Maryn McKenna

Journalist and Author

Antibiotics in chickens, and links to human infections

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From the January issue of Emerging Infectious Diseases, published by the CDC (and therefore free. Must I keep urging you to read it? Go, already), here’s a roundup of bad news about bad bugs.

In Canada, researchers from that country’s Public Health Agency have found a “strong correlation” between the use of ceftiofur, a third-generation cephalosporin, in chickens; the rates of a resistant strain of Salmonella in chickens; and the appearance of that same strain in humans. The strain is Salmonella enterica serovar Heidelberg, one of the most common salmonella strains in North America, and one which can be nasty: It may cause mild illness, but also causes septicemia and myocarditis and can kill. Quebec created an unplanned natural experiment: Hatcheries there were broadly using ceftiofur until 2004, backed off from its use in 2005 and 2006, and then began using it again in 2007 in response to a growing problem with a particular infection. When the drug was withdrawn, resistant infections in birds and humans plunged; when it was reintroduced, they rose again. (Look at the black and red lines in the graph above left.)

Meanwhile, broiler chickens in Iceland are passing fluoroquinolone-resistant E. coli to humans there. Researchers at the University of Iceland were puzzled by an earlier finding that bacteria resistant to fluoroquinolones (a family that includes the human drug Cipro) were increasing among chickens raised in Iceland, despite strict controls on antibiotic use in food animals and stringent disinfection in chicken batteries after cohorts of birds were sold for slaughter and removed. They have two findings: The source of the resistant bacteria in the birds appears to be feed contaminated with resistant E. coli; and resistant bacteria in Iceland residents are microbiologically indistinguishable from those in the birds. Because E. coli is a very diverse organism, the very close resemblance between the isolates from chickens and the isolates from humans pins chickens as the likely source.

And just to make clear we’re not blaming every microbiological evil on farming: Seagulls in Portugal have been found carrying multi-drug resistant E. coli in their feces. The public health concern here is obvious: Just think back to the last time you were at a beach, or anywhere else seagulls frequent, and envision a seagull perch — and the masses of seagull droppings streaking it. Now imagine those droppings transmitting antibiotic-resistant E. coli into the surrounding environment: the boardwalk, the beach, the towels… Additional problem: Seagulls are migratory birds, so the resistant bacteria easily cross borders and oceans.

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.

Antibiotics in animals – a warning from the poultry world

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Constant reader Pat Gardiner guided me to an enlightening post at the website of the agricultural magazine World Poultry that questions the routine use of antibiotics in food animals. It’s written by Wiebe van der Sluis, a Netherlands journalist from a farming background, founder of World Poultry and also the magazines Pig Progress and Poultry Processing.

The Netherlands, let’s recall, is the place where MRSA ST398 first emerged, and also the place where that livestock-MRSA strain has caused the most serious human cases and triggered the largest changes in hospital infection-control practices. In the Netherlands, swine farmers and veterinarians are considered serious infection risks because of their exposure to animals, and are pre-emptively isolated when they check into hospitals until they can be checked for MRSA colonization.

Van der Sluis takes seriously the tie between the use of antibiotics in animals and the emergence of MRSA:

Although most of the time MRSA is linked to pig production, it is also related to the veal and poultry industry. The industry, therefore, cannot shrug its shoulders and move on if nothing was wrong. In this case it would be wise to redefine the term prudent use of antibiotics. Time is up for those who use antibiotics to cover up bad management, poor housing conditions or insufficient health care. The standard rule should be: Do not use antibiotics unless there is a serious health issue and no other remedy applies. Veterinary practitioners, who usually authorise producers to use antibiotics, should also take responsibility and prevent unnecessary antibiotic use and the development of antibiotic resistance in animals and humans.

It’s unusual in the US context so hear someone so immersed in agriculture speak so candidly about antibiotic use. It’s refreshing.

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.

NEJM: Antibiotics for pneumonia in H1N1

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The New England Journal of Medicine has been running an open-access blog on H1N1 flu, and they’ve put up a post on when to give antibiotics to prevent secondary bacterial pneumonia, including MRSA pneumonia, in flu patients.

