Politics vs. science II: Meat, sex and drugs

This is a GoogleMaps picture of a farm near Goldsboro in North Carolina (map). The two salami-colored ponds on either side are lagoons, but not the kind where you want to swim. They’re open basins full of feces. To get a feel for the size, try comparing them with the cars in the dirt lot. As the Google Map will demonstrate, there are several more of these lagoons situated nearby. (You can imagine the breeze downwind of these facilities must have a rather bracing quality to it, especially on warm summer afternoons.)

Livestock agriculture in the US produces manure on a truly titanic scale — some ~133 million tons’ dry weight per year, ~13 times more than the sanitary waste produced by the human population [1]. Sometimes this manure enters the environment directly. Poorly constructed lagoons sometimes leak manure, for example, or overflow during rainstorms. Manure is also spread on many crop fields as fertilizer; from there, some of it enters lakes and streams in runoff. Since animals like pigs routinely receive low doses of antibiotics as part of their feed, manure often contains both antibiotic-resistant bacteria and low concentrations of antibiotics.

A number of studies have looked at concentrations of antibiotics in soil on farmland fertilized with manure; the results vary, depending on how you extract the antibiotic from the soil samples. How quickly the antibiotics break down in the environment also depends on the drug. Generally the antibiotic concentrations in soil samples are very low, although the manure often contains antibiotic-resistant bacteria into the bargain. The vast majority of these bacteria, of course, are poorly adapted to life in the soil and perish without heirs in their new environment.

What consequences (if any) does all this have for us? It’s difficult to say, partly because soil is teeming with bacteria anyway, and soil bacteria are a bountiful reservoir of antibiotic resistance genes in any case. The truth is we don’t really know. But it illustrates an interesting point: no farm animal is an island. Antibiotics and antibiotic-resistant bacteria from farm animals are introduced into soil and water all the time. Nor is this all, for antibiotic-resistant bacteria from the gut of a pig or a cow can work their way into the human population by a much more direct route: through contact with farm workers and through the meat consumers eat.

Microbial Porn

First, I have a sexy picture I’d like to share with you. It’s a little shocking, so don’t say I didn’t warn you:

All right, so maybe it’s not as sexy as all that. But it’s definitely rather interesting. This picture is a false-color electron micrograph of two bacteria linked by something resembling a slender thread. These microbes have been caught red-handed having bacterial sex.

This isn’t sex in the usual sense of the word, of course. It has nothing to do with reproduction, because bacteria reproduce by binary fission, which is an asexual process. What you see here is something more remarkable altogether.

Most (though not all) bacteria have only a single chromosome. Unlike human chromosomes, which are linear, bacterial chromosomes are circular, like a rubber-band-shaped loop of DNA. In addition, many bacteria have one or more plasmids, small loops of DNA separate from the chromosome, as illustrated in the cartoon below:

DNA can get transferred from one bacterium to another in one of three ways. Some bacteria can pick up DNA from their environment. Occasionally, viruses called bacteriophage can also transfer genes between bacteria. Finally, bacteria can swap genes through bacterial sex (aka conjugation).

A pair of “mating” bacteria initially make contact by means of a sex pilus, a slender hairlike filament like the one you see connecting the two bacteria in the electron micrograph. Next, the two cells pull closer together and establish more intimate contact, and finally the “donor” transfers DNA (usually a plasmid) to its partner.

Transfer of resistance genes between bacteria “in the wild” is a concern from a public health standpoint, because genes that confer antibiotic resistance can end up going from one species to another. Feeding low doses of antibiotics to farm animals creates a breeding ground for antibiotic resistance. The products of that breeding ground have many opportunities to mingle with the human population.

Meat and Bugs

The first route by which they do so is through farm workers, who come in frequent contact with the animals. We already have some evidence to suggest that antibiotic-resistant bacteria sometimes go from animals to farmers — although how often it happens is difficult to say. Take Staphylococcus aureus, for example. Somewhere around 1 in 3 of you are probably carrying S. aureus bacteria up your nose right now. In and of itself this isn’t cause for concern. Since S. aureus can cause serious and potentially deadly infections under various circumstances, however, strains resistant to methicillin and various other antibiotics are considered a major public health threat. These strains are collectively called MRSA, and only a small percentage of us are carrying MRSA (as opposed to more susceptible strains).

