Shorter is Better Is Not Just for Human Antibiotics

MADELEINE KLEVEN , PROJECT ASSISTANT, FOOD SAFETY PROGRAM AT FOOD ANIMAL CONCERNS TRUST

 FDA allows some medically important antibiotics to be used for the whole life of the animals receiving them.  This creates an increased risk of antibiotic resistance which can harm human and animal health. In 2016, FDA proposed adding limits on how long an antibiotic could be used in food animals. FDA must move forward with this proposal and in doing so make sure that durations are short enough to lower the risk of resistance and other negative side effects.  Evidence from human medicine shows that using antibiotics for shorter periods or durations usually works just as well and leads to less resistance and other side effects. Read further to learn more.

Overusing antibiotics contributes to the spread of antibiotic resistance which in turn increases the likelihood that these lifesaving drugs will be ineffective when needed. One way antibiotics are overused is using them for longer periods of time than necessary. The Food and Drug Administration (FDA) knows this and has long acknowledged that using medically important antibiotics in food animals for long or unlimited durations increases the risk of antibiotic resistance. As far back as the 1970s, FDA required specific safety studies on antibiotic resistance to support applications for antibiotics that were to be given in feeds for more than 14 days.[1] In 2003, FDA issued Guidance for Industry #152 (GFI#152), which establishes a risk management approach to resistance for all antibiotic drugs used in food animals. The Guidance recommends, for example, that antibiotics found to have high or medium risk of an adverse human health effect related to resistance not be administered to a group of animals for more than 21 days (see Tables 7 and 8).[2]  In 2013, FDA issued Guidance for Industry #213, which calls for “explicitly defined duration of dosing” on new drug label indications because “giving antimicrobial drugs to food-producing animals at low levels for long periods of time and in large numbers of animals may contribute to antibiotic resistance.”

Yet, according to the FDA, some 32% of the products containing medically important drugs for use in feed or water have label indications without duration limits. This means a farm can legally feed these drugs for the whole life of an animal. In September 2016, FDA announced that the agency intends to take action to “establish appropriately targeted durations of use” for these drugs and requested comments on the drugs with unlimited durations. However, its formal request for comments includes examples of “acceptable” duration limits that are troubling. By indicating that durations of 112 days in chickens and up to 15 weeks in pigs may suffice, FDA’s request casts doubt on whether the agency intends to undertake meaningful change. Both examples are much longer than the 14 and 21 days in existing regulation and guidance, which were set to protect human health.

In order to reduce the risk to public health from antibiotic resistance that results from overly long durations, FDA SHOULD set duration limits for drug labels consistent with GFI#152. This means that for any veterinary drug that the agency has found to have a high or medium risk to human health, based on an FDA assessment under GFI #152 or one submitted to FDA by a drug sponsor, the maximum duration limit should be no more than 21 days. An even simpler solution would be to prohibit any “continuous use” (i.e., 14 days or more as defined in the Code of Federal Regulations see 21 CFR 558.3 (b)(3)) of a medically important antibiotic in feed or water. If a farmer wants to use a medically important antibiotic for longer, they should be required to go back to the veterinarian to reconsider the need for the antibiotic.

Though there are limited scientific studies designed to solely analyze the role of durations of use on antibiotic resistance development in food animals, there is a large body of evidence from human studies indicating that shorter courses of therapy are effective in reducing the risk of antibiotic resistance. Members of the Keep Antibiotics Working Coalition have recently completed a rapid review of the literature analyzing the role of antibiotic durations on resistance development, and we’ve found shorter therapies are not only effective in lowering antibiotic resistance and incidence of superinfections but in many instances antibiotic therapy costs as well. Shorter course treatment regimens for several diseases including pyelonephritis, intra-abdominal infection, COPD, sinusitis, and cellulitis are just as effective as longer courses of treatment, and are safer alternatives for patients. Shorter courses of therapeutic intervention are able to reduce selective pressure driving resistance and lower the risk of developing serious infections with superbugs. 

In an animal setting, researchers found that the use of certain classes of antibiotics (macrolides and lincosamides) in long-acting injections as well as in-feed result in low concentrations of the active substance in the animal for long periods of time contributing to the risk of antibiotic resistance.

The use of any class of antibiotic agent in an animal or a human will inevitably lead to a selection pressure in favor of resistant subpopulations. This selection pressure is heavily influenced by antibiotic characteristics as well as the dose, treatment interval and duration of treatment. In order to mitigate resistance development, the length of time that antibiotics are given must be reduced to the shortest duration possible. 