There’s a table of key clinical points to consider, and these important points are made:

For the child or adult admitted to a hospital intensive care unit in respiratory distress, we believe that empirical initial therapy with broad-spectrum antibiotics to include coverage for MRSA, as well as Streptococcus pneumoniae and other common respiratory pathogens, is appropriate.
For the previously healthy child or adult with influenza who requires admission to a community hospital and has features that suggest a secondary pneumonia (Table 1), we would recommend empirical treatment with a drug such as intravenous second- or third-generation cephalosporin, after an effort has been made to prove the association with influenza and to get adequate lower respiratory tract specimens for Gram’s stain and bacterial culture.
If the Gram’s stain suggests the presence of staphylococci or if there is a rapidly progressive or necrotizing pneumonia, an additional antimicrobial agent to cover MRSA is appropriate. …
We do not believe that initial coverage for MRSA is indicated in all patients who are thought to have secondary bacterial pneumonia.

So, to recap:

  • Development of apparent pneumonia in the presence of flu should be met with antibiotics that will treat drug-sensitive bacteria, along with a test to show which bacteria are causing the illness.
  • If staph is present (or the pneumonia appears very serious), then the antibiotics should be upped to one that can control MRSA.
  • But if the pneumonia is serious enough to send a patient straight to the ICU, then drugs that can quell MRSA should be started right away.

For anyone concerned about pneumonia in the aftermath of H1N1, this is worth bookmarking.

Wednesday a.m.: Congressional briefing on antibiotics in livestock – live-tweeted!

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Folks: On Wednesday 2 December, at 9:30 a.m. EST, Rep. Louise Slaughter (D-NY) will host a Congressional briefing about antibiotic use in food animals. As a reminder, Rep. Slaughter is an MPH and Congress’s only microbiologist, and the chief sponsor of PAMTA, the Preservation of Antibiotics for Medical Treatment Act that proposes restricting antibiotic use in animals to therapeutic uses under the guidance of a veterinarian and phases out “growth promotion” with sub-therapeutic doses, which consumes millions of pounds of antibiotics every year, many of them close analogs to human drugs.

Appearing at the briefing along with Rep. Slaughter are leaders of efforts that have produced an important string of reports on antibiotic overuse — the Pew Commission on Industrial Farm Animal Production and the Extending the Cure project of Resources for the Future:

  • Michael Blackwell, DVM, MPH–former Vice Chair, Pew Commission on Industrial Farm Animal Production; Assistant Surgeon General, USPHS (ret.); Former Dean, College of Veterinary Medicine, University of Tennessee, Knoxville, TN.
  • Robert Lawrence, MD–Director, The Johns Hopkins Center for a Livable Future, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.
  • Ramanan Laxminarayan, PhD, MPH–Senior Fellow, Center for Disease Dynamics, Economics, and Policy, Resources for the Future, Washington, DC
  • Robert Martin–Senior officer, Pew Environmental Group; former Executive Director, Pew Commission on Industrial Farm Animal Production, Washington, DC
  • Lance Price, PhD– Director, Center for Metagenomics and Human Health, Translational Genomics Research Institute, Flagstaff, AZ

Here’s a post explaining the importance of this issue from the blog of the Center for a Livable Future, a Johns Hopkins University research group that has produced some of the most mportant papers on leakage of antibiotic-resistant bacteria and antibiotic residues from CAFOs (“confined” or “concentrated” “animal-feeding operations” — very, very large-scale farms). And here’s some video on the issue from last summer from Lou Dobbs Tonight.

Because the event Wednesday is an informational briefing, not a hearing, I can’t find any link for a live webcast. (I’ll update if I find one.) But the hearing will be live-tweeted by the staff of the Center for a Livable Future (@LivableFuture) at the hashtag #CLF09. BLOGGERS: They will take tweeted questions toward the end of the hearing, ~10:45 a.m. — use the hashtag.

Antibiotics – the EU pipeline is empty too

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We’ve talked before about the shrinking number of drugs available to treat MRSA and about the challenges of getting new drugs to market. Well, it’s not just a problem in the United States.

A new report from the European Centre for Disease Prevention and Control (ECDC) and the European Medicines Agency (EMEA) — that’s the CDC and the FDA of the European Union — analyzes the bench-to-market “pipeline” of new drug development in the EU and finds… not good news. Out of 167 antibacterial agents that are somewhere in the pipeline of development, only 15 look likely to improve treatment of resistant organisms over drugs that already exist — and 10 of those 15 are in early-stage trials and will not come to market anytime soon.