One study in the Netherlands in 2005 found that MRSA colonization was far more common among pig farmers than among patients admitted to Dutch hospitals. A more recent study[6] found that 49% of 299 pigs at nine farms (two production systems) in Iowa and Illinois were carrying MRSA, together with 9 out of 20 workers.  The authors of this second study compared the MRSA strains using a method called PFGE typing, where you digest the DNA from the bacteria with a restriction enzyme (an enzyme that cuts DNA wherever specific sequences occur*) and separate the fragments by size on a gel. A comparison of the resulting pattern of bands suggested the MRSA bacteria from the humans and the pigs were closely related yet distinct from other common MRSA strains*. Another study in 2007 [7] found that MRSA was remarkably common among healthy pigs; some 39% of 540 pigs sampled at 9 slaughterhouses were carrying MRSA strains.

The number of farm workers in both of the first two studies I mentioned was small, of course, and it’s difficult to know how widespread transfer of MRSA (or other antibiotic-resistant bacteria) from animals to farm workers may be. Nonetheless, these and other studies suggest it happens, and could happen more often than we’d like to think.

Another and more obvious route of entry is meat. And here again there’s evidence to suggest retail meats contain antibiotic-resistant bacteria far more often than we might like.

NARMS is the product of a collaboration between FDA, the USDA, and the CDC. This program tries to track antibiotic resistance in bacteria that can potentially cause foodborne illness. In 2007, 4282 retail meat samples were collected as part of NARMS; you can find the full report here. The first chart gives you the percentage of samples that tested positive for Campylobacter, Salmonella, Enterococcus and E. coli, and the graphs illustrate what percentage of these bacteria were resistant to various antibiotics. I’ve included the graphs for chicken breast only, although definitely check out the report if you are curious about other meats/the methodology used. Also click on any of the graphs to enlarge.

There are lots of interesting variations by type of meat, type of antibiotic etc, although for now I’ll just stick to my main point: raw meat often contains bacteria that exhibit a high level of resistance to various antibiotics.

Another interesting question concerns MRSA. There have been several studies on MRSA in retail meats, each of which came back with different results. One study in 2011 looking at 136 retail meat samples from 5 cities found MRSA in one sample of beef, one sample of turkey and one sample of pork. But those numbers by themselves don’t tell the whole story. As you’d expect, S. aureus bacteria were fairly common among the meat samples (77% of the turkey samples, 41% of the chicken, etc.), and 52% of the S. aureus bacteria from meat samples that contained S. aureus were multidrug-resistant (i.e. exhibited intermediate or complete resistance to at least three classes of antibiotic drugs).

None of this is very reassuring, of course, but there’s a caveat we should bear in mind. Typically meat is cooked before it’s eaten (unless you like steak tartare), and cooking should in general kill the bacteria if done properly. But foodborne illness isn’t the only issue here. We could imagine, for example, that if you are preparing raw meat containing S. aureus, there is some chance you could unintentionally colonize yourself with the bacteria, and as you see there is also some chance these S. aureus might be carrying genes that confer resistance to various antibiotics. So although food poisoning is one concern, colonization during meat preparation and the potential for cross-contamination is another.

To what extent does all of this contribute to antibiotic resistance in humans? Again, we don’t really know. But clearly it plays some role — and possibly a more significant role than we once imagined.

*There are different types of restriction enzymes, and some are much less specific about where they make cuts, although these are not the kinds we generally use in the lab. Moreover, you have to set up the digest properly, because under certain conditions you get so-called “star activity”, where an enzyme that normally cuts at specific sites loses some of its specificity.

*The restriction enzyme used in this case was EagI. SmaI has generally been used for PFGE typing of S. aureus, but so-called NT-MRSA cannot be PFGE-typed in this way owing to methylation of the SmaI restriction site. One Dutch study found that NT-MRSA seemed to be much more common among pig or cattle farmers than the general population (see [8])

It’s that time of year again

To recap, here’s the case against nontherapeutic use of antibiotics in a nutshell:

1) Antibiotic resistance is a serious public health threat that is growing in magnitude (and will likely continue to grow in the future).

2) We use large quantities of antibiotics in animals for nontherapeutic applications, which has the undoubted effect of promoting antibiotic resistance among their gut bacteria.

3) We know that antibiotic resistant bacteria from animals enter the environment on a large scale, together with a significant fraction of the antibiotics we feed to animals.

