Meat animals, antibiotics and resistance

Just published: Two big, thought-provoking reports that should do a great deal to illuminate the murky debate over the use of antibiotics in animal feed and the question of how much that promotes antibiotic resistance.

Extremely brief back-story:

• For roughly the past 50 years, animal production in the US has morphed from a horizontal industry of small family farms to a vertical one populated mostly by very large breeding-feeding operations that are closely tied to slaughter-processing-distribution businesses.
• These industrial farms — commonly called CAFOs for "concentrated animal feeding operations" — start at about 1,000 cattle or 10,000 chickens and often are orders of magnitude larger. That many animals crowded together exceeds the carrying capacity of any pasture, and CAFO animals are commonly fed industrial feed.
• Those conditions obviously do not match the ones for which the animals evolved, and as a result the animals do not grow well in them. So to keep them healthy and speed their growth — they are an industrial product after all, and production speed affects profit — industrially raised animals are routinely fed small doses of antibiotics; by one estimate, 70% of all antibiotics used in the United States are given to food animals not humans.
• And as human medicine has demonstrated, the more that antibiotics are used, and therefore the more that organisms are exposed to them, the more likely it is that antibiotic resistance will develop.

The reports just published attempt some next steps in addressing those concerns.

• CAFOs Uncovered, by Doug Gurian-Sherman and the Union of Concerned Scientists, estimates that the cost to taxpayers of CAFOs' promotion of resistance equals $1 billion to $3 billion per year.
• Putting Meat on the Table, a joint project of the Pew Charitable Trusts and the Johns Hopkins Bloomberg School of Public Health, calls on Congress to phase out and then ban all non-therapeutic use of antimicrobials in animals (that is, in any animals that are not sick or have not been exposed to disease).

And in a lovely bit of either synergy or serendipity, the nonprofit Trust for America's Health released today a report that illuminates the near-complete breakdown of the US food safety system and the increasing vulnerability of Americans to food contamination and foodborne disease — proof, in case anyone needed it, that all those antibiotics fed to animals are doing us no good at all.

(For earlier posts on MRSA in food animals, go here.)

Child deaths from flu + MRSA

Steve Smith of the Boston Globe (who is really good, and I say that as someone who used to compete against him) has a story up regarding state and national concern over children's deaths from MRSA pneumonia. There have been two such deaths in Massachusetts this year. These are the sort of deaths that make headlines, as they did last October with the death of 17-year-old Ashton Bonds in Virginia: The pneumonia is very fast-moving and very destructive of lung tissue, and young children have died from it in less than 24 hours.

The CDC is concerned about this: Twice in two years (last May, blogged here, and last January), the agency pushed out an advisory to state health departments, asking them to report any children's deaths in which flu played a role. Surveillance for pediatric flu deaths is a relatively new thing for the CDC — the agency set up a system after the bad early flu season of 2003-04, in which more than 150 children died — so there is relatively little history to draw on. But MRSA has played a role in child deaths in each of the past three years, according to that January bulletin:

From October 1, 2006 through September 30, 2007, 73 deaths from influenza in children were reported to CDC from 39 state health departments and two city health departments. Data on the presence (or absence) of bacterial co-infections were recorded for 69 of these cases; 30 (44%) had a bacterial co-infection, and 22 (73%) of these 30 were infected with Staphylococcus aureus.

The number of pediatric influenza-associated deaths reported during 2006-07 was moderately higher than the number reported during the two previous surveillance years; the number of these deaths in which pneumonia or bacteremia due to S. aureus was noted represents a five-fold increase. Only one S. aureus co-infection among 47 influenza deaths was identified in 2004-2005, and 3 co-infections among 46 deaths were identified in 2005-2006. Of the 22 influenza deaths reported with S. aureus in 2006-2007, 15 children had infections with methicillin-resistant S. aureus (MRSA).