That leaves 5 potential new drugs, for an epidemic of antibiotic resistance that, just in the EU, causes 25,000 deaths and $1.5 billion Euros ($2.27 billion) in extra healthcare spending each year.

(Within that epidemic of resistance, by the way, the single most common organism is MRSA.)

It’s worth understanding how the agencies conducted their analysis. When we look for new drugs to treat resistant organisms, we ideally need several things:

  • a formula or molecule that is new (and not just an improved version of an existing one, because if bacteria have developed resistance against the existing one, they have a head start in developing resistance against the new one)
  • a new mechanism or target on the bacterial cell, and not an improved version of an existing one (ditto)
  • evidence that it works in living organisms, and not just in lab dishes (in vivo, not just in vitro)
  • evidence that it can be given internally, not just topically (necessary for addressing the most serious infections)
  • and some indication that it is making its way through the regulatory approval process in time to achieve some practical good.

Here’s what the EU pipeline looks like:

  • 167 agents in process
  • 90 that have shown effectiveness in vivo
  • 66 that are new substances
  • 27 that have a new target or mechanism
  • 15 that can be administered systemically

If you’re wondering whether you should be depressed, the answer is Yes.

… it is unclear if any of these identified agents will ever reach the market, and if they do, they may be indicated for use in a very limited range of infections.

The agencies call for a concerted government effort to turn this around, and ask for quick action because it takes years to get drugs through the pipeline:

…a European and global strategy to address this serious problem is urgently needed, and measures that spur new antibacterial drug development need to be put in place.

This echoes a call that has already been made in this country by the Infectious Diseases Society of America, which has asked for changes in incentives to drug-makers, and has backed what’s known as the STAAR Act (STrategies to Address Antimicrobial Resistance). With this latest EU report — which comes on the heels of a US-ER agreement to work cooperatively on resistance — the IDSA is asking for an international commitment to bringing forth 10 new drugs in 10 years, what they are calling 10 x ’20.

Antibiotic misuse in animals – one example

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Via the Minneapolis Star Tribune and the excellent blog Fair Food Fight comes the story of two cows, from two Minnesota farms, that have been reprimanded by the US Food and Drug Administration for bringing cows to slaughter that turned out to have been massively overdosed with antibiotics.

From the Strib:

In a rare move, federal officials sent stern warning letters to two central Minnesota dairy farms, which were among only 30 farms nationwide reprimanded so far this year for violating the rules governing how animal drugs can be used.
J&L Dairy, in Clarissa, Minn., sent a dairy cow to slaughter in March, even though it was drugged with 129 times the amount of penicillin allowed under federal regulations.
Another farm, Evergreen Acres Dairy, LLC, in Paynesville, Minn., was warned by the FDA last month, after one of its cows was found to have more than four times the allowed amount for a certain type of antibiotic. Further inspection found that the farm had misused 10 other drugs. (Byline Lora Pabst)

From one of the FDA’s reprimand letters, to J&L Dairy of Clarissa, Minn.:

Our investigation … found that you hold animals under conditions that are so inadequate that medicated animals bearing potentially harmful drug residues are likely to enter the food supply. … Our investigation found that you routinely administered penicillin G procaine to dairy cows without following the daily dosage amount or dosage amount per injection site as stated in the approved labeling. Your extralabel use of penicillin G procaine was not under the supervision of a licensed veterinarian, in violation of 21 CFR 530.11 (a), and your extralabel use of penicillin G procaine resulted in illegal drug residue, in violation of 21 CFR 530.11(d).

From the other reprimand letter, to Evergreen Acres Dairy of Paynesville, Minn.:

Our investigation … found that you hold animals under conditions that are so inadequate that medicated animals bearing potentially harmful drug residues are likely to enter the food supply.
…The investigation … found that you adulterated the new animal drugs neomycin sulfate, sulfadimethoxine oral solution, oxytetracycline injection, oxytetracycline hydrochloride injection, ceftiofur hydrochloride, ceftiofur crystalline free acid, ceftiofur sodium, penicillin G procaine aqueous suspension, florfenicol, tetracycline hydrochloride soluble powder, and tylosin. Specifically, the investigation revealed that you did not use these drugs as directed by their approved labeling. Use of these drugs contrary to their approved labeling is an extralabel use.

