Why Antibiotics Fail

Bovine respiratory disease (BRD) continues to be the most common cause of feedlot death loss, despite improved vaccines and expensive long-acting antibiotics formulated specifically against the bugs commonly found in a diseased bovine lung. Beyond death loss due to severe pneumonia, the costs of treatment (antibiotics) and prevention (vaccines), loss of production, and reduced carcass value in chronic cases must also be considered to understand the full economic loss to the industry. In the face of these challenges, consumers are increasingly demanding reduced antimicrobial use in the production of wholesome beef. FDA has already limited the use of antibiotics in feed through the Veterinary Feed Directive and many cattle producers are concerned injectable antibiotics may be FDA’s next target. While antibiotic resistance does occur, it is not the only reason for treatment failure. Given the need to continue using antibiotics, it is important to review correct usage and why antibiotics may fail to save a calf.

BRD relies on the mixture of host susceptibility, pathogens (viral and bacterial) and the environment to cause disease. Mannheimia hemolytica (formerly known as Pasteurella hemolytica), the most common bacteria found in bovine pneumonia, is an opportunist that gets in the lungs when the calf’s defenses are down due to a respiratory virus and stress. Weaning, commingling, transportation, castration and dehorning, bad weather, overcrowding, and poor quality air are known to compromise a calf’s immune system. A persistently- infected (BVD-PI) calf in a pen results in continuous exposure of the pen mates to the BVD virus and a constant reduction in their white blood cells needed to fight sickness. Lightweight calves that are not eating and drinking are also at exceptionally high risk for disease and death.

It is easy to see why successful treatment of pneumonia is not simply a matter of grabbing a bottle of the latest and greatest antibiotic, drawing up a dart-full, shooting it in the sick calf and waiting for the magic bullet 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 the bacteria “in check” and give the calf’s immune system time to gear up and effectively fight the disease. Treatment failure may be due to calf factors including overwhelming stress, infection with BVD, or nutrition-related factors such as trace mineral deficiencies or subacute ruminal acidosis. Sound nutrition and management, especially around weaning, will substantially increase the response to antibiotics. Calves vaccinated 2-3 weeks pre-weaning against respiratory viruses are known to respond faster and better to antibiotic therapy if needed. A good environment with plenty of shade, space, clean water and bunk space reduces stress. Identification and removal of PI calves is through a simple, inexpensive ear notch skin test. Trace mineral deficiencies can be addressed quickly through an injectable trace mineral while calves are transitioning to a trace mineral mix.

Treatment failure due to human errors may 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.

The “MIC” is the “minimum inhibitory concentration” or the minimum level of the drug needed to fight bacteria.

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 perhaps 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 antibiotic classes use against bacterial cells. Beta-lactams (penicillin, Excede®, Naxcel®, Excenel®) cripple production of the bacterial cell wall that protects the cell from the external environment. Aminoglycosides (gentamicin) and Tetracyclines (LA-300®, Biomycin®, and many others) interfere with protein synthesis by grabbing on to the machinery in the ribosome 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 Fluoroquinolones (Baytril®, Advocin®) block genetic replication by interfering with DNA and RNA synthesis. Why is this information important? If a calf requires retreatment, selection of an antibiotic from a different class will attack the bacteria through a different route and often enhance treatment response. Another good example is treatment for Mycoplasma bovis , a bacteria frequently found in chronic pneumonia cases. It has no cell wall so treatment with a Beta-lactam (such as penicillin or Excede®) will prove absolutely useless. A veterinarian is well-trained in antibiotic selection and is the best source of information when choosing 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. Sometimes treatment failure is not 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 just needs time to fully recover since fever is one of the last clinical signs to disappear.

Figure 2: Drawing of a bacterium illustrating the wats different “classes” of antibiotics fight against them. By Kendrick Johnson (Own work) [CC BY-SA 3.0 (http://creativecommons.org/licenses/by-sa/3.0)], via Wikimedia Commons

Strategic and correct use of antibiotics will continue to be of importance for the cattle industry from this point forward. Careful attention to timing of treatment, drug selection, dose, and handling of the product will reduce the human factors that contribute to antibiotic failure. Calf factors including overwhelming stress, infection with BVD, environmental or nutrition-related disorders must also be addressed in order for the calf’s immune system to work with the antibiotic to stop disease in its tracks.