Maryn McKenna

Journalist and Author

"Pig MRSA": New human infections in France

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It’s one of the touchiest topics under the broad category of antibiotic resistance: Whether the drug-resistant organisms that emerge on farms as a result of antibiotic use stay on farms, or pose a risk to humans who have no connection to agriculture.

That drug resistance emerges under any selective pressure is basic biology: Resistance is an inevitable process. That they emerge on farms when antibiotics are used broadly — that is, in growth-promoting or prophylactic ways, not to treat disease in individual animals — really isn’t in dispute any more. It’s now a question of economics and politics, not science. (See this bibliography, stretching back to 1969; and the news I broke yesterday of FDA’s estimate of US farms using almost 29 million pounds of antibiotics last year.)

So the argument over farm antibiotic use now tends to focus on whether the resistant organisms that emerge on farms are only an issue within a farm’s confines, or rather pose a broader human health threat — and that’s where the continuing story of the “third epidemic” of MRSA becomes so important. Recapping, this is a strain known as MRSA ST398 that emerged in pigs and passed to pig farmers in the Netherlands in 2004, subsequently spread across the European Union, and crossed to Canada and then to the United States. (Key posts on ST398: here, here, here and this archive at my old site. Yes, it will be moved soon, promise.)

Most of the identifications of MRSA ST398 in humans, including those first identifications above, were colonizations, the term for symptomless carriage of staph in the nostrils and on the skin; in other words, it wasn’t making people sick. News of actual illnesses has been rare — especially illnesses among people who have no contact with farming, such as the post-surgical infections found in Canada earlier this year.

But they’re getting a little less rare, as demonstrated by a letter just posted ahead-of-print to the journal Clinical Infectious Diseases. It recounts the finding, via annual surveys of bloodstream infections, of four cases of ST398 in four different hospitals in France. One may have been due to animal exposure. Three were hospital-acquired.

Examination of patient histories revealed exposure to animals in 1 case, a fatal idiopathic community-acquired bloodstream infection in an 84-year-old man who lived on a farm at which 1 pig was being raised. The remaining cases were hospital-acquired and included 1 case of catheter-associated infection observed in a 58-year-old man with advanced multiple myeloma, 1 case following elective digestive tract surgery in a 69-year-old woman, and 1 case following cardiac surgery in a 68-year-old man.

There’s an especially interesting thing about these cases. In Europe and the US, ST398 has particular characteristics: It is resistant to tetracycline (the drug most commonly given to pigs) and does not manufacture the toxin Panton-Valentine leukocidin or PVL, which is suspected to be a cause of community-strain MRSA’s uncommon virulence. (See this story, from the book SUPERBUG, of how PVL-positive pneumonia almost killed a toddler.) The strain in the French cases, though, does manufacture PVL, and shares some virulence characteristics with the dominant community strain, USA300. It is less like the European strain of livestock-associated MRSA and more like a livestock-associated strain that appears to be emerging in China, ST9 (more on that here).

The argument against the significance of these cases is likely to be that they are, again, just one data-point, and may be just rare and random. That is worth considering. But it is also worth considering that they continue to be found.

And, also, that the community epidemic of MRSA was first flagged in a discovery of 25 cases in children in Chicago back in 1998, a finding that was also dismissed at the time as rare and random — and that grew into an epidemic of millions of cases a year.

(H/t to constant reader Pat Gardiner for flagging this paper for me.)

Cite: van der Mee-Marquet N et al. Emergence of Unusual Bloodstream Infections Associated with Pig-Borne–Like Staphylococcus aureus ST398 in France. Clin Infect Dis. (2011) 52 (1): 152-153. doi: 10.1093/cid/ciq053

Image via Flickr user johnmuk under CC

News break: FDA estimates US livestock get 29 million pounds of antibiotics per year

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This afternoon, the Food and Drug Administration posted without fanfare a report that many people have been waiting a long time for: Its first-ever estimate of the amount of antibiotics sold for use in food animals in the United States.

And the number is: almost 29 million pounds in 2009.

That’s a lot.

Is it more or less than was expected? It’s almost impossible to say. Estimates of the amount of antibiotics given to food animals in the United States are ferociously contested and plagued by squishy definitions and category creep. In 2000, the Animal Health Institute, which represents veterinary drug manufacturers, put total use at 17.8 million pounds. In 2001, the Union of Concerned Scientists, which campaigns (among other issues) to dial back use of agricultural antibiotics, estimated that 24.6 million pounds per year are used only for “non-therapeutic purposes” — that is, to make animals grow to market weight faster and to prevent them catching diseases in the close quarters of confinement agriculture.