There are some important points to make here.

As we’ve talked about before, many of the antibiotics used in food animals are effectively over-the-counter drugs; farmers can buy them in feed stores and administer them without a veterinarian’s supervision. (Putting an end to OTC animal antibiotics is the goal of Rep. Louise Slaughter’s legislation, the Preservation of Antibiotics for Medical Treatment Act (PAMTA), supported by the Obama Administration supports; post here.) Without such supervision, it is easier for a farmer to make a mistake in dosing, or to give the drugs too close to animal’s slaughter time, so that the drug’s don’t wash out of the animal’s system but remain in its meat after death.

A second important point is that we talk a lot here about the dangers of industrial-scale farming, in which antibiotics are given to animals that are not sick, either in small doses as growth promoters or in treatment-size doses to prevent illness spreading through a flock or herd. Antibiotic misuse has become linked in the public mind with the enormous animal-raising operations known as CAFOs. But both these reprimanded farms were family farms, not CAFOs. These reprimands underline that inappropriate antibiotic use is not a function of farm size — it’s a by-product of market pressure.

It's (European) Antibiotic Awareness Day

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UK and EU readers can hug themselves with self-congratulation this morning (OK, admittedly, for you it’s afternoon already): It’s Antibiotic Awareness Day across the European Union, featuring a slate of public-awareness activities, public-service announcements, educational efforts, and random appearances by the charming little hedgehog above (kicking antibiotics, don’t you see). It’s all meant to convince people that antibiotics are a precious resource and that misusing them encourages antibiotic resistance.

The campaign is organized by the European Centre for Disease Prevention and Control (the EU equivalent of the US CDC) and is being carried out by an enviably long list of national agencies within the EU. It’s accompanied by the publication in the journal Eurosurveillance of an article setting out the challenges of controlling antibiotic resistance across such diverse nationalities and geographies.

There are materials on the site that would be useful for anyone attempting to get the message of antibiotic stewardship across to physicians, family members or friends: There’s a fact sheet for the general public, one for physicians and other experts, and one that specifically addresses the temptation to take antibiotics in cases of H1N1 flu.

There’s also a short film explaining the genesis of Antibiotic Awareness Day and the basics of antibiotic resistance, and a marvelous set of pull-no-punches short video spots. This one — comparing antibiotics to a lightbulb slowly burning out — is my favorite.

Antibiotic-resistant infections: millions in cost to hospitals, families, all of us

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Folks, I mentioned that I’m way behind in working down a stack of great articles. Here’s a very good one that I missed when it came out two weeks ago and is well worth your time.

A team from John H. Stroger Hospital (the new location of the iconic Cook County Hospital, public hospital for downtown Chicago) and from the Alliance for the Prudent Use of Antibiotics at Tufts University (headed by Dr. Stuart Levy, dean of antibiotic resistance scholarship in the US) has analyzed the direct and distributed costs of resistant infections, and their results are stunning. They took a random sample of patients seen at the hospital, sorted out a subgroup that suffered from resistant infections, and computed the costs that those infections imposed: in medical costs, increased length of stay, and excess deaths. Those sort of calculations have been done before at other institutions (cf. for instance the excellent work of Susan Cosgrove of Johns Hopkins), but what makes this Chicago study striking is an additional layer of analysis that computes the “social cost” to the families of those infected.

In the study’s words:

In a sample of 1391 patients, 188 (13.5%) had [antibiotic-resistant infections]. The medical costs attributable to ARI ranged from $18,588 to $29,069 per patient in the sensitivity analysis. Excess duration of hospital stay was 6.4–12.7 days, and attributable mortality was 6.5%. The societal costs were $10.7–$15.0 million.

(Just to underline: These are almost certainly underestimates of the current problem and its current costs — because to get very solid data, the Stroger team went back in their database to patients who were treated in 2000. That’s before the emergence and dominance of CA-MRSA USA300 nationwide, and its subsequent movement into hospitals. Since 2000, the MRSA epidemic has gotten worse.)

