On Nov. 25, 2008, the Food and Drug Administration (FDA) revoked the order prohibiting the extralabel use of cephalosporin antimicrobial drugs in food-producing animals so that it may fully consider the many substantive comments it received on the order of prohibition.

The order, which was to take effect on Nov. 30, 2008, would have changed 21 CFR 530.41 to list cephalosporins as prohibited from extralabel use in food-producing animals. It was originally announced in the Federal Register on July 3, 2008 with a 60-day comment period and a 90-day effective date for the final rule; however, on Aug. 18, 2008, the agency extended the comment period to Nov. 1 to allow adequate time for interested persons to submit comments, thus delaying the implementation of the rule.

Bovine Veterinarian asked noted veterinary clinical pharmacologist, Mike Apley, DVM, PhD, Dipl. ACVCP, Kansas State University, about the impact of this ruling and what it might mean for future situations involving antimicrobials used in food-animal medicine.

Bovine Veterinarian: How significant of a ruling is this to the food-animal community?

Mike Apley: The proposed prohibition was concerning to me and many others because it lumped all extralabel cephalosporin uses together from a 30,000-foot view with-out taking into account the different risks that may occur with the many possible extralabel uses. I believe the risk of a resistant food-borne illness differs dramatically depending on the class of animal and the disease being treated.

The proposed rule would have had  a huge effect on our ability to address infectious disease in food animals.

If the goal was simply to reduce the use of cephalosporins in food animals, then I think the dialogue should have been initiated based on specific target uses with a reasoned argument for each. The fact of the matter is that the FDA/CVM has absolutely no data to quantify extralabel use either in total or by application.

BV: Does this decision indicate that the FDA will listen to the science and expertise of food-animal industry on the use of food-animal drugs in the future?

Apley: I think they have listened to us in the past and will continue to do so in the future. But realize that we are in an environment where listening to stakeholders by the agency includes those of us closely tied to the food-animal industry as well as those opposed even to our existence as an industry. The goal of the anti-food animal groups is to take away every tool from us that they possibly can in an attempt to “cost us out of business” in incremental steps.

I do not consider the FDA/CVM as anti-food-animal, and I recognize their primary mission of protecting human health in relation to regulation of drugs used in food animals; however, I think that balance in seeking input on the proposed rule was not achieved prior to release of the initial rule. I am not attempting to vilify the agency or people working there, I just don’t think the big picture was looked at hard enough in this case. On the bright side, the system worked the way it is supposed to, where input from stakeholders caused the agency to step back and take another look. I very much appreciate them doing that.  

BV: What’s wrong with using the “precautionary principle” for decision-making?

Apley: One of the terms that quickly becomes “fightin’ words” is precautionary principle. This is the regulatory approach that resulted in the European Union withdrawing drugs such as ionophores from feed use in food animals. If there was ever evidence that an approach was broken, this is it. The principle has been invoked overseas to bring about sweeping regulatory changes, with little or no evidence of adverse effects in some cases. If there is actually no adverse effect of the practice, and the precautionary principle led to an erroneous decision, then the precautionary approach is that the sponsors can prove that; basically it’s a guilty-until-proven-innocent system.

Without insinuating that this approach was taken in the proposed rule, we need to understand that the food animal industry and veterinary profession in the United States must absolutely not tolerate the application of this principle for regulation in this country. The real danger arises when issues such as methicillin-resistant Staph. aureus (MRSA) gets blamed on food animals. The data is there that MRSA in animals can colonize the noses of people working with them. The data is also there that the isolates causing human outbreaks are not related to the animal isolates.

BV: What steps does the industry need to take to ensure that antimicrobials are used in a prudent manner to prevent restrictive legislation in the future?

Apley: First, we can’t afford to have publicized infractions of regulations and laws. We should be as intolerant of illegal and ill-advised drug use as we are of egregious violations of animal welfare.