The reason why antibiotic use on farms is a concern, of course, is because such use stimulates the emergence of drug-resistant organisms that move off the farm in animals, in groundwater, in dust, on the wind and in the systems and on the clothes of those who work there, and makes new resistance factors available to be swapped among bacteria. (For much more about that, see these three posts and this long archive at my former blog.)

The FDA’s estimate comes as the agency has been moving to curb agricultural antibiotic use after years of non-action. Today’s report, which is very short — basically a table and a bunch of footnotes — is the direct result of a 2008 amendment to the Animal Drug User Fee Act of 2003, which required manufacturers to report yearly on sales of agricultural antimicrobials. (Here’s an FDA Q&A on the report background.)

More important, though, today’s report dovetails with the FDA’s new effort to curb antibiotic use in agriculture, which Commissioner Dr. Margaret Hamburg said in October would involve “very serious scrutiny.” (Video here.) The main instrument of that effort is a “draft guidance” that the FDA opened for public comment over the summer, “The Judicious Use of Medically Important Antimicrobial Drugs in Food-Producing Animals” (pdf here). The point of that guidance is to ask agriculture to voluntarily withdraw from use the ag drugs that are functionally identical to drugs that are important in human medicine — because if bacteria become resistant to those drugs when they are used in animals, that newly derived resistance will also affect humans, making common diseases difficult or impossible to treat.

In addition to the volume figure, the real value of today’s brief report may be simply to make clear just what antibiotics are used in agriculture. Take a look at the report table at right, which lists the animal drugs used by amount sold within drug classes. (Note that the amounts are given in kilograms.) It lists:

Aminoglycosides: Human versions include streptomycin and amikacin.

Cephalosporins:  Human versions include Keflex and Rocephin.

Lincosamides: Human versions include clindamycin.

Macrolides: Human versions include erythromycin.

Sulfas: Human versions include half of the very common drug combos Bactrim and Septra.

Penicillins and tetracyclines: Yup, just what they sound like.

“NIR”: That’s FDA shorthand for “not independently reported” because they have few manufacturers or make up a small portion of the market. Among them are fluoroquinolones. Human versions: Cipro and Levaquin.

There’s much more to be said about the issue of antibiotic use in agriculture, especially because the lone piece of legislation addressing it, the Preservation of Antibiotics for Medical Treatment Act, is currently in lame-duck limbo. This report is an important piece of data for the ongoing debate.

Update: I asked some experts in the field to comment on the release of this data. Dr. David Wallinga, director of the Food and Health program at the Institute for Agriculture and Trade Policy in Minneapolis (also William T. Grant Foundation Distinguished Fellow in Food Systems and Public Health at the University of Minnesota School of Public Health) replied:

Clearly, antibiotic use in animal agriculture is huge, and as the FDA and CDC and WHO all agree, much of it is unnecessary. Data collection is important. But, because resistant bugs quickly adapt, we can’t afford to wait for data to take action to reduce antibiotic use wherever possible. That includes routine uses of antibiotics for cattle developing liver abscesses because they’re force-fed grain rather than grass, as well as antibiotics used to make animals get fatter faster.

Update 2: A day after the release of this report, Rep. Louise Slaughter (D-NY), author of PAMTA and a public-health microbiologist, commented on the data — and also said she’ll be reintroducing the legislation again in the next Congress in January.

This report illustrates the overuse of antibiotics in food animal production and makes a strong case for some common-sense limits on antibiotic use. We are putting millions of pounds of antibiotics into the food supply unnecessarily every year. This cannot continue and it’s my hope that these new data from the FDA will encourage even more members of Congress to join me next year when I reintroduce this legislation.  Moreover, the FDA must move fast to issue strong regulations on antibiotic usage in agriculture.

Update 3: Tom Philpott, senior food and agriculture writer at Grist — and a farmer, so he knows the territory — covered the FDA report and this post in a very kind and typically forthright post of his own.

Update 4: Helena Botttemiller, ace food-policy reporter for Food Safety News, covers this as well, noting how little mainstream media interest there has been. Any opinions why?