Efforts to minimize antibiotic use must be prioritized in both an agricultural and medicinal setting. If we are to preserve the effectiveness of antibiotics and minimize the public health hazard that antibiotic resistance poses, antibiotics must be used more judiciously in not only hospitals and doctor’s offices but on the farm as well. Shortening durations of use for medically important antibiotics to under twenty-one days is an essential part of judicious use. FDA, consistent with its public health mission can and must make this happen to ensure the lives of animals and humans are protected.

Notes

[1] See 21 CFR 558.15; https://www.fda.gov/ohrms/dockets/ac/02/slides/3816s2_01_Gilbert.ppt).

[2] Guidance for Industry #152 Table 7 ranks extent of use as high, medium, or low. In Table 7, any flock- or herd-wise use is considered high extent of use independent of time and any use in a select group of animals for more than 21 days is ranked as high extent of use. GFI #152 Table 8 describes potential risk management steps based on risk, with more restrictive steps recommended for drugs found to have a higher risk. Table 8 lists low extent of use for high-risk drugs and low or medium extent of use for medium-risk drugs. In either case, according to Table 7 any use over 21 days is considered high or medium, so if the tables are applied as written then a duration of over 21 days would not be considered appropriate for drugs that are found to have high or medium risk. 

FDA Five-year Plan on Antibiotics Falls Short

Steven Roach, Food Safety Program Director, Food Animal Concerns Trust

 On September 14, the Food and Drug Administration (FDA) Center for Veterinary Medicine (CVM) released a Five-Year Action Plan to slow the spread of antibiotic resistance by reducing antibiotic overuse on the farm. While it is great that FDA continues to recognize the problem and take steps to address it, the plan does not do enough and does not include concrete goals for success. With the world on the brink of a post-antibiotic era where routine infection will once again kill and the threat of infection makes routine surgery dangerous, the FDA needs to do much more.  

 The World Health Organization (WHO) recommends much greater action than the FDA on curbing antibiotic overuse. Of the WHO recommendations, the FDA plan fails to include targets for antibiotic use reductions, allows the continued use of antibiotics for routine disease prevention, and does nothing to address the overuse of the drugs that are most important for human health.

 FDA’s plan commits to asking makers of medically important antibiotics to set limits on how long an antibiotic can be used and to require that these antibiotics only by used with a prescription. FDA in 2016 completed a previous plan that required drug makers to require prescriptions for medically important antibiotics in feed and water. The new plan extends this to any remaining medically important drugs for animals including those used by injection. Medically important antibiotics are antibiotics that are the same as or related to those used in human medicine that create a risk of spreading resistance to humans when used in animals. The plan also includes goals for improvements in the collection and reporting of data on antibiotic resistance and antibiotic use in food producing animals.

 Duration limits

One of the major ways that the FDA plans to address antibiotic overuse in food animals is by adding duration limits on all medically important drugs that do not already have them.

 Most antibiotics have a duration limit on them. This tells the user how long they should be taking any particular drug.  When antibiotics are used for treatment, the duration should be long enough to treat the disease but no longer. If a patient continues to use an antibiotic after the disease is cured, the drug does not be help the patient but will create resistance. If the duration limit has passed and the animals still have not gotten better, the antibiotic is probably not effective.

 Because drug use in animals can spread resistance to humans, the FDA in 2003 put in place new requirements for animal drug makers that limited how long farms could give antibiotics to food animals. FDA recognized that longer durations can create resistance and restricted the use of most new medically important drugs in food animals to less than 21 days.

 However, these restrictions do not apply to drugs approved before 2003, so almost 40% of existing medically important antibiotic approvals have no duration limit.  Most of these approvals without durations are not to treat disease but are instead given routinely to prevent illness – a practice WHO would like to see eliminated because it creates resistance while not being needed to treat sick animals. The Keep Antibiotics Working Coalition agrees with the WHO and supports improving how animals are raised to prevent disease not giving them routine antibiotics.

 Instead of eliminating preventive use of medically important antibiotics, the FDA plan lays out steps to add duration limits to all medically important drugs.  This will help reduce the overuse of antibiotics for disease prevention by eliminating continuous use, but does not go far enough.   Under the FDA plan, farms can still feed antibiotics to animals that have no signs of illness resulting in many more animals receiving antibiotics and an increased risk of resistance. The Keep Antibiotics Working coalition supports FDA requiring appropriate duration limits, but continues to push for the restriction of the preventive use of medically important antibiotics as recommended by WHO. In addition, FDA has not indicated that it will require duration limits to be short. Longer durations means bacteria are exposed to antibiotics for longer with the result being more resistance. We will continue to ask that FDA keep duration limits shorter than 21 days consistent with the 2003 requirements for new drugs.