An accompanying editorial takes the next step in logic, stressing that if we’re not going to work to reduce ARIs because it is good medicine to do so, we should do it because it is critically cost-saving:

…[T]he findings of Roberts et al [11] are significant, making a strong case for both the medical and financial benefits of reducing antimicrobial resistance. This is an important and timely question, considering the national focus on the prevention of health care–acquired infections, a significant proportion of which are caused by antimicrobial-resistant organisms, and the call for institutions to develop antimicrobial stewardship programs. These data should help inform decisions regarding the structure and implementation of health care initiatives designed to improve patient care while controlling unnecessary costs.

The cite for the study is: Rebecca R. Roberts, Bala Hota, Ibrar Ahmad et al. Hospital and Societal Costs of Antimicrobial‐Resistant Infections in a Chicago Teaching Hospital: Implications for Antibiotic Stewardship. Clinical Infectious Diseases 2009 49:8, 1175-1184.

New reports on animals, food, MRSA ST398

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Well, constant readers, didn’t expect to be gone *that* long. Many apologies. There was a good reason — actually, several: I attended a journalism meeting, and spoke at a second meeting. But most important, I received, marked up, and returned the galleys of SUPERBUG. Yes, it’s really starting to look like a book now. There will be things to share, soon.

Meanwhile, I’ll try to roll out some of the many, many pieces of news and research related to staph that have emerged in the past few weeks. Today: News on animals, and our old opponent, MRSA ST398.

First: A team from the Universidad de La Rioja reports in the Journal of Antimicrobial Chemistry the first finding of MRSA ST398 (“pig MRSA,” archive here) in food in Spain. They tested 318 raw meat and wild-game samples (chicken, pork, veal, lamb, turkey, rabbit, game bird, wild boar, deer, hare) and found ST398 and other MRSA strains in 5 of them, an incidence of 1.6%. The authors write: “Although MRSA prevalence in raw food is low, the risk of its transmission through the food chain cannot be disregarded.”

Importantly, one of the other strains found in the meat of these animals is an uncommon variant, ST125-t067, that has already been implicated in large numbers of hospital infections in Spainand is resistant to ciprofloxacin (Cipro), erythromycin and a third antibiotic, tobramycin, in addition to the usual suspects. The other non-ST398 strain is ST217, which is a variant of a long-known hospital strain, and is also resistant to Cipro, a very valuable drug for skin and soft-tissue infections. So it appears the contamination may cross both ways, from animals, and to animals as well.

No link, but the cite is: Lozano, Carmen, et al. Detection of methicillin-resistant Staphylococcus aureus ST398 n food samples of animal origin in Spain. Journal of Antimicrobial Chemistry. e-pub Oct. 21 2009 AOP doi:10.1093/jac/dkp378

Next: If the prevalence of ST398 is so low in food, why do we care? We care because of where those organisms go next — into hospitals, among other places. A Dutch/German team that includes the original identifier of ST398 in humans are reporting that they have found an association between the density of pig-farming in parts of Germany and the probability that patients admitted to hospitals will be carrying ST398 with them, creating a possible source for nosocomial infections. R. Kock and colleagues screened 1,600 pigs on 40 German farms, and also reviewed screening results for every MRSA-positive patient admitted to the University Hospital-Munster from 2005 through 2008. They found ST398 on 70% of the farms, and also found that ST398 represented 15% of the MRSA isolates at the hospital in 2005, rising to 22.4% in 2008. The key association: The patients carrying St398 were more likely to have contact with pigs in their daily lives, and also with cattle, than patients who had other forms of MRSA or no MRSA at all.

The cite for that paper: Kock, R. et al. Prevalence and molecular characteristics of methicillin-resistant Staphylococcus aureus (MRSA) among pigs on German farms and import of livestock-related MRSA into hospitals. European Journal of Clinical Microbiology and Infectious Diseases, e-pub Aug 25, 2009. DOI 10.1007/s10096-009-0795-4

And finally: How do you stop the evolution and spread of antibiotic-resistant organisms in livestock? One good way is to stop giving teh livestock antibiotics in the first place. In a column at the Huffington Post, Laura Rogers, project director of the Pew Campaign on Human Health and Industrial Farming, takes on the oft-repeated assertion that you can’t farm without them without risking the lives and market place of your livestock, and offers the example of Denmark, which did ban antibiotics in animals, and which has healthier, more profitable livestock as a result:

American agribusiness often has criticized Denmark’s 1998 ban on antibiotics, calling it an outright failure. But compelling new research presented by a Danish scientist earlier this year showed the opposite, revealing that antibiotic use on industrial farms has dropped by half while productivity has increased by 47 percent since 1992. Danish swine production has increased from 18.4 million in 1992 to 27.1 million in 2008. A decrease in antibiotic-resistant bacteria in food animals and meat has followed the reduced use of these vital drugs.

