Michael D. Apley, Brian V. Lubbers, and Nora D. Schrag Antimicrobial options for cattle have changed dramatically in the past 50 years. Novel properties of new drug groups, changes in route of administration, and advances in drug formulations have significantly altered characteristics of treatment regimens. Many antimicrobials are single‐injection products, which minimizes the need for animal handling and greatly improves regimen compliance. These drugs are used in an environment of increasing regulatory and political pressure, an expanding array of branded food product lines, and increased scrutiny by consumer and special interest groups. Antimicrobial resistance in both veterinary and human bacterial pathogens threatens the effectiveness and access to these drugs in cattle. This chapter addresses important areas of consideration in constructing antimicrobial regimens in cattle within this context, including reasonable antimicrobials for selected diseases and an extended discussion of some common therapeutic challenges. When giving treatment instructions to clients, especially in large‐scale production facilities where lay personnel will be identifying and treating ill animals, the veterinarian is obligated to provide written treatment guidelines. The treatment guidelines should be constructed to contain the following information, where appropriate. It is essential that the treatment protocols not be altered except after agreement by all parties involved. Consistency of protocol application is an absolute necessity in order to evaluate therapeutic and preventive programs in production systems. In constructing these regimens, the veterinarian must make several key decisions. The search for antimicrobial synergy is prevalent in all branches of medicine. Clinical studies and metaanalyses in human medicine evaluating combination versus single antimicrobial therapy are equivocal, with some studies showing no statistical reduction in patient mortality with combination therapy (Bowers et al., 2013; Heffernan et al., 2020) and others demonstrating a reduced mortality risk with combination antimicrobial therapy (Schmid et al., 2019). There is little evidence to either support or refute the routine use of combination therapy in cattle. An in vitro study of M. haemolytica and P. multocida failed to demonstrate antimicrobial synergism with antimicrobials commonly used to treat BRD (Sweeney et al., 2008). One clinical study evaluating the concurrent use of ceftiofur and tulathromycin versus a single dose of florfenicol demonstrated a reduction in BRD mortality and relapse rates for the combination regimen; however, the study authors concluded that “the relative in vivo effects of concomitant therapy compared to monotherapy with these antimicrobials cannot be determined” as neither drug in the combination treatment was studied individually (Booker et al., 2017). Anecdotal reports often claim that the preferred combination reduces relapses or improves initial treatment response. Arguments that combination therapy will suppress resistance development must be evaluated considering that the bacterial population will also be exposed to a wider variety of antimicrobials. If the animal did not respond to the initial antimicrobial regimen, was it because of antimicrobial resistance in the pathogen or other factors that lead to therapeutic failure? By convention, many treatment protocols specify that subsequent treatments consist of an antimicrobial from a different class, with the rationale being that if antimicrobial resistance contributed to drug failure, a drug with another mechanism of action might circumvent the particular resistance mechanism. There is not strong evidence to support or refute the practice of changing drug classes for follow‐up antimicrobial therapy. While switching to a different drug class seems logical, the reality is that there are many reasons why an antimicrobial may fail to elicit a clinical response (improper diagnosis, advanced disease states, disease‐induced alterations in pharmacokinetics, etc.) that will not be resolved by changing drug classes. In the lead author’s personal experience with randomized, controlled respiratory disease trials, repeating the first drug regimen in first treatment failures resulted in a similar second treatment response as trials where a therapeutic from a different antimicrobial class was selected. This is dependent on the first treatment providing satisfactory treatment response and isolates with similar susceptibility profiles being present in all cases. Furthermore, recent reports of integrative‐conjugative elements (ICE) that confer resistance to multiple drug classes would appear to make class switching a relatively futile exercise. As a counterpoint, while there are many reasons why antimicrobials may not cure an infection, the most significant improvement in clinical outcomes is probably realized when an effective antimicrobial is used. If antimicrobial resistance truly contributed to the clinical failure (something that is very rarely known at the time subsequent treatment is administered), it would be of benefit to change to a drug with a different mechanism as cross‐resistance is not uncommon for antimicrobials used to treat bovine respiratory disease. In the diagnosis of undifferentiated fever/respiratory disease, the animal may have from three to 10 days to respond to the initial regimen before being classified as a treatment failure. Extended durations of antimicrobial coverage are commonplace among current antimicrobials, such as approximately seven days for ceftiofur crystalline free acid and 300 mg/ml long‐acting oxytetracycline, up to approximately two weeks for tulathromycin and gamithromycin, and a