What’s Next for Food Animal Antibiotics?

– Dr. Michelle Arnold, UK Veterinary Diagnostic Laboratory

What is “antibiotic resistance”? When an antibiotic is no longer useful against an infection because the targeted bacteria changed in some way that protected it from the effects of the drug (antibiotic), this is referred to as “antibiotic resistance”. The FDA Center for Veterinary Medicine is the government agency responsible for ensuring the safety and effectiveness of animal drugs for their approved uses. FDA has already restricted the use of antibiotics in feed and water through the Veterinary Feed Directive. Now they are gearing up to remove all over-the-counter “medically important” antibiotics approved for foodproducing animals within the next two years and place them under veterinary oversight (“Over-the-counter” means available for purchase at any farm supply or internet retailer without the need for a prescription). FDA has established three goals to accomplish from 2019 to 2023:

1. Align antimicrobial drug product (antibiotic) use with the principles of antimicrobial stewardship;
2. Foster stewardship of antimicrobials in veterinary settings;
3. Enhance monitoring of antimicrobial resistance and antimicrobial drug use in animals.

This process will begin after the agency considers comments on the draft Guidance for Industry (GFI) #263 and issues the final guidance. In addition, the FDA plans to “engage with affected stakeholders and state partners at public events, such as meetings and conferences, to hear feedback and answer questions about the changes proposed in the draft guidance document”. The list of drugs affected by the new draft GFI # 263 is available at the following link: https://www.fda.gov/animal-veterinary/judicious-use-antimicrobials/listapproved-new-animal-drug-applications-affected-draft-gfi-263

Although antibiotic resistance is a concern for the livestock industry, it is not the only reason to re-evaluate how and when antibiotics are used. There are simply no new antibiotics currently in development for future use. Given the need for antibiotics to continue to work for treatment of disease, it is important to review why disease develops, correct antibiotic usage and reasons why antibiotics fail. A good illustration is Bovine Respiratory Disease (BRD) in feeder calves. BRD relies on the combination of host susceptibility, pathogens (viral and bacterial), and the environment to overwhelm the immune system and cause disease. Mannheimia hemolytica (formerly known as Pasteurella hemolytica), the most commonly found bacterium in bovine bronchopneumonia, descends into the lungs when the calf’s defenses are depressed due to concurrent respiratory virus infection and excessive stress. Weaning, co-mingling, transportation, castration and dehorning, bad weather, overcrowding, and poor-quality air are known stressors that compromise a calf’s ability to produce antibodies and fight disease. A deficiency in trace minerals, specifically selenium and copper, prevents proper function of immune mechanisms for protection so vaccines do not work as they should. If a high risk calf is placed in an environment where sick calves have been before, that pen is literally full of bacteria and viruses if not cleaned out between groups. Watering troughs, if not regularly drained and sanitized, are known risk factors for pneumonia as the organisms can live in the water and around the edges where calves stand and drink. A persistently-infected (BVD-PI) calf in a pen results in continuous exposure of the pen mates to the BVD virus and a constant suppression in their white blood cells needed to fight sickness. Recently weaned, lightweight calves that are placed on a ration of rapidly fermentable carbohydrates (such as ground corn) can develop acidosis, placing them at exceptionally high risk for respiratory disease and death. Many of these “risk factors” for disease are management problems that can be addressed and changed.

Successful treatment of diseases like pneumonia is not simply a matter of grabbing a bottle of antibiotic, drawing up a dart-full, shooting it in the sick calf and waiting for the drug to take effect. Instead, full recovery is a joint effort between the calf’s immune system and the selected drug to stop the growth of bacteria and destruction of lung tissue. Antibiotics are designed to hold bacterial growth “in check” while the calf’s immune system produces protective cells and mobilizes them to the site of infection. Treatment failure is often due to a delayed immune response because of overwhelming stress, infection with BVD, or nutrition-related factors including trace mineral deficiencies or subacute ruminal acidosis (SARA). Sound nutrition and management, especially around the time of weaning, will substantially improve the immune response to disease challenge and antibiotic therapy. A clean environment with plenty of space and air movement, clean water and ample bunk space reduces calf stress and their exposure to contagious organisms. Transition rations formulated to meet nutrient needs while gradually introducing grain in the diet help keep calves on feed and rumen microorganisms healthy. Identification and removal of BVD-PI calves is through a simple, inexpensive ear notch skin test. Trace mineral deficiencies can be addressed through an injectable trace mineral product while calves are transitioning to a trace mineral mix provided in the diet. Vaccines for the respiratory viruses (IBR, BVD, PI3 and BRSV) are most effective when given during times of low stress; 2-3 weeks prior to weaning is best.

Treatment failure due to human errors include poor timing, use of the wrong drug, improper dose or route of administration, mishandling issues or failure to recognize treatment response. Timing is crucial; if calves are treated early in the course of disease, almost any antibiotic will work. Conversely, if calves are treated late in the course of the disease, nothing will work. In addition to timing, dosage is crucial because antibiotics work by different mechanisms. Figure 1 graphically displays the difference between antibiotics that are considered “time dependent” (effectiveness depends on exposure to the drug for a certain length of time) versus “concentration dependent” (bacteria must be exposed to a high concentration of the drug). If label directions are not followed and only a partial dose is administered or when a second dose is required but not given, the drug is unlikely to work effectively because it cannot reach the necessary minimum target concentration. Selection of the best antibiotic class or “family” is an equally important success factor.

Figure 2 is an illustration of the mechanisms different antibiotic classes use against bacterial cells. Beta-lactams (penicillin, Excede®, Naxcel®, Excenel®) interfere with production of the bacterial cell wall that protects the cell from external threats. Aminoglycosides (gentamicin) and Tetracyclines (LA-300®, Biomycin®, and many others) interfere with protein synthesis within the bacterium by grabbing on to the machinery in the ribosome (the 30S subunit) needed to build proteins. Macrolides (Draxxin®, Micotil®, Zactran®, Zuprevo®, Tylan®) and Chloramphenicol derivatives (Nuflor®) also interfere with protein synthesis although at a different location on the ribosome, the 50S subunit. The Fluoroquinolones (Baytril®, Advocin®) block genetic replication by interfering with DNA and RNA synthesis. Why is this information important? If an animal requires retreatment, selection of an antibiotic from a different class will attack the bacteria through a different route and often improve treatment response. Another good example is treatment for Mycoplasma bovis, a bacterium frequently found in chronic pneumonia cases. It has no cell wall so treatment with a Beta-lactam (such as penicillin or Excede®) is useless. A veterinarian is trained in antibiotic selection and is the best source of information when choosing a therapy. Another issue that may affect success is mishandling the product; an antibiotic that gets too hot or is allowed to freeze will inactivate the drug in most cases. Lastly, treatment failure is not always a “failure” but rather an inability to recognize recovery. A calf that is eating, drinking and looks better after treatment but still has a slight fever often needs additional time to fully recover since fever is one of the last clinical signs to disappear.

Strategic and correct use of antibiotics will continue to be of importance for the cattle industry from this point forward. Consumers are increasingly aware and demanding reduced antimicrobial use in the production of wholesome beef. FDA is responding by decreasing antibiotic availability to the public and will soon place this responsibility completely in the hands of veterinarians. Careful attention to timing of treatment, drug selection, dose, and handling of the product will reduce the human factors that contribute to antibiotic failure. However, by addressing the underlying management factors that contribute to disease in the first place, including reduction of stressors, prompt identification and removal of BVD-PI cattle, and correction of environmental or nutrition-related disorders will lead to better overall health and less reliance on all medications in cattle operations.