Mike the Mad Biologist

…high levels of resistance to cephalosporins and beta-lactam antibiotics are sure to follow. Sunday, the Washington Post covered the FDA approval of the use of cefquinome in cattle to treat respiratory pneumonia. The article provides a pretty good synopsis of what happened, so I won’t summarize the whole thing, but this decision represents a complete corruption of the regulatory process by industry. It’s that simple.

Here’s why cefquinome use in agriculture is really stupid: bacteria that evolve resistance to cefquinome, also become resistant to cefepime, a vital drug in the treatment of pneumonia and other diseases in humans, as well as most (or all) other cephalosporin and beta-lactam antibiotics. Essentially, we lose an entire class of drugs. In Europe, after cefquinome was approved, resistance to cefepime skyrocketed, reducing the effectiveness of cefepime. Rather than cefepime working almost all the time, it now is ineffective roughly 20% of the time, which means it can no longer be viewed as a ‘magic bullet.’

In the Washington Post article, “Guidance #152″ is referred to repeatedly. This is the standard the FDA uses to determine whether antibiotics should be approved for use in agriculture. I’ve blogged about this before, but it’s worth covering the relevant criteria of risk assessment that the FDA used:

The overall risk estimation is based upon the following theoretical assumptions:

*The proposed use of cefquinome in cattle may cause resistance in Salmonella spp. (and E. coli) present in the bovine intestinal tract, and

*These resistant Salmonella spp. may contaminate the carcass at slaughter and may transfer to humans via food, and

*These resistant Salmonella spp. may cause infections in humans which require treatment with a fourth-generation cephalosporin (cefepime), and the effectiveness of treatment may be compromised.

And my take on this:

I really don’t worry about cefepime resistant Salmonella infections. There just aren’t that many serious Salmonella infections. What I worry about are cefepime resistant Klebsiella and E. coli infections, which can cause pneumonia, sepsis, and urinary tract infections (don’t laugh about UTIs; they kill about 9,000 people/year in the U.S.). The entire focus on Salmonella is foolish. When a cow is treated with cefquinome, all of the harmless E. coli living in it (and there are a lot–around 100,000,000,000 per cow) are exposed to the antibiotic too. That means any E. coli that are cefepime resistant will be favored and increase. These E. coli can then enter the human population directly or transfer these resistance genes to other bacteria (for some reason, this point is made in the first assumption and then ignored in much of the report). Yet for some reason the FDA is obsessed with Salmonella. Salmonella is the tip of the iceberg; you would expect to find resistance genes in Salmonella last, simply because E. coli are so much more numerically dominant in cattle.

(an aside: I would also add Pseudomonas and Acinetobacter to the list of bugs I worry about. It’s a blog, not a policy paper…)

What is even more obscene about this regulatory failure is that there are twelve agriculturally approved and effective antibiotics for treating bovine respiratory disease. Not one. Not two. Twelve. That the FDA could not consider the European situation, where cefquinome approval was followed by cefepime resistance, should indicate just how broken the regulatory scheme for antibiotics is. In fact, the FDA can’t even suggest inappropriate off-label use, which means vets can use it for anything–and if enrofloxacin is any indication, they will*.

This is an utter public health failure. Next time, rather than writing a polite letter, I’m going to use dirty words, because presenting a sober, rational argument failed big time.

* I was at a conference about a year ago, and someone announced that a survey of dairy farmers in Washington state indicated that about five percent of farmers were treating cattle with enrofloxacin. Not only is this off-label, but it’s illegal. The table full of FDA people had a joint head explosion. It was ugly.

Comments

#1 Joshua
March 5, 2007

The article crossed my radar yesterday, and I knew you’d have something to say about it. I have nothing to add, of course. You’ve been talking about the dangers of livestock antibiotics for a while. I still fail to understand why this is so hard to understand; I hate to violate Hanlon’s Razor, but the only option in this case is clearly malice, or at least greed.

On a somewhat related topic, then, I have to wonder what your opinion is on antibiotic-free “organic” meats. It seems like a solution to the resistance problem, but I wonder if they have higher bacterial content that makes the risk of infection more likely, or some other trade-off that I can’t think of.
#2 Joshua
March 5, 2007

(Never mind about that question. You wrote something on it last summer!)
#3 Steven
March 5, 2007

Nice article again.

Doing a talk on Acquired microorganism resistance in plants : Phytoalexins.

Know of any good resources?

-Steven
#4 Michael Schmidt
March 5, 2007

My question for the FDA: Why do you hate America?
#5 Aggiemicro
March 8, 2007

Mike, Just a note, as of today (3/7) despite the catchy headlines FDA has made no decision- perhaps the Wash. Post is catering to KAW-driven alarmism? I haven’t taken a position either way, but I think we need to give CVM space to analyze the risk/benefit for this particular AB. Also, if a member of Congress happens to have a micro. degree does that qualify him/her to override FDA? Seems to me if you go into politics you’ve gone that route and need to leave the science to the scientists.
#6 Mike the Mad Biologist
March 8, 2007

Aggiemicro,

The FDA has analyzed the evidence, and the expert microbiology VMAC panel voted against approval. As far as risk/benefit goes, there is very little benefit (12 antibiotics still remain useful), and considerable risk based on the European experience.

As to leaving science to the scientists, I don’t know any staff scientists for the FDA or CDC who think this is a good idea; off the record, they think this is atrocious. Likewise, European veterinary lobbyists that I’ve spoken to also think there’s no question that this is a stupid idea. The industry people think this.

This isn’t ‘alarmism’ but consensus among the experts in the field.
#7 John Emerson
April 2, 2007

This is so depressing. I had an argument about this 25 years ago. I don’t know my sources then, but I had a basic understanding of the problem. The guy I was talking to had just taken an free-market econ class explaining that we have to consider all factors and come to a balanced view, and not jump to any conclusions about restricting agricultural use of antibiotics. Fake rationality. The guy I was arguing with was headed to med school too, but for him econ trumped medicine.
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I haven’t taken a position either way, but I think we need to give CVM space to analyze the risk/benefit for this particular AB. Also, if a member of Congress happens to have a micro. degree does that qualify him/her to override FDA? Seems to me if you go into politics you’ve gone that route and need to leave the science to the scientists.
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Likewise, European veterinary lobbyists that I’ve spoken to also think there’s no question that this is a stupid idea. The industry people think this.thak you for artcyle..
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The guy I was talking to had just taken an free-market econ class explaining that we have to consider all factors and come to a balanced view, and not jump to any conclusions about restricting agricultural use of antibiotics. Fake rationality.