Maryn McKenna

Journalist and Author

Antibiotic resistance: Scandinavia gets it

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Odd but interesting fact: Scandinavia takes antibiotic resistance incredibly seriously. Denmark has one of the most thorough programs for preventing antibiotic misuse in agriculture; Norway has very tough regulations regarding antibiotic stewardship in hospitals (as captured in this AP story last year). Sweden has pressed the issue as well; drug resistance was a major issue for the Swedish Presidency of the European Union in the last half of 2009 and led to a major conference there on creating incentives to bring antibiotic manufacturers back into the market.

The presidency has since been relinquished to more southern countries (Spain in the first half of this year and now Belgium) but the Swedish focus on resistance persists, pushed along by the nonprofit organization ReAct, based at Uppsala University. Earlier this week, ReAct hosted a three-day international conference on antibiotic resistance in Uppsala. They haven’t posted the full conference report yet, but they have come out with a closing press release, which says some interesting things (emphases mine):

At a historic three day conference at Uppsala University, Sweden, 190 delegates representing 45 countries and many leading stake holders – civil society, academia, industry, governments, authorities, supranational organizations – agreed on Wednesday to turn a new page and move towards concerted action on antibiotic resistance…
The new signals from the Uppsala meeting include:
– A shared conviction that antibiotic resistance is a universal problem. Like global warming, it requires joint action, not least by governmental alliances.
– A clear signal from the pharmaceutical industry that return of investment on research and development of new antibiotics and diagnostic tools will have to be de-linked from market sales in order to boost necessary innovation while yet limiting the use of antibiotics. This requires a new business model where private and public sectors cooperate.
– A strong recommendation to all stakeholders to speed up the efforts to limit unnecessary use of antibiotics, while at the same time making the medicines affordable and accessible in developing countries.
– A commitment to improve the monitoring of antibiotic resistance across the world, through shared data and increased efforts. A global network of surveillance will require common methods, and is crucial for both prudent use and needs driven development of new agents.

The release also mentions some promising events coming next year:

– A final report from TATFAR, The Transatlantic Task Force on Antibiotic Resistance.
– A policy meeting on antibiotic resistance in Delhi, India.
– A WHO Action Plan on Antibiotic Resistance.
– A number of regional initiatives, including in Southeast Asia, Africa and The Middle East.

(Hmm. Surely it is time for me to go back to India…)

People who’ve worked in this field for a long time will know, of course, that up-front commitments are easy to make; it’s downstream action, carried out over the long term, that makes a difference. But this looks like a promising start: Even just stimulating international recognition of the program is an encouraging beginning.

Until the final conference report is posted, you can see video of the opening and final sessions here.

Antibiotics and farming — how superbugs happen

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Constant readers: There’s an important new paper that’s been out for a week that I haven’t gotten to you. I apologize; it’s been busy. (Let’s not even talk about the important paper that’s been out for two weeks. Maybe over the weekend…)

We’ve talked for ages now about the potential dangers of unrestricted antibiotic use in agriculture, and how it’s analogous to the inappropriate antibiotic use that human health authorities disapprove of in humans. The main culprits, in farming, are subtherapeutic dosing, also known as growth promotion — that’s giving routine smaller-than-treatment doses to animals to increase their weight — and prophylactic dosing, which is giving a treatment dose to an entire herd or flock either routinely, if there is thought to be a disease threat, or when there is known to be disease in some members of the herd/flock. In either case, animals are getting antibiotics when they do not need them — when they are not sick. And just as in humans who take antibiotics when they are not sick, or take too-low doses when they are sick (such as not finishing a prescription), these practices in animals encourage the development of resistant bacteria.

(Necessary comment here: No one, to my knowledge, objects to giving the appropriate doses of antibiotics to animals that are sick. Why would you?)

The interesting research question is how, exactly, resistance develops. (My real scientist readers may want to take a break, or cut me a break, for the next few sentences. Please.) The classical assumption has been that, through a variety of stimuli and the random copying errors of reproduction, bacteria are constantly acquiring small mutations. Some of those may give the bugs an advantage when they are exposed to a drug, some slight difference that allows the bacteria to disarm or turn aside that drug’s particular method of assault — so that the weak die, the strong survive, and the strong then reproduce more abundantly into that extra living space freed up by the death of the weak. The survivors and their descendants retain that mutation, because it gave them an advantage against the drug. And because bacteria can share resistance factors not only vertically mother-to-daughter, but horizontally in the same generation, once the resistance has emerged, it is likely to spread.