Cite: 2009 Summary Report on Antimicrobials Sold or Distributed for Use in Food-Producing Animals, FDA, Dec. 9, 2010

Image via Flickr user net_efekt under CC

Triclosan, allergies and the "hygiene hypothesis"

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When I talk to people about drug-resistant organisms and how to protect yourself against them, hand-washing and hand hygiene — for individuals and especially for health-care workers — are at the top of my list. Inevitably, I’ll get asked next about hand sanitizers, the alcohol-based gels that now are just about everywhere: outside hospital rooms, in public bathrooms, near elevators in public buildings, and in cute little bottles in bins next to the cash register in almost any drug store.

Hand sanitizer is a good thing: If it’s used properly, it kills reliably. (Except for Clostridium difficile; you need proper hand-washing to keep that down, because alcohol can’t penetrate the hard wall of the spore that the bacterium forms.) That observation usually moves the conversation pretty quickly to the more-is-better impulse that seems so central to American culture. If it’s protective to use regular hand sanitizer, surely highly antibacterial, super-duper-extra-protective, Kills Everything Smaller Than Your Head ™ sanitizer would be better?

The answer to that, counter-intuitively, is no. When it comes to the rise of resistant organisms, topical-antiseptic hand sanitizers seem likely to be part of the problem. And very new research published over the Thanksgiving holiday suggests that they may be problematic in more dimensions than we know.

The chemicals that antibacterial products use for bacterial killing work on organisms in a manner similar to antibiotics’ effect, though they are less potent — and just as organisms have evolved resistance to antibiotic compounds, they have begun to develop resistance to antibacterial compounds too. Which would be a risk worth taking if the compounds provided necessary protection; but studies show that in regular household use, regular soap provides the same amount of protection against disease organisms that antibacterial soaps do. [Read more…]

ResistanceMap and Get Smart About Antibiotics Week

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Among the many skills admired by journalists (always finding the free food; never going out of the office; yes, those are said in jest), skidding in just under deadline may be the most valued. I am making a flourish of that skill here, sliding in a mention of an important observance this week just as the week ends.

(Sorry. There was a lot of news this week.)

So: In case you hadn’t yet noticed, this is (was) Get Smart About Antibiotics Week, 2010.

The Get Smart week is co-sponsored by the CDC and the FDA, and its goal is to alert people to the continuing overuse of antibiotics in human medicine. (A separate but just as important issue as overuse of antibiotics on the farm, which I’ve talked about a number of times here.)

If you’re concerned about this — and who shouldn’t be — the CDC’s sites have a plethora of information about this crucial issue. There are briefings, posters, brochures, radio and TV PSAs, a blog by federal researchers and others and — possibly the most directly useful to parents in the whole campaign — a form letter that doctors can download and fill out to give to working parents, explaining why a child with a sniffle or a sore ear can be admitted to daycare without an antibiotic prescription. [Read more…]

NDM-1, the supergene: Further (community?) spread

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Yesterday and today are early-publication days for the December issue of Emerging Infectious Diseases, the free peer-reviewed journal published by the Centers for Disease Control and Prevention. (Are you reading it? Why not? Your tax dollars pay for it. Go, now.) Among many interesting stories — more on those in later posts — there are two important, complex and saddening papers updating the relentless spread of the “Indian supergene,” New Delhi metallo-beta-lactamase or NDM-1.

(Pause for commentary: I hope we’ve put to rest by now the canard that naming this gene after New Delhi indicates some secret agenda to inflict stigma on the subcontinent’s burgeoning medical-tourism industry. It is a long-standing convention that the acquired metallo-beta-lactamases are named for their point of origin: Holland, Singapore, Germany, et al. You don’t see Vienna complaining, do you? ‘Nuf said.)

A brief recap, for those who spent August focused on something more interesting that bacterial resistance: NDM-1 is a gene that produces an enzyme that confers resistance on gram-negative bacteria to almost all the drugs used to treat them. The American Type Culture Collection, which sells isolates for research, recently published the table of resistance results, and it’s phenomenal: All Rs, all the way down. It was first identified in 2008 in a native of India, resident in Sweden, who had been hospitalized while on a visit back home; then found in the UK in 2009; and then found in the US in June this year. It renders bacteria that are common causes of hospital-acquired infections — Klebsiella, Acinetobacter, E. coli — resistant to all but one or two drugs. It’s extremely bad news. (My NDM-1 posts are here.)

It’s been clear since 2009 that NDM-1 is spreading around the world with great speed. The newest papers in EID confirm that and fill in the details — and wow, some of them are so sad.