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.

A parent's plea and confusion

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I want to highlight a comment that was left on Labor Day by a woman named Valorie in Arkansas (thank you for reading, Valorie). She said:

I am just now learning about all of this and am very concerned about my 12 year old daughter. We were only 10 days into the school year, and she came down with the flu about a week ago. The rate at which it spread within her school as well as to me (her mother) and 2younger siblings was astonishing! We were all running high fevers within 24 hours of the onset of her first noticeable symptoms. Her junior high (which has approximately 500 students) had between 130 and 140 students absent last week due to flu like symptoms. However, the school is saying this is not H1N1 because it is too early in the season to be the actual flu. (This is absurd in my opinion.) Now, on our oldest daughter’s 5th day into the illness she has developed an MRSA infection from a small boil on her tummy. Within a day, it has swollen from a golf ball size to larger than a baseball in size. She now has 2 places of infection and is running a fever of about 101.7 on her 6th, almost 7th day of illness. Her doctor has placed her on a high powered antibiotic, but she is feeling so ill that I am scared to death for her, especially reading about the complications from having both the flu and MRSA. Do you think the oral antibiotics should take care of it, or do you think we need to have her admitted for IV antibiotics. I’ve just been surprised at how long this illness has lasted and how ill she still seems to be. No one seems to want to talk about the flu, much less any other possible complications in order to keep everyone else from panicking. I just want to get my daughter well and keep her safe. Any advice? Thanks so much for your time.

I wanted to highlight Valorie’s comment for a couple of reasons.

First, because it captures the way in which H1N1 has been ripping through schools in most places where school has returned to session. Schools in the Southeast tend to go back before the Northeast or the West; in Atlanta, where I used to live and where schools reopen long before Labor Day, H1N1 has gone through schools like a hot knife. Second, it shows how little the education about flu being pushed out by the CDC (and by others including my colleagues at CIDRAP) has penetrated: There has been H1N1 flu all over the place this summer, and it’s precisely because it is “too early in the season” that we know it is H1N1 and not the seasonal flu.

But what is most concerning and touching is Valorie’s confusion over which drugs her daughter should be taking, and whether her daughter’s physician is giving enough attention to her illness. Despite years of clinical experience, figuring out which drugs to give for MRSA is not easy. That’s first because many of them are old and now generic-only drugs for which clinical trials (in the context of this disease) were never done; and second because community MRSA’s resistance profile keeps changing as it picks up additional resistance factors.

The CDC dealt with this problem of what drugs to give in a meeting held in 2004 and a report issued in 2006. The report, going drug by drug, is here (caution, it’s 24 pages) and a flow chart summarizing the findings is here. Either is useful to have and to take to doctors if you feel uncomfortable about what is being prescribed or about a patient’s lack of progress.

Valorie, I hope your daughter does better. Keep us posted.

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.

New England Journal editorial: MRSA, H1N1 parallels

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There’s a very interesting piece in a recent New England Journal of Medicine (unfortunately, only the abstract is online) that draws parallels between MRSA and public expectations for pandemic flu. Written by Dr. Kent Sepkowitz, chief of infection control at Memorial Sloan-Kettering Cancer Center in New York and one of the authors of the “Medical Examiner” column at Slate, it’s an exploration of microbial sleight of hand: We were looking in one direction for a problem to develop, and — like Wile E. Coyote staring after the Road Runner but missing the Acme anvil — the problem came around and socked us in the back of the head.

