Posted by Burt Humburg on March 4, 2007 10:28 AM

It would come as no surprise to us here at the Thumb that our readers would accept a physician not giving antibiotics for an ailment unless that physician felt that the infection was bacterial, that the therapy was warranted, and that the selection of antibiotics was appropriate for the suspected organism. Doctors restrict their antibiotic use because of evolution: indiscriminate use of antibiotics leads to the evolution of resistance to those antibiotics in those bacteria that survive the infection. I suspect many of our readers also know that antibiotics are given to livestock routinely to help them grow bigger, faster. Our friends at ScienceBlogs are all over this topic and the problems it presents. By way of summary, if you give animals an antibiotic that looks and acts like one you give humans, resistance will also evolve there, just as surely as it will from a doctor who reaches for his prescription pad before he’s taken an adequate history or completed an adequate exam.

This morning’s Washington Post has a disturbing article on the approval of cefquinome for use in cattle. It’s disturbing for a number of reasons, and we’ll discuss them on the flipside.

First, cefquinome is a fourth-generation cephalosporin, a class of antibiotics that have extremely broad spectra of activity against bacteria. From my experience as a physician, I can tell you that when someone is extremely sick in the ICU, fourth-generation cephalosporins like cefepime are often the first drugs we reach for, especially if the patient has a penicillin allergy.

Now we don’t give cefepime to everyone with a bacterial infection for the same reason we don’t give every person with a cough or cold an antibiotic: setting aside the fact that antibiotics can lead to life threatening infections, indiscriminant use of fourth-generation cephalosporins would increase the risk of bacteria evolving resistance to those antibiotics.

So approving the use of fourth-generation cephalosporins in cattle is a healthcare version of being penny-wise and pound-foolish: what good does it do to have discerning physicians who limit their use of fourth-generation cephalosporins when bugs can just evolve resistance to them when they’re given to cattle indiscriminately?

Second, the Washington Post article talks about the conditions under which those cattle are raised. This is not a situation where Bessie the family cow is sick and needs antibiotics to continue making milk for Farmer Jim and his wife; this is not a case of isolated antibiotic use. This is a situation where cattle are kept in such high density that disease transmissibility goes up and immune strength goes down. It makes sense that it is easier and cheaper to simply give those closely-packed cattle fourth-generation cephalosporins than it is to take steps to prevent disease virulence in the first place. It also makes sense that these analyses probably didn’t put as much weight on the risk of evolving resistance to fourth-generation cephalosporins as would, say, people worried about dying from it. (Unfortunately, we can’t know the answer to that question because the Washington Post tried to interview InterVet representative several times, probably to ask them how strongly they weighed the risks of increased human morbidity or mortality if their drug were approved. InterVet declined several requests for interviews communicating to the Post only via statements which included such facile boilerplate as the company “fully supports the prudent use of antibiotics in animals.”)

Recognizing the risks of antibiotic reistance evolution, the AMA, along with several other concerned groups, warned the FDA that the approval of the drug might lead to the evolution of resistance. They cited much evidence in support of their concerns, including the fact that the approval of fourth-generation cephalosporin use in Europe led to increased fourth-generation cephalosporin resistance in bacteria there. Recognizing this, the FDA’s own advisory board voted to not approve the drug. Everyone and their dog, it seems, want the FDA to not approve the drug, but the FDA will probably have to approve it thanks to a “recently implemented ‘guidance document’ that codifies how to weigh the threats to human health posed by proposed new animal drugs” known as Guidance #152.

Industry representatives say they trust Guidance #152’s calculation that cefquinome should be approved. “There is reasonable certainty of no harm to public health,” Carl Johnson, InterVet’s director of product development, told the FDA last fall….

“The industry says that ‘until you show us a direct link to human mortality from the use of these drugs in animals, we don’t think you should preclude their use,’ “ said Edward Belongia, an epidemiologist at the Marshfield Clinic Research Foundation in Wisconsin. “But do we really want to drive more resistance genes into the human population? It’s easy to open the barn door, but it’s hard to close the door once it’s open.”

Let me get this straight. Thanks to Guidance #152, the FDA has limited power to disapprove drugs that cannot currently be shown to have a risk to humans? This guidance appears to not account for the effects of evolution at all. Evolving resistance evolves. The fact that resistant organisms don’t exist at the Time A doesn’t negate the fact that resistance is highly likely to evolve when conditions (like indiscriminant use of the antibiotics or their use in densely packed livestock) are optimal for the evolution of resistance at Time B. After resistance has evolved to broad-spectrum antibiotics is not the time to prevent the evolution of resistance.

The article goes on to explain how the drug would have been denied approval had it led to the evolution of resistance in food-bourne illness. Since fourth-generation cephalosporins treat diseases other than food-bourne illnesses, the FDA is limited in its power to disapprove it due to the specific language of Guidance #152. The restriction that the FDA can only deny antibiotic approval in those agents likely to impact only food-bourne illnesses is arbitrary and indefensible.

Finally, the article discusses indirectly the phenomenon of multidrug resistance traits, which can get passed to other bacteria. Briefly, if a bacterium evolves resistance to fourth-generation cephalosporins, they can often resist third-generation cephalosporins as well.

Guys, this is concerning stuff. Creationists hem and haw about this or that aspect of evolution, but the evolution of bacterial resistance is life-and-death stuff. When your kid has meningitis and 48 hours after starting a third-generation cephalosporin there’s no improvement, that is not the time to be wondering whether steps should have been taken to limit the evolution of resistance to antibiotics. When your ailing mother has a pneumonia involving an organism that ought to be susceptible to fourth-generation cephalosporins but isn’t, that is not the time to wonder whether a guidance document that permits the exclusion of drugs that could lead to resistance in food-bourne illness but not for others might unduly restrict the FDA’s oversight power.

Write your congressperson and senator and demand that Guidance #152 be revised to reflect resistance to antibiotics in any disease, not just food-bourne illnesses. The FDA needs to have the power to regulate all antibiotics and to disapprove of any drug to which such broad opposition exists.

Edit: Mike the Mad Biologist has already covered this, it seems. (Check out his letter to the FDA written ages ago.)