Antibiotics and farming — how superbugs happen

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

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

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

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

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

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

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

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

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

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

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

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

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

Antibiotics and farming — CBS follow-up video

Constant readers, CBS News has posted some follow-up video to its two-part series last week on antibiotics in agriculture. It features Dr. David Kessler, former Commissioner of the Food and Drug Administration (which under its current leadership has vowed to re-examine farm-antibiotic use), and Eric Schlosser, author of Fast Food Nation.

They talk about the protests CBS has received for airing the package, the concerns public health authorities have over the lack of  data on the amounts and types of antibiotics used, and much more. I especially love Schlosser's comment: "I'm a meat-eater." It's important, I think, to say that being critical of antibiotic use does not mean being opposed to animal agriculture, or wanting to see farms shut down. It means being concerned for the health of farm animals, farm families, and everyone affected by growing antibiotic resistance — which is, you know, everyone.

(H/t @EdibleSF for flagging the video's release.)


Watch CBS News Videos Online

(Hey, that's my first embedded video!)

New film on organic farming (for European readers and others)

This is a little outside our usual subject matter, but it follows nicely on the past two days' discussion of the CBS packages on antibiotics in farming, so:

What looks like a marvelous new documentary exploring environmental damage and human illness from pesticides and other farming chemicals is coming out in France, but needs assistance to get onto the international festival circuit. It's called Nos enfants nous accuseront (Our Children Will Hold Us Responsible), and among other things, looks at the efforts of a French village to make all the food served in its schools organic — which, even in food-centric France, is much harder than it sounds.

You can view the trailer here. The more clicks, the more the film will be taken to have support, and the higher its rankings will go for festival consideration.

It comes well-recommended by friends of mine in Paris, so I hope you'll take a look.

CBS antibiotics and farming, day 2 - and more on the Danish experience

Constant readers, I hope you watched the second day of CBS News' series on antibiotic use in farming, and how it promotes the emergence of antibiotic-resistant infections in animal and humans. I found it surprisingly hard-hitting. Here's the video and the text version.

Most of the report explored the farm experience in Denmark, which in 1998 banned its farmers from using small doses of antibiotics to make animals gain weight faster — the practice that's various called subtherapeutic dosing or growth promotion. Important distinction: The country still permits sick animals to be treated with antibiotics; the ban extends only to giving drugs to animals who are not sick.

That ban has often been represented as a failure for Danish farming [NB: See the update below], but research on the results shows that it was actually a success. Here's an article by Laura Rogers of the Pew Charitable Trusts explaining what happened in Denmark from her own on-the-ground reporting:

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. ...

The average number of pigs produced per sow per year has increased from 21 to 25 (this is an important indicator of swine health and welfare, according to veterinarians). Most important, total antibiotic use has declined by 51 percent since an all-time high in 1992. Plus, the Danish industry group told us that the ban did not increase the cost of meat for the consumer.

 There are multiple scientific papers done by Danish authors backing up her observations. Here are just a few from just last year:

• Antibiotic-resistant organisms in chickens raised in Denmark declined since the ban — but they remain high in chicken meat imported from other countries that do not have such bans, and passed to Danish consumers who ate that imported meat. (Skjot-Rasmussen et al., May 2009)
• Antibiotic resistance in E. coli in pigs increases when pigs are given antibiotics, and those antibiotic-resistant organisms pass to humans (Hammerum et al., April 2009)
• Antibiotic-resistant organisms found in pigs when they are slaughtered increase when pigs receive more antibiotics (Abatih et al., March 2009)

The industry that supports industrial-sized farms has strongly objected to the CBS series. You can see one detailed response here, from Pork Magazine. The Minneapolis-based Institute for Agriculture and Trade Policy predicts that this is likely just the first wave, and that opposition to any change in agricultural practices will grow stronger as a bill to curb unnecessary antibiotic use gains traction in Congress.

And — you knew I had to do this — here comes the obligatory self-promotion: There is a primer on antibiotic use in farming, and an account of the emergence of MRSA ST398 as a result of antibiotic use in pigs, in SUPERBUG. Which is now 41 days away from publication. And is available for pre-order at a discount! But you knew that.)

UPDATE: FairFoodFight has a great post and a long comments conversation about the CBS series, ag antibiotic use, and particularly the World Health Organizaton research that originally made people doubt the "Danish experiment," The WHO report is here and a Pew analysis of it is here.

