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* Reuters data analysis shows sharp rise in misuse of ceftiofur
* Ceftiofur accounted for one-fourth of USDA drug-residue violation reports in 2013
* Manufacturer Zoetis says ceftiofur safe when used as directed
* Research shows ceftiofur can promote development of superbugs
By Michael Erman and Brian Grow
NEW YORK/ATLANTA, Dec 4 (Reuters) - It is one of the most potent antibiotics used by U.S. cattle and dairy farmers, the key component in the top-selling drug line of Zoetis, the world's largest animal health company.
But the strength of the antibiotic ceftiofur - and the frequency with which it's being misused on farms across America - has created a threat to human health that may overshadow the drug's effectiveness, a Reuters examination shows.
The U.S. Food and Drug Administration cautioned in 2012 that ceftiofur could pose a "high public health risk," in part because the drug belongs to a class of antibiotics considered critically important in human medicine. The warning is the FDA's strongest kind. The concern is that ceftiofur in animals could spawn antibiotic-resistant bacteria, superbugs that can infect people and defeat conventional medical treatment, even when the drug is used as directed.
A Reuters analysis of government data indicates that the risks to human health may be more significant than previously known. Since last year, records kept by the U.S. Department of Agriculture show that traces of ceftiofur were found at illegal levels in slaughtered animals more frequently than with any other drug. In 2013, ceftiofur alone accounted for one-fourth of all residue violations logged by the USDA, the data show.
The ceftiofur residues are not themselves considered dangerous to people if ingested, because the government sets its standards well below hazardous levels.
But the traces serve as a warning sign that the drug was used shortly before the animal was killed, thus increasing the chances that the meat contains superbugs, said Guy Loneragan, a veterinary epidemiologist at Texas Tech University. Studies show that ceftiofur, more than most other drugs, can sharply increase the amount of antibiotic-resistant bacteria in an animal.
"It kills off weaker bugs and allows stronger ones to survive and multiply," Loneragan said. The effect is especially pronounced soon after the drug has been used, studies show.
Zoetis says ceftiofur is safe to use as directed. "The use of ceftiofur continues to be appropriate when used according to the label directions in those animals that are in at-risk situations," said Scott Brown, vice president of global therapeutics research at Zoetis.
The stakes are especially high because the drug is part of a crucial class of antibiotics called cephalosporins. The class includes ceftriaxone, a drug that's vital to treating pneumonia, meningitis and salmonella infections in children, according to the FDA. The use of one type of cephalosporin can compromise the effectiveness of others in the same class.
"There is a very clear link between ceftiofur use and ceftriaxone resistance," said Paul Fey, a professor of microbiology at University of Nebraska Medical Center. "We know that ceftiofur-resistant salmonella are clearly ceftriaxone-resistant."
Despite the perils, there are economic incentives to misuse ceftiofur. The potent drug can keep a sick cow alive long enough for a dairy farmer to sell the animal to a slaughterhouse. A course of treatment can cost from $20 to more than $100, relatively high for veterinary antibiotics. But that is far less than what the farmer stands to make if the animal survives until it can be sold for meat. Dairy cows for slaughter are now fetching $1,500 or more, according to farmers and USDA data.
Hugh Byron ran a dairy farm in Hillsboro, Kentucky, until 2011 and kept cattle until this year. He says he frequently used ceftiofur to treat common infections in his cows. In July 2010, a dairy cow sent to slaughter from Byron's farm tested positive for 5.61 milligrams of ceftiofur residue per kilogram of tissue sample. That was 14 times higher than the 0.4 milligram per kilogram tolerance level set by the FDA.
Byron admits that he has administered ceftiofur at the end of his animals' lives hoping they'd hang on, so that a slaughterhouse would accept the cows and pay him.
"We're talking about our livelihood, our money. We're trying to save the cow and if we can't save the cow, we're trying to salvage it," said Byron. "In other words, send her to the stockyard and get something out of it. So there's a temptation to fudge on it."
Zoetis features the drug's economic advantages in its marketing to farmers and veterinarians. One of ceftiofur's features is a short withdrawal period - the FDA-mandated time between when an animal stops taking an antibiotic and when its milk or meat is certain to be sufficiently free of residue to pass inspection.