Among MRSA researchers, concern over these necrotizing pneumonia cases has been growing for a few years. Some surveillance suggests that such cases may be increasing, though that could be an issue of, "once you start looking for something, you find it." And the cases are undeniably severe: 56% of children with MRSA pneumonia die, according to a 2007 paper.

But at leaast some of those deaths may be avoisable — or would be if doctors in the community were more attuned to the possibility of MRSA. In a poster at last autumn's ICAAC meeting (first author AJ Kallen) CDC researchers reported thay reviewed charts of all the children admitted with a stah infection at Atlanta's three children's hospitals during the 2006-07 flu season. There were 53 cases of Staph aureus pneumonia; 22 of the children saw a physician an average of 3.5 days before being admitted to the hospital, and THREE of them got drugs that would work against staph.

And yes, you read that right: Active case-finding in Atlanta in 2006-07 found 53 cases of flu-related staph pneumonia; 22 of them, according to the paper, were MRSA. But from the entire country during 2006-07, according to the advisory quoted above, the CDC received reports of 22 flu/staph pneumonias, 15 of them MRSA. Which suggests that flu/MRSA pneumonias in children are more common than current surveillance reveals.

Natural remedies - upsides and downsides

For obvious reasons there is a lot of interest in finding new sources for antimicrobial compounds that work against MRSA, and in finding non-drug remedies as well. There's been a small upsurge in reports of such research recently, which may be coincidence or may simply be due to the timing of certain scientific meetings.

Notably there was the report of "four or five super-active peptides" found in the blood of alligators and reported at the American Chemical Society's annual meeting a few weeks ago (first author Lancia Darville. Louisiana State University; Science News' take on the story is here), and another report at the same meeting of antimicrobial compounds in clay (authors Lynda Williams and Shelley Haydel of Arizona State University; press release here).

And just a few days ago, the journal Clinical Infectious Diseases posted ahead-of-print a study from the Netherlands on a "medical-grade honey" named Revamil that reduced skin colonization by resistant bacteria 100-fold.

That study's authors raise a red flag: that while honey has an antibacterial reputation that reaches back into prehistory, most investigations of honey as an antimicrobial have tripped up on the lack of product standardization, with batches from different areas, or even the same area at different times, showing significant variations in antibacterial activity. (Standardization of active ingredient is a long-standing problem for herbal remedies as well; regulatory authorities in Europe, where herbal preparations are more mainstream, are far ahead of the US on tackling this.)

It's important to remember that, naturally-sourced or not, antimicrobials are antimicrobials and must be handled with care, or they may invoke the sort of unintended consequences that brought us resistant organisms in the first place. For an excellent example of this, see a little-noticed paper from Irish researchers published last year in the the Journal of Antimicrobial Chemistry. That group found problems with the well-researched natural antimicrobial tea tree oil (Melaleuca alternifolia), which is commonly used in "natural" toiletries and cleaning products (and which I have in my own medicine cabinet). When tea tree oil was applied to bacterial colonies at a lower-than-lethal dose, the surviving bacteria developed resistance not only against the oil's active ingredient, but also against a range of antibiotics including vancomycin.

Rumors of the blog's death are only slightly exaggerated (2nd ed.)

Apologies to all readers: I was traveling nonstop for a month doing research, got back, collapsed, and then dove into sorting out my month's worth of materials. Blogging fell by the wayside for a week. I think I'm back now. But I am starting to actually write the book, and I can't predict how that new process is going to fit with this. As with so much in the online world, no way to find out but to try it...

Now, this is going to be a bit meta: Today's post is not about MRSA, but about the phenom of distributed conversation on the intertubes that allows us to talk about MRSA. The California Health Care Foundation has published an interesting report, The Wisdom of Patients, that explores how Web 2.0 and the social networks it enables are changing consumers' experience of healthcare and potentially healthcare itself.

The initial observations in the report will not be new news to anyone who has made it here: The "positive network effect," aka the wisdom of crowds, allows those who come to the Web for health information to be smarter in aggregate than any member of the community could manage individually. And it makes the point — again, as MRSA searchers will already know — that consumers do this much more than, for instance, clinicians do. (Though I have been interested to notice, on another disease community that I monitor, an increasing participation of nurses and alternative-health professionals, though no doctors.)

