It is well known that antibiotic-re­sistant bacteria have created an increasing challenge to healthcare providers and have caused signifi­cant morbidity and mortality in our society. The Centers for Disease Con­trol and Prevention (CDC) estimates 23,000 deaths and 2 million illnesses occur each year in the United States as a result of resistant bacteria.
The global burden far exceeds this threshold, howev­er, with many countries experiencing far higher rates of gram negative—resistant organisms than are present in the United States. The continuous threat of increas­ing antibiotic resistance may throw society back into a pre-antibiotic era, significantly curtailing many of the advances made in medicine that require antibiotics to work to remain viable treatment modalities, including surgery, ventilator/ICU care, and many aggressive cancer chemotherapy regimens.
Many forms of antibiotic-resistance mechanisms are ancient and have evolved over the millennia, as many of our current antibiotics are derivatives of naturally occur­ring antibiotics. Our antibiotic derivatives were designed to initially overcome resistance mechanisms; however, as the sheer volume of antibiotics utilized increased in concentrated environments, such as farms and hospi­tals, the bacteria's resistance mechanisms have evolved to counter our antibiotics. Overall resistance rates have swelled and spread worldwide as a result of inadequate infection control practices and the availability of inter­national travel.
Despite recent efforts to curtail antibiotic use in hu­mans through programs such as the CDC’s Get Smart About Antibiotics and recent proposals by the Joint Commission and the Centers for Medicare & Medicaid Services to enhance both infection control practices and antibiotic stewardship, these programs do nothing to control over 70% of the antibiotics made and distrib­uted by humans. Most antibiotics are actually given to animals for the purpose of growth promotion to increase food production.1
The Society of Infectious Diseases Pharmacists recent­ly published a position statement outlining the dangers caused by antibiotics used in agriculture in the April is­sue of Pharmacotherapy.
The article reviews data that led to the belief that antibiotics increased animal food efficiency, but notes that these data are dated and based on old food production practices and feeds that poten­tially render the results invalid in modern agriculture.
The authors also describe methods of antibiotic-re­sistance transfer from the farm to humans other than through consumption of undercooked meats. Resistance can also spread through direct contact with the animal handlers who then have contact with the rest of society indirectly via waste water runoff from farms harboring both resistant bacteria and therapeutic levels of antibiot­ics, as well as through direct inoculation of flies that har­bor resistant bacteria from the farm to sources outside of the farm. These modes of documented resistant-bacteria transfers highlight the complex nature of the problem.
Although not all antibiotics used on farms are the same products used in humans, many are close analogs of those used in healthcare clinics and hospitals worldwide. The US Food and Drug Administration's (FDA) Guidance for Industry #152 classifies these antibiotics into risk cat­egories based on their importance to human health. For example, the third-generation cephalosporin ceftiofur, although not marketed for use in humans, is considered critically important to human health based on its struc­tural similarity and shared resistance mechanisms with third-generation cephalosporins used in human med­icine. Additionally, compared with human antibiotic prescribing requirements, there are very few mandatory regulations for the antibiotics used, by the ton, on farms. This is particularly alarming since the use of antibiotics not only affects the animal they were given to, but also disrupts the bacterial ecology within, and on the animal that is then consumed by people in our society.
The FDA has introduced two new regulations to ad­dress the use of antibiotics on farms that will go into full effect on January 1, 2017. FDA Guidance #213 recom­mends the removal of growth promotion from antibiotic product labels. Once manufacturers revise the condi­tions of use on their approved labels by removing growth promotion, food animal producers would not be able to legally use the antibiotic for growth promotion pur­poses.
This guidance is voluntary; however, all affected companies indicated they intend to comply.
Guidance #213 is being introduced in conjunction with the Veterinary Feed Directive (VFD) that outlines a pro­cess to ensure veterinary oversight of drugs available for use in animal feed that will move all medically import­ant antibiotics out of OTC status. Additionally, the VFD requires a valid veterinarian client—patient relationship, including that the veterinarian assumes responsibility for making clinical judgement about the animal’s health and provides any necessary follow-up care.
Although Guidance #213 and the VFD are positive steps in the right direction, they will not solve the prob­lem of antibiotic resistance and do not have the same rigor as standards in some European countries. The FDA regulations will not prevent the use of antibiotics at identical, or near identical, doses for the purposes of disease prevention rather than growth promotion. Nor is there adequate infrastructure in place to measure if the guidance actually reduces the use of antibiotics in agri­cultural production. Luckily, increasingly assertive and health-conscious consumers have begun to demand an­tibiotic-free food. This has led many large corporations to begin to phase out animals given feed mixed with anti­biotics while other corporations have promised to solely distribute antibiotic-free animals in the near future.
Healthcare providers should continue to educate both the public and elected officials regarding the problems of growing antibiotic resistance and mechanisms that contribute to it. They should also advocate for stronger regulations regarding the use of antibiotics in animals grown for human consumption, fund research into alter­native agriculture practices that do not use antibiotics and the ongoing impact of antibiotics in agriculture on human health, and provide incentives to develop new antibiotics, particularly from novel antibiotics classes not derived from nature.
Michael Nailor, PharmD, BCPS-AQ ID, holds a joint position as a clinical associate professor at the University of Connecticut School of Pharmacy and clinical specialist in infectious diseases at Hartford Hospital. Dr. Nailor also is the director of the Hartford Hospital Infectious Diseases Residency Program.
Emily Heil, PharmD, BCPS-AQ ID, is an assistant professor in the Department of Pharmacy Practice and Science at the University of Maryland School of Pharmacy. She also serves as the coordinator of the Antimicrobial Stewardship Program at the University of Maryland Medical Center.
1. Aitken SL, Dilworth TJ, Heil EL, Nailor MD. Agricultural applications for antimicrobials. A danger to human health: an official position statement of the Society of Infectious Diseases Pharmacists. Pharma­cotherapy 2016;36(4):422-32. doi: 10.1002/phar.1737.
2. Guidance for Industry #213: new animal drugs and new animal drug combination products administered in or on medicated feed or drinking water of food-producing animals: recommendations for drug sponsors for voluntarily aligning product use conditions with GFI #209. FDA website. fda.gov/downloads/animalveterinary/guid­ancecomplianceenforcement/guidanceforindustry/ucm299624.pdf. Published December 2013. Accessed July 6, 2016.
3. FDA. Veterinary feed directive. Federal Register website. https:// www.federalregister.gov/articles/2015/06/03/2015-13393/veteri­nary-feed-directive. Published June 3, 2015. Accessed July 6, 2016