claimed 28 days for tildipirosin. These longer durations of therapy bring forth the challenge of deciding when concentrations are low enough that nonresponders should receive additional therapy. Trials evaluating the effect of a longer PTI for bovine respiratory disease demonstrate that longer PTIs did not negatively impact mortality or treatment success rates. These limited data suggest that a 5–7‐day PTI is reasonable for most antimicrobial products. In the authors’ opinion, the success of longer PTIs is likely less about the prolonged concentration of antimicrobial and more about the time needed for the drug and host immune system to resolve the disease process. The current evidence for extended PTIs is notable; however, the successful implementation of PTIs in treatment protocols should consider the impact of “withholding treatment” on animal welfare and employee moral distress. In the United States, regulations for ELDU were promulgated as directed by the Animal Medicinal Drug Use Clarification Act (AMDUCA, 1996). The regulations should be consulted for actual guidance, but the overall order of expected use may be summarized as follows. One component of the AMDUCA regulations is that the veterinarian must determine an extended slaughter withdrawal time for animals subjected to ELDU. In the United States and Canada, this information may be obtained by consulting with the US Food Animal Residue Avoidance Databank (FARAD) or Canadian gFARAD (see Chapter 26). If adequate information for construction of an extra‐label slaughter withdrawal time is not available, then the drug may not be used in food animals. Extra‐label drug use regulations vary in other countries/regions. The European Union has very strict regulations regarding the ELDU of antimicrobials (Regulation 2019/6). The AMDUCA regulations also specify certain pharmaceutical products for which ELDU is prohibited or restricted. The following antimicrobials are prohibited from being used in any extra‐label manner in food animals: chloramphenicol, fluoroquinolones, nitroimidazoles, nitrofurans, and glycopeptides. These regulations also prohibit the extra‐label use of sulfonamides in lactating dairy cows. In 2012, these regulations were amended to also prohibit the extra‐label use of cephalosporins for disease prevention, at unapproved dosages, frequencies, durations, or routes of administration in cattle, swine, chickens or turkeys (21 CFR Part 530, 2012). Furthermore, use of cephalosporins that are not approved for use in one of these species, and for extra‐label disease prevention is also prohibited. The extra‐label use of cephapirin in food‐producing animals is exempt from these restrictions. The extra‐label use of cephalosporins in these species is permitted for the treatment or control of an extra‐label disease indication provided this use adheres to a labeled dosage regimen approved for that particular species and production class. Extra‐label use of a cephalosporin in a food‐producing minor species, such as ducks or rabbits, is also allowed. Veterinarians should be familiar with regulations in their respective countries in order to protect the interests of their clients and the consuming public. Concerns about the proper use of antimicrobials in food animals, especially related to the development of antimicrobial resistance, have prompted development of antimicrobial stewardship guidelines. For example, the American Veterinary Medical Association (AVMA) has made antimicrobial stewardship definition and core principles available to veterinary professionals (AVMA, 2021). These principles include a commitment to stewardship, continuously improving disease prevention practices, judicious selection and use of antimicrobials, evaluation of antimicrobial use practices, and encouraging the development of expertise in antimicrobial stewardship. While these guidelines do not give specific recommendations for antimicrobial applications, they do highlight some of the key considerations that should guide veterinarians as they design antimicrobial regimens for cattle. Some antimicrobials have specific limitations in cattle that either preclude their use or that require special consideration. The extra‐label, systemic use of aminoglycosides in cattle has been the subject of resolutions or policy statements by the AVMA, American Association of Bovine Practitioners (AABP), Academy of Veterinary Consultants (AVC), and the National Cattlemen’s Beef Association (NCBA). In general, these statements discourage the extra‐label use of aminoglycosides in cattle due to the prolonged slaughter withdrawal potential due to renal accumulation. Veterinarians should pay special attention to these statements, especially when a producer organization joins with veterinary organizations in discouraging the extra‐label use of a drug in cattle. Some antimicrobials have significant potential for tissue damage when injected intramuscularly. These include the macrolides (e.g., tilmicosin, tylosin, erythromycin) and some oxytetracycline formulations. Although a visible lesion is not necessary for an adverse effect on tenderness, persistent visible lesions add to trim loss when primal cuts are fabricated into retail cuts. Intravenous use of tylosin and erythromycin is a possibility, but the nonwater‐soluble properties of these drugs in commercially available forms combined with the propylene glycol carriers make adverse reactions a possibility. In addition, repeated intravenous injections have become less attractive in light of effective alternatives with less frequent, subcutaneous administration routes. The answer to this question depends on both the testing methods used in the laboratory and which interpretive criteria were used. Standardized