nature on May 11 caught my attention. As I explained in my previous blog, it is lateral gene transfer between bacteria that poses the great challenge to antibiotics. The movement of these resistance genes is what gives common pathogenic bacteria such resilience. Overuse of antibiotics in animals and humans poses the danger of creating a permanent reservoir, a virtual library of resistance genes in the ambient environment from which pathogens can draw what they need to survive and evolve in safety. Understanding the “resistome” present in the environment, especially in developing countries, is of utmost importance. The authors of the Nature paper reported collecting 263 fecal samples and 209 environmental samples from rural communities in El Salvador and Peru. Using 16S and metagenomic sequencing, the researchers found 1,100 encoded resistance proteins collectively conferring resistance to 16 antibiotics. They reported that 121 of these resistance proteins were novel. However, the ecological complexities of this study were high. Nevertheless I think the relevance of the resistome should be self-explanatory to readers of bLogPhase.
Which brings me back to both the Pew and Wellcome reports. Both were thorough and thoughtful, especially in their calls for new leadership on all fronts of the resistance wars. It is interesting that these reports were released the same week as the White House announcement of the National Microbiome Initiative. This, in turn, drew on the earlier White House National Action Plan for Combating Antibiotic-Resistant Bacteria that was written under the leadership of ASM member Marty Blaser.
The stakes here are frightening. We take antibiotics for granted today and have lost the memory of the millennia in human history when every scratch or minor surgery could turn septic. We have forgotten the helplessness of physicians as recently as 1945 to deal with serious bacterial infections. Could we go back into a dark age of medicine where antibiotics are once again few, feeble, and unpredictable?
It is clear that we are confronted with daunting problems, and yet again our field needs to be in charge of finding solutions. ASM is doing its part and is looking forward to collaborating with other organizations on this front. During the ASM Microbe meeting later this month in Boston, we will host a special workshop in collaboration with the Pew Charitable Trust and we’ll also launch, through the Academy of Microbiology, the Antimicrobial Resistance Coalition under the leadership of ASM members Jim Tiedje and Jim Hughes. Stay tuned—lots happening at ASM, lots happening in microbial sciences!