Bacterial resistance to chronic antibiotics, and why it’s a problem

Unlike climate change, where there’s a large contingent of denialists who spread doubt about the scientific evidence, no one denies that antibiotic resistance is a problem. There is controversy, however, on the question of just how much the widespread use of antibiotics contributes to the problem.

The mechanism is not in dispute: If you expose bacteria to antibiotics, they will mutate to become resistant. But “overuse” of antibiotics is not the only thing that creates antibiotic resistance. Is there irrefutable scientific evidence that the overuse of antibiotics in raising livestock, for example, is harmful to human health? It’s not easy to prove direct cause and effect. If you feed a pig a steady diet of antibiotics, can you irrefutably prove that this results in the illness or death of someone who later eats that pig?

Follow the money

The speed with which we address the increasingly urgent problem of antibiotic resistance will depend on financial interests, not just scientific evidence or common sense. Just as with climate change, we can follow the money to identify the opponents. Who has a financial interest in convincing the public — and in turn politicians — that the overuse of antibiotics is not a problem?

It’s not the medical profession, which understands that overprescribing antibiotics contributes to the increase in antibiotic resistant bacteria. The financial interests of doctors are a little complex here. Unfortunately, because the public is not well educated about the subject, doctors find they need to satisfy the demands of their patients by offering prescriptions. Otherwise patients would simply take their business elsewhere. It takes time for doctors to educate their patients, and today’s doctors are very short of time. This is not sufficient grounds, however, to say that doctors have a financial incentive to overprescribe. Although doctors practicing today have no personal memory of the pre-antibiotic era, they are certainly among the first to appreciate that practicing medicine would become a nightmare without antibiotics.

Pharmaceutical companies aren’t really the problem either, since they’re not interested in selling or developing antibiotics. These drugs are not sufficiently profitable. This is a problem in itself, since the world desperately needs new antibiotics. Although drug companies might like to see more antibiotics prescribed and sold, this is such a small part of their overall business that there’s little motivation for them to question the dangers of overuse.

Where we can expect pushback is from the agricultural industry. This is a battle that’s just beginning to heat up. Katie Couric did a story on the CBS Evening News in February that got some attention: “Animal Antibiotic Overuse Hurting Humans?

Well, maybe it’s a problem, but maybe it’s not

Publications that serve the livestock community – the beef, chicken, and hog industry – have been following the issue closely. It was interesting to see what a balanced approach Voice of America took on the issue.

Over-use in animal husbandry is not the only source of antibiotic resistance. Health experts point to doctors over-prescribing antibiotics, and patients misusing them, as another part of the problem.

And the growth-promoter ban [a Danish ban on drugs used as growth promoters] does not appear to have made much difference in the overall rates of resistant infections in people, says Rich Carnevale with the U.S. industry-sponsored Animal Health Institute. He says Denmark may have over-reacted.

He says, “They saw resistance. They said, ‘Well, it could be due to use of drugs in animals. And certainly some of that resistance was. But the real question is, was it harming humans? And to this day, they have not been able to really conclude that it’s actually harming humans.”

This is where opposition to attempts to reduce the use of antibiotics reminds me of those who oppose climate change legislation.

The controversy about the overuse of antibiotics in raising livestock is background for an interesting scientific study that took place in the Galapagos. It looked at the spread of antibiotic resistant strains of bacteria among animals that were totally removed from antibiotics.

Would antibiotic resistance become widespread in the absence of antibiotics?

The immediate motivation for the research was two contradictory studies. In a wooded area of northwest England, researchers had found that wildlife developed antibiotic resistance even though they had not been exposed to antibiotics. This would argue against the idea that antibiotic use in animals should be restricted, since it suggests that antibiotic resistance would develop anyway.

Another study, however, found that wildlife in a remote area of Finland had an almost complete absence of antibiotic resistance. This would argue that resistance could be reduced by restricting antibiotics.

So which was it? How could you design an experiment that controlled possibly confounding factors, such as climate, animal interaction, and human interference?

Coprophagial iguanas

The researchers chose to study a species of iguanas (Conolophus pallidus) on an isolated island (Santa Fe) in the Galapagos . Unlike the English countryside, the island was uninhabited by humans, though tourists made daytime excursions to a restricted area. It offered an example of what life was like in a pre-antibiotic era. This tropical island, which was near the equator, was also unlike the remote area of Finland, where winters were long and cold, the population density of animals was low, and there was limited interaction among animal species.

The island was ideal for the spread of bacteria: It was warm, humid, with constant periods of daylight and high animal density. Plus, juvenile iguanas acquired their intestinal microorganisms through coprophagy (eating feces). This results in bacteria spreading readily throughout the community of iguanas.

This was the perfect setting to test the following: If there are no antibiotics present, and an antibiotic resistant strain of bacteria is present, will it spread throughout the community?