antimicrobial susceptibility test methods are approved by the Clinical and Laboratory Standards Institute (CLSI) – Veterinary Antimicrobial Susceptibility Testing (VAST) for bacteria isolated from animals to promote harmonization and reduce inter‐ and intralaboratory variation. The approved methods are prescriptive in terms of bacterial inoculum, media, incubation conditions, and routine use of quality control testing. Alterations to the approved methods may lead to a test result that is not correlated to clinical outcome (see Chapter 2 for additional discussion of antimicrobial susceptibility testing). Interpretive criteria (“susceptible”, “intermediate,” and “resistant” breakpoints) are approved by the CLSI‐VAST through the evaluation of microbiological, pharmacological, and clinical data and are specific to the antimicrobial, bacterial pathogen, host species, drug regimen, and disease process. The CLSI‐VAST has approved veterinary‐specific breakpoints for bovine respiratory disease (BRD), metritis, and mastitis for common bacterial pathogens and commonly used antimicrobials (CLSI, 2024a). Approved BRD‐specific breakpoints have been established for ampicillin, ceftiofur (sodium, hydrochloride, and crystalline free acid formulations), enrofloxacin, florfenicol, gamithromycin, penicillin G, spectinomycin sulfate, tetracycline, tildipirosin, and tulathromycin for Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni. Danofloxacin breakpoints are approved for M. haemolytica and Pasteurella multocida, while tilmicosin breakpoints are only approved for M. haemolytica. There are no approved test methods or breakpoints for any antimicrobials for Mycoplasma bovis. For other antimicrobials, laboratories may extrapolate the breakpoints developed from other animal species, including humans. Examples of this include breakpoints reported for potentiated sulfonamides, aminoglycosides, and erythromycin. It should be noted that there are no veterinary approved breakpoints for enteric disease in any species. For in‐depth information on the conduct and interpretation of susceptibility testing in cattle, and all veterinary species, the reader is referred to the most recent editions of the Clinical and Laboratory Standards Institute publications VET01, VET01S, and VET09 (CLSI, 2024a,b). Arguments that susceptibility testing results have no utility in antimicrobial selection are often based on the fact that animals with “susceptible” organisms have failed to resolve infections and animals with “resistant” pathogens have recovered. It is important to realize that antimicrobial susceptibility testing does not guarantee a specific clinical result in an individual animal. Rather, for veterinary approved breakpoints, it places the animal/drug regimen/pathogen combination in a population where clinical resolution is more (for susceptible isolates) or less (for resistant isolates) likely compared to other categories. The veterinarian must determine when susceptibility testing may be of use in monitoring a population of animals and pathogens. Veterinarians should also consider the utility of cumulative antimicrobial susceptibility data (“antibiograms”) for guiding empiric therapy of future cases. By monitoring susceptibility test results over time, veterinarians may detect changing patterns of antimicrobial resistance that would necessitate a change in treatment protocols. Specific therapeutic antimicrobial application suggestions in cattle are reported in Table 29.1. Where appropriate, justifications for drug recommendations are presented in a referenced narration. These suggestions should be considered as starting points for application of evidence‐based therapeutic decision processes. Additional discussions for Mycoplasma bovis, enteric Salmonella spp. and E. coli, and Cryptosporidium parvum are provided in the text. There has been debate as to whether M. bovis is a primary respiratory pathogen in cattle. However, in the United States, M. bovis is now listed as a label respiratory pathogen for tulathromycin, gamithromycin, enrofloxacin, and florfenicol. Standardized susceptibility testing methods and interpretive criteria have not yet been established for M. bovis for any indication. Variations in methods may contribute to variations in minimal inhibitory concentrations (MIC) results reported in Table 29.2. It is apparent in this table that there is a wide range of MICs determined for each drug, suggesting that some isolates will be refractive to therapy, although the maximum MIC correlated with therapeutic efficacy has not been established. No clinical trials evaluating antimicrobial therapy of arthritis or tenosynovitis due to M. bovis are available. The antimicrobial selected by the veterinarian should have at least the potential for effectiveness; beta‐lactam antimicrobials (penicillins and cephalosporins) are not reasonable choices as Mycoplasma spp. lack the cell wall that these drugs target. It is reasonable to begin consideration of those antimicrobials with M. bovis on the label for respiratory disease, even though the site of infection is different. For some cases, the tetracyclines may be appropriate, although it is important to recognize that the pharmacokinetics of injectable and oral tetracyclines are markedly different. The MICs for tilmicosin reported in Table 29.2 are considerably higher than those reported for respiratory pathogens against which this antimicrobial is effective, making effectiveness questionable for Mycoplasma spp. Table 29.1 Specific antimicrobial use suggestions. Individual product labels should be consulted for indications and complete instructions for use. Label applications are US labels except for those in bold print which are EU labels.
