Politics vs. science, part I: The FDA drops the ball

You know someone’s thinking too hard when it takes them thirty years to make up their mind. But when it takes them thirty years to make up their mind and to top it off they make a bad decision — that’s when you know politics is involved.

Back in 1977, the US Food and Drug Administration proposed restrictions on the use of antibiotics in animal feed. Congress intervened to block FDA, directing them to await the results of ongoing research, and the FDA continued to research the issue for another three decades. Earlier this year a nonprofit group filed a lawsuit demanding the FDA take action. Evidently FDA didn’t feel so moved, because last week they withdrew their 1977 proposal instead.

That doesn’t mean FDA is no longer worried about antibiotics in animal feed. On the contrary: their announcement notes that “today’s action should not be interpreted as a sign that FDA no longer has safety concerns” and that “medically important drugs in food-producing animals should be limited to those uses that are considered necessary for assuring animal health.”

So if FDA is concerned and doesn’t like the status quo, why won’t they take action? Apparently, they’ve decided “voluntary reform” by industry is a more “resource-efficient” approach.

In their own words:

Because the process of reviewing safety information for antimicrobial drugs approved before 2003 (and pursuing withdrawal proceedings if appropriate in some cases) would take many years and would impose significant resource demands on the Agency, FDA began thinking about alternate approaches to address safety concerns…

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For now, FDA’s efforts will focus on promoting voluntary reform and the judicious use of antimicrobials in the interest of best using the agency’s overall resources to protect the public health.

How likely is it the US livestock industry will voluntarily choose to phase out antibiotics in animal feed? Right now, over 70% of US antibiotics are used on livestock, and most of it is fed to healthy animals for nontherapeutic purposes (e.g. promoting growth). Frankly, I’m a little doubtful that agribusiness and pharmaceutical companies will cut their revenues out of the sheer goodness of their hearts. That’s not human nature.  And some industry associations have already made it clear they see no reason to do so. From the Wall Street Journal article:

…the National Pork Producers Council, a group that supports the use of antibiotics by its members, called the lawsuit “spurious” and the group’s president, Doug Wolf, said there’s no evidence that human health is threatened by the use of antibiotics in livestock feed.

Somehow, remarks like these remind me of the tobacco industry’s long struggle to portray cigarettes as safe. Nobody opposes appropriate use of antibiotics to treat sick animals, but non-therapeutic use is another matter. No cow* is an island, as John Donne would point out, and there’s excellent reason to believe nontherapeutic use threatens public health in a serious way.

*Or pig, for that matter. Or chicken, come to think of it.

Rogue Mutants

Repeatedly exposing bacteria to low concentrations of antibiotic is unwise because it drives the evolution of resistance. Just like human populations, bacterial populations can be genetically diverse. It can often happen that some bacteria in a large population are more susceptible to a given antibiotic than others. If the concentration of antibiotic is high enough to kill some but not all of the bacteria, the most susceptible die, and only the more resistant bugs pass on their genes. As a result, the genetic makeup of the population changes across generations, and the population becomes more resistant to the drug — a classic example of evolution in action.

Describing resistance this way makes the process sound straightforward, but the details are more complex. Many different genes and mutations can make bacteria more resistant to certain types of antibiotics. You could easily write a dozen blog posts about the genetics and the molecular biology of all this, but to keep it simple, the following are the top four tactics bacteria employ against us:

1) Destroy the antibiotic.

Many drug-resistant bacteria produce enzymes that chemically alter or break down certain kinds of antibiotics. Beta-lactam antibiotics like penicillins, for example, owe their name to a chemical feature called a beta-lactam ring:

Lactam is just chemist-jargon for an amide that forms a ring (an amide is the group shown on the left), and the “beta” part indicates the ring is made of four atoms. The bond angles in the ring create some strain and makes the bonds easier to break, a little like the way a plastic coat hanger would be easier to break if you bent it out of shape first, so a beta-lactam ring is unusually reactive compared to other amides.

Ordinarily, beta-lactam antibiotics* react with an enzyme the bacteria use to construct their cell wall. The reaction cripples the enzyme and renders it useless, so the bacterium dies when it tries to divide. Many resistant bacteria deal with this problem by producing proteins called beta-lactamases; these enzymes catalyze the breakdown of the beta-lactam ring:

rendering the antibiotic utterly useless. Unfortunately, Nature has invented a whole palette of these beta-lactamases, and nearly all our beta-lactam drugs are vulnerable to destruction by one or another of these enzymes. Still other bacteria feature enzymes that disable various antibiotics by adding chemical groups to them, like enzymes that modify aminoglycoside antibiotics.

*Some beta-lactam antibiotics are only effective against Gram-positive bacteria; others can target Gram-negative as well. Carbapenems, penicillins and cephalosporins are all beta-lactam antibiotics.