But no matter how quickly it spreads, that process I’ve just described involves acquiring resistance to just one drug or drug family at a time. Provocative new research from Boston University’s medical school and deoartment of biomedical engineering now suggests, though, that multi-drug resistance can be acquired in one pass, through a different mutational process triggered by sublethal doses of antibiotics — the same sort of doses that are given to animals on farms.

In earlier work, the authors found that antibiotics attack bacteria not only in the ways they are designed to (the beta-lactams such as methicillin, for instance, interfere with staph’s ability to make new cell walls as the bug reproduces, causing the daughter cells to burst and die), but also in an unexpected way. They stimulate the production of free radicals, oxygen molecules with an extra electron, that bind to and damage the bacteria’s DNA.

That research used lethal doses of antibiotics, and ascertained that the free-radical production killed the bacteria. In the new research, the team uses sublethal doses, and here’s what they find: The same free-radical production doesn’t kill the bacteria, but it acts as a dramatic stimulus to mutation, triggering production of a wide variety of mutations — what the researchers, in a press release, called “a zoo of mutants.” The plentiful, scattershot mutations included ones that created resistance to a number of different drugs — in some cases, even though no mutation was present that created resistance to the drug being administered.

You can easily see how this is applicable to factory farming: The sublethal dosing applied experimentally is analogous to the subtherapeutic dosing used in agriculture. Is it applicable to MRSA? Yes, absolutely. The two organisms the researchers used to test their hypothesis were S. aureus and E. coli.

making the implication clear, senior author James J. Collins said on the paper’s release:

“These findings drive home the need for tighter regulations on the use of antibiotics, especially in agriculture; for doctors to be more disciplined in their prescription of antibiotics; and for patients to be more disciplined in following their prescriptions.”

The cite is: Kohanski MA, DePristo MA and Collins, JJ. Sublethal Antibiotic Treatment Leads to Multidrug Resistance via Radical-Induced Mutagenesis. Molecular Cell, Volume 37, Issue 3, 311-320, 12 February 2010.

UPDATE: There’s a great discussion of the paper at the blog Mental Indigestion.

Postscript: I suppose I’ve been working too long without a break, because while I was reading about this process of creating multiple resistance factors at once, what I heard in my head was Mickey Mouse chirping: “Seven at one blow!”

Another resistant bug rising: Acinetobacter

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From the excellent and forward-thinking research team at Extending the Cure comes a dismaying report: over 7 years, a more than 3-fold increase in resistance in the Gram-negative bacterium Acinetobacter baumanii to its drug of last resort, imipenem.

Because MRSA is a Gram-positive, we don’t talk much here about the Gram-negatives — the two categories of bacteria have different cell-wall structures and thus are treated using different categories of drugs. (That structural difference causes them to react in different ways to a stain invented by a scientist named Gram in the 19th century.) But the resistance situation with Gram-negatives is at least as dire as with MRSA, possible more so, because there are fewer new drugs for Gram-negatives in the pharmacology pipeline (as discussed in a New Yorker article by Dr. Jerome Groopman last year.)

And Acinetobacter is one nasty bug, as science journalist Steve Silberman ably documented in Wired in 2007 when he traced the spread of the organism through the military medical-evacuation chain from Iraq, demonstrating that the vast increase in resistant Acinetobacter among US forces was due to our own poor infection control.

The Extending the Cure paper (which will be published in February in Infection Control and Hospital Epidemiology) puts hard numbers to the Acinetobacter problem. Drawing on data from the private Surveillance Network, which gathers real-time electronic results from 300 US hospitals, they find:

  • full resistance to imipenem rose from 4.5% of isolates in 1999 to 18.2% in 2006 — a 300% increase
  • intermediate resistance rose from 1.3% of isolates to 9.4 — a 623% increase
  • susceptible isolates declined from 94.1% to 72.4% — a 23% decrease.