The report, written by health care economist Jane Sarasohn-Kahn, raises thoughtful questions about the inefficiency of the 2.0 experience (think of digging through the many posts on a disease-community board to find the ones that fit your situation), the emerging legal and privacy concerns, and the business potential of health-related social networking, and ends with some examples of high-traffic health-related blogs, wikis, and new formats that bring health plans into the conversation.

The press release that gives a brief precis of the report is here and the full report (pdf, 807k) is here. (UPDATE: The link to the full report was broken but is now fixed; sorry.)

In a slight irony — and a sign of how new all this is — the CHCF site where the report is posted is not itself 2.0: It has no comment or talkback functions. Coming soon, the foundation says.

HAIs: Congress weighs in

Today, the House of Representatives Committee on Oversight and Government Reform held a hearing on hospital-acquired infections, led by committee Chairman Henry Waxman (D-Calif.).

The witness list is here. A Government Accountability Office report that was presented during the hearing is here. Its title captures the committee's point of view: "Leadership Needed from HHS to Prioritize Prevention Practices and Improve Data on These Infections."

In opening the hearing, Waxman said:

[HHS] is not providing the necessary leadership. It has not identified for hospitals the most important infection control practices, and it is not coordinating the collection of data from hospitals in order to avoid duplication and unnecessary burden.
The failure of HHS leadership is particularly regrettable because these illnesses, deaths, and costs are preventable. Moreover, the preventive measures don’t require new technologies or large investments.

The witness list includes links to testimony, including some very powerful remarks delivered by HA-MRSA survivor Edward F. Lawton:

We possess the knowledge and capabilities to fight this enemy; we possess the educational and professional expertise to overcome and destroy it. The only question is whether we have the will to fulfill the mission!

(And BTW, apologies to loyal readers for disappearing for a week. I was speaking at the American Society of Journalists and Authors, and doing book-related research in New York. Back now.)

A staph vaccine: How much would it help?

One more post on research from the meeting of the Society for Healthcare Epidemiology of America: Many MRSA researchers believe that the only way to truly control the pathogen — especially out in the community — will be through a vaccine.

Lay aside for the moment how problematic introducing a new vaccine can be these days, since the cost issues, along with shifts in the public's willingness to accept new vaccines, are ferocious hurdles. And lay aside also the difficulties that pharma companies have already faced in attempting to develop a staph vaccine.

But if such a vaccine were achieved, how many people could it help? Researchers from the Centers for Disease Control and Prevention attempted to answer that question in research presented at SHEA.

Background assumptions, part 1: The number of invasive MRSA infections now tops an estimated 105,000/year (a recalculation of the 94,000/year estimate from last October); more than 40% of invasive infections occur in those over 65; more than 50% are associated with a recent hospitalization; and 15% of MRSA infections recur at least once. And background assumptions part 2: A vaccine would have an efficacy rate of 40-75%, and an acceptance rate similar to flu-vaccine uptake: 20-50% among those 15-44, 35-70% among those 45-64, and 50-70% among those 65 and older.

Given those assumptions, Cynthia Lucero, MD and colleague predicted:

• If given only to those 65 and older, a vaccine would prevent from 12,720 to 32,270 invasive MRSA infections;
• If given to those over 65 and also those 15 and older who have already had an invasive infection, a vaccine would prevent 14,130 to 38,310 invasive MRSA infections;
• And if given to those over 65 and also anyone over 15 who is being discharged from a hospital, a vaccine would prevent from 17,240 to 49,940 invasive MRSA infections.

The best bang for the buck, the agency said, would be the middle strategy: It would prevent from 660 to 1,170 cases for every million doses of vaccine used. And since the vaccine would also cover methicillin-sensitive staph, it would likely prevent an equal number of serious MSSA cases as well.

