ANIMAL FORUM

>The following Washington Post article leaves no doubt about two
>things: 1) Cows and Bulls
>are raised in such stressful, inhumane conditions that their immune
>systems is severely compromised, and 2) the cattle industry will
>likely be the death of all of us. So enjoy yourself the next time
>you eat your meat. It maybe countless human lives you are devouring
>with each bite.
>
>WASHINGTON POST
>
>FDA Rules Override Warnings About Drug
>Cattle Antibiotic Moves Forward Despite Fears of Human Risk
>
>By Rick Weiss
>Washington Post Staff Writer
>Sunday, March 4, 2007; A01
>
>The government is on track to approve a new antibiotic to treat a
>pneumonia-like disease in cattle, despite warnings from health groups
>and a majority of the agencys own expert advisers that the decision
>will be dangerous for people.
>
>The drug, called cefquinome, belongs to a class of highly potent
>antibiotics that are among medicines last defenses against several
>serious human infections. No drug from that class has been approved in
>the United States for use in animals.
>
>The American Medical Association and about a dozen other health groups
>warned the Food and Drug Administration that giving cefquinome to
>animals would probably speed the emergence of microbes resistant to
>that important class of antibiotics, as has happened with other drugs.
>Those super-microbes could then spread to people. Echoing those
>concerns, the FDAs advisory board last fall voted to reject the
>request by InterVet Inc. of Millsboro, Del., to market the drug for
>cattle.
>
>Yet by all indications, the FDA will approve cefquinome this spring.
>That outcome is all but required, officials said, by a recently
>implemented guidance document that codifies how to weigh the threats
>to human health posed by proposed new animal drugs.

>The wording of Guidance for Industry #152 was crafted within the FDA
>after a long struggle. In the end, the agency adopted language that,
>for drugs like cefquinome, is more deferential to pharmaceutical
>companies than is recommended by the World Health Organization.
>
>Cefquinomes seemingly inexorable march to market shows how a few
>words in an obscure regulatory document can sway the governments
>approach to protecting public health. Industry representatives say
>they trust Guidance #152s calculation that cefquinome should be
>approved. There is reasonable certainty of no harm to public health,
>Carl Johnson, InterVets director of product development, told the FDA
>last fall.
>
>Others say Guidance #152 makes it too difficult for the FDA to say no
>to some drugs. The industry says that until you show us a direct
>link to human mortality from the use of these drugs in animals, we
>dont think you should preclude their use, said Edward Belongia, an
>epidemiologist at the Marshfield Clinic Research Foundation in
>Wisconsin. But do we really want to drive more resistance genes into
>the human population? Its easy to open the barn door, but its hard
>to close the door once its open.
>
>The FDA knows how hard it can be to close that door. In the mid-1990s,
>overriding the objections of public health experts from the Centers
>for Disease Control and Prevention (CDC), the drug agency approved the
>marketing of two drugs, Baytril and SaraFlox, for use in poultry. Both
>are fluoroquinolones, a class of drugs important for their ability to
>fight the bioterror bacterium that causes anthrax and a food-borne
>bacterium called campylobacter, which causes a serious diarrheal
>disease in people.
>
>Before long, doctors began finding fluoroquinolone-resistant strains
>of campylobacter in patients hospitalized with severe diarrhea. When
>studies showed a link to poultry, the FDA sought a ban. But while
>Abbott Laboratories, which made SaraFlox, pulled its product,
>Baytrils manufacturer, Bayer Corp., pushed back. They fought this
>tooth and nail. It took years, said Kirk Smith, an epidemiologist at
>the Minnesota Department of Health. Finally, late in 2005, Bayer gave
>up, but not before fluoroquinolone resistance had spread even further.
>
>A Question of Resistance
>Microbes are constantly mutating, and some of those mutations happen
>to confer immunity to one drug or another. Exacerbating the problem,
>bacteria constantly exchange bits of DNA with each other, spreading
>that resistance. Given those realities, experts agree that all
>antibiotics should be used judiciously. If a drug is used less,
>then less resistance emerges, said Patricia Griffin, chief of
>intestinal disease epidemiology for the CDC. Prudence is especially
>important for medicines of last resort, which is why the cefquinome
>application stirred such a storm.
>
>Cefquinome is a fourth-generation cephalosporin, the most recent of
>several steadily improving versions of the cephalosporin family of
>antibiotics. Only one medicine from that family has been approved in
>the United States -- a powerful human drug called cefepime (brand name
>Maxipime), which is the only effective treatment for serious
>infections in cancer patients and a reliable lifesaver against several
>other nearly invincible infections.