29
Antimicrobial Therapy in Beef Cattle
General Considerations of Antimicrobial Use in Beef Cattle
Monotherapy or Combination Antimicrobial Therapy in Each Regimen
Same or Different Second‐line Therapy
Timing of Second‐line Therapy Administration
Extra‐label Drug Use (ELDU)
Antimicrobial Stewardship Guidelines
Is Susceptibility Testing Useful in Selecting Antimicrobials for Use in Beef Cattle?
Antimicrobial Use in Cattle
Mycoplasma bovis
Category
Disease/Pathogen(s)
Drugs for which this disease is a label application (therapy and/or prevention)
Reasonable extra‐label antimicrobial choices
Unreasonable extra‐label antimicrobial selections for this disease
Comments
Respiratory disease
Pneumonia: Mannheimia haemolytica, Pasteurella multocida, Histophilus somni
Amoxicillin trihydrate, ampicillin trihydrate, ceftiofur (sodium, hydrochloride, and crystalline free acid salts), chlortetracycline, danofloxacin, enrofloxacin, erythromycin, florfenicol, gamithromycin, oxytetracycline, procaine penicillin G, penicillin G benzathine/penicillin G procaine, spectinomycin sulfate, sulfabromomethazine, sulfadimethoxine, sulfaethoxypyridazine, sulfamethazine, tetracycline, tildipirosin, tilmicosin, tulathromycin, tylosin, cefquinome, trimethoprim/sulfadiazine. trimethoprim/sulfadoxine, procaine penicillin/dihydrostreptomycin, amoxicillin trihydrate, amoxicillin/clavulanic acid
Gentamicin due to potential for toxicity in dehydrated animals and prolonged renal residues in cattle.
Antimicrobials with bovine respiratory disease on the label may be indicated for one or all of these pathogens. The italicized antimicrobials are the authors’ primary choices for cattle in the US in advanced stages of the disease or which have experienced extensive stress. Antimicrobials in bold are available in other countries.
Respiratory disease
Pneumonia – Mycoplasma bovis
Enrofloxacin, gamithromycin, florfenicol, tulathromycin, tylosin
Oxytetracycline, spectinomycin, tildipirosin, fluoroquinolones*
Any beta‐lactam (penicillins, cephalosporins) due to lack of a cell wall.
*In the US, fluoroquinolones would only be legal when used for the purpose of respiratory disease due to the primary label pathogens.
Respiratory disease
Diphtheria (necrotic laryngitis) Fusobacterium necrophorum
Oxytetracycline, sulfabromomethazine, sulfadimethoxine,
Sulfamethazine, tylosin
Ampicillin, ceftiofur, florfenicol, penicillin G, other macrolides
Enrofloxacin/ danofloxacin. Fluoroquinolones would be prohibited for ELDU in the US and anaerobic bacteria are not
Extra‐label recommendations are made based on the expected spectrum of activity (anaerobes) of the antimicrobial and/or label inclusion of foot rot due to Fusobacterium necrophorum.
within the spectrum of activity for these drugs.
The nature of the site of necrotic laryngitis may make therapy with less lipid‐soluble antimicrobials more of a challenge.
Infectious enteric disease
Scours, neonatal diarrhea due to E. coli
Amoxicillin trihydrate, ampicillin trihydrate, chlortetracycline, neomycin, oxytetracycline, streptomycin sulfate, sulfabromomethazine, sulfachlorpyridazine, sulfaethoxypyridazine, sulfamethazine, tetracycline (all these antimicrobials display consistently high MICs that suggest the drugs would be ineffective), amoxicillin/clavulanic acid bolus, apramycin, cefquinome (septicemia), danofloxacin, enrofloxacin (septicemia and colibacillosis), marbofloxacin bolus, trimethoprim/sulfadiazine, trimethoprim/sulfadoxine
Ceftiofur, potentiated sulfonamides (all only after susceptibility testing)
(These extra‐label indications demonstrated very high MICs to most isolates.) Macrolides penicillin, ampicillin, florfenicol.
Fluoroquinolones are likely active against the pathogen, but ELDU is prohibited in the US.
Recommended extra‐label antimicrobials are based on susceptibility data and serum pharmacokinetics and should therefore be interpreted as relating to septicemia associated with enteric disease. See text for additional discussion.
Infectious enteric disease
Scours, neonatal diarrhea due to Salmonella spp.
Chlortetracycline, oxytetracycline, streptomycin, tetracycline (these antimicrobials display consistently high MICs that suggest the drugs would be ineffective), apramycin, enrofloxacin, trimethoprim/ sulfadiazine, trimethoprim/ sulfadoxine, procaine penicillin/ dihydrostreptomycin
Ceftiofur, potentiated sulfonamides (all only after susceptibility testing)
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