CBS antibiotics and farming package, day one

Constant readers, I hope you saw the CBS News package on antibiotics in farming Tuesday night. (It continues Wednesday.) MRSA played a prominent role, in an account of infections among workers at a chicken plant (the same outbreak, I think, as was described by Prevention magazine last August) and in questions about MRSA in pig farms in the Midwest (with a prominent mention of Tara Smith's research into "pig MRSA" ST398).

Here's the 7-minute video and the text version.

Earlier Tuesday, CBS's Early Show ran an additional package on the death of a Chicago toddler from MRSA. That toddler's name is Simon Sparrow, and you'll be able to read his sad story — told by his mother, Everly Macario — in SUPERBUG.

Farming and antibiotics - and voices from the ag side

There's a tremendous amount of buzz in the blogosphere about a series of pieces that are supposed to run on CBS News over the next several days, looking at the use of antibiotics in agriculture. For one of many posts on the topic, look at this piece from Food Safety News, an online newsletter founded by the food-safety attorney Bill Marler.

[UPDATE: CBS has put up the first video teaser for the package.]
[SECOND UPDATE: An excerpt from the Early Show, likening growth promoters to a "ticking time bomb" and to "putting (antibiotics) in your kid's cereal so they won't get sick"] 

The whole issue of how antibiotics get used in agriculture — as growth promoters, as prophylatic treatment to prevent spread of infection within a farm, or as true treatment — is intensely controversial. For a sense of how farmers feel embattled, read the comments to this entry at FairFoodFight on whether there is a distinction between "Big Ag" and "small ag." and consider that the PAMTA legislation I posted about in December, which would require veterinarian oversight of farm use of antibiotics,  has been strongly opposed by agricultural interests every time it has been introduced. (Large-farm use of antibiotics, let me remind you, has been concluded to be the driver behind the emergence of "pig MRSA" ST398.)

But I recently ran across two pieces online that I want to draw your attention to, because they demonstrate that thinking in agriculture about antibiotic use is not monolithic, and may be changing. Both were posted on the same site, the Illinois-based Agri-News Online.

First, from James Pettigrew, a professor of animal sciences at University of Illinois, a pessimistic but realistic assessment of how changing public attitudes about antibiotic use will affect what farmers can do, "Broad restrictions on antibiotic use would reduce animal welfare and productivity":

Many of us hope there will not be a broad ban on antibiotic use, but it is difficult to predict what will happen. Restrictions on antibiotic use may come from Congress, from regulatory agencies or from customers. The nature and extent of future restrictions are now unknown, but the direction is clear. There will be tighter restrictions on antibiotic use in the future. ...
...Planning for restrictions on antibiotic use can be valuable even if those restrictions are never imposed. The things you might do in the absence of antibiotics are also likely to be quite valuable if you continue to use antibiotics as you do now....

Second, from a writer named Darryl Ray, who isn't otherwise identified, a plea for refraining from demonizing critics of antibiotic use, "Animal producers should take antibiotics criticism seriously":

...Many — and we would suggest it is the vast majority — of those who question the present practices of antibiotic use in animal agriculture eat meat on a regular basis.
Rather than malign the critics, a better course of action for meat animal producers might be to take the issue seriously.
...To categorically claim that it is a reasonable practice to routinely administer antibiotics to animals that are not diseased will strike many as being outside what they have come to believe to be an appropriate use of antibiotics.
...It is important to consider the possibility that indisputable evidence will emerge that the continued and persistent “overuse” of antibiotics in livestock production causes or accelerates the development of super-germs for which there are virtually no effective medications.That would be a public relations and economic nightmare for production agriculture. Thought of in that light, taking the issue seriously and making meaningful adjustments in antibiotic use may have the most appeal of all.

I don't know that I agree entirely with either writer. But I'm tremendously encouraged that a publication that speaks entirely about farming, to farmers, can run thoughtful pieces looking at ag antibiotic use from several angles, as something to be evaluated, debated and potentially adjusted, and not as a practice that cannot be examined but must be maintained unchanged.

Bad news in the President's budget request

It's been a few days since the rollout of the White House's proposed 2011 budget request, time enough for people to dig deep into the minutiae and figure out what that massive document really says. The Infectious Diseases Society of America has done the drilling for the health and infectious disease line items, and I'm sorry to say the news is not good.

