• The antibiotic era is over. And we are cutting health research funding?

    The US has significantly cut spending on health research and public health. The sequestration legislation requires that we continue to cut it. Yet there are many life and death problems that urgently require research and public health intervention. One of them is antimicrobial resistance. I want to convey the urgency of this problem, and then point out how ill-advised our current health research funding policies are.

    US hospitals and communities are increasingly colonized by bacteria that are highly resistant to antibiotic treatment. Perhaps you were aware of this problem, but thought that it was an issue for the future. But a new CDC report makes clear that this is a serious US health problem, right now. The CDC estimates that more than two million people are sickened and that more than 23,000 Americans die each year of antibiotic resistant infections. Compare that to 15,000 deaths per year from AIDS.

    Dr. Arjun Srinivasan, an associate director at the CDC, summarizes where we are this way:

    For a long time, there have been newspaper stories and covers of magazines that talked about “The end of antibiotics, question mark?” Well, now I would say you can change the title to “The end of antibiotics, period.” We’re here. We’re in the post-antibiotic era… we are literally in a position of having a patient in a bed who has an infection, something that five years ago even we could have treated, but now we can’t.

    CDC Director Dr. Tom Frieden explains that the danger is not just that we will lose the ability to fight infectious diseases. Many other life saving medical interventions depend on antibiotics for their effectiveness.

    The loss of effective antibiotics will undermine our ability to… manage the infectious complications common in vulnerable patients undergoing chemotherapy for cancer, dialysis for renal failure, and surgery, especially organ transplantation, for which the ability to treat secondary infections is crucial. When first-line and then second-line antibiotic treatment options are limited by resistance or are unavailable, healthcare providers are forced to use antibiotics that may be more toxic to the patient and frequently more expensive and less effective. Even when alternative treatments exist, research has shown that patients with resistant infections are often much more likely to die, and survivors have significantly longer hospital stays, delayed recuperation, and long-term disability.

    Many Americans will at some point in their lives require medical treatments that include concomitant antibiotics. For example, an American has a 44% lifetime risk of developing cancer. Many cancer patients require surgery or chemotherapy regimes that compromise the immune system. If antibiotics lose their efficacy these treatments become increasingly risky.

    Why antimicrobial resistance is increasing is well-understood. The pathogens are simply evolving. Applications of antibiotics selectively cull the least resistant organisms, favouring drug-resistant strains in the next bacterial generations. The bacterial populations become increasingly resistant and the antibiotics stop working. The more intensively we use antibiotics, the more rapidly the pathogens evolve.

    This means that the current problems will get worse as additional pathogens acquire resistance and currently resistant pathogens acquire new forms of resistance. Moreover, because the underlying problem is evolution, there is likely no definitive solution to the problem of antimicrobial resistance. We take for granted that medical care always improves, because we have never experienced anything else. But Drs. Srinivasan and Frieden are telling us that essential medical interventions are becoming less effective.

    The best we can hope for is to keep the pathogens at bay by evolving faster than they do. We are like the Red Queen, forced to run as fast as we can just to stay in the same place.

    RedQueen

    We are not, however, helpless. To keep up with the pathogens, we need to slow the rate of evolution of antimicrobial resistance through responsible use of antibiotics. From the CDC:

    up to 50% of all the antibiotics prescribed for people are not needed or are not optimally effective as prescribed. Antibiotics are also commonly used in food animals to prevent, control, and treat disease, and to promote the growth of food-producing animals. The use of antibiotics for promoting growth is not necessary, and the practice should be phased out.

    We also need to speed up the rate at which we develop new antibiotics. However, antibiotic development has actually slowed due to many scientific, regulatory, and economic obstacles.

    In short, we urgently need policy action and we need science. But in the face of this problem, the US is cutting its scientific research budget.

    On May 21, the House Appropriations Committee approved… the 12 appropriations bills in FY 2014… [For] the NIH, the committee provides $121.8 billion for FY 2014. This represents an 18.6 percent cut below the FY2013 post-sequestration level… for NIH in FY2014.

    Capture6
    The CDC is being cut by similar amounts.