4) We know that humans come in contact with antibiotic resistant bacteria from farm animals on a fairly regular basis, both by way of raw meat (which often contains antibiotic resistant bacteria) and farm workers/vets etc (who work closely with both farm animals and their manure).

5) We know resistance genes have been and can be transferred between species.

6) Based on the above, we have every reason to believe that antibiotic resistance in farm animals contributes to antibiotic resistance in humans, although it’s difficult to determine how much and to what extent.

And no doubt we could argue about “how much” forever. But let’s ask a more illuminating question instead: what benefit do we derive that compensates for this threat to public health? We make it possible to produce meat more cheaply, but meat is in any case an inefficient use of our natural resources — hardly worth the risk nontherapeutic use may pose for us.

Now I don’t expect the industry to come this conclusion of their own accord. But that’s why we have regulatory agencies, to set rules that protect the public interest. And that’s why I initially found the FDA’s decision disappointing.

During the week since my last post, however, FDA made another move. They’ve decided to ban certain nontherapeutic agricultural uses of cephalosporins (a class of beta-lactam antibiotics). Although farmers don’t use cephalosporins as often as certain other classes of antibiotics, this is definitely good news. Nonetheless, I have to admit it leaves me somewhat perplexed about what FDA is planning to do. It seems to suggest they won’t necessarily stick to the “voluntary reform” approach described in their earlier announcement, and they’re moving slowly in the right direction.

So what can we make of all this? It’s difficult to say. I don’t understand or claim to understand all the “wheels and gears” that turn in Washington. I recognize, however, that idle uninformed blathering is one of our country’s oldest and most venerable political traditions, if not the very soul of American politics. So in the interests of doing my election-year duty as an American citizen, I’d like to indulge in some futile speculation about the motives for the FDA’s earlier decision.

Is it possible our government is waiting for a better time to take more decisive action? Our Fearless Leader must be re-elected to ensure we get more Hope and Change, after all, and yes, Sir Romney is nearly as charismatic as a wombat with crooked teeth, but given the state of the economy, Captain Change may be facing an uphill battle nonetheless. So I imagine it would be to the interests of all involved that issues likely to provoke powerful interest groups slumber until after the election. But wait! I must be mad! what am I thinking? We all know that political pressure never plays a role in policy decisions on science, don’t we? I mean, why would it? No rational person would make decisions about climate change or antibiotic use or science funding or energy policy or the “morning-after pill” based on political calculations. Of course not. Shame on me for thinking otherwise. Ah, thank goodness it’s Monday.

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[1] JoAnn Burkholder et al. “Impacts of waste from concentrated animal feeding operations on water quality.” Environmental Health Perspectives February 2007: 115(2), 308-312.

[2] Charles Gerba and James Smith, Jr. “Sources of pathogenic microorganisms and their fate during land application of wastes.” Journal of Environmental Quality Jan-Feb 2005: 34(1), 42-8.

[3] Waters, A., Contente-Cuomo, T., Buchhagen, J., Liu, C., Watson, L., Pearce, K., Foster, J., Bowers, J., Driebe, E., Engelthaler, D., Keim, P., & Price, L. (2011). Multidrug-Resistant Staphylococcus aureus in US Meat and Poultry Clinical Infectious Diseases, 52 (10), 1227-1230 DOI: 10.1093/cid/cir181

[4] Holger Heuer et al. “Antibiotic resistance gene spread due to manure application on agricultural fields.” Current Opinion in Microbiology June 2011: 14(3), 236-243.

[5] Kanika Bhargava et al. MRSA in retail meat, Detroit, MI. Emerging Infectious Diseases June 2011, 17(6). DOI: 10.3201/eid1706.101905

[6] Smith TC, Male MJ, Harper AL, Kroeger JS, Tinkler GP, et al. (2009) Methicillin-ResistantStaphylococcus aureus (MRSA) Strain ST398 Is Present in Midwestern U.S. Swine and Swine Workers. PLoS ONE 4(1): e4258. doi:10.1371/journal.pone.0004258

[7] A. J. de Neeling et al. “High prevalence of MRSA in pigs.” Veterinary Microbiology June 2007: 122(3-4), 366-372.

[8] Inge van Loo, et al. “Emergence of MRSA of Animal Origin in Humans.” Emerging Infectious Diseases December 2007: 13(12), 1834-1839.

[9] Patrizia Messi et al. “VRE in meat and environmental samples.” International Journal of Food Microbiology March 2006: 107(2), 218-222.

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