In the case of flu, Sepkowitz writes, we concentrated on the threat of H5N1 avian influenza — the focus, until H1N1/swine flu arrived, of billions of dollars and years of effort in pandemic preparation — but were surprised by the sudden catastrophic emergence of seasonal flu strains resistant to oseltamivir (Tamiflu), one of the few antiviral drugs that can reduce illness and death from flu if taken early enough. In the case of MRSA, medicine focused on containing the spread of hospital MRSA and its rare transformation into VRSA, vancomycin-resistant staph — and mostly discounted, until far too late, the enormous threat of community MRSA strains:

The intensity of our concern and the frequency of the doomsday dispatches were appropriate. We were simply chasing the wrong microbe. It is community-acquired MRSA, not VRSA… that now occupies the center of the public health stage. And just about everything predicted for VRSA has come true for community-acquired MRSA. It’s everywhere; it’s deadly; it has changed the day-to-day management of skin infections and pneumonia in clinics, emergency rooms and intensive care units. It’s a true public health disaster. It’s just a different disaster from the one we were exercised about.

As we wrangle the new threat of H1N1, Sepkowitz warns that it is vital to remember how many millennia of practice microbes have in foiling our expectations:

We should marvel at the raw, restless power of microbes. They have the numbers — trillions and quadrillions and more that replicate wildly, inaccurately and disinterestedly. Nothing microbes do, whether under the duress imposed by antimicrobials or from some less evident pressure, should surprise us. It’s their world; we only live in it.

(Image courtesy Sansceo Design)

Antibiotic overuse in animals: Obama administration comes out against

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For anyone who cares about the overuse of antibiotics in food animals, and the resistant bacteria that overuse has been shown to produce, this is important news.

In testimony today, new FDA Commissioner Dr. Joshua Sharfstein announced the administration’s opposition to the use of growth promoters: sub-therapeutic doses of antibiotics used not as disease treatment, but to encourage animals to put weight on rapidly. Further, he also came out against the administration of antibiotics in food animals without the involvement of a veterinarian — a common situation out here in farm country, where veterinary antibiotics are freely available over the counter. (We discussed Scott Weese’s proposal to end that practice here.)

Both of these practices have been repeatedly linked to antibiotic resistance, and for the administration to come out against them is highly significant — not just for the struggle against resistant bacteria, but also for the movement to reduce industrial-scale agriculture, which relies on antibiotics to keep food animals healthy while they are in the close confinement of CAFOs.

Sharfstein made the announcement while giving testimony on behalf of Rep. Louise Slaughter (D-NY)’s Preservation of Antibiotics for Medical Treatment Act of 2009, which has been introduced (and opposed into nonexistence) multiple times over the past decade. (Earlier post on the legislation, including its text, here.) He said:

To avoid the unnecessary development of resistance under conditions of constant exposure (growth promotion/feed efficiency) to antibiotics, the use of antimicrobials should be limited to those situations where human and animal health are protected. Purposes other than for the advancement of animal or human health should not be considered judicious use. …
Important factors in determining whether a prevention use is appropriate include evidence of effectiveness, evidence that such a preventive use is consistent with accepted veterinary practice, evidence that the use is linked to a specific etiologic agent, evidence that the use is appropriately targeted, and evidence that no reasonable alternatives for intervention exist. FDA also believes that the use of medications for preventino and control should be under the supervision of a veterinarian. …
FDA supports the treatment of ill animals according to appropriate veterinary practice within a valid veterinary-client-patient relationship.

Also on the docket at Slaughter’s hearing:

  • Margaret Mellon, PhD, of the Union of Concerned Scientists (who specifically discussed MRSA ST398): “As long as the massive use of antibiotics continues, animals … will remain a fountain of resistant pathogens, dangerous to both animals and humans. The straightforward solution to the problem is to reduce the use of antibiotics in animal production and thereby diminish the pool of resistant organisms and traits.”
  • Robert Martin of the Pew Environment Group (Pew Charitable Trusts): “The present system of producing food animals in the United States is not sustainable and presents an unacceptable level of risk to public health, damage to the environment, as well as unnecessary harm to the animals we raise for food.”
  • And statements of support from the Chipotle restaurant chain and the Bon Appetit Management Company (which operates catering services in corporations and universities).

Of note, the Pew Commission on Human Health and Industrial Farming, which supports Slaughter’s bill, said after the hearing that Sharfstein’s proposals are only necessary but not sufficient: ““The proposed FDA position does not go far enough in this regard and would allow the continuation of conditions that necessitate the improper use of antibiotics in the first place.”