But what about the legal and prudent uses where we are definitely having a positive impact on animal welfare and production? Our production systems have co-evolved with antimicrobials; this is at the base of the whole issue. How would we run our current systems without them and still be efficient enough to produce a commodity product for the prices we receive? If you took antimicrobials away, the markets would adjust, that’s what happens to a commodity. However, another round of us would go out in the adjustment because a decreased supply would be necessary to get prices up high enough to offset the loss in production efficiency.

The message to the industry is that new antimicrobials will be few and far between (if any) and some will likely be taken away from us. When we look at the combination of increasing production costs, regulation, legislation, and consumer sentiment (at least as perceived by food retailers) there are some huge changes coming for us. Those who have developed production practices that require the least amount of antimicrobials will be way out in the lead.   

BV: How should organizations such as the American Association of Bovine Practitioners and the Academy of Veterinary Consultants, etc. and their members mobilize together with science-based responses when these threats arise?

Apley: You have to have people interested in the subject and in positions to take time to stay plugged in. For the AABP and AVC it requires being plugged in to the appropriate producer organizations and groups in Washington, D.C. The availability of antimicrobials for food animals will be decided by both regulation and legislation.

For regulation, providing arguments combined with data is the answer if the agencies are truly looking for stakeholder input. If the agencies start to utilize the precautionary principle, then that doesn’t work. That’s why every indication of precautionary principle adoption in the United States must be met with the full resources of the industry. Keep in mind that the regulatory agencies work in a pressure environment with a lot of the pressure coming from the legislative and executive branches, neither of which has impressed me with their ability to go deeper into issues than public opinion polls. Pressure on regulatory agencies from a viewpoint of removing many of our antimicrobial tools is about to increase dramatically.

For legislation, what matters is the ability to put experienced, savvy people on the ground in D.C. armed with good arguments, and combine this effort with grass roots engagement of congressional representatives. But think about that latter part; do more people live in the country or in the cities? The key is engaging congressional staffers on a consistent basis, both in time and in message. One of the most frustrating parts is that someone such as myself is considered biased because of my relationship with the industry, but a twenty-something spouting propaganda from a vegan website is considered agenda-free.

If you have sat out the previous rounds, you had better find the websites of your congressional representatives, get involved with an organization that can put people in D.C., and stay tuned to what is going on. The AABP and AVC listservs are good places to get up-to-the-minute updates when surges occur in these issues. Understand that the cephalosporin issue is just the tip of the iceberg.   

BV: What would you say as a veterinary pharmacologist about the prudent use of these products and the potential or non-potential for resistance issues?

Apley: I think the vast majority of our antimicrobial applications have a rational target and within these most of the applications make a definite difference. But, it isn’t really about whether we can justify the uses on a drug:bug basis. It is about whether we can justify the production systems that put us in the situation of having the diseases that make the drug:bug interaction necessary. I hope everyone understands that this is the core issue. We have to be able to defend our production systems that the uses occur in, not just the uses.

As for resistance, I know that application of an antimicrobial has the potential of altering bacterial populations. I know that bacterial population susceptibility distributions have changed for some antimicrobial/bacterial combinations. What I don’t know is the relationship between the amount of antimicrobials used and the shift in population makeup and susceptibility profile, the stability of the new profile, and the probability that the new profile will cause human problems. I do know that we are only able to work with about 5-10% of the estimated bacterial genera and species in the lab and that genetic resistance determinants can move between genera and species. My conclusion is that no bacterial population is truly isolated from another.

I don’t think the sky is falling, but I also don’t think we are doing the best we can do yet. The systems have evolved the way they have based on a lot of good sound science related to production and food safety. I think the bright people who brought us to this point will be called on again for major revisions as we continue to experience volatility in availability and cost of inputs (including antimicrobials). I’m not conceding the issues, but it is unrealistic to assume that no changes will occur.

The fringe activists criticizing us are easily dismissed (by us, anyway). But there are some groups more to the sensible side of them that have some points we ought to engage at a common table.

For more information on the ruling, visit click here.