[Read more…]

Another new bad resistance factor. (Bonus: Another city stigmatized!)

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The subcontinent can cease fretting over the naming of that new bacterial resistance factor NDM, for New Delhi. There’s a newer resistance factor in town, and this one stigmatizes… Italy.

Welcome, Verona integron-encoded metallo-beta-lactamase, or VIM.

To be precise, VIM isn’t new — its very first identification was at the Verona University Hospital in 1999 — but it has just been found in the United States for the first time. The CDC said Wednesday evening that it has identified VIM in an American woman who took a Mediterranean cruise this summer, got diarrhea, was hospitalized (twice) in Greece, developed sepsis and C. diff, and eventually was transferred home and hospitalized here for a further 26 days. In the US, she was found to be infected with Klebsiella pneumoniae, a gram-negative bacterium that’s a common cause of serious-hospital acquired infections — urinary tract infections, abdominal infections and pneumonias. This strain, though, was resistant to all the drugs usually used to treat Klebsiella. (The woman did recover.)

To anyone who followed the NDM-1 news a few weeks ago, this should sound familiar. (If you didn’t, here’s my archive. No, go ahead; we’ll wait.) A resident of one country is unexpectedly hospitalized in another. That second country happens to have high rates of a novel, serious resistance factor — in Greece, 50 percent of Klebsiella isolates in ICUs are multi-drug resistant — that clusters in the organisms most likely to cause hospital infections. The person picks up a resistant infection without knowing it, travels home, and transports the novel resistance factor into his or her home country.

And because the gene that directs production of the problematic enzyme resides on a mobile genetic element — meaning it can move easily from one bacterium or species to another — the public health authorities in the unlucky person’s home country begin a very nervous waiting game.

That’s what happened with the identification of NDM-1, which was first noted in a man of South Asian origin, living in Sweden, who was unexpectedly hospitalized in India in 2007 and then hospitalized again in Sweden in 2008. (NDM was found in the US in June.) Like NDM, VIM has spread across the world; within a few years of its original identification it was in France, Spain and Taiwan. Nor are those two enzymes the only bad actors — they’re merely the most recent and notable in successive waves of multi-drug resistance in gram-negative organisms that are washing across the world. (Almost all of them, by the way, are named for their points of origin. GIM, Germany. SPM, Sao Paolo. DIM, Dutch. And so on.)

And those waves (to torture my metaphor until it whimpers) are really just the most visible points of an ocean of gram-negative resistance that has flooded the globe, and certainly the US. And, just to slosh home the point: These resistance mechanisms knock out the drugs of last resort for gram-negatives, the carbepenems, and there are no new drugs to replace them. The drug-development pipeline for gram-positives such as MRSA has a few drops still rolling down it; the pipeline for gram-negatives, as the Infectious Diseases Society of America has documented in several reports, has just about dripped dry.

The CDC on Thursday warned labs and hospitals to start taking action, in ways that will at least require additional staff time and attention, and probably will cost extra money too :

Cases of (carbepenem-resistant Enterobacteriaceae) are a significant, emerging public health problem regardless of the mechanism of carbapenem resistance, and procedures to rapidly recognize and report CRE cases to infection prevention personnel should be in place in all acute and long-term–care facilities. Facilities that have not identified cases of CRE should undertake periodic laboratory reviews to identify cases. Patients with CRE should be managed using contact precautions, and patients exposed to CRE patients (e.g., roommates) should be screened.

The problem with writing about increases in antimicrobial resistance is that, sooner or later, you inevitably end up sounding like Chicken Little. (Or Cassandra. I’m not sure which is worse. Chicken Little is probably cuter.) Every one of these sounds like the worst possible news. Problem is, every one of them is… until the next one comes along.

Image of Klebsiella pneumoniae courtesy of the Public Health Image Library, CDC.

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.

Pan-resistant?? The rise of Acinetobacter

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A set of papers published this month in two journals provide an unsettling glimpse into the rocketing incidence and complex epidemiology of one really scary pathogen, Acinetobacter baumanii.