The authors write:
Our results demonstrate substantial national and regional increases in carbapenem resistance among clinical isolates of Acinetobacter species over the period 1999–2006. Increasing carbapenem resistance among Acinetobacter species is particularly troubling, because it is very often associated with multidrug resistance and because it is occurring in the context of increases in the incidence of Acinetobacter infection.

There’s a further point to be made that is not explicit in the paper that I can see (though it is often made by Extending the Cure researchers). Acinetobacter needs attention, just as MRSA does — but if we focus just on the individual organisms, we are not going far enough. Antibiotic resistance is a system problem: It is an issue of infection control, of drug development, of agricultural organization, of federal priorities. It needs sustained attention and comprehensive, thoughtful, wide-ranging response. Now would not be too soon.

Guest Q&A: Dr. Brad Spellberg and RISING PLAGUE

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I’m thrilled today to present another guest blogger: Dr. Brad Spellberg, associate professor of medicine at the David Geffen School of Medicine at UCLA and author of the new book Rising Plague: The Global Threat from Deadly Bacteria and Our Dwindling Arsenal to Fight Them (Prometheus Books). This new book is important reading for anyone concerned, as all of us are here, about the narrowing pipeline for new antibiotics against MRSA and other resistant pathogens. That pipeline problem is something Dr. Spellberg knows well: He is not only a practicing infectious-disease physician, but also a member of the Antimicrobial Availability Task Force of the Infectious Diseases Society of America, the specialty society that produced the “Bad Bugs” reports that I’ve posted on before.

Below, Dr. Spellberg thoughtfully answers some questions about the difficulties of treating resistant infections and of developing drugs to control them.

From your point of view as a practicing ID physician, why is it so difficult to prevent resistant infections?

It’s difficult to prevent all infections period. Not more difficult to prevent infections caused by resistant organisms than any other organisms. However, also difficult to prevent the spread of resistance among bacteria that are causing infections.

So, why is it difficult? People have this crazy belief that hospital acquired infections are the result of sloppy medicine. Not so. They are the result of very sick people with tremendously sophisticated levels of intensive medical care being delivered in a concentrated environment (i.e., a hospital). Crowd a bunch of sick people together with plastic catheters, mechanical ventilators, and nasty bacteria, and such infections are inevitable. What we are learning is that we have to go above and beyond normal to stop these infections from happening. Research is needed on how best to do this. It’s not as simple as people think.

You can’t stop the spread of the resistance itself. It is inevitable.

You say in Rising Plague that physician misuse and overuse of antibiotics is not the cause of antibiotic resistance. What do you consider the primary driver?

This is by far the biggest misperception among the public. Let’s start from first principles. Who invented antibiotics? Who invented antibiotic resistance? When were both invented?

Humans did NOT invent antibiotics. Bacteria did…about 2 billion years ago. And they invented antibiotic resistance at the same time. So, bacteria have been creating and defeating antibiotics for 20 million times longer than humans have even known that antibiotics exist (about 78 years, as the original sulfa compound was developed in late 1931 by Gerhard Domagk). Over the past 2 billion years, bacteria warring among themselves have learned to target virtually every targetable biochemical pathway with antibiotics, and have learned to create defense mechanisms to defeat virtually all such antibiotics. They are already resistant to drugs we haven’t even developed yet. It is bacteria that cause antibiotic resistance, not humans.

What humans do, is we apply natural selection when we use antibiotics. We kill off susceptible bacteria, leaving behind already resistant bacteria to replicate and spread their resistance genes.

This may seem like a subtle distinction: We don’t create antibiotic resistance, we just increase its rate of spread. But, from the perspective of effective response planning, this is a critical distinction. If inappropriate antibiotic use caused antibiotic resistance, all we would have to do to defeat resistance is never prescribe drugs inappropriately. Unfortunately, that won’t work. All antibiotic prescription, even appropriate antibiotic prescription, increases selective pressure, which increases the rate of spread of resistance.

Eliminating inappropriate antibiotic use, and always using antibiotics appropriately is indeed critical, because it will slow the spread of resistance, buying us time to develop new antibiotics. But if 100% of our efforts are focused on antibiotic conservation, all we will achieve is a slowing of the inevitable exhaustion of the antibiotic resource. What is needed is to marry antibiotic conservation with antibiotic restoration. That is, we need new drugs to be developed. Just conserving what we have is not enough.