 Surveillance

The FDA plan is strongest in its expansion of the National Antimicrobial Resistance Monitoring System (NARMS). NARMS is the federal program that tracks antimicrobial resistance in foodborne bacteria in humans, retail meats, and food producing animals. The 5-year plan would expand the number of bacterial and animal species monitored as well as the food products sampled. The FDA plan also has a goal to improve information-sharing systems, and building on research on antimicrobial resistance with new genomic technologies and bioinformatic tools. NARMS is an invaluable resource to help us understand emerging bacterial resistance, and expanding what it already covers would help fill numerous gaps in our knowledge. Keep Antibiotics Working has long supported NARMS and is happy to see it being strengthened.

 What is more is needed

In addition to further restricting preventive use of medically important antibiotics, we believe an effective plan would also include antibiotic reduction targets and more detailed and more ambitious goals surrounding collection of antimicrobial use data. Regarding antibiotic use data, the plan contains only limited intermediate steps at a long time scale. One these intermediate steps is to finish the development of a biomass adjustment metric. This would allow the FDA to understand better the antibiotics used per animal, rather than just looking at aggregate sales data. With the biomass adjuster, we'd be able to have a better understanding of trends, and be able to see if we're really getting better at stewardship or not. The European Union already has a functional method for adjusting antimicrobial use data by number of animals. As the FDA develops a more nuanced, us-specific measure, we see no reason why they can't also use this internationally accepted method in the interim. We need better data on antimicrobial usage, and we need it now.

 This 5-year plan is all about stewardship, but if we don't have reduction goals or metrics that establish the baseline of where we're at today, then how can we judge our progress on improving our stewardship practices? We need to know if our policies are actually working, and this involves setting targets and the ability to benchmark. It's worth remembering that our ultimate goal is to preserve the effectiveness of antibiotics, because a future without antibiotics is a future where modern medicine is crippled. The FDA five-year plan has many worthy goals, but it does not go far enough to tackle the urgent problem of antibiotics overuse on farm.  

#Q�

All Hands on Deck!

New report highlights the critical role of state and local antibiotics initiatives

Thomas Gremillion, Director, Food Policy Institute at Consumer Federation of America

In a more perfect world, the United States would rival trading partners like Denmark and the Netherlands in developing national policies to curtail animal antibiotic use. In reality, recent federal reforms have yet to yield reductions in use, and public health authorities continue to operate without the most rudimentary data on which drugs are going to which animals.

Only time will tell how FDA Commissioner Scott Gottlieb responds to the antibiotic resistance crisis, but the early signs from the Trump Administration are not good. The President has pledged to cut regulations indiscriminately, and proposed drastic funding cuts for federal programs that address antibiotic resistance.  The proposed presidential budget cuts funding for FDA’s Center for Veterinary Medicine, the agency with primary responsibility over antibiotics in agriculture, by almost a third. 

Fortunately, the federal government is not the only game in town when it comes to public institutions with the power to change animal agriculture. A new report from Consumer Federation of America shows how advocates are making progress from state legislatures to local school boards. The report is meant to serve as a roadmap for advocates to advance similar legislation and initiatives across the United States. It should also provide a source of encouragement.

Consider California. It boasts the third largest livestock industry in the country, and on January 1, 2018, California farmers will have to comply with new state law requirements that go beyond FDA rules, restricting certain uses of antibiotics for “disease prevention,” and generating important data on the drivers of animal antibiotic use. By demonstrating that real progress is possible, California’s example can fuel similar legislative reforms across the country, many of which are already underway.

Or consider Ordinance 170763, passed by the San Francisco Board of Supervisors just earlier this week. It requires the city’s large grocers, with 25 or more outlets worldwide, to submit reports to city officials on suppliers’ use of antibiotics, including the average number of days of antibiotic use per animal, the percentage of animals treated with antibiotics, and the different purposes for which antibiotics are used.  This first-of-a-kind legislation affects some 122 stores in San Francisco—including Safeway, Walgreens, CVS, Grocery Outlet, Whole Foods and Bristol Farms—with impacts on suppliers of these stores around the world.   

Or consider the Los Angeles Unified School District. In 2016, it became the first large school district to serve only chicken raised without antibiotics, approving some $50 million in contracts for the chicken in 2017 alone.  The reform fits within a broader procurement strategy to support local, environmentally sustainable producers that treat their workers and animals well, and similar strategies are taking root in a growing number of city departments, school districts, hospitals, and universities across the country, some with help from KAW members like Health Care Without Harm.

The prospect of a post-antibiotic future is perplexing, but it need not be paralyzing. Leaders across the country are creating demand for better products and fostering awareness. As more people learn about how animal agriculture is contributing to antibiotic resistance, the opportunities to make meaningful change are growing.