Worst first: The proposed budget would cut funding for the CDC's antimicrobial resistance programs by 50%, $8.6 million. That means that only 20 state or local health departments, or health care institutions, will get money from CDC for surveillance and control of resistant bugs. That's only 40% of what was funded this year, when 48 health departments and health systems were funded. Which is very disturbing: If there's one thing almost everyone agrees on with regard to MRSA, it's that we need more surveillance, not less.

In addition, all state grants in the Get Smart About Antibiotics program, which runs campaigns to reduce inappropriate use, get zeroed out.

There are other cuts as well to infectious-disease program at CDC and elsewhere in HHS, including to to a major childhood immunization program and to pandemic defenses. And funding for HIV/AIDS, TB and other NIH research programs barely tiptoe upward.But these frank cuts in programs to combat antimicrobial resistance, at a time when MRSA is burgeoning, Gram negative organisms such as Acinetobacter are gaining ground, and drug development is stalling, surely cannot be smart.

The IDSA analyis is here.

SUPERBUG named a Top 50 public health blog

Constant readers, the website The Science of Health has named SUPERBUG one of its Top 50 public health blogs. I'm flattered to say we're in excellent company — the other blogs listed there are very good. Please go take a look.

Back again to MRSA in animals, and spreading to humans

There are two new reports out regarding new findings of "pig MRSA" ST398 (about which we have talked a lot; archive of posts here.)

First, researchers from the Complejo Hospitalario Universitario de Vigo and Complejo Hospitalario de Pontevedra, both in Pontevedra in northwest Spain, report that they have identified that country's first human cases of infection with ST398. (It was only last fall that Spain reported the first identification of the strain in animals.)

The age of the three patients was 59, 82, and 83 years, respectively. Two patients owned pigs and the other a calf. Two patients were diabetic and were hospitalized because they developed skin and soft-tissue infections by MRSA ST398. The third patient had bronchitis and the strain was isolated from a respiratory secretion submitted to the laboratory from an outpatient clinic. The three patients had had multiple hospital admissions in the last 12 months.

Tellingly, the researchers spotted these particular isolates (out of 44 analyzed at the two hospitals in 2006) because they were resistant to tetracycline. Tetracycline resistance is not common among community strains of MRSA, because the drug isn't the first-line choice for skin and soft-tissue infections; and when it is given, it's usually for a short course, so the drug does not exert much selection pressure on the bug. But tetracycline is a very common animal antibiotic, and tetracycline resistance is a hallmark of ST398; it is one of the factors that led the Dutch researchers who first identified the strain to take a second look at the bug.

Second, researchers from several institutions in Italy report a very troubling case of ST398 infection that produced necrotizing fasciitis — better known as flesh-eating disease.

In early April 2008, a 52-year-old man was admitted to an intensive care unit in Manerbio, Italy, because of severe sepsis and a large ulcerative and suppurative lesion on the right side of his neck. His medical history was unremarkable. He was a worker at a dairy farm, was obese, and did not report any previous contact with the healthcare system.

Necrotizing fasciitis is a terrible disease: If doctors don't respond very quickly, it can kill, whle the emergency surgery that forestalls death often carves away large areas of flesh or sacrifices entire limbs. This patient was fortunate: He was in the hospital for 31 days, but recovered and went home.

The Italian researchers are alert to, and troubled by, the larger meaning of this case:

... cattle-to-human transmission cannot be proven. However, because our patient did not have any other potential risk factor, dairy cows were probably the source of the human infection. ... It is difficult to prevent persons with constant exposure to MRSA in their work or home setting from becoming MRSA carriers. Revisiting policies for the use of antimicrobial drugs on livestock farms, as well as improving hygiene measures, may therefore be necessary in infection control programs.

Cites for these papers:

Potel C et al. First human isolates of methicillin-resistant Staphylococcus aureus sequence type 398 in Spain. Eur J Clin Microbiol Infect Dis. 2010 Jan 23. [Epub ahead of print] DOI 10.1007/s10096-009-0860-z

Soavi L, Stellini R, Signorini L, Antonini B, Pedroni P, Zanetti L, et al. Methicillin-resistant Staphylococcus aureus ST398, Italy [letter]. Emerg Infect Dis 2010 Feb

Recommending: Consumer Reports on hospital infections

Constant readers, the magazine Consumer Reports has done an extended, state-by-state analysis of which hospitals do well, or very badly, in preventing one important category of infections: central line-associated bloodstream infections, or CLABSIs (pronounced klab-sees). It's a comprehensive package in easily understandable language. It's based on the state reporting data that some activists have managed to persuade states to disclose, along with another set of data that some hospitals voluntarily tender to the nonprofit firm The Leapfrog Group.