The drug's time advantage is significant. In the case of milk, if a cow takes penicillin, the farmer must discard all the milk produced for at least two days and as many as 15 days after the drug is last given. There's often no withdrawal period for certain ceftiofur products, so a cow can keep producing milk while taking it.
"No wasted milk ensures a better return on investment," Zoetis says on its website about its ceftiofur-brand drug Excenel.
THE WITHDRAWAL PERIOD
The residue-testing program is supposed to help the government ensure that farmers are not misusing the drugs. The regulations contain a gap, however. The USDA tests animals for traces of antibiotics, to prevent excess levels of drugs such as ceftiofur from entering the food supply. But the residue program doesn't test for the presence of resistant bacteria. In the case of ceftiofur, those bugs can survive in an animal past the end of the drug's required withdrawal period, studies show.
Loneragan of Texas Tech said his research suggests the FDA should analyze whether high levels of resistant bacteria remain beyond the withdrawal period. A longer period may be warranted, he said, to ensure that the resistant bacteria population is reduced before the animal is slaughtered.
The reason for the rise in ceftiofur violations isn't clear. The USDA implemented a new test in 2012 that it says is better at identifying traces of all drugs. But the USDA residue data don't show as large an increase in violations for penicillin and other antibiotics as they do for ceftiofur.
FDA spokeswoman Juli Putnam said the agency "is aware of the increase in ceftiofur residue violations" and is gathering more information to "better understand the matter." She said the agency is aware of Loneragan's research findings as well, "and we continue to consider the evolving science related to the impact of antimicrobial use on bacterial populations."
Zoetis said the FDA has evaluated ceftiofur's impact on antibiotic resistance in bacteria and has approved drugs containing the compound as recently as last year.
Those caught misusing veterinary antibiotics face light consequences. Penalties include condemnation of the animal. FDA inspectors review a violator's practices, which can result in warning letters ordering farmers to change how they administer the medicines. Further action is extremely rare, an examination of regulatory and court records shows.
The residue testing program has been harshly criticized by federal auditors. A 2010 report by the Government Accountability Office found that the program "is not accomplishing its mission of monitoring the food supply for harmful residues." One result of the audit was the implementation two years later of the new residue testing methodology now used by the USDA and FDA.
The widespread application of antibiotics in veterinary medicine poses enormous challenges for health authorities. Today, 80 percent of all antibiotics used in the United States are given to livestock, not to people. In September, Reuters documented how some of America's largest poultry companies routinely mix low levels of antibiotics into the feed given to chickens, a practice that scientists believe is especially conducive to the growth of superbugs.
About 2 million people in the United States are sickened each year by bacterial infections that resist conventional antibiotics, and at least 23,000 people die, according to the U.S. Centers for Disease Control and Prevention. The World Health Organization called antibiotic resistance "a problem so serious it threatens the achievements of modern medicine."
Despite such concerns, sales of antibiotics for use in food animal production rose 16 percent by volume from 2009 to 2012, government data show. Sales of cephalosporins increased at more than twice that rate.
The government has made some effort to curb ceftiofur use because of concerns about antibiotic resistance. The FDA requires farmers to obtain a prescription from a veterinarian. In 2012, the agency issued an order prohibiting most off-label uses of the drug, pointing to residues as one contributing factor.
The rise in ceftiofur use is a boon to its largest maker, Florham, NJ-based Zoetis, the former animal drug unit of pharmaceutical giant Pfizer Inc. Ceftiofur-based brands are the company's top-selling line, generating about $300 million in revenue per year since 2011, according to company financial reports.
Zoetis markets its ceftiofur brands to veterinarians, who must prescribe the drug, and to farmers in YouTube videos and in veterinary and dairy publications. The drug has become one of the most popular antibiotics on American cattle farms. Veterinarians and farmers praise its potency, efficiency and ability to treat multiple ailments, from foot rot to bovine respiratory disease.
"SUCH A HUGE EFFECT"
"We had to use so little of it for such a huge effect," said H. Morgan Scott, a veterinary epidemiologist at Texas A&M University's College of Veterinary Medicine.