In the all-star annals of resistant bugs, A. baumanii is an underappreciated player. If people — other than, you know, disease geeks — recognize it, that is because it’s become known in the past few years for its propensity to attack wounded veterans shipped to military hospitals from Iraq and Afghanistan, earning it the nickname “Iraqibacter.” (Important note: Steve Silberman of Wired magazine took an early look at this phenomenon in 2007, in a great story that analyzed the epidemiology of Iraqibacter to show that military infection control, not the environment of Iraq, was to blame for the bug’s rapid emergence.) A. baumanii is a nasty bug, causing not just wound infections but pneumonia, urinary tract infections, meningitis and bacteremia. Even more nasty, it collects resistance factors like baseball cards, and is commonly resistant to at least 4 antibiotic classes. The most resistant strains are susceptible only to the so-toxic-we-put-it-back-on-the-shelf-decades-ago antibiotic colistin.

This is a particular concern because A. baumanii is a Gram-negative bacterium — and while the drug-development pipeline for Gram-positives such as MRSA has slowed practically to a trickle, the one for Gram-negatives has dripped itself dry. As the Infectious Diseases Society of America and Jerome Groopman of the New Yorker highlighted back in 2008, drugs for Gram-negatives are barely on the agenda for the few companies still conducting antibiotic development.

So, the first piece of bad news. In Infection Control and Hospital Epidemiology (ICHE), a team from Brooke Army Medical Center in San Antonio take a look at their incidence of resistant Ab and find it exploding. Between 2001 and 2008, the percentage of A. baumanii isolates that were resistant to at least 3 classes of drugs went from 4% to 55%; of all the isolates, 17% (127) were resistant to at least 4 drug classes, and one was resistant to, well, everything.

How does A. baumanii spread so fast? A second paper in ICHE suggests a reason: The bug seems to do a better job than other resistant pathogens of contaminating the gear and hands of health care workers. A study done at University of Maryland found that when health care workers took care of A. baumanii patients, they ended up with contaminated gowns and gloves 39% of the time, and with contaminated hands (after glove removal) 4.5% of the time. Those are higher rates than for MRSA (18.5% of encounters) or VRE (8.5%).

A review article in Clinical Infectious Diseases reminds us why we should care about this: It examines the drugs to which some strains of A. baumanii are still susceptible, and finds all of them significantly toxic to different organs (kidneys, liver, pancreas, red blood cells, ) at the doses necessary to wipe out the bug.

Which is all troubling by itself. But a paper and editorial also appearing in Clinical Infectious Diseases make the case for A. baumanii as a bigger threat than has been understood. The bug’s recent epidemiology has shown a distinct split, between the highly resistant forms affecting veterans, most of them being treated in the military evacuation chain, and less-resistant forms affecting civilians in hospitals (including in the Brooks data in the paper above). The severe wounds, aggressive treatment and rapid multiple transfers of personnel in the military system inadvertently created an environment that not only put A. baumanii under great selective pressure, but also spread it with startling efficiency.

The paper, reporting data from 4 community hospitals near Detroit, shows that the civilian medical system — that would be the one that most of us live in — has duplicated that churning as well. Between 2003 and 2008, all A. baumanii in their network increased 25%. A. baumanii resistant to the first 2 front-line drugs went from 2% to 33% of isolates. And “pan-resistant” A. baumanii — resistant to all 8 drugs available for it, an essentially untreatable strain — went from nonexistent to 14% of all the isolates that network found.

The effect on the patients was dramatic, of course: The more resistant their strains were, the more likely they were to never go home from the hospital, but (if they did not die there) to be discharged instead to a nursing home, long-term acute care facility, or hospice. But the larger point is that they carried that multiply-resistant strain with them, distributing it throughout the region: Patients came to those 4 hospitals, carrying A. baumanii, from 17 different nursing homes; from the 4 hospitals, carrying A. baumanii, they were transferred out to 28 different nursing homes.

This is a smart analysis, and devastating in its implications. American hospitals do a debatable job right now of handling infection control — but overwhelmingly, they are handling infection control as individual institutions, not as competitors in a local market, and certainly not as members of a geographic region. Yet this data demonstrates clearly that cooperation between hospitals and other healthcare institutions — most of which don’t have hospitals’ infection-control budgets or personnel — is going to be essential if we want to put the brakes on Acinetobacter before it soars in the civilian medical system in the same way it did in the military one.

News break: Developing-world drug resistance

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This is an addition for archival purposes of a post that originally appeared at Scienceblogs.

The Center for Global Development, a DC think-tank, is releasing what looks like a thoughtful report aimed at refocusing policy debates over drug resistance toward the epidemic’s global impact, with particular attention to the the developing world.