Why are “antibiotic stewardship” policies not a sufficient remedy for controlling resistance?

See above. Stewardship leads to conservation. That is half the battle, but by itself it will only lead to a slowing of the inevitable exhaustion of the resource.

Furthermore, the initial calls for stewardship were made by people like Max Finland in the late 1940s and early 1950s. This is not a new call. It’s more than a half century old. It just doesn’t work very well. An analogy is the temptation to say that we don’t need condoms to stop the spread of STDs, we just need abstinence. It is true that abstinence will stop the spread of STDs. But, an abstinence-only policy just doesn’t work. You’ve got to have the condoms too. Well, stewardship, by itself, just hasn’t worked after more than 60 years of calls for it. It is too hard to change behavior, and the pressures on physicians not to be wrong about their patients’ illnesses is too great.

What do you consider the chief impediments to developing newer/better antibiotics?

The two major impediments are: 1) economic, and 2) regulatory.

The primary economic impediment is that antibiotics have a lower rate of return on investment than other classes of drugs. You make a lot more money back on your R&D investment if the drug is taken every day for the rest of the patient’s life (e.g. cholesterol, hypertension, dementia, arthritis) than if it is taken for 7 days and then the patient stops because he/she is cured.

The regulatory problem is a startling degree of confusion at the FDA regarding what types of clinical trials should be conducted ot lead to approval of new antibiotics. There has been a total rethinking of antibiotic clinical trials at the FDA over the past 5 years. Right now, companies don’t know what trials they are supposed to do to get drugs done, and increasingly the standards are calling for infeasible study designs that simply can’t be conducted. This revisionist thinking is being driven by statisticians who know nothing about clinical medicine or patient care. They are asking for things to be done that can’t be done to human beings. The balance of clinical and statistical concerns is totally out of whack, and must be restored if this problem is to be solved.

What types of policies are needed to kick-start development of new antibiotics?

Simple. Solutions follow the problems above.

For the economic problem, we need Congress to pass legislation that creates special economic incentives for companies to re-enter the antibiotic R&D market. The return on investment calculation must be changed. Antibiotics are a unique, critical public health need. Congress should recognize this. Examples of programs that would work include increase in funding to scientists (e.g. via NIH) who study bacterial resistance and antibiotic development. Increased small business grants to help translate basic science discoveries to lead compound antibiotics. Tax credits, guaranteed markets, patent extensions, and prizes to serve as pull strategies to help companies improve the return on investment for antibiotics.

For the regulatory problem, Congress needs to stop hammering the FDA into a state of paralysis, where fear permeates every decision to approve a drug. We should be encouraging a balance between statistical concerns and clinical concerns, and we need to restore a sense that the agency is regulating drugs used by physicians for patients, and that trials showing those drugs are safe and effective must be feasible to conduct and relevant to how the drugs will be used in clinical medicine after they are approved.

Non-medical use of antibiotics: A whole new problem with ethanol

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Constant readers, we’ve talked frequently about the emerging recognition that the enormous use of antibiotics in agriculture is fueling the development of resistance, both directly in the case of specific organisms such as MRSA ST-398, and indirectly in that it pushes the evolution of resistance factors that bacteria then trade amongst themselves. (For a superb overview of the antibiotics/agriculture problem, see this article in the June issue of the Johns Hopkins (University) Magazine. Hopkins is the home of the Center for a Livable Future, which is doing excellent research on this issue.)

And we’ve also talked about the related issue of antibiotic residues elsewhere in the environment, in sewage and wastewater supplies.

But here’s a whole new peril: Antibiotic resistance generated by ethanol production, that vast corn-based industry that has been pitched as a homegrown biofuel alternative to foreign oil.

