09 September 2005

Applications of Evolution 2 - Bayer Withdraws Cipro

From a story in today's WaPo, I learned that Bayer has withdrawn it's poultry anitbiotic Baytril from the market. This marks the end of a five-year battle with the FDA over the drug.

The FDA first proposed withdrawing Baytril in October of 2000, due to concerns regarding the development of antibiotic resistance. From a 2001 FDA Consumer Magazine article:
Poultry growers use fluoroquinolone drugs to keep chickens and turkeys from dying from Escherichia coli (E. coli) infection, a disease that they could pick up from their own droppings. But the size of flocks precludes testing and treating individual chickens--so when a veterinarian diagnoses an infected bird, the farmers treat the whole flock by adding the drug to its drinking water. While the drug may cure the E. coli bacteria in the poultry, another kind of bacteria--Campylobacter--may build up resistance to these drugs. And that's the root of the problem.

People who consume chicken or turkey contaminated with fluoroquinolone-resistant Campylobacter are at risk of becoming infected with a bacteria that current drugs can't easily kill. Campylobacter is the most common bacterial cause of diarrheal illness in the United States, according to the Centers for Disease Control and Prevention. It's estimated to affect over 2 million persons every year, or 1 percent of the population.

Commonly found in chickens, Campylobacter doesn't make the birds sick. But humans who eat the bacteria-contaminated birds may develop fever, diarrhea, and abdominal cramps. In people with weakened immune systems, Campylobacter can be life-threatening. Eating undercooked chicken or turkey, or other food that has been contaminated from contact with raw poultry, is a frequent source of Campylobacter infection. Not washing utensils, countertops, cutting boards, sponges, or hands after coming into contact with raw poultry can also spread the bacteria and cause infection. People infected with Campylobacter may be prescribed a fluoroquinolone--which may or may not work.

But the damage doesn't stop there. "Cross-resistance occurs throughout this class of drugs," says Stephen F. Sundlof, DVM, PhD, director of CVM. "So resistance to one fluoroquinolone can compromise the effectiveness of all fluoroquinolone drugs."


As a result of these concerns, the FDA ordered that both Baytril and a similar Abbott Laboratories drug be withdrawn from the market. Abbott complied with the ruling, and Bayer appealed. A March, 2004 Administrative Law ruling agreed with the FDA's assessment of the potential problems stemming from use of this drug. Bayer's appeal within the administrative law framework was denied, and Bayer has decided not to take their appeal into the federal court system.

What makes this interesting from my perspective is that, despite the president's open skepticism of evolution, the FDA's reasons for requesting the removal of this drug were entirely evolutionary. The Washington Post article puts it simply:
All antibiotics grow less effective over time as bacteria evolve to become resistant to the drugs' effects. Experts say wider use of an antibiotic -- by either animals or people -- leads to a speedier development of resistance.


The FDA Administrative Judge's ruling gives an explanation that is slightly more complex:
Use of Baytril in poultry acts as a selection pressure, resulting in the emergence and dissemination of fluoroquinolone-resistant Campylobacter


Baytril acts as a selection pressure. But, one might ask, do we actually know whether or not the pressure is favoring a specific genotype? Is there a "resistance gene" in this bacteria? If so, do we know the sequence of mutations that lead to this? In this case, we do.

Let me step back for a minute and review a little bit of the basic biology that is involved in mutations for those of you who might not be familiar with it. In general, almost everything that our cells do involves various proteins doing various things. Our cells make the proteins based on the instructions found in our DNA. Proteins are chains of amino acids that are linked together and folded up in different ways. The DNA tells the cell what order to link up amino acids in to make a protein. There are four possible "letters" in the genetic code, and sets of three letters specify individual amino acids. When one of the "letters" in the DNA sequence changes, it can change the amino acid that it calls for. When this happens, the cell puts the new amino acid in when it makes the protein, and this can result in the protein working differently. (For more information on this, follow the links in the paragraph.)

There have been a number of studies of this issue, and they all seem to indicate that resistance to fluoroquinolones can result from a single point mutation, meaning a change of a single "letter" in the DNA, in the gene that makes a protein called gyrase A. Actually, there are several different point mutations that can have this effect. Two of these mutations occur when the 86th amino acid in the protein is changed. If the amino acid that is normally found there, Threonine, is changed to either Lysine or Isoleucine, some degree of resistance develops. Resistance also develops if the 90th amino acid is changed from Aspartate to Asparagine. Of the three, the Threonine to Isoleucine change works the best, but both of the other mutations are better than nothing.

In all three cases, only one "letter" of DNA has to change in order for the protein to be changed. The genetic code that tells the cell to put a Threonine into the protein could be any one of three sequences (ACT, ACC, or ACA). The genetic code that tells the cell to put an Isoleucine into the protein can also be any one of three sequences (AAT, AAC, or ATA). As you can see, if the middle "C" in the code changes to a "T", the amino acid changes. If "ACA" is changed to "AAA", the Threonine is replaced with Lysine. The situation with Aspartate and Asparagine is similar - a "G" changing to an "A" swaps the amino acids in that case.

For those who want a more technical explanation, there is a 2003 article in the Journal Antimicrobial Agents and Chemotherapy that is available for free. The full reference can be found at the bottom of this post. Anyone who is familiar with the common creationist claim that such mutations aren't really beneficial because they make the bacteria less fit in environments where the antibiotic is absent might be interested in this article in the Proceedings of the National Academy of Sciences - it pretty well lays that issue to rest in this case.

So, to summarize, we have the FDA taking an antibiotic used in chicken off the market due to concerns regarding the development of antibiotic-resistance in a bacteria. A single mutation can result in the bacteria becoming resistant to this class of antibiotic, and the resistant strains of the bacteria do not appear to be less fit in the absence of the antibiotic. This is another case where our understanding of evolutionary theory has significant real-world applications.

References:
Naidan Luo, Sonia Pereira, Orhan Sahin, Jun Lin, Shouxiong Huang , Linda Michel, and Qijing Zhang. 2005. Enhanced in vivo fitness of fluoroquinolone-resistant Campylobacter jejuni in the absence of antibiotic selection pressure. PNAS. Vol 102 p. 541

Naidan Luo, Orhan Sahin, Jun Lin, Linda O. Michel, and Qijing Zhang. 2003. In Vivo Selection of Campylobacter Isolates with High Levels of Fluoroquinolone Resistance Associated with gyrA Mutations and the Function of the CmeABC Efflux Pump. Antimicrobial Agents and Chemotherapy. Vol 47, p. 390

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