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FDA Rules Override Warnings About Drug

The institute contends that the risk to human health posed by animal antibiotics has been overblown.

Officials at InterVet declined several requests to be interviewed. In a statement, the company said it "fully supports the prudent use of antibiotics in animals."

The statement also said that in Europe, fourth-generation cephalosporins similar to cefquinome have been used in animals for the past decade "without compromising the interests of public health."

Yet recent European data indicate that resistance against this class of antibiotics is on the rise.

An analysis of E. coli bacteria in pigs and other animals in Spain, published in December, found high levels of the resistance that renders fourth-generation cephalosporins useless. A January report from Britain documented similar resistance patterns emerging at 10 farms.

Microbes resistant to fourth-generation cephalosporins have also begun to pop up in European patients. Such resistance is virtually unknown in the United States, where fourth-generation cefepime has been used in patients since 1997. That suggests that the resistance emerging in Europe is a result of veterinary use, said Steve Roach of the Food Animal Concerns Trust, a Chicago public interest group.

Roach says he is concerned that history is about to repeat itself. U.S. cattle were free of bacteria resistant to third-generation cephalosporins in 1997, but by 2003 one of every five samples was resistant. "This is exactly what should be avoided with cefquinome," he said.

Merely Suggestions

At the FDA advisory meeting in September, the agency's experts defied Guidance #152 and voted 6 to 4 against approval of cefquinome. But that day, and in follow-up interviews, Sundlof, the agency's veterinary chief, made it plain that the vote was "not binding."

"I think we all agreed . . . that Guidance for Industry #152 would be the criteria against which we would base our decisions on safety," Sundlof said at the meeting.

Concerned that the FDA is poised to approve cefquinome, Congress's only microbiologist recently wrote to the agency.

"Given the recent outbreaks of E. coli and other food borne illnesses across the nation, it is hardly the time to ignore the advice of scientists, and potentially impair our ability to treat deadly infections," wrote Rep. Louise M. Slaughter (D-N.Y.), who chairs the House Rules Committee.

Yet, being realists, the FDA advisers in September said more than just no. They told the FDA that if it approves cefquinome, then it should at least impose limits to minimize the potential consequences. One suggestion was to explicitly preclude "off label" use of the drug -- that is, to tell veterinarians that it can be used only for bovine respiratory disease.

But Sundlof said that, under FDA rules, those decisions must be left up to veterinarians unless there is clear evidence that wider use is causing harm.

"We have to take a fairly legal interpretation," Sundlof said in an interview. "If we have no evidence of a problem, or sparse evidence, we would not be able to make the prohibition prior to approval."

However, raising a point that opponents do not find very reassuring, he noted: "As soon as we have the first glimpse of evidence that off-label use of a drug is causing resistance, we have the authority to prohibit off-label use."

The advisers also urged that as a condition of approval, the FDA should demand that InterVet provide annual reports on how much cefquinome was used and in which animals -- data that would help scientists detect links between the drug's use and patterns of resistance that emerge in people.

"Without reliable, meaningful data on the quantity of use, the purpose of use, the type, number and location of animals treated, it will be exceedingly difficult to interpret fluctuations in rates of resistance," said Susan Prolman of the Union of Concerned Scientists.

But Sundlof offered little hope for that outcome.

"That is information that would be useful to have," he said. But the agency does not have the authority to demand it.

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