The CDC is not by law allowed to lobby — or even, for the most part, allowed to offer a professional opinion unless Congress has asked it to do so. So these numbers are purely a thought experiment. But they're also a strong argument for the broad usefulness of a staph vaccine if one could be achieved.

"Leaky" hospitals redux: When HA is CA

The CDC work below and several other papers published recently attribute a good proportion of CA-MRSA to hospital strains that have left the institution in a colonized patient and sickened that patient at some point post-discharge. But several papers presented at the annual meeting of the Society for Healthcare Epidemiology of America underline that MRSA traffic is two-way: Community strains can enter the hospital and cause outbreaks there as well.

Cases in point:

• Between 2004 and 2007, the Medical University of South Carolina in Charleston identified 272 hospital-acquired infections that were caused by USA300, the dominant CA-MRSA clone. That's 21.3% of all HAIs in that hospital in those years. (Lead author K Hardman)
• At Johns Hopkins University in Baltimore, nine out of 757 patients admitted to the pediatric intensive care unit became colonized or infected with MRSA 48 hours or longer after they were admitted. Six of the nine were found to have USA300, and one developed invasive MRSA disease. (Lead author AM Milstone, MD)
• And at New York-Presbyterian Hospital, a 5-day-old baby who had not yet left the hospital became infected with USA300, the first casualty in a complex outbreak involving several MRSA strains that eventually comprised 21 infants (12 colonized and nine with infection; 14 of the 21 with USA300) and 10 mothers (five infected Caesarean incisions, two with breast abscesses, two with mastitis and one with a skin infection; six out of 10 with USA300). (Lead author Jean-Marie Cannon, RN)
  

New news on invasive MRSA rates: headed down?

I am at the annual conference of the Society for Healthcare Epidemiology of America, where authentic news was released Sunday, in a very quiet way.

Last fall, a team of authors from the Centers for Disease Control and Prevention published a paper in the Journal of the American Medical Association that for the first time estimated the burden of invasive MRSA disease in the United States. Using data from the Active Bacterial Core Surveillance System — which comprises nine sites around the country and takes in about 14 million people — the team estimated that the annual incidence of invasive MRSA in the US is 94,360 cases, including 18,650 deaths. In an important (and to some researchers controversial) contribution to defining MRSA disease, the team also estimated that 13.7% of the invasive infections were community-associated, 26.6% were hospital-acquired (which they called "hospital-onset"), and by far the largest proportion, 58.4%, were a new category they called "hospital-acquired, community-onset" — the patients acquired the bug while in the hospital, but did not develop disease until after they were discharged. (Cite: Klevens RM et al., Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA, 2007 Oct 17;298(15):1763-71. Full text here.)

The important event Sunday was the first release of an update to that data, adding a second year of analysis. The news: Hospital-acquired infections declined in a small but significant way, by 8.1% — though community-associated and community-onset cases did not change.

The original paper analyzed data from July 20o4, when the ABC system expanded from a pilot program to the full nine sites, through December 2005. The update both reslices that data and adds fresh numbers: It compares calendar year 2005 to calendar year 2006. It finds small downward trends as well in community-onset and community-associated cases, but judges those trends not statistically significant. But Dr. Scott Fridkin, who presented these numbers and was an author on last fall's paper, said the dip in nosocomial cases is statistically robust and a true decline, though adding a third year of data will make the analysis yet more solid.

The decline is intriguing and raises the question: If infection-control interventions in hospitals are pushing down rates of hospital-acquired cases, then why are "hospital-acquired/community-onset" cases not down as well?

As usual with conference papers, the abstract is not online; the CDC says it will be posted today and I'll update when they do. (NB: The data presented at the conference is actually an update of the data in the abstract, and so when the abstract goes up the numbers will not match; the decline presented today is a few percentage points smaller, due to a re-cut of the data after the abstract was written.)

UPDATE 8 April 08: The abstract is now online here.

(Financial disclosure: I am at SHEA for book research and to participate in a session on interactions between researchers and media. In exchange for that session, the organization paid my airfare.)