Food-policy blogger (and farmer and chef) Tom Philpott has been doggedly following this story for more than a year at Grist. And in a study published last month the Institute for Agriculture and Trade Policy brings some important numbers-based analysis. The gist of the problem is this:

  • Ethanol production uses yeast to convert corn starches into alcohol
  • Bacterial contamination, usually by lactobacilli, can hijack the process and covert the starches to unusable lactic acid instead
  • To prevent that from happening, ethanol producers dose their corn mash with antibiotics
  • Because contamination is frequent and persistent, producers use increasing amounts of antibiotics to overcome bacteria that have become resistant
  • After ethanol is extracted, the mash residue remains tainted with those resistant bacteria and with antibiotics — including penicillin, erythromycin and streptogramin (an analog of the human antibiotic Synercid)
  • The dried mash residue is sold to farmers as livestock feed, exposing livestock to resistant bacteria and dosing them with unsuspected additional antibiotics as well.

If there is any good news in this, it is that (according to the IATP), some of the faltering ethanol industry is aware of the problem and working on it, with about 45% of plants now working on non-antibiotic alternatives. The bad news is that 55% — more than 90 of the 170 ethanol facilities in the United States — are not.

Media round-up: recommending MRSA stories

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By chance — or is it because interest is really picking up? — a couple of worthwhile stories on MRSA have been published almost simultaneously:

  • For when the science gets wonky: Environmental Health Perspectives has an excellent lay-language explanation of how drug resistance emerges and spreads — with gorgeous graphics!
  • For when yet another drug doesn’t work: Scientific American covers development of new antibiotics, and even more important, development of new ways of creating antibiotics.
  • For yet more depressing news about MRSA in meat: Prevention adds to the discussion of MRSA in the food supply with a “special report” review. Constant readers who have been following along as we’ve drilled into this topic over the past two years won’t find a lot new, except for an intriguing account of an outbreak of MRSA in an Arkansas chicken plant (in which the bug went disappointingly untyped, so we don’t know whether it was a human strain or ST398). The story hits on issues we have talked about here: Surveillance for MRSA in animals is non-existent, practically speaking, and when the bug is found, investigation falls between human and animal health agencies. It’s a longer than usual story for Prevention, and should bring the knotty food-policy questions around MRSA in meat to a new audience.

Antibiotics in water supplies

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Via the journal Environmental Health Perspectives comes an important, comprehensive review article by scientists from Environment Canada and the Universite de Montreal on the presence of antibiotics in water supplies and waste water.

The news is not good. If you are concerned about the possibility that antibiotic residues in the environment create another setting in which resistance can develop, it is worth reading. It is long (10 pages in pdf) but has a comprehensive bibliography. Also, it’s open-access.

Where do these antibiotic residues come from? From us, in some cases: We urinate out up to 90% of some drugs, wash off topical formulations, flush old prescriptions down the toilet. Sometimes from industrial residues, or from leaky hospital sewage, or from sewage treatment plants, or — of course — from industrial-scale agriculture administration and run-off.

And where do they go? According to the paper, over more than 20 years of research, 126 different antibiotics and anti-infectives have been identified in processed waste water, natural surface water and groundwater, and drinking water supplies. Among them are all the antibiotics that we are concerned about here: the drugs that MRSA is already resistant to (beta-lactams, lincosamides, macrolides) and the drugs that still work, for community MRSA at least (sulfonamides, trimethoprim, tetracycline).

Moreover, the trend is expected to get worse, the authors warn: because of increased urbanization; because many urban areas are consciously setting water-saving policies, reducing the volume of wastewater and therefore increasing the concentration of drugs in the water that remains; and because, well, CAFOs aren’t exactly going away right now, are they? As they say:

…even if our results show that high concentrations … of anti-infectives in these waters are more the exception than the rule, the existence of a few locations where these concentrations can be reached are enough to contribute to the global spreading of anti-infective resistance. Given that large populations of bacteria are being exposed to a selective pressure, environmental waters and especially wastewaters become ideal settings for the assembly and exchange of mobile genetic agents encoding for resistance in bacteria. … Anti-infectives, the miracle drugs of the 20th century, have become environmental contaminants of emerging concern in the 21st.

The cite is: Segura PA et al. Review of the Occurrence of Anti-infectives in Contaminated Wastewaters and Natural and Drinking Waters. Environmental Health Perspectives, 117 (5) May 2009.