Another selling point is the drug's short withdrawal times. FDA withdrawal guidelines are based on the presence of antibiotic residue in meat. Compared with other antibiotics, ceftiofur is metabolized rapidly by cows - and so regulators require a shorter waiting period. The drug's withdrawal periods are zero to three days for milk and four to 13 days for meat. With other drugs, the ranges can be four weeks or more for meat.
Those short windows leave a potential safety gap. Even when ceftiofur is used as approved, one 2007 study shows, antibiotic-resistant bacteria remained present in the guts of cattle long after the drug was given. The FDA cited the study, whose authors include Loneragan and Scott, in the 2012 order reining in use of the drug.
The study, published in the American Journal of Veterinary Research, found that one properly administered dose of a ceftiofur-based medication made by Zoetis resulted in 40 percent of the surviving E. coli in cattle having resistance to ceftiofur six days after the dose. The resistant bacteria population remained above 20 percent of the total for two weeks. Resistant bacteria did not return to levels typical in untreated cattle for 28 days, well after ceftiofur's withdrawal period, the study found.
As part of the USDA's National Residue Program, food safety regulators test meat for drugs and chemicals that could prove dangerous to consumers. In 2012, the USDA tested for drug residues in about 185,000 cattle - far less than 1 percent of the more than 33 million cattle slaughtered in the United States that year. The percentage of pigs, poultry and other animals tested is lower.
If high drug residues are found, the results are turned over to the FDA for investigation and enforcement.
In 2013, no single drug residue was found more frequently in slaughtered animals than ceftiofur, the Reuters analysis shows.
Violations involving high levels of ceftiofur in meat rose by 323 percent between 2008 and 2013 - from 98 violations to 415. Last year alone, more than a quarter of all 1,634 residue violations were for ceftiofur - more than four times its share of violations in 2008, the analysis shows. Violations involving ceftiofur have continued at a similar rate during the first half of 2014.
Dairy cows are one of America's major sources of ground beef, which in turn is the beef product most prone to bacterial infections. Dairy cows are also the leading source of ceftiofur residues, representing 76 percent of the 415 violations in 2013. Last year, 45 percent of the 1,634 residue violations for all drugs were found in dairy cows.
Zoetis said it was aware of the residue violations but that they were small in number, and most - perhaps all - of the animals were pulled from the food supply when residues were found.
"These are animals that probably should not have gone to slaughter, or there were mistakes and animals go to slaughter that didn't follow withdrawal periods," said John Hallberg, director of U.S. regulatory affairs at Zoetis.
"YOUR BOTTOM LINE"
Ceftiofur can save farmers money by keeping a cow milking longer and by preserving her value at the slaughter stage. In its marketing materials, Zoetis zeroes in on some of the savings.
In one pitch, it says that using its Excede brand instead of penicillin to treat dairy cows with bovine respiratory disease could save a farmer more than $30 per animal, after factoring in the value of milk production not lost to withdrawal.
The company makes a similar case for Excenel. "Protect your cows and your bottom line with EXCENEL," its website says.
There are also gains to be had at life's end. Because of the short withdrawal times, farmers can get paid more quickly after treating the animal.
"Shorter meat withdrawals. You'd have to wait 29 days longer" when using a rival drug, says an advertisement for Excede.
Time is money for a farmer with a gravely ill cow on his hands. Interviews with farmers, veterinarians and field researchers, and a review of FDA warning letters, show ceftiofur has been administered to animals by farmers eager to keep a sick animal alive long enough to sell it.
Byron, the 66-year-old retired dairyman in Kentucky, says ceftiofur is a wonder drug. It's one of the more effective antibiotics, he found, and treated animals and their milk don't have to be kept off market for long.
"Our attitude, most of us, was if (ceftiofur) worked, if it'll save a cow, we'll spend the money," Byron said. "You're talking about a thousand-dollar animal or more."
After the USDA found high traces of ceftiofur in the cow he'd sold for slaughter, Byron received a letter from the FDA warning him to improve his processes. The agency evaluated his operation later that year, found it to be in order and closed the case. The agencies took no other action. (Additional reporting by Mimi Dwyer in New York; edited by Blake Morrison and Michael Williams)
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