From the Consumer Reports story:

Poorly performing hospitals included some major teaching institutions. For instance, New York University Langone Medical Center in New York City reported 39 infections in 10,119 central-line days in 2008, roughly twice the national average for its mix of ICUs. The University of Virginia Medical Center in Charlottesville didn't do much better, reporting 77 infections in 18,572 days for the 15 months ending in September 2009, also about two times the national average.

More encouragingly, nationwide, we counted 105 hospitals whose most recent public reports tallied zero central-line infections. They ranged from modest rural institutions to urban giants such as the University of Pittsburgh Medical Center Presbyterian hospital, which reported no infections among patients who were on central lines a total of 13,596 days in 2008.

It's well worth reading, and checking to see whether a hospital you may have used, or may be considering using, is on the good list or the bad list. Take a look.

Once again, flu and bacterial co-infection

With the H1N1 pandemic trending down, it may seem that the question of how much bacterial co-infection affects the outcome of flu is less important than it was. But though the pandemic is subsiding — for ever, for this season, or just until a third wave, who can say — researchers are just now getting enough good data to be able to make solid observations about what happened during the past 10 months.

Case in point: Writing in the journal Public Library of Science (PLoS) ONE, a team of researchers from Australia has pinpointed the incidence of MRSA co-infection during flu in two hospitals in Perth last summer, which was the Australian winter and the height of their flu season. Of 252 patients admitted for H1N1 infection, 3 were identified during treatment as having MRSA pneumonia. They survived, but two other patients who died were found to have MRSA pneumonia during post-mortem exams.

There were 3 female and 2 males, aged between 34 and 79 years... Two patients lived at the same long-term care facility, whilst the other patients lived independently in the community. Four of the 5 patients had conditions that may have increased their risk of pneumonia, including quadriplegia (two patients) asthma (one patient), cirrhosis (one patient) and diabetes mellitus (one patient). Two of the 5 cases (patients 3 and 4) had known MRSA infection/colonization prior to the onset of their illness (with the same cMRSA clone that subsequently caused their co-infection).

 There are some interesting points embedded here. First, incidence: In the Australian patients, MRSA pneumonia was much more common. The Perth researchers found 5 MRSA cases out of 252 flu patients. When the CDC analyzed the occurrence of MRSA pneumonia in flu last summer, it found only 1 case out of 272. Second, treatment: None of the 5 patients got antibiotics that would have affected MRSA — even though two of them were already known to be MRSA carriers. The possibility of MRSA pneumonia subsequent to flu seems not to have occurred to the health professionals taking care of them.

And third, the pathogen: The 5 Australian cases were caused by 3 community MRSA strains that are common in Australia — but only one of the 3 made PVL, the toxin that has so frequently been associated with MRSA pneumonia. That is interesting, and troubling at the same time. At this point, the association of PVL and necrotizing pneumonia has become practically taken for granted; and yet here are two strains that did not make PVL and yet caused severe and fatal pneumonia. It may be an indication that the inflammation that flu causes in the lung can open the door to more severe damage even when PVL is not present; it's certainly an indication that the absence of PVL does not signal a mild or not-dangerous strain.

The cite is: Murray RJ, Robinson JO, White JN, et al. 2010 Community-Acquired Pneumonia Due to Pandemic A(H1N1)2009 Influenzavirus and Methicillin Resistant Staphylococcus aureus Co-Infection. PLoS ONE 5(1): e8705. doi:10.1371/journal.pone.0008705.

Simultaneously, a new paper in the American Journal of Pathology seeks to clarify how often and in what circumstances bacterial superinfection becomes a risk during flu. Using a range of mice — both healthy ones, and "knockout" mice bred to be without particular immune-system components — researchers from San Diego confirmed that infections with flu and with Haemophilus influenzae can be lethal when the flu infection precedes the bacterial one. That was true even for infections that, if experienced separately, would not have been lethal; it was the synergy of the two infections, flu first followed by the bacterial infection, that caused the high mortality rate. The results may not be directly applicable to human medicine (Do you all know the old flu-research saying, "Mice lie and ferrets mislead?"), but they are an important indicator both of the seriousness of bacterial infection after flu, and also of the potential vulnerability of even healthy beings to that one-two punch.

The cite is: Lee LN, Dias P, Han D, et al.: A mouse model of lethal synergism between influenza virus and Haemophilus influenzae. Am J Pathol 176: 800-811.