There is a war that has been raging for a very long time. Different groups have constantly been developing ever more devious weapons, with counter-measures springing up almost as quickly. This war has been waged all day, every day, for eons. It is into this context that we humans blithely wandered 70 years ago when we first started prescribing antibiotics to treat infection. To start with, everything went spectacularly well. A timetable for the end of infection was duly announced.
Only, that's not what happened. Not at all. The scale of what we stumbled into has since become increasingly apparent. Bacteria have been engaged in a microscopic chemical war for a lot longer than we have been walking the Earth. In 2011, a paper published in the scientific journal Nature brilliantly illustrated that bacterial resistance to vancomycin is at least 10,000 years old. Vancomycin is often described as a drug of last resort, as it is generally only used when all others have failed. Soil samples taken from permafrost in the Yukon were shown to contain the requisite bacterial genes. These samples had last been in liquid form long before humans had even embarked on what we might recognize today as scientific inquiry. In the context of a conflict almost as old as life on Earth, is it really any wonder that we are struggling to hold onto our early gains? The decline in our own efforts to compete with the bacteria, as evidenced by the increase in antibiotic resistant infections and the dire consequences thereof has unfortunately only compounded the problem. Research and development of new antibiotics has dropped off disturbingly in comparison to what it was 20 years ago. In 1990, there were estimated to be 20 pharmaceutical companies actively engaged in antibiotic research, and today there are approximately four.
Why has this drawback in our efforts occurred? The reasons are many and varied. One issue that we have run into is that bacteria just aren't that complex. They only have so many systems that we can target with antibiotics. We are being taught a very hard lesson in diminishing returns. With the spread of resistance to antibiotics that attack the more obvious targets we are left to try and take advantage of increasingly more difficult alternatives. Once resistance is out there in the bacterial population, we can't take it back. Most likely it was there all along; it just took a little while for our liberal use of antibiotics to select for it. New classes of antibiotics will become more and more scientifically demanding to discover and develop. This isn't to say we should stop trying, but we should also expect to have to put more effort in to achieve useful results, and as it stands, we are putting in less and less effort over time. There will always be a need for antibiotics but we will need to become increasingly strict about their use in a way that reflects how much more difficult it has become to successfully develop them.
Another problem that has impeded new antibiotics coming to market is the regulatory burden. The demands of FDA clinical trials have only increased since penicillin use began. These clinical trials are essential to best ascertain the safety of any drugs that might be used in humans. Nobody wants to see anything like thalidomide or Vioxx happen again. While neither drug was an antibiotic, all medications must be properly tested in order to avoid catastrophic side effects once they hit the market. One hurdle that faces those wanting to conduct clinical trials of new antibiotics is the number of people who become infected with resistant pathogens. In September 2013 the CDC estimated that 23,000 Americans died from antibiotic resistant bacteria in the previous year. While this is a shockingly large figure and is only set to increase, it represents resistance to several different drugs from several different bacteria. The numbers of patients per drug is unfortunately quite low in the context of a full scale clinical trial thus making testing of new alternatives difficult given the current requirements for such trials. However, the consequences of allowing the growth of antibiotic resistance to a level at which patients are queuing up to participate in a clinical trial before coming to a solution will be disastrous, not to mention unethical. The vision of a post-antibiotic world is not a pretty one, with relatively simple operations like hip-replacements, becoming increasingly riskier, or simple scrapes becoming life-threatening due to infection setting in.
It would be wholly irresponsible of us to allow circumstances to degenerate to the point of being overrun by rampant, uncontrollable pathogens before attempting novel solutions.
What some of these solutions are and who is pushing them forward will be the topic of my next post just so this doesn't come across as all doom and gloom.