Call it over-reaction to a hypothetical problem or necessary intervention between man and nature. But the tempest raging over how antibiotics used in animal agriculture may contribute to increased antibiotic resistance in humans will likely change the way beef producers combat animal health challenges.

"I think the industry should expect a drought of new antimicrobial compounds being developed for food production," says Mike Apley, a clinical pharmacologist at Iowa State University's College of Veterinary Medicine.

"It's clear the Food and Drug Administration (FDA) has determined antibiotic use in animals is a cause for concern in human health. They've indicated antibiotic use will be controlled with this Framework (see below) or something with a similar format," he says.

That Framework is FDA's Proposed Framework for Evaluating and Assuring the Human Safety of the Microbial Effects of Antimicrobial New Animal Drugs Intended for Use inFood-producing Animals.

The FDA Framework In a nutshell, the FDA Framework, a potential precursor to new regulations, is billed as a conceptual risk-based framework for evaluating the human safety of using antibiotics in animals. Specifically, the Framework seeks to manage the risk of antibiotic resistance in humans by addressing the possibility of increased resistance transferred through food.

Among other things, it would classify new and existing antibiotics based on their importance to human medicine, set thresholds based upon acceptable levels of susceptibility of food borne pathogens to different antibiotics, then monitor susceptibility over time.

The Framework has drawn criticism from animal health professionals for being too restrictive to antibiotic use in animals. Some human health professionals say they're not strict enough.

On the animal side, critics say a lack of science makes it impossible for manufacturers, or anyone else, to define acceptable levels of susceptibility. They say subjective thresholds and the dynamic nature of bacteria, including changes in susceptibility to antibiotics over time, set the stage for less new product development.

The thinking is that manufacturers may be reluctant to invest years and millions of dollars to develop new products if, once approved, they could be removed from the market. Most every class of antibiotic used in animal agriculture today is common to those used in human medicine; ionophores are one exception.

At a time when he says more rather than fewer products are needed to combat animal disease, Lyle Vogel says the Framework will make it more difficult to approve new drugs and retain existing ones. He's director of the Division of Scientific Activities for the American Veterinary Medical Association (AVMA).

"AVMA is concerned with antibiotic resistance that could be transferred through the food supply, and its potential impact on human health. But, we don't know the magnitude of the risk to human health," he says. "Therefore, FDA's Framework may be an over-reaction to the problem."

From a public health perspective, however, Fred Angulo, medical epidemiologist at the Center for Disease Control and Prevention, says FDA's Framework is the only acceptable alternative to the current drug approval process.

"The only safeguard currently is when the drug is approved. That means FDA has to determine whether a new drug will result in resistance and cause a problem," says Angulo. Short of a declared emergency, he says there's no way to pull an approved drug off the market. He believes the Framework will provide this safeguard.

Is Resistance A Problem? FDA's Framework is just the latest entry in the debate that began when antibiotics were approved for animal use in 1951. No one questions that resistance is a documented consequence of the use of antibiotics.

"Clearly antibiotic resistance takes place. It also takes place outside of pathogens being exposed to antibiotics. These pathogens always look for ways to protect themselves. In that sense, there are hazards from using antibiotics in human and animal medicine because of the potential for bacteria to select for resistance," says John Keeling, vice president of legislative and public affairs for the Animal Health Institute.

"The question is, considering all of the variables such as usage and dosage, does the risk of using antibiotics rise to a level of being a risk to human health?" he asks.

The real debate revolves around questions like:

-- How much resistance do non-targeted organisms build as the result of attacking a target organism with antibiotics?

-- To what degree is resistance passed from animals to humans via the food chain?

-- At what level does resistance passed through the food chain become a public health risk?

-- How much does the use of human antibiotic use contribute to increased resistance? For that matter, how much does the use of antibiotics in animal agriculture reduce the number of bacteria humans are ultimately exposed to?

Given the science that exists, Apley says people have their heads in the sand if they believe bacterial populations in animals and humans are completely separate.

That said, Apley adds, "A lot of the predicted links between the use of antimicrobials in animal health and efficacy in human medicine are pretty loose. Regardless, we must be responsible stewards of antimicrobials in food animals, and that includes learning all we can about minimizing the development of resistant organisms."

But, Keeling says data from the National Antimicrobial Resistance Monitoring System indicates there's not a significant change to susceptibility taking place. He says recent studies by the World Health Organization and the National Research Council indicate that, while there's concern that resistant bacteria in food animals can be transferred to humans, more data is needed.