CA-MRSA increasing in Denmark

Again from the annual meeting of the Society for General Microbiology, a report that CA-MRSA cases are rising in Denmark, a country with a very low incidence rate of HA-MRSA — about 1% of isolates — thanks to aggressive screening of any patient who has been treated abroad as well as any health care worker who has worked outside the country.

But a team from the Statens Serum Institut in Copenhagen says that is now changing as CA-MRSA moves into the country. From an SGM press release:

"We have managed to hold the frequency of MRSA cases down to under one per cent in Denmark for over 30 years. But in 1997 we recognised the first cases of community acquired MRSA, a new strain independent of hospital and nursing home contacts, in a young adult and two families in a rural town", says Professor [Robert] Skov [of Statens]. "From the families we traced the superbug being transmitted through a kindergarten, a school, a factory and a farm. Between 1999 and 2006 the number of community acquired MRSA infections increased from 11 to 175 a year, making up more than 22% of all MRSA infections, as a rising proportion."

As is commonly the case, the paper presented at the SGM is not online. The press release was carried by the site Medical News Today. It contains no details on whether the cases were identified as CA-MRSA by risk factor or by microbiology, and therefore doesn't answer the obvious question of whether they are truly CA-MRSA, or hospital-acquired/community-onset HAIs.

However: A 2005 paper on which Skov was an author did include typing results, and suggests that Denmark now is seeing cases of a new MRSA type, similar (allowing for the vast difference in scale) to what has happened in the US since the 1990s. From the abstract:

Comparison of the 45 community-onset MRSA (CO-MRSA) infections with the 36 hospital-acquired MRSA (HA-MRSA) infections showed several striking contrasts. Most CO-MRSA were recovered from skin and soft tissue infections caused by isolates carrying the Panton-Valentine leucocidin toxin genes, and the majority (84%) of isolates belonged to a single clonal type, ST80-IV, which has been found in the community in other European countries. Clone ST80-IV could be traced in Denmark back to 1993. ST80-IV was rarely found in HA-MRSA infections.

The paper is Faria, NA et al. Epidemiology of Emerging Methicillin-Resistant Staphylococcus aureus (MRSA) in Denmark: A Nationwide Study in a Country with Low Prevalence of MRSA Infection. J Clin Micro April 2005, 43 (4) 1836-1842. The abstract is here.

Antibiotics and the tragedy of the commons

I've been turfing through the pile of research materials I've gathered over the past two years and finding gems I had forgotten about. Here's one, from a post at Pioneering Ideas, a blog dealing with projects funded by the Robert Wood Johnson Foundation. One of RWJF's projects is "Extending the Cure," which seeks to reframe thinking about antibiotic use and stewardship by viewing them as economic and social-science problems rather than as medical problems.

In a guest post last year, Ramanan Laxminarayan, PhD, a senior fellow at Resources for the Future, explains the central problem in beautifully clear language:

[A]ntibiotic resistance is not always going to show up as a ‘crisis’ type of problem. ...

Sure - a set of circumstances such as a new strain of influenza that facilitates secondary infections such as Staphylococcus aureus that cannot be treated easily would result in a crisis. But the more likely scenario is one where, ten years from now, we are all using antibiotics that cost $1,000 or more a treatment course and none of the cheaper antibiotics work. This has a ripple effect on productivity of other medical technologies such as transplants and surgeries and on overall health care costs and insurance premiums. Since no one insurer is affected differently than others, there is no incentive for anyone to act.

Just as there is not going to be a single ‘day that the oil runs out’ and we have to think of solutions to our energy needs twenty-to- fifty years from now, we also have to start thinking of our antibiotics portfolio twenty-to-fifty years from now.

The full post is here.

Everything old (in drug treatments) is new again

From the annual meeting in Edinburgh this week of the Society for General Microbiology comes an intriguing report of a new use for a very old antimicrobial tool.