When there’s no chronic antibiotic exposure, resistance doesn’t spread

The researchers discovered that no, it would not spread. A small minority of animals did have bacteria that exhibited resistance – probably acquired from a visiting tourist — but the rest of the community was uncontaminated with these resistant bacteria.

Here’s the conclusion of the study. Let me restate the first sentence in non-academese: Will an antibiotic resistant strain of bacteria spread readily throughout a community if there are no antibiotics present? If so, then this was the ideal situation to observe that happening.

[B]acteria colonizing the gut can easily spread within the reptile community and, if an introduced resistant strain should not need the presence of antibiotics to become widespread, in Santa Fe it would find the optimal conditions for this to occur. In this scenario, the detection of two E. coli isolates with acquired resistance traits of likely human origin as non-dominant microbiota in a small minority of animals, reveals that even highly isolated ecosystems are susceptible to contamination by multiresistant strains. However, in the absence of a chronic antibiotic exposure sustaining resistance, these strains failed to disseminate despite the fact that environmental conditions and animal habits were highly favourable to inter-individual spread, and that contamination from humans to wildlife could recurrently occur at that site. … [L]imited human-driven contamination, in the absence of a chronic antibiotic exposure, is not sufficient for the diffusion of acquired antibiotic resistance in wildlife.

This is not a definitive answer to the question of whether antibiotic use should be reduced or banned in raising livestock. But it certainly does suggest that when antibiotics are not present, antibiotic resistant bacteria do not thrive and spread.

Jan Henderson is a historian of medicine who blogs at The Health Culture.

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  • HJ

    “Unfortunately, because the public is not well educated about the subject, doctors find they need to satisfy the demands of their patients by offering prescriptions. Otherwise patients would simply take their business elsewhere.”

    Do doctor’s really prescribe antibiotics to people to retain them as patients? Perhaps that is why doctors are frustrated with their patients’ demands.

    • zzz05

      On a related note, the frequency of antibiotic prescription for kids with otitis varies widely, in little localized clusters where the local standard of care could be anything from “give them all antibiotics just in case” to “don’t give any of them antibiotics, they’ll all get better just the same”. Needless to say, they can’t all be correct.

  • http://www.TheHealthCulture.com Jan Henderson

    “Do doctors really prescribe antibiotics to people to retain them as patients?”

    Good question. There is anecdotal evidence, like this comment on the website of a hospital in New Jersey (http://tinyurl.com/2bz6rll):

    “When I was completing my fellowship in infectious disease, I worked evenings at an urgent care center. Some of the patients had true emergencies, but many of them had colds. Once, I was called on the carpet for not prescribing antibiotics to patients who had viral infections. I was told by another doctor, ‘People are coming to you and expecting treatment. They’ll stop coming if they don’t feel they are receiving care.’”

    In an emergency room setting, there may be concern that a parent will not return for follow-up if a sick child’s condition worsens. If this is a doctor’s only opportunity to provide treatment, and there’s a chance the problem is viral, the doctor has to make a difficult call. (http://www.slate.com/id/2191908/)

    There are undoubtedly many factors that influence the decision to prescribe antibiotics. A recent article in Family Practice described a study of primary care physicians. They were interviewed in focus groups about their behavior when prescribing antibiotics (http://tinyurl.com/2g92sb6).

    “Important factors identified for antibiotic prescriptions by doctors were diagnostic uncertainty, perceived demand and expectation from the patients, practice sustainability and financial considerations, influence from medical representatives and inadequate knowledge. For public sector doctors, besides the above, overstocked and near-expiry drugs and lack of time were the factors that promoted antibiotic overuse. Doctors also identified certain patient behaviour characteristics and laxity in regulation for prescribing and dispensing of antibiotics as aggravating the problem of antibiotic misuse.”

    Although both public and private sector doctors participated in the study, it took place in Dehli, India, where the reimbursement system may provide different motivations than in the US. Also, the study was limited to 36 doctors.

    One interesting study on a related issue looked at why patients believe antibiotics cure colds (http://tinyurl.com/ybzdqeo). 716 patients were divided into three groups: one group was prescribed antibiotics, another was told to watch and wait, and the third group was given a delayed prescription. Each group recovered at the same rate, but patients given antibiotics were much more likely (87% vs. 55%) to believe antibiotics were effective. A year later, patients prescribed antibiotics were 33% more likely to see their physician for a sore throat.

    The evidence-based medicine journal Bandolier turned this finding into a projection (http://tinyurl.com/2vv756o).

    “If a GP prescribed antibiotics to 100 fewer patients with throat infection in a year, 33 fewer would believe antibiotics were effective, 25 fewer would intend to consult with the problem in the future and 10 fewer would come back within the next year.”

    Thanks for the question. I find this subject interesting and important. Guess I should write this up as a post.