"There is no documented case where antibiotic use in animals has caused treatment failure in people," says Keeling. What's more, the system for collecting needed information, and the need for standardization between existing studies, which could provide more concrete answers, doesn't currently exist.

Angulo, however, says it is clear increased resistance is related to the use of antibiotics in animals. He points to one study showing a dramatic 34% increase (between 1980-97) of studied salmonella poisoning cases in which bacteria were resistant to five commonly used antibiotics.

Vogel, however, counters that the study Angulo refers to is misleading because it attempts to compare data from three different studies; data, he says, is not comparable.

Only one of the five antibiotics described in the study is commonly used to treat Salmonella infections in the rare cases where treatment is required, Vogel says. Plus, the percentages represent only a subset of Salmonella infections. In two other studies, Vogel says increased resistance of the same Salmonella isolates to antibiotics is 7-8%, rather than 34%.

What is the contribution of food animals to overall resistance? Angulo says that's difficult to answer.

"But, a more focused question is whether antibiotic resistance is increasing in food borne pathogens. And, it's clear the use of antibiotics in animals is increasing resistance in those pathogens," he says.

While not conclusive, a number of studies convinced FDA it had enough evidence to act. What's more, the threat of losing the latest and most popular antibiotic choice for combating food borne illness in humans convinced them time was of essence (see "A Chat With Stephen Sundlof," page 34).

"The kind of criticism we hear is that we haven't done enough to identify the impact on public health, so we shouldn't be doing anything. We've already made the statement in the Federal Register that there is sufficient evidence, that this is a public health issue that needs to be addressed," says Stephen Sundlof, director of FDA's Center for Veterinary Medicine.

Proceed With Caution Still, animal health organizations like AHI believe the science is too tenuous, and the potential downside of the Framework too severe, to implement sweeping policy and regulations without further study.

"It is impossible for drug companies to predict 10 years in advance which Framework category a new drug would fall into," says Vogel. "Plus, future changes of human antibiotic susceptibility patterns will cause unpredictable changes in the human importance categories for animal drugs. Who would spend 10 years of research and millions of dollars speculating on whether or not they will be able to market it?"

If it's tougher for new antibiotics to gain approval, and the use of existing products is restricted, Keeling says, "a smaller array of products would put more resistance pressure on the products already there ... You could wind up with a food supply that has more pathogens than it does today."

What's more, with fewer weapons, Vogel says animal morbidity and mortality would increase. Along the way, one would think cost of production should increase and that the ultimate product cost for consumers would rise as well.

Angulo sees it differently. "If we want to be free of risk, then the solution is not to have any antibiotics used in animals, but that's not practical. We are trying to take a practical approach, enabling the use of antibiotics in animals without having a public consequence."

Rather than limit and restrict antibiotic approval, Angulo believes the Framework sets the stage for bringing new products to animal health more rapidly. "It provides a mechanism for even the most precious drugs in human medicine to be used in animals," he says. The Framework is just the current approval process with safeguards, he adds.

"The impetus for this is not coming from perceived misuse in animal medicine, but by a perception we're at the last line of defense in human medicine," says AHI's Keeling.

"The industry is committed to do the right thing, but to do the right thing, we have to have the data," says Keeling. AHI suggests a comprehensive risk assessment to determine the extent of the problem before creating a cure.

"There is no immediate human health crisis, so we have the luxury to address this in a way to produce a solution relative to the problem."

Closer to home, producers probably won't see the impact of this debate for a couple of years. In the meantime, the industry is increasing awareness among veterinarians and producers to optimize the use of antimicrobial products.

Judicious Use Principles Last fall, AVMA approved judicious use principles for veterinarians that are now being massaged into more specific species guidelines. Among other things, those principles promote preventive management and alternative therapies, where possible, to minimize the use of antimicrobials. FDA is involved in that process as well. Ultimately, they will probably endorse the guidelines.

As well, AVMA and others are helping fund the computerized Antimicrobial Decision Making System for veterinarians which is being developed by Apley and other clinical pharmacologists. Upon completion it will be a fast resource for veterinarians to use in determining optimum therapy. If antibiotics are called for it will lead them through product choices, which include known susceptibility of the organism to that product, along with its common use and any potential effects to human medicine.

"We don't want to dismiss the issue. We are concerned and are aggressively addressing the potential problem," says Vogel. We believe our judicious use principles and the supporting educational program go a long ways toward a potential solution."

Likewise, Keeling says, "We need to be vigilant, but we also need to be skeptical of people telling us the sky is falling ... Everyone from the producer to the housewife has to be sure to use antimicrobials properly so that usage doesn't jeopardize their long-term efficacy."