Restricting antibiotics in animals: Start by restricting access

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Constant readers, those of you who follow the pressing issue of MRSA in animals will know the work of J. Scott Weese, DVS, associate professor of pathobiology at the University of Guelph in Ontario and supervising author of many crucial papers on MRSA in food and companion animals, including the first finding of MRSA in pigs and pig farmers in North America.

You may not know that Weese and his postdoc Maureen Anderson publish an excellent blog on veterinary and zoonotic diseases called Worms and Germs. This weekend they have an important post that deserves wider attention: Antibiotics: A Dose of Common Sense. In it, they propose that one way to reduce the overuse of drugs in food animals is to make animal antibiotics prescription-only. It’s worth taking the time to read it.

Those of you in the cities may not know this, but out here in the Great Flyover, antibiotics for veterinary use are surprisingly easy to buy (as I discovered when I stumbled into a farm-related store in search of a Carhartt jacket against the Minnesota winter). They’re not even over-the-counter — they’re on the shelf, or stacked on the floor with the implements and feed, or blended into the feed itself. And as Weese points out in this post, they are also available without prescription over the Internet (as human antibiotics are too).

It’s a potentially controversial proposal: I don’t think I have any farming readers, but I would imagine their response would start with an objection to the extra cost of hiring a veterinarian to assess whatever situation might require the drugs. And since most farmers (NB: not the overarching ag-biz companies, but the farmers themselves) exist on razor-thin economic margins, they would have a point. But as we know from the excellent work of Extending the Cure and the Center for a Livable Future, unnecessary antibiotic use comes with a cost as well — one that is borne by all of us when antimicrobial resistance prevents antibiotics from working.

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.

MRSA strains crossing borders: US CA-MRSA to Italy

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Swine flu continues to dominate the headlines, but other pathogens don’t read the papers. Case in point: New news about a US community strain being found and treated in a woman in Italy — better treated, as it turns out, than she was in California, where she was infected.

In a new letter in Emerging Infectious Diseases (a free journal published online and in print by the CDC — it’s your tax dollars at work, just read it, already), Carla Vignaroli, Pietro E. Varaldo, and Alessandro Camporese of the Polytechnic University of Marche in Ancona amd the Santa Maria degli Angeli Regional Hospital, Pordenone report the case of

a 36-year-old Italian woman (who) was seen at Pordenone Hospital (northeastern Italy) for spider-bite–like skin lesions on the face, characterized by rapid evolution to furuncles and small abscesses. The infection had started ≈1 month earlier in California, where she had spent several months on business (wine import-export), and where she had been treated empirically with amoxicillin/clavulanate for 10 days (1 g, 3×/day), with no clinical improvement.

(At this point, I know every clinician reader and everyone who has had a MRSA skin infection is shaking his or her head. Surely by now the knowledge that “spider bite” is practically diagnostic for CA-MRSA has penetrated? But apparently not, since she was given amoxicillin/clavanulate, AKA Augmentin, which is partially penicillin-based.)

When the woman’s lesions were cultured, they turned out to be caused by USA400, the original community strain, which back in the 1990s was known as MW2. That’s interesting, especially in California, since USA300 has become such a dominant strain. Nevertheless, the key point is that USA400, as with USA300, has barely been recorded in Italy:

All 3 previously reported cases of CA-MRSA infection in Italy were caused by type IV SCCmec, PVL-positive strains, none of which, however, belonged to the ST80 clonal lineage that predominates in Europe (7). The first case (in 2005) was a necrotizing pneumonia caused by an ST30 isolate; the 2 other cases (2006) were severe invasive sepsis and a neck abscess, both caused by ST8 (USA300) isolates.

The concern, of course, is that once imported, they will not remain rare:

The case we note here documents the importation of a US pathogen into a country in Europe, from an area where the pathogen is widespread and has been highly virulent since the late 1990s, to an area where its penetration in the past has been poor.

The cite is: Vignaroli C, Varaldo PE, Camporese A. Methicillin-resistant Staphylococcus aureus USA400 clone, Italy [letter]. Emerg Infect Dis. 2009 Jun; [Epub ahead of print]. DOI: 10.3201/eid1506.081632