From the report’s preface:

Problems with drug resistance have moved from the patient’s bedside to threaten global public health. Drug resistance has dramatically increased the costs of fighting tuberculosis (TB) and malaria, has slowed gains against childhood dysentery and pneumonia, and threatens to undermine the push to treat people living with HIV/AIDS effectively. Global health funders and development agencies have cause to worry about whether their investments in access to drugs, and global health programming more broadly, are being undone by the relentless advance of drug resistance.

It calls out a sustained lack of leadership:

Past efforts to energize global action to more comprehensively address drug resistance have been sidetracked by poor timing or over-stretched budgets… In an unfortunate coincidence of timing, a WHO Strategy on Antimicrobial Resistance was launched on September 11, 2001. As a result, the action plan prepared for the Strategy did not get carried out, and over time the interest in cross-cutting drug resistance at WHO withered, even while disease-specific attention grew. For many years, the U.S. Government provided support for research, technical support, surveillance, and policy development on drug resistance in developing countries through an annual budget appropriation to the U.S. Agency for International Development (USAID). That support has become narrowed to programming in only a few areas.

It recommends 4 specific steps:

  1. Improve surveillance by collecting and sharing resistance information across networks of laboratories
  2. Secure the drug supply chain to ensure quality products and practices
  3. Strengthen national drug regulatory authorities in developing countries
  4. Catalyze research and innovation to speed the development of resistance-fighting technologies

A policy brief is here and the full report is here.

News break: House hearing on antibiotic pipeline

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The Subcommittee on Health of the Energy and Commerce Committee of the House of Representatives has announced a hearing for Wednesday: “Promoting the Development of Antibiotics and Ensuring Judicious Use in Humans.”

The witness line-up is:

  • Janet Woodcock, M.D., Director, Center for Drug Evaluation and Research, Food and Drug Administration
  • Robin Robinson, Ph.D., Director, Biomedical Advanced Research and Development Authority, Department of Health and Human Services
  • Brad Spellberg, M.D., F.I.D.S.A., Associate Professor of Medicine, David Geffen School of Medicine at UCLA and Member, Infectious Diseases Society of America Antimicrobial Availability Task Force
  • Sandra Fryhofer, M.D., Council on Science and Public Health, American Medical Association
  • John S. Bradley, M.D., American Academy of Pediatrics, Chief, Division of Infectious Diseases, Department of Pediatrics, University of California, San Diego, School of Medicine, Clinical Director, Division of Infectious Diseases, Rady Children’s Hospital
  • Barry Eisenstein, M.D., F.A.C.P., F.I.D.S.A., Senior Vice President, Scientific Affairs, Cubist Pharmaceuticals
  • Jeffrey Levi, Ph.D., Executive Director, Trust for America’s Health

This is the second hearing the Health Subcommittee has had this spring, apparently at the prompting of the chairman of Energy and Commerce, Rep. Henry Waxman, who made the opening statement at the first such hearing in April:

We need to debate the health care bill and review its implementation. But we ought to be able to chew gum and walk at the same time. Because it is not going to make much difference if you have health insurance or not if you are going to die from something that could have been prevented from an antibiotic. And we are seeing more and more antibiotic resistance. (Transcript)

Reading between the lines, I’m going to guess this hearing will lean heavily on the IDSA’s campaign to improve market conditions for pharma companies in order to revive antibiotic development (an issue I discussed recently at the old Superbug — we’re working on getting the archives moved over).

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?)

[Read more…]

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.

Get Smart About Antibiotics Week, Oct. 5-11 (now!)

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Every year, the CDC sponsors a week-long observance called Get Smart About Antibiotics Week, intended to bring attention to this issue of antibiotic misuse that all of us here are so concerned about, and to link the efforts of federal and state agencies, nonprofit groups, and anyone else with an interest.

Today marks the start of the 2009 week, and of course it comes as a crucial time: With the H1N1 flu pandemic causing so many people to seek care for upper respiratory illnesses, the possibility of antibiotics being misprescribed for a viral illness is greater than usual.

The homepage for the CDC campaign is here. There is an abundant list of materials, images, campaign strategies and suggestions for framing the conversation, along with graphics (I’ve lifted the one at left from a poster aimed at parents of young children), PSA sound files, and cute little web widgets such as the image at right above (sorry for the poor layout skills, it’s a busy morning).

Since this comes from the CDC and is therefore taxpayer-funded, all of it is open-access. So go, already.

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.