Antimicrobials for bovine respiratory disease (Proceedings)

Bovine respiratory disease complex includes bacterial components, which cause the classic clinical signs of lethargy, depression, and fever, with variable nasal discharge, cough, or other signs. This bacterial component of BRD (most commonly Mannheimia haemolytica, Pasteurella multocida, Histophilus somni, and Mycoplasma bovis) may be treated with antimicrobial drugs designed to kill or inhibit the growth of the pathogenic bacteria. Veterinarians may use antimicrobial drug characteristics, such as physiochemical properties (e.g., lipid solubility), mechanisms of action, and effects on in vitro bacterial growth (e.g., bacteriostatic, bactericidal, peak-dependent, time-dependent), to help make a decision about which drug to use and how to use it (regimen: dose, route, frequency, duration, withdrawal time). While these characteristics may add to the discussion and provide pieces of evidence, the ultimate and most convincing evidence is clinical efficacy. For the treatment of bovine respiratory disease, there is considerable good quality published evidence for the efficacy of a number of antimicrobials, as exemplified in the table below. These drugs, all approved in the U.S. for BRD, span the spectrum of antimicrobials, including lipid-soluble and water-soluble, peak-dependent and time-dependent, and bacteriostatic and bactericidal. Therefore, using drug characteristics to make drug decisions for respiratory disease does not address the real questions related to how well the drug works. With this many drugs approved for the treatment and control of respiratory disease, how does one make a decision about which drug to use, and equally important, how to use it?

Table: drugs approved in the U.S. for bovine respiratory disease

Drug selection

Drugs can be selected by using the principles of evidence-based veterinary medicine:

     1. Based on a need for information (a single animal or herd outbreak of respiratory disease), ask a clinically relevant question, including Patient, Intervention, Comparison, and Outcome (PICO).

          • The purpose of the clinical question is to focus your information search and to identify what you are really interested in answering. A vague clinical question will not result in good clinical decision-making.

          • Some examples of relevant clinical questions associated with the therapy of respiratory disease include: In high risk recently weaned calves that have just arrived at a feedlot, which drug product has been shown to decrease mortality? In pre-conditioned, recently-weaned calves headed for backgrounding, has metaphylaxis been shown to reduce costs of disease, including morbidity, mortality, and cost of gain? In dairy cows with signs of respiratory disease, has a particular drug product been show to be more effective at return to production?

          • Clinical questions can be asked about a current problem, or they can be anticipated: a plan to wean calves in the fall suggests a need for information on treating respiratory disease in these calves prior to the fall season.

     2. Using the clinical question, search for all the available published evidence to answer the question.

          • Typically, this step is searching in the published biomedical and animal science literature. While this may be a prolific source of data, in some cases, evidence may be lacking in the published literature and must be found elsewhere. Technical reports from animal health companies on the subject of bovine respiratory disease therapy abound. In addition, well-designed animal record systems with good acquisition of high quality data may also be a source of evidence, although the emphasis needs to be on "high quality data". Bad data is usually worse than no data at all. The use of anecdotal data or clinical impression is always fraught with opportunities for misinterpretation and should generally be avoided. Our minds are not designed to retain the best evidence but rather to retain the interesting, unusual, and exciting evidence. This is not to argue that we do not recognize patterns – that is the basis of many clinical diagnoses. However, patient outcomes are best analyzed via written record rather than recollection of clinical cases.

     3. Once the available evidence is found, it must be reviewed for relevance and quality.

          • Many more thorough pieces have been written on how to evaluate evidence, but here are a few of the important things to look for when reviewing a published paper, a technical report, or your own clinical data related to pharmacotherapeutics.

          • Were animals randomized to treatment group?

          • Were the outcomes (like days with fever) similar to what you expect from successful therapy?

          • Are the animals in your patient population the same as or similar to those in the paper?

          • What did the investigators not mention that you wanted to know about?

          • Are the conclusions appropriately specific, or do they over-generalize?

          • Who paid for the study? Is it possible that information was left out of the report?

          • If the authors find no difference between treatment groups, did their study actual have enough statistical power to find a difference (usually related to number of animals)?

     4. Making the decision about which drug to use and how to use it is the last step. An informed clinical decision come from high quality evidence. Low quality evidence leads us to ask another clinical question, continue our search for data, or search for alternative therapies.

Because of the number of drugs approved for the treatment of respiratory disease in cattle, it would be very difficult to justify any extralabel use of antimicrobial drugs. The AMDUCA hierarchy for extralabel use demands that there are no drugs approved for the condition that are clinically effective for extralabel use to be considered. A veterinarian would have to be convinced that none of the drugs in the table below are clinically effective, which would be challenging.

Use of selected drug

How to use the drug we selected entails making decisions about when to treat, how long to treat, how to monitor therapy, how to evaluate success of therapy, when to switch drugs, and whether to use ancillary therapy.

     1. When to treat: Should we treat animals after clinical signs develop, treat all animals in a group if some are showing clinical signs, or treat all animals in a group due to expectations of disease prior to development of clinical signs? In particular, we might ask about whether to practice "metaphylaxis". This is the treatment of animals at high risk of developing respiratory disease, meaning animals which are likely in the early stages of disease but have not yet all developed clinical signs. Research has shown that waiting until all animals have clinical signs of disease may result in unsuccessful therapy or chronic infections. This practice, when used prudently (and not used in groups of animal that are not likely to need therapy), can successfully reduce the need for further antimicrobials as well as decrease morbidity, mortality, and economic losses.

     2. How long to treat: In other words, how many courses of therapy should we use when faced with an individual animal not immediately responding to therapy. Knowledge of the pathogenesis and pathophysiology of respiratory infections in cattle should suggest that an infection requiring significantly more than 10 days of antimicrobial therapy has another component: non-respiratory infection, abscess formation, permanent compromise of organs, or other factor contributing to the lack of response to therapy.

     3. How to monitor therapy: We nee good case definitions in order to determine if the therapy is working. Respiratory disease case definitions vary somewhat depending on the type of animal and production system, but most involve at the least fever and depression. Lack of these clinical signs or presence of signs unrelated to the respiratory system suggests other infections, which may or may not respond to the therapy directed at respiratory pathogens.

     4. How to evaluate success of therapy: This refers to the need for record-keeping, particularly when treating groups of animals. Accurate records are always indicated when treating animals with antimicrobials in order to (1) withhold animals appropriately from the food chain, (2) treat individuals at the appropriate time/to adhere to dosing regimens, and (3) evaluate success of therapy. Clinical impression of success vs. failure will lead to inaccurate gauging of therapeutic success, as discussed above.

     5. When to switch drugs: Given the number of available therapies for BRD, we might assume that we have the option of deciding to use a different drug than the one currently being used. This could be for a single patient or for a herd. This is decision should not be taken lightly. Switching antimicrobials indiscriminately in the face of unsuccessful therapy will not solve any problems, and may expose animals unnecessarily to antimicrobials. It could be argued that animals that are not responding to an antimicrobial during the treatment period may just require additional time WITH THE SAME antimicrobial in order to respond completely.

     6. Use of ancillary therapy: The use of adjuncts to antimicrobial therapy are becoming more common as anti-inflammatory drugs are approved for cattle. Whether these drugs provide desirable outcomes should be considered: For example, days of fever may be reduced, but how was pounds of gain or feed efficiency impacted? Can we determine if the disease course was altered by use of ancillary therapy? These are clinical questions that need to be answered in order to decide whether and which ancillary therapy to use.

References available on request