The old tool is phages, viruses that infect bacteria and that were used as treatments for bacterial diseases in the pre-antibiotic era. (Does anyone going into medicine read Sinclair Lewis's Arrowsmith any more? The heroic doctor protagonist of that novel uses phages against diphtheria.) Following the development of penicillin, phage work was abandoned in the West but remained an active area of research in the former Soviet Union. (See this Slate.com story for details; this webpage looks like a good phage resource, though I can't figure out who the authors are.)

To be hopelessly reductionist, the upside of phages is that they are less likely to provoke resistance and have few side-effects; the downside is that they have to be precisely tuned to the bacteria they are used against. There is no such thing as "empiric therapy" with phages.

Comes now a team from the University of Strathclyde to say they have found what may be a promising new use for phages: chemically bonding them to polymers that can then be used in sutures and wound dressings to prevent infections in surgical sites and implanted catheters and devices.

The abstract (first author Janice Spencer) is not online, but the BBC has posted a short story based on the press release.

UPDATE: My colleague Nick Kelley at CIDRAP, a phage phanatic (sorry), says this is the best phage page he knows of. The index page has a gorgeous electronmicrograph of a phage inserting its stuff into a bacterium.

CA-MRSA — not just a US problem

One of the mysteries of MRSA research has been the apparent difference in MRSA prevalence in different countries. Hospital-associated MRSA is a well-understood foe in Europe, but identification of CA-MRSA is infrequent. So is CA-MRSA actually less common in other countries, or is that an artifact produced by less surveillance there or more awareness here?

A new journal sheds some light on the question, and also sounds a warning. A team from University College-London's Centre for Infectious Disease Epidemiology analyzed data that are easily available in the UK because the country has a national healthcare system: "hospital episode statistics" (hospital admissions by primary diagnostic code) from 1989 to 2004. The team chose the codes that would indicate admissions for a variety of community-onset staph-related diseases: septicemia, pneumonia, bone and joint infections, and an array of skin and soft-tissue infections.

What they found: Over those 15 years, admits for staph septicemia, pneumonia and scalded-skin syndrome rose 5-fold; abscesses and cellulitis, 3-fold, and bone and joint infections, 1.5-fold. These were much larger increases than in the only national surveillance system which collects voluntary reports just of Staph bacteremia and showed a 2.5-fold increase from 1990 to 2004.

Because the study is based on ICD-9/ICD-10 codes, it contains no microbiological information. However, the authors point out that the invasive diseases captured by the codes are associated with PVL toxin, which in turn is associated with CA-MRSA more than HA-MRSA or MSSA. They say:

We identified a previously undescribed but major increase in pathogenic community-onset staphylococcal disease over the past 15 years. These trends are of concern given the international emergence of invasive community-onset staphylococcal infections.

The paper has been published ahead of print by Emerging Infectious Diseases. The cite is: Hayward A. et al. Increasing hospitalizations and general practice prescriptions for community-onset staphylococcal disease, England. Emerg Infect Dis. 2008 May; [Epub ahead of print]

On personal MRSA stories

I don't write here about MRSA victims' stories, for two reasons. First, there are excellent other sites on the net where MRSA communities have already formed, such as MRSA Resources and MRSA_Support; it seems disrespectful to the leaders of those very vibrant communities to try to duplicate their work.

And second and more selfishly, the roughly 50 victims who have spoken to me so far — with more to come — have done so on the understanding that their stories will appear first in my forthcoming book SUPERBUG. When the book is ready to go and its static site is built, I hope we'll have a page that features victims' stories and invites others to post theirs as well.

That being said, if you've come to this site because you have had MRSA, please get in touch! Post a comment: They are moderated, so I see them first and can take them out of the queue if you prefer to be private. Or email me: My email address is in the profile box on the right.

And with all that said, there is one additional victims' site that I want to recommend. Consumers Union (yes, the people who publish Consumer Reports magazine) has a campaign called Stop Hospital Infections that is pushing for legislation requiring mandatory reporting of all HAIs including MRSA. The site combines advocacy tools with heartbreaking accounts of lives changed; take a look.