19 February 2010

Antibiotics and farming — how superbugs happen

Constant readers: There's an important new paper that's been out for a week that I haven't gotten to you. I apologize; it's been busy. (Let's not even talk about the important paper that's been out for two weeks. Maybe over the weekend...)

We've talked for ages now about the potential dangers of unrestricted antibiotic use in agriculture, and how it's analogous to the inappropriate antibiotic use that human health authorities disapprove of in humans. The main culprits, in farming, are subtherapeutic dosing, also known as growth promotion — that's giving routine smaller-than-treatment doses to animals to increase their weight — and prophylactic dosing, which is giving a treatment dose to an entire herd or flock either routinely, if there is thought to be a disease threat, or when there is known to be disease in some members of the herd/flock. In either case, animals are getting antibiotics when they do not need them — when they are not sick. And just as in humans who take antibiotics when they are not sick, or take too-low doses when they are sick (such as not finishing a prescription), these practices in animals encourage the development of resistant bacteria.

(Necessary comment here: No one, to my knowledge, objects to giving the appropriate doses of antibiotics to animals that are sick. Why would you?)

The interesting research question is how, exactly, resistance develops. (My real scientist readers may want to take a break, or cut me a break, for the next few sentences. Please.) The classical assumption has been that, through a variety of stimuli and the random copying errors of reproduction, bacteria are constantly acquiring small mutations. Some of those may give the bugs an advantage when they are exposed to a drug, some slight difference that allows the bacteria to disarm or turn aside that drug's particular method of assault — so that the weak die, the strong survive, and the strong then reproduce more abundantly into that extra living space freed up by the death of the weak. The survivors and their descendants retain that mutation, because it gave them an advantage against the drug. And because bacteria can share resistance factors not only vertically mother-to-daughter, but horizontally in the same generation, once the resistance has emerged, it is likely to spread.

But no matter how quickly it spreads, that process I've just described involves acquiring resistance to just one drug or drug family at a time. Provocative new research from Boston University's medical school and deoartment of biomedical engineering now suggests, though, that multi-drug resistance can be acquired in one pass, through a different mutational process triggered by sublethal doses of antibiotics — the same sort of doses that are given to animals on farms.

In earlier work, the authors found that antibiotics attack bacteria not only in the ways they are designed to (the beta-lactams such as methicillin, for instance, interfere with staph's ability to make new cell walls as the bug reproduces, causing the daughter cells to burst and die), but also in an unexpected way. They stimulate the production of free radicals, oxygen molecules with an extra electron, that bind to and damage the bacteria's DNA.

That research used lethal doses of antibiotics, and ascertained that the free-radical production killed the bacteria. In the new research, the team uses sublethal doses, and here's what they find: The same free-radical production doesn't kill the bacteria, but it acts as a dramatic stimulus to mutation, triggering production of a wide variety of mutations — what the researchers, in a press release, called "a zoo of mutants." The plentiful, scattershot mutations included ones that created resistance to a number of different drugs — in some cases, even though no mutation was present that created resistance to the drug being administered.

You can easily see how this is applicable to factory farming: The sublethal dosing applied experimentally is analogous to the subtherapeutic dosing used in agriculture. Is it applicable to MRSA? Yes, absolutely. The two organisms the researchers used to test their hypothesis were S. aureus and E. coli.

making the implication clear, senior author James J. Collins said on the paper's release:
"These findings drive home the need for tighter regulations on the use of antibiotics, especially in agriculture; for doctors to be more disciplined in their prescription of antibiotics; and for patients to be more disciplined in following their prescriptions."
The cite is: Kohanski MA, DePristo MA and Collins, JJ. Sublethal Antibiotic Treatment Leads to Multidrug Resistance via Radical-Induced Mutagenesis. Molecular Cell, Volume 37, Issue 3, 311-320, 12 February 2010.

UPDATE: There's a great discussion of the paper at the blog Mental Indigestion.

Postscript: I suppose I've been working too long without a break, because while I was reading about this process of creating multiple resistance factors at once, what I heard in my head was Mickey Mouse chirping: "Seven at one blow!"


Eve Harris said...

More bad news about superbugs. While reading I am seeing in my mind's eye the alluring yet dangerous strawberry fields in Watsonville, CA. And of course the lettuce fields -- remember e coli?

Thanks for doing this important work.

- Eve Harris
A Healthy Piece of My Mind @ eveharris.net

Anonymous said...

New study shows factory farms breed mutated superbugs with antibiotic feed


Boy did you get this just plain WRONG! The Boston University study looked at products used in human medicine to evaluate concerns over protocols such as missed doses. The categories of drugs that they evaluated are NOT USED IN LOW DOSES IN ANIMAL FEEDS - they are not even available as oral medications for animals. Even Superman couldn't make the leap that you try to make in this article. If you are going to advocate for a position, at least do so honestly instead of misusing bits of data that have no relevance to the discussion.

Clarification ??

Anonymous said...

are Hemolytic Uremic Syndrome deaths being underreported ?

Jim said...


There is a term for the over-confident declarations such as "Boy did you get this just plain WRONG!" By being more understated, you look less foolish when you later discover that you were not exactly correct.

The type of drug used was not so important as the concentration. The studies by Collins have been demonstrating that low dose a/biotics may result in resistance to multiple (unrelated) a/biotics, whilst still remaining sensitive to the original a/biotic.

Whether a specific drug used n agriculture is used in human clinics is also not a sound basis for your statement. Frequently, bacterial resistance mechanisms can confer resistance to multiple individual drugs within a given class of a/biotic (and there are only 7 classes, on last count). Thus specific resistance developed against an agricultural-use only a/biotic can result in resistance that can be viable against clinical a/biotics.

If prophylactic use of a/biotics is limited or fully abated, then this is a step in the right direction, but the concerns highlighted by these studies, and this blog, still stand for any such use.