Farm animals and antibiotics – a new campaign

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I was gobsmacked to discover today, a few days late, that the Pew Campaign on Human Health and Industrial Farming (authors of the report discussed here) have launched a marvelously in-your-face series of ads in Washington DC, aimed at bringing the issue of antibiotic use in farm animals to people who might not think about it.

The ads have been placed in the Capitol South and Union Station Metro stops, which are the stops that bracket Capitol Hill, and in Metro cars on the red and blue/orange line trains, which are the main commuter trains down to the Hill. In other words, they’ve been made to be the morning reading of the people most engaged in the health reform debate right now — and if you think those folks are not thinking about healthcare spending and the growth of antibiotic resistance, well, umm, oh never mind.

The campaign says:

The American Medical Association, the American Academy of Pediatrics and other leading medical groups agree that the growth of bacterial infections resistant to antibiotic treatment is a looming public health challenge. The groups also agree the misuse of antibiotics on industrial animal farms plays a significant role in this crisis. While antibiotics are prescribed to people for short-term disease treatment, these same critically important drugs—like tetracycline, erythromycin and ciproflaxin—are fed in low doses to large herds or flocks daily, often for the lifespan of the animal. This creates ideal conditions for the breeding of new and dangerous antibiotic-resistant bacteria.

For statistics and arguments, along with more images — cows! chickens! pills! — go to the site of the commission’s campaign, Save Antibiotics.

How sewage plants birth resistant bacteria

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At the always-excellent public health blog Effect Measure, there’s a fascinating dissection of a new paper still in press at the journal Science of the Total Environment. The paper unpacks what happens to Acinetobacter in effluent as they move through sewage treatment. Answer: Many are eliminated, but the ones that survive become significantly more resistant.

I am deep in the final book chapter, so blogging will be light for a week. In the meantime, I recommend this paper and the accompanying post for explicating a little-explored aspect of antibiotic resistance in the environment (which we also talked about in this earlier post.)

The cite is: Zhang, Y. et al. Wastewater treatment contributes to selective increase of antibiotic resistance among Acinetobacter spp. Sci Tot Env doi:10.1016/j.scitotenv.2009.02.013.

Back soon.

Do not, do not, do NOT do this

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Hi from down the rabbit hole, readers (is there an echo?) — I am deep into a chapter and not surfacing much. Therefore, I’m once again behind in my reading, and so just stumbled across this from last week: a New York Times article called out by Liz Borkowski on the excellent public health blog Pump Handle.

The NYT story — which ran in the New York regional section and thus may not even have made it (on paper) out here to the Great Flyover — is primarily about young adults going naked on health insurance, what happens when that goes wrong, and how they practice a kind of do-it-yourself medicine to cope. But what made Liz’s hair stand on end (and mine, now that I’ve read it), is the way that the characters describe taking each other’s unused antibiotics:

Nicole Polec, a 28-year-old freelance photographer living in Williamsburg, Brooklyn, said she has attention deficit hyperactivity disorder and has a client who procures Ritalin on her behalf from a sympathetic doctor who has seen Ms. Polec’s diagnosis. Ms. Polec’s roommate, Fara D’Aguiar, 26, treated her last flu with castoff amoxicillin — “probably expired,” she said — given to her by a friend. (Byline: Cara Buckley)

You all got what was going on there, right? Flu — or even a cold — is a viral illness. Antibiotics don’t work against viruses. But antibiotics taken inappropriately do contribute to the evolution of drug-resistant bugs everywhere, and do make you more vulnerable to such bugs if they wipe out your own protective bacterial flora.

(NB: Let’s be clear, by criticizing this, I do not at all mean to be unsympathetic to the plight of the uninsured. My brother, a film composer, has been uninsured his entire career; as a freelancer, I have insurance only by the generosity of my in-all-ways-excellent spouse. And, just to editorialize, I consider it an international embarrassment that, what, one-sixth? of our population lacks the ability to pay for their health care. But there are things that are smart to do, in coping with the unworkability of the American health care system, and there are things that are not smart. Under-dosing and self-mis-dosing are, categorically, not smart.)

If you have time, please go read Liz’s analysis, it’s very good. If you don’t, please just listen to this take-away message: DON’T DO THIS. (Sorry to shout.)