Antibiotic Selection in Bovine Respiratory Disease
– Dr. Michelle Arnold, DVM-Ruminant Extension Veterinarian (UKVDL)
Figure 1: Drawing of a bacterium illustrating the ways different “classes” of antibiotics fight against them. By Kendrick Johnson (Own work) [CC BYSA 3.0 (http://creativecommons.org/licenses/bysa/3.0)], via Wikimedia Commons
“Antimicrobial or antibiotic resistance” occurs when bacterial populations change in some way that reduces or eliminates the effectiveness of the drugs designed to remove them. When antibiotic treatment fails, it is often assumed that resistance has developed, and changes must be made in treatment protocols such as using combinations of antibiotics or using a different sequence of drugs to improve the outcome. While the threat of resistance development is real, there is much more involved in recovery from bovine respiratory disease (BRD) than the interaction of a chosen antibiotic with the bacterial pathogens in lung tissue. In other words, antibiotic selection is important but is only one piece in the very complex puzzle of treatment success or failure.
The antibiotic’s ability to stop the growth of bacteria (“bacteriostatic”) or kill bacteria (“bactericidal”) depends on its mechanism of action and the concentration of the drug at the infection site. Once an antibiotic is given, it is absorbed then distributed by the bloodstream throughout the body. The liver, kidneys, and other organs then chemically change or metabolize the antibiotic to allow it to be excreted through urine or feces. The chemical properties of the drug and how it is ultimately metabolized affect its ability to penetrate infected tissues and contact the bacteria inside them. How quickly this process works depends on the individual animal’s physiologic state (hydration, acid/base status) and the chosen antibiotic. Successful antibiotic therapy depends on early exposure of pathogenic bacteria to effective concentrations of the right drug for an optimum period of time.
Broadly, livestock antibiotics target one of three sites: the bacterial cell wall, the bacterial nucleic acid or at a site of bacterial protein production on the ribosome. An antibiotic is classified within a family based on its mechanism of action used to fight against bacterial organisms (see Figure 1 above). The Beta-lactam antibiotic class that includes penicillin, ampicillin (Polyflex®), and ceftiofur (Excede®, Naxcel®, Excenel®), inhibits production of the bacterial cell wall that protects the cell from harm, causing bacterial death. Aminoglycosides (spectinomycin, gentamicin, and neomycin) and Tetracyclines (LA-300®, Biomycin®, and many others) interfere with protein synthesis by binding to the machinery in the 30S subunit of the ribosome needed to build essential proteins for replication. Macrolides (Draxxin®, Micotil®, Zactran®, Zuprevo®, Tylan®) and Chloramphenicol derivatives or “phenicols” (Nuflor®, Resflor®) also interfere with protein synthesis although at a different location (the 50S subunit) on the ribosome. The Fluoroquinolones (Baytril®, Advocin®) block genetic replication by interfering with nucleic acid (DNA and RNA) synthesis while Sulfonamides (Albon®, Sulfamethazine) block production of folic acid necessary for bacteria to survive. The beta-lactams, aminoglycosides, and fluoroquinolone families are generally considered to be bactericidal while the macrolides, phenicols, and tetracyclines are classified as bacteriostatic. If a calf requires retreatment, selection of an antibiotic from a different class will attack the bacteria through a different route and will often enhance treatment response. Current research is exploring the difference in treatment response based on the order of drugs used; some studies suggest that using a bacteriostatic drug followed by retreatment with a bactericidal drug may increase the risk of BRD relapse. Similarly, if using combination therapy (two different antibiotics given at the same time), selection of antibiotics from different families theoretically should increase the chances of at least one of the drugs being effective. However, it has long been taught that using a “cidal” and “static” drug at the same time increases the potential for antagonism and poor treatment success. Unfortunately, much of the antibiotic research to date has been conducted in vitro, otherwise known as “in the lab”, rather than out in the field. As more studies are conducted on the calves themselves, the differences between “static” and “cidal” antibiotics have become less distinct and are not considered nearly as important as in years past.
Besides the mode of action, antibiotics also differ in their “pharmacokinetic (PK) curves”. The minimum inhibitory concentration (MIC) is the lowest concentration of an antibiotic that stops the growth of a certain strain of bacteria. Some antibiotics (Beta-lactams, Tetracyclines, Chloramphenicol derivatives) are considered “time dependent”, meaning their effectiveness depends on reaching the MIC threshold and staying there over a certain length of time to be effective. If label directions are not followed and a second dose is required for a time-dependent drug but not given, treatment is less likely to be effective because the drug cannot stay above the MIC for the necessary minimum target time. “Concentration dependent” or “dose dependent” drugs such as macrolides and fluoroquinolones require bacterial exposure to a critical concentration above the MIC to be effective. If a partial dose is administered of a concentration-dependent drug, its effectiveness is severely compromised.
An important part of antibiotic selection and use is duration of therapy. Research has shown that at each retreatment, the BRD bacteria become more resistant to multiple antibiotics and response rates decline. Additionally, many of the bovine respiratory pathogens today contain a piece of genetic material known as an Integrative Conjugative Element (ICE) which codes for resistance to up to 7 antimicrobial families and may be transferred from one bacterial species to another through a process known as conjugation. Treatment protocols in many feeder cattle operations consist of one antibiotic used on arrival for metaphylaxis, a 2nd antibiotic or combination for first pulls, a 3rd antibiotic for the next treatment and possibly a 4th antibiotic for a final treatment before calling the calf a “chronic” and treatment ceases. To make these antibiotics effectively last throughout the first month on feed and decrease drug resistance, it is important to understand and observe the antibiotic’s “post-treatment interval” or PTI. This interval is the time when an effective antibiotic is already in the calf and the treated animal is not eligible for retreatment until the end of this period. All the upper tier respiratory antibiotics, including Draxxin®, Excede®, Baytril®, Zactran®, Zuprevo®, Micotil®, Advocin® and Nuflor®, have a 5 to 7-day PTI. During the PTI, the antibiotic suppresses and delays disease onset while the calves are fighting the infection, adapting to their new environment, feed, social structure, and daily activity. Conversely, by shortening the treatment interval and becoming overly aggressive with retreatments, the antibiotic choices are essentially used up before the disease risk has passed for the group. Although it is very difficult to refrain from retreating an expensive calf that is not showing improvement after 1-2 days with an antibiotic on board, conserving antibiotic effectiveness for the rest of the calves has got to be a priority.
BRD is not a disease complex managed solely through a needle. Purchased calves should be assessed on arrival as either at high, medium, or low risk of respiratory disease and managed according to risk. The known factors predisposing calves to BRD include recent weaning, commingling, long distance transportation, castration and dehorning, bad weather (hot or cold), overcrowding, and poor-quality air and water. Disease control should begin with exceptional management and nutrition to minimize the stress on incoming calves. Successful treatment of bronchopneumonia 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. Timing is crucial; if calves are treated early in the course of disease, antibiotics will have the best chance of making it into the tissues and increasing the odds of recovery. Conversely, if calves are treated late in the course of the disease, nothing will work.
Antibiotic selection needs to be intentional. 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, exposure to the bovine viral diarrhea (BVD) virus through a persistently infected (PI) calf, environmental or nutrition-related factors must also be addressed for the calf’s immune system to work together with the antibiotic to stop disease progression. A veterinarian is well-trained in the complexities of antibiotic selection and is the best source of information when choosing or changing any BRD treatment regimen.
This article has been reposted from the Ohio BEEF Newsletter. To view the original article, click HERE
