From the October issue of Bovine Veterinarian: FDA is moving forward with policies intended to minimize risk of antibiotic resistance in pathogens.

For better or worse, veterinarians and livestock producers face imminent changes in the ways they use antimicrobials. Under constant pressure from advocacy groups over the issue of antibiotic resistance, FDA has taken several well-documented steps aimed at reducing the risk of emergence of antibiotic-resistant pathogen populations in production settings or the food supply.

While there is no universal agreement regarding the necessity of these steps, or their likelihood of achieving those goals, veterinarians will need to keep abreast of emerging rules to ensure compliance.

During the recent Academy of Veterinary Consultants (AVC) conference, William Flynn, DVM, MS, deputy director for science policy at FDA’s Center for Veterinary Medicine (CVM), updated veterinarians on the FDA’s efforts to ensure judicious use of antibiotics in food animals.

The key principles behind FDA’s policy direction, Flynn says, are:

  • Limit the use of medically important antibiotics to those necessary for animal health.
  • Increase veterinary involvement in decisions regarding antibiotic use in animals.

Toward those goals, FDA finalized its Guidance for Industry (GFI) 209 in April 2012, focusing on the judicious use of antimicrobials in food animals. The framework included the principles of phasing in such measures as:

  1. Limiting medically important antimicrobial drugs to uses in food-producing animals that are considered necessary for assuring animal health.
  2. Limiting such drugs to uses in food-producing animals that include veterinary oversight or consultation.

Guidance for Industry 213, finalized in December 2013, provides a road map for implementing the principles in GFI 209, including guidance for drug sponsors to voluntarily withdraw performance uses from specific antimicrobials and combination products. The FDA-CVM website includes a list of affected products.

As of early July, all 26 drug manufacturers affected by GFI 213 agreed to fully engage in the strategy by phasing out the use of medically important antimicrobials in food-producing animals for food production purposes and phasing in the oversight of a veterinarian for the remaining therapeutic uses of such drugs. While GFI 213 specified a three-year timeframe (until December 2016) for drug sponsors to complete the recommended changes to their antimicrobial products, some sponsors have already begun to implement them.

Also in December 2013, FDA-CVM published a proposed veterinary feed directive (VFD) rule, and a comment period on the proposed rule ended in March 2014. This rule will require producers to work through a veterinarian to obtain and file a VFD for use of medically important antimicrobials in feed. While the rule expands the list of VFD drugs, it intends to provide flexibility by revising the current VFD requirement for a valid veterinarian-client-patient relationship, replacing it with veterinarian “supervision or oversight,” and saying veterinarians ordering the use of VFD drugs must do so “in compliance with all applicable veterinary licensing and practice requirements.”

FDA has been working on revisions to the proposed VFD rule, based on public comments, including details such as the expiration date of a VFD, premises ID versus animal ID requirements, application of the rule to feed products containing combinations of VFD and over-the-counter drugs and options for electronic filing of VFD documents. Flynn anticipates a final VFD rule to be announced in the spring of 2015.

Tested in court

It does appear the FDA will be able to continue with its current strategy and course of action regarding judicious use of antibiotics. In late July, the 2nd U.S. Circuit Court of Appeals overturned earlier district court rulings resulting from a lawsuit filed by activist groups seeking to end the use of antibiotics in livestock feed.

The lawsuit, intending to force the FDA to hold hearings on the safety of using antibiotics in feed and ultimately eliminate the practice, was filed by the National Resources Defense Council, Center for Science in the Public Interest, Food Animal Concerns Trust, Public Citizen and Union of Concerned Scientists in May 2011. Two district courts ruled in favor of the activist groups in 2012, and FDA appealed the rulings, leading to the July decision in the Court of Appeals.

“Our survey of the text, the context, the regulations and the background legal principles leave us firmly persuaded that Congress has not required the FDA to hold hearings when FDA officials have scientific concerns about the safety of animal drug usage,” wrote the two judges in their majority opinion.

In his dissenting opinion, Judge Robert Katzmann wrote: “Today’s decision allowed the FDA to openly declare that a particular animal drug is unsafe, but then refuse to withdraw approval of that drug. It also gives the agency discretion to effectively ignore a public petition asking it to withdraw approval for an unsafe drug. I do not believe the statutory scheme can be read to permit those results.”