  • William Nuesslein

    If there were no antibiotics to select for antibiotic resistance, then antibiotic resistance would be unexpected. Isn’t that an essential tenet of evolution?

    • http://www.TheHealthCulture.com Jan Henderson

      That’s an excellent point, and the Galapagos study – for the time being at least – seems to establish precisely that. The distinction that creates confusion here is between the bacteria themselves and animals that carry bacteria in their intestinal tract (detected in their feces).

      If you expose a population of bacteria to antibiotics, selective pressure favors the survival of those bacteria that are resistant. The question here was: If antibiotic resistant bacteria are present in an environment, will those bacteria spread throughout the animal population in that environment.

      The two studies – the one in England and the one in Finland – seemed to give contradictory results. In the English study, there were no antibiotics present, but the animals had antibiotic resistant bacteria in their systems.

      In the Finnish study, there were no antibiotics present, and the animals did not have antibiotic resistant bacteria in their systems. The problem with the Finnish study, however, was that the animals didn’t interact with each other, their territories were distinct, it was very cold, and there was little sunlight. One of those factors could have had an impact on what was observed.

      The idea of the Galapagos study was to control for as many of those variables as possible.

    • zzz05

      Yeah. At a very minimum, the cost to the bacteria of carrying around the extra DNA that accounts for the resistance would eventually cause it to get diluted out in the population if it isn’t selected for. And in addition, resistant bacteria that lose those DNA would similarly have an “economic” advantage over those which still had to carry it around. (Transmissible antibiotic resistance genes tend to be prepackaged in plasmids or otherwise modular little chunks of DNA, which ensures that they are transmitted together) More true in organisms like bacteria where there seems to be pressure to keep DNA size to a minimum, than in higher organisms which seem to carry around all sorts of “junk DNA”.

      • http://www.TheHealthCulture.com Jan Henderson

        Very interesting. I wonder if you think the recent excitement in the press over NDM-1, which focuses on a gene carried on a plasmid, is overblown. The story started with an article in The Lancet, but the press profits from scaring the public, so it can be hard to get an objective opinion.

  • zzz05

    The amount of antibiotics used in agriculture is both large, and unknown. No records are required, so none are kept. However, analysis of gross pharmaceutical sales records generates estimates like 40% of all antibiotic use in USA, by the AMA, or more than 70%, by the Union of Concerned Scientists. Again, although no records are kept, it is estimated that about 80% of this is routinely administered in sub-therapeutic levels in the feed and water of livestock, rather than as a cure for a specific animal or animals with a specific disease. This would be a pretty good technique if you were actually trying to create a wide spectrum of antibiotic-resistant bacteria. Needless to say, the industries involved estimate both the amounts involved and the risk as being much lower.

    It’s somewhat reminiscent of the recent revisionist history regarding environmentalism in general and Rachel Carson in particular as “being worse mass-murderers than Hitler” because “banning DDT led to the preventable deaths of millions from malaria”. In fact, DDT is only banned internationally for agricultural use, with no restrictions on use for prevention of disease; and, in fact, the similarly vast oversuage on crops like cotton engendered DDT resistance in the mosquitos in the regions where it was used, making it useless to fight insect disease vectors to this day. And in fact, as noted many times in the literature, ending this agricultural overuse allowed the chemical to retain whatever usefulness it still possesses in some countries, so that it is beyond doubt that the agricultural ban actually saved lives.

    It’s definitely true; history repeats itself.

    • http://www.TheHealthCulture.com Jan Henderson

      I’ve seen those estimates and like your comment “This would be a pretty good technique if you were actually trying to create a wide spectrum of antibiotic-resistant bacteria.”

      I wasn’t familiar with the Rachel Carson revisionism. Thanks for that. There seem to be quite a few issues these days where it’s very difficult to act in our best interest. We’re up against powerful financial interests, including those that encourage the public to be suspicious of or even antagonistic to science.

  • William Nuesslein

    The DDT is more nuanced than indicated by zzz05′s comment In that indoor spaying in Africa was resisted although it was effective. NGO dogooders insisted on a much more expensive and less effective use of bed nets. Further, there has been a resurgence of bed bugs in the New York City area. DDT is perfect for this problem but can not be used.

    I will never forget when my first father-in-law told me how wonderful DDT was for the relief from bed-bugs.

    • http://www.TheHealthCulture.com Jan Henderson

      Bed bugs — interesting topic. I see the EPA held a National Bed Bug Summit in 2009, in response to the resurgence of this insect. The resurgence is attributed not only to new pest-control methods, but increasing pesticide resistance. Also, there are three geographic epicenters, all at poultry farms.

      Bed bugs don’t seem to spread disease, although it’s estimated they can be a host to as many as 41 known pathogens. I wonder why that is?