>
>InterVet developed cefquinome to treat bovine respiratory disease, the
>most common disease in cattle. Recognizing the potential public health
>implications of using a close cousin of cefepime in animals, the FDAs
>Center for Veterinary Medicine, which oversees animal drug approvals,
>convened its expert advisers in September.
>
>One of the first things the group learned was that more than a dozen
>medicines are already on the market for the respiratory syndrome, and
>all are still effective.
>If we have no susceptibility problem, why do we need one more new
>drug? asked James E. Leggett Jr., a professor of medicine at Oregon
>Health & Science University, whom the FDA brought in as a consultant
>on the cefquinome question.
>
>The panel also learned that the disease would be a relatively minor
>issue but for the stressful conditions under which U.S. cattle are
>raised, including high-density living spaces and routine shipment on
>crowded trains for hundreds or thousands of miles. Those production
>dynamics suppress the animals immune systems, explained feedlot
>consultant Kelly Lechtenberg of Oakland, Neb., and virtually guarantee
>that bovine respiratory disease will be a major problem.
>Yet Stephen Sundlof, head of the FDAs Veterinary Medicine Center,
>told the panel members that under agency rules they should ignore
>those issues and consider only the language in Guidance #152.
>Flaws Seen in Rules
>
>Guidance #152 is essentially a checklist of points to consider when
>weighing the potential human impact of a new animal drug.
>
>After the Baytril debacle, the public health community embraced the
>idea of a guidance document. A formalized risk-assessment process
>promised to minimize the chances of making a bad regulatory call. But
>a struggle ensued when the FDA hosted meetings to spell out the
>criteria to be used for measuring risk, often with veterinarians and
>veterinary drug companies on one side and doctors and public health
>experts on the other.
>
>When differences could not be resolved after repeated drafts and
>months of work, the agency sidestepped some tough issues and adopted
>language that both sides agree can block approval of the most
>worrisome drugs -- those such as Baytril that are put in animal feed
>or water, and so are easily overused. But public health experts say
>the wording tilts the playing field toward industry for other kinds of
>drugs. They want to see it revised.
>
>Most glaring, they say, is that the guidance makes it almost
>impossible to say no to a new animal drug unless it is likely to
>threaten the effectiveness of an antibiotic that is a critical player
>against food-borne illnesses. By contrast, the World Health
>Organization recommends saying no if approval would spur resistance to
>any antibiotic that is important for fighting serious human disease
>-- not just food-borne illnesses.
>
>Cefquinomes primary threat is that it may undermine the usefulness of
>the closely related human drug, cefepime. But as it turns out, the FDA
>does not consider cefepime a front-line drug against food-borne
>infections. So although it is a highly important drug in human
>medicine generally -- and although the Infectious Diseases Society of
>America even recommends it against some food-borne bacteria -- that
>risk does not count under the terms of Guidance #152.
>
>A related problem is that the guidances definition of food-borne is
>conservative, said Margaret Mellon of the Union of Concerned
>Scientists, a science policy advocacy group. For example, most urinary
>tract infections are caused by intestinal bacteria acquired from food,
>and cefepime is prescribed for those infections. If the FDA counted
>those infections as food-borne, then the guidances formula would call
>for rejecting cefquinome for cattle.
>
>But FDA didnt do that, Mellon said. That restricted the analysis
>right there.
>Moreover, the guidance does not take into account that when microbes
>become resistant to fourth-generation cephalosporins, they often gain
>resistance to third-generation versions, too.
>
>Third-generation cephalosporins are among the only effective therapies
>for serious gastrointestinal diseases in children and are the sole
>therapies for many cases of meningitis. That means the emergence of
>resistance to fourth-generation cephalosporins could have a much more
>far-reaching effect than is considered under the terms of Guidance
>#152, John H. Powers, a medical officer at the FDAs Center for Drug
>Evaluation and Research, told the agencys panel of experts.
>
>How Great a Risk?
>Richard Carnevale, vice president for scientific and regulatory
>affairs at the Animal Health Institute, which represents veterinary
>drugmakers, said critics should not presume that a dozen drugs
>effective against bovine respiratory syndrome are enough. Its not a
>question of whether there is a need or not, Carnevale said. The
>answer is, theres always a need.
>
>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 agencys experts defied
>Guidance #152 and voted 6 to 4 against approval of cefquinome. But
>that day, and in follow-up interviews, Sundlof, the agencys
>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, Congresss
>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 drugs 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.