Activist groups do not think GFI 213 goes far enough, claiming companies will re-label the affected products for disease prevention, allowing producers to continue using them.

Tracking trends

The issue, of course, is the risk of pathogens developing resistance to medically important antibiotics and public perception of that risk. And while scientists generally agree some risk exists and steps to reduce it are prudent, public perception of that risk can far exceed reality.

A common concern among veterinarians and producers regarding limits on antibiotic use is whether new rules will have any positive effect and how the impact of the rules will be measured.

During a question and answer session at the AVC conference, a veterinarian asked Flynn if, and how, FDA plans to measure the results of the new rules in terms of antibiotic resistance and animal health. He responded, saying FDA plans to analyze trends in the quantity of antibiotics sold for use in food animals, looking for an overall decline once the rules are in place. He acknowledged there probably is only a limited relationship between the quantity sold and the actual risk of resistance, but he says a reduction in use appears to be the primary goal of special-interest groups involved in the issue.

He also points out the FDA’s National Antimicrobial Resistance Monitoring System (NARMS) will continue to track trends in resistance. Finally, Flynn says, FDA-CVM is developing, with input from industry, ideas for actually measuring the relationships between antibiotic uses and practices and resistance trends.

As Flynn mentioned, NARMS, which was established in 1996 as a partnership between the FDA, the Centers for Disease Control and Prevention, and the USDA, conducts continuous testing in livestock, food and people to track trends in the prevalence of antibiotic-resistant pathogens. In August, NARMS released its latest executive report, listing trends through 2011 and showing both increasing and decreasing antimicrobial-resistance trends.

The executive report summarizes data from each of the three agencies, including findings from sampling from human, food-producing animal and retail meat sources, focused specifically on non-typhoidal Salmonella, Campylobacter, Enterococcus and Escherichia coli (E. coli) found in retail meats and chickens.

Key findings from the NARMS 2011 executive report include:

  • Eighty-five percent of non-typhoidal Salmonella collected from humans had no resistance to any of the antibiotics tested.
  • In people, the five-drug resistance pattern “ACSSuT” (resistance to ampicillin, chloramphenicol, streptomycin, sulfonamide, and tetracycline) in Salmonella typhimurium has declined to 19.5 percent in 2011 from its peak in 1997 at 35.1 percent.
  • During its 16-year history, NARMS has found Salmonella resistance to ciprofloxacin, one of the most common antibiotics to treat Salmonella infections in humans, to be very low (less than 0.5 percent in humans, less than 3 percent in retail meat and less than 1 percent in animals at slaughter).
  • Multi-drug resistance in Salmonella from humans, slaughtered chickens and slaughtered swine was the lowest since NARMS testing began. However, multi-drug resistance in Salmonella from retail poultry meats generally increased, with slight fluctuations.
  • Erythromycin resistance in Campylobacter jejuni (C. jejuni) has remained at less than 4 percent in isolates obtained from humans, retail chicken and slaughtered chicken since testing began. The antibiotic erythromycin is the drug of choice for treating Campylobacter infections, more than 90 percent of which are caused by C. jejuni.
  • Campylobacter resistance to the fluoroquinolone ciprofloxacin has increased slightly in isolates from humans since 2005. Ciprofloxacin is not approved for use in poultry, and FDA withdrew approval for the use of enrofloxacin in poultry in 2005. Ciprofloxacin and enrofloxacin are both in the same class of drugs (fluoroquinolone).
  • Resistance to third-generation cephalosporins, another important drug class for the treatment of Salmonella infections, rose among isolates from retail ground turkey between 2008 and 2011 and among certain Salmonella serotypes in cattle between 2009 and 2011. In April 2012, FDA prohibited certain uses of cephalosporin drugs in cattle, swine, chickens and turkeys. NARMS will continue to monitor these trends over time.

The authors note that while some encouraging trends were observed, these findings underscore the need for continued efforts to curb antimicrobial resistance, and that monitoring antimicrobial resistance “is an important component of the overall effort to minimize antimicrobial resistance and promote appropriate and judicious use of antimicrobial drugs in both humans and animals.”

See this article and others about the Whisper electronic stethoscope system, JHS in dairy cows and beef cow-calf nutritional consultation in the October digital edition of Bovine Veterinarian.