    These cuts are a result of the sequester. Sequestration cuts discretionary federal spending across the board, without regard to the relative priority of different types of spending. Worse, as John McDonough points out, the cuts do not stop in FY2014:

    Unless repealed or replaced, sequestration requires $109 billion annually in new federal cuts each year through fiscal year 2021. An important difference in 2014 and beyond is that Congressional appropriators may distribute reductions as they choose, provided that Congress agrees on a budget plan. Without such an agreement, cuts will be across the board, as they have been in FY2013.

    I don’t know how to express my feelings about this matter without risk of melodrama, but these cuts are insane. We are slowing down science when we need to speed it up. The sequester will become an issue again this winter, when we face another budget and debt limit crisis. The US must find a way to return to a rational budgeting process that prioritizes our health and wellbeing.

    @Bill_Gardner

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    • I’ve read that the resistance tends to come at a fitness cost for the bacteria in question, so that when the selection pressure for resistance weakens, they quickly get outbred by vulnerable strains. So if we could just tighten down the use of antibiotics, we might be able to seriously cut back on the emergence of resistant strains.

      • Brett,
        I’m sure that’s the right policy and I hope it would have the results you anticipate. Unfortunately, I don’t get the sense that we are making strong progress on better antibiotic managment.

      • I think that most antibiotic resistance comes from low dose chronic feeding of antibiotics to farm animals. If we could stop this use (against powerful farm interests), we would go a long way towards decreasing antibiotic resistance.
        Of course, we still need new antibiotics.

    • Good piece but your ellipsis is potentially misleading (about absolute numbers not relative cuts). The $121.8 billion in House appropriation for 2014 is not for NIH but all scientific programs combined. If cuts are spread out evenly, it would translate into 18.6% cut from an NIH budget of roughly 31 billion or over $5 billion. In reality, other programs like NSF and CDC have been hurt much more than NIH by sequester cuts.

      • David Atkins: I am not convinced that moving cuts from the NIH to the CDC helps the argument any as the CDC does some really good work on infectious diseases.

      • David,
        I think you may be right; will check. If so, the overall point stands, but the 18.6% may exaggerate the severity of the cuts to NIH proper.

    • Bill,

      Thanks for talking about this issue – it really is underappreciated as a 21st century brewing crisis. However, I disagree that the way to solve this crisis is to invent more new antibiotics. I say this for a few reasons:

      1) Discovering new antibiotics was super easy when there were 0 antibiotics. As the decades have passed, we have discovered less and less new antibiotics. I don’t think this is just a regulatory issue – instead we are running out of ways to attack bacteria. Think of it like a logarithmic curve where the further you go on the X-axis (time) the harder it is to increase Y (amount of Abx)
      2) Many of the older antibiotics are superior because they have either less side effects, or we are aware of all the side effects. A lot of the highly engineered newer antibiotics like linezolid or or the carbapenems carry significant risks. We should strive to have to use the weakest antibiotics possible
      3) The primary problem is antibiotic resistance spreading. It is spreading for many reasons, but the most important are: A) Globalization spreading new bugs B) Proper antibiotic use creating selective pressure C) Improper antibiotic use leading to overuse in animals, people with viruses, or those who don’t need ABx.

      If we’re trying to run against the red-queen, we better have a fighting chance. In a world of 10 billion people crossing borders with unregulated antibiotic overuse we will not outcompete the trillions (quadrillions?) of bacteria we encounter. The rates of mutation will simply overwhelm our scientific capabilities to create new drugs at some point.

      Once you accept this conclusion (which I will admit, is a prima facie argument), the approach to fixing it comes into focus.