2) Man the bilge pumps.

Many drug-resistant bacteria deal with antibiotics using the molecular equivalent of a bilge pump: proteins embedded in the membrane that grab drug molecules and chuck them back out of the cell. This process takes energy, and the higher the antibiotic concentration outside the cell, the more work it takes. Ordinarily bacteria employ these pumps to fill other roles, like dumping junk they’ve encountered in their environment. Some mutations equip the bacterium with more bilge pumps by making the bilge-pump genes more active. Many bacterial bilge-pumps expel a remarkably broad range of compounds, and sometimes the genes are transferred between bacteria, just like the genes for enzymes like beta-lactamases.

3) Move the target.

Antibiotics work by interfering with a vital process (e.g. cell wall construction) or crippling an enzyme the bacteria can’t do without. Some mutations change the structure of a target so the drug molecule binds much more weakly. Now you need a much higher concentration of the drug to knock out the target, to the point where the antibiotic may become completely useless. Fluoroquinolone drugs like Cipro, for example, bind to DNA gyrase*, an enzyme that prevents bacterial DNA from getting tangled up during DNA replication. Mutations that alter the structure of the DNA gyrase can result in quinolone-resistant strains.

*Also to topoisomerase IV.

4) Don’t be so permeable.

The Gram stain is a simple test microbiologists use to distinguish two broad groups of bacteria, Gram-positive and Gram-negative. Gram-negative bacteria have both an inner and an outer membrane, and changes that make this outer membrane less permeable to antibiotics can blunt some of our chemical weapons. Various antibiotics cross the bacterial outer membrane by way of channels called porins, for example, and changes to porin structure or the loss of certain types of porins can reduce the rate at which these antibiotics make their entry.

Clearly tactics like these are advantageous if an antibiotic is present. But what about when the antibiotic is absent? You’d think a bacterium that produces beta-lactamase, for instance, would ordinarily be at a disadvantage, because it’s spending precious energy to make a fancy enzyme while its neighbors spend their energy into growth. Unfortunately, many resistant bacteria have found ways to regain the edge. Additional mutations can mask problems created by a drug-resistance mutation, for example, and in many strains that produce beta-lactamases, the gene coding for the beta-lactamase is regulated so it’s only turned on when needed. So reversing the rise of resistance may be more difficult than we might expect — and if we can help it, we’d rather avoid fostering resistance in the first place.

When we continually feed low doses of antibiotics to animals, we’re promoting antibiotic resistance among the bacteria that inhabit the animal’s digestive tract. You only need to understand evolutionary biology at a 101 level to see that. It’s difficult, in fact, to see how it could be otherwise, unless you’re a Creationist who believes the Earth is 10,000 years old and the Intelligent Designer periodically makes new antibiotic-resistant strains to punish people for being descended from Adam and Eve. (And I don’t think you believe that — at least I hope you don’t.)

Even industry trade groups wouldn’t deny this point. That’s why they’re making another argument instead. They claim antibiotic resistance in bacteria in livestock does not contribute to antibiotic resistance in humans. This claim conflicts with logic, it conflicts with what we know about bacteria, and most importantly of all, it conflicts with the evidence. Not only do bacteria from livestock enter the environment, but they can transfer antibiotic resistance genes to other bacteria through mechanisms like bacterial sex*. Next week, we’ll take a look at how this works.

Coming up: How antibiotic resistance from livestock threatens public health, and more thoughts on the FDA’s decision.

*Not sex in the usual sense of the word! The technical (and rather boring) name for this process is “conjugation”.

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[1] Elena Breidenstein et al. “Pseudomonas aeruginosa: all roads lead to resistance.” Trends in Microbiology August 2011: 19(8), 419-426.

[2] Henrik Wegener. “Antibiotics in animal feed and their role in resistance development.” Current Opinion in Microbiology October 2003: 6(5), 439-445.

[3] Joshua Hayes et al. “Prevalence and antimicrobial resistance of Enterococcus species isolated from retail meats.” Applied Environmental Microbiology December 2003: 69(12), 7153-7160.

[4] Brooks, Geo, Carroll, Karen et al. Medical Microbiology. New York, NY: McGraw-Hill Medical, 2007.

[5] Anne Delcour. “Outer membrane permeability and antibiotic resistance.” Biochimica et Biophysica Acta May 2009: 1794(5), 808-816.

[6] Dan Andersson and Diarmaid Hughes. “Antibiotic resistance and its cost: is it possible to reverse resistance?” Nature Microbiology Reviews April 2010: 8, 260-271.

Wegener, H. (2003). Antibiotics in animal feed and their role in resistance development Current Opinion in Microbiology, 6 (5), 439-445 DOI: 10.1016/j.mib.2003.09.009

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