      I think the only real solutions will come down to:
      1) Reducing the spread of infection. The more sterile we make our hospitals, the more we keep sick kids out of school, the better hand hygeine we all have bacteria will spread less. This will limit the amount of mutations and plasmid transfers of antibiotic resistance. Also, if you can shorten the length of infections you are less likely to transmit bacteria and allow for mutation. Considering that many of the scariest bacteria started in hospitals, we can implement better procedures at hospitals/clinics to keep this from happening. Similarly, if a patient comes in with a super-resistant bug – PUT THEM IN ISOLATION. Places like Hong Kong that deal with scary pandemics frequently know how to do these things. We will have to learn.
      2) Not giving ABx out without a definite clinical diagnosis and reason. ABx are over the counter in India. Many ABx are simply offered prophylactically. Some ABx are given to patients who likely have viruses and aren’t at risk of serious progression of their illness.
      3) Strictly limiting the use of newer/better antibiotics to treatment failure. The new carbapenems should be avoided unless there truly is no other option. If we have the attitude “well the drug pipeline will make us new drugs eventually” we may over use newer antibiotics, spurring resistance that could be avoided. The way to think about this is, antibiotic efficacy is a public good that must be protected for future generations. It is not endless, and every time we use an antibiotic we are dwindling our reserves.
      4) Rotation of antibiotics. As Brett mentioned, antibiotic resistance carries fitness costs to the bacteria themselves. So in the absence of an antibiotic being used, selective pressure will lead to bacteria becoming less and less antibiotic resistant. Once the rate of resistance to an antibiotic becomes so high as to make it inefficient, we should stop making that antibiotic, full stop. Stop using it for a year, two years, five years. However long it takes for the community of bacteria to slowly evolve back to that antibiotic working. Then we can start using it again. If we have 250 antibiotics available, you could have 20 or so that aren’t produced at any one time, leaving you 230 other options.
      5) Ending ABx use in factory farming. It’s the most wasteful, counter-productive drag on a public good that I can conceive of. It’s already outlawed for certain ABx and in certain countries (like Denmark).

      Producing new antibiotics is #6 on my list, because until we do the other 5, it won’t even matter.

      The difference between my view and yours is I don’t think we need any research to do #5. #3 is largely an issue of will and systems-planning. #1 will require behavioral research, but not basic science research. #4, #2 and #6 will need quite a bit of research. So I agree we shouldn’t cut funding – but just increasing funding is grossly inadequate.

      • Will,
        I support all six of your recommendations; that is, better use of antibiotics + increased efforts to develop new ones. I don’t have any confidence in my ability to rank them, so I think that we should pursue all of them.

        I also agree that just increasing funding is not an adequate solution. I’d like to see a lot of changes at the NIH. That’s a whole other post.

    • Being a geek, I track technology a lot. I rememer a couple years ago reading about a device that uses plsma to disinfect. The theory being that the ionizing plamsa breaks down particles at the molecular level, with the side effect being anything organic is essentially disintegrated, instantly killed. The idea being to create a prototype unit as say (for ex) a floor cleaneing device that you push over the floor, and presto the floor is 100% germ free.

      Have you heard of this or any advances in that regard? It was touted as a possible solution to the resistant bacteria issue.

    • I live in Kansas. Our politicians and much of the public have decreed that evolution doesn’t happen. So, we don’t have bacteria that evolve. Problem solved!

    • I wonder if uncertainty that surrounds the entire medical sector might play a part in the reduction of research in this area.

      Suppose a company found a drug that could treat all the resistant bugs. That would be wonderful, but we would want to restrain its use to protect it from overuse and thus loss of its efficacy? That makes good sense and I am sure if we took a national vote on what to do the public would vote to preserve its value and restrict its use. That seems to make sense.

      The pharmaceutical company putting in a billion dollars to get the drug to market will start questioning how it will get its profit back. After all at any time a competitor might come up with an alternative. Thus the company will want to get its investment back right away along with a good profit. They deserve a big profit for figuring out how to create this new antibiotic that can save many lives.

      Thus the pharmaceutical company places a high cost on the drug’s sale. The public understandably will demonstrate some sort of outrage saying how can you charge so much when a human life is at risk and needs the drug. The typical arguments will fly and the arguments on all sides will have merit. In the meantime the investors that stood to lose a lot of money will want their principle and profits as soon as possible.

      But, we don’t have that miracle drug just yet and perhaps today the investors are thinking about the future and what happens should they invest and produce that miracle drug. No one wants their picture and their lavish home shown on the news saying the greedy person wants this poor mother of four to die rather than to give her the drug for free.

      These investors love to invest and they look for the best investment that doesn’t cause them grief, so perhaps they think it better for themselves to skip investing in the miracle drug and invest in a new type of i phone where no one will complain about the price and the investors will be hailed as heroes.