Sarah Wagner and Sarah Depenbrock In dairy cattle production, good antimicrobial stewardship requires changes in the way bacterial infections are identified and mitigated to reduce antimicrobial interventions. This chapter provides evidence‐based information on antimicrobial use decisions for the more common diseases of dairy animals: intramammary infections (IMI, also commonly called mastitis), metritis, bovine respiratory disease (BRD), and calf diarrhea. The reader is encouraged to consider that herd‐wide disease risk identification and mitigation improve overall animal health outcomes more than the use of antimicrobials after disease prevention efforts have failed. The intended use of the dairy animal is very important when making antimicrobial use decisions. Consideration of residue avoidance to protect the food supply and avoid costly mistakes such as contamination of a bulk tank is imperative in dairy practice. Ideally, the antimicrobial selected for use should be one that is labeled for the specific production group(s) indicated on the label. Specific dairy age groups that are commonly defined on antimicrobial labels include preruminating calves, ruminating calves, and adult female dairy cattle (20 months of age or older). Male calves that are used for veal production include bob veal – calves slaughtered by 21 days of age; milk‐fed veal – calves fed only milk or milk replacer that are slaughtered at 18–20 weeks of age; red veal – calves that get additional grain and hay and are slaughtered at 18–20 weeks; and free raised veal – calves that remain with their dams on pasture and are slaughtered at 24 weeks. In veal production, antimicrobial use is limited as many antimicrobials carry the disclaimer “not to be used in veal calves” due to physiological differences in very young calves compared to older animals. Residue depletion is complicated by the common disease conditions being treated (e.g., dehydration from diarrhea) and short lifespan for drug withdrawal prior to processing for human consumption. Adult female dairy cattle are considered lactating animals, even if they are not actually lactating, because these animals are at risk for lactation. For example, an animal may inadvertently get bred early and calve early, or abort prior to the anticipated due date but late enough to come into milk, and thus produce milk unexpectedly early. Dairy replacement heifers may have more flexible antimicrobial treatment as long as animals are maintained until adulthood prior to entering the food chain. When label dose, route, volume per site, frequency, duration, indication, and production group/age are followed, the label withdrawal time (WDT) can be used. Any time any one of these conditions is altered, an extended withdrawal interval (WDI) must be provided by the prescribing veterinarian. When an appropriate antimicrobial is not available for the desired age group or lactation status, extra‐label drug use (ELDU) may be considered, and the jurisdictional regulations should be followed (see Chapter 26). Commercial tests validated for antimicrobials in milk can be purchased for on‐farm use. When antimicrobials are used in severely compromised animals in which drug elimination may be delayed, it is prudent to prolong the withdrawal recommendation past the label WDT for on‐label use or greatly extend the recommended WDI for ELDU. The most common use of antimicrobials on dairy farms is to treat mastitis, which is caused by IMI. The expenses associated with IMI (decreased milk production, decreased milk quality, drug treatment costs, and discarded milk) are considerable, and require dairy producers to implement management programs focused on IMI prevention and treatment. A farm that is experiencing high somatic cell counts, frequent occurrence of clinical IMI, a high prevalence of subclinical IMI, or all of these should investigate the reason and develop a program to mitigate the cause and prevent new occurrences. Money spent on effective prevention of IMI is likely to provide an overall financial benefit to the dairy, and treatment alone is not an effective way to resolve herd‐level IMI problems. Even on well‐managed farms with IMI prevention protocols in place, treatment of clinical or subclinical IMI may be desirable when there is a good chance that treatment will improve the milk quality, productivity, well‐being, and longevity of the cow. Subclinical IMI may be detected through a combination of individual cow somatic cell counts (SCCs) as measured by dairy herd improvement (DHI) testing, or estimated using the California Mastitis Test (CMT) and confirmed by microbial culture of milk samples. Clinical IMI is described as mild when abnormal milk is the only sign; moderate when abnormal milk and udder swelling are present; or severe when milk and udder abnormalities are accompanied by signs of systemic illness such as fever, hypothermia, recumbency, or depression. The discussion presented here focuses on clinical cases of IMI, but the principles described are also generally applicable to the treatment of subclinical IMI. In some cases, it is more rational not to treat IMI, either because treatment is unnecessary or because treatment is unlikely to result in resolution of clinical signs. Risk factors that have been found to decrease therapeutic efficacy include increasing cow age, high SCC before treatment, long duration of infection, multiple infected quarters, and infections caused by Staphylococcus aureus. Questions to ask about the cow before deciding to treat mastitis are presented in Table 30.1. Many dairies implement a standardized approach to IMI prevention and therapy. Key benefits to standardizing IMI therapy are that treatment decisions are made in advance instead of “cow‐side” and that a consistent approach is developed. Less time is spent deciding whether or not to treat a case of IMI, selecting a drug and treatment regimen, and assigning an appropriate WDT for milk and meat from treated cows. Moreover, when treatments are standardized and good records are kept, it is simple to evaluate whether or not a given treatment is successful on the farm. A key component of a standardized approach to IMI treatment is regular veterinary review of protocols to ensure that they are being followed and continuing to generate expected outcomes. Table 30.1 Questions to ask about the cow before deciding to treat mastitis. Simple on‐farm microbial culture systems (or local laboratories that provide rapid milk culture results) allow culture results from each case of IMI to be incorporated into treatment protocols. The simplest and most common approach is to perform aerobic milk culture on agar gel plates with multiple selective media types used to categorize results as Gram‐positive pathogen growth, Gram‐negative pathogen growth, or no pathogen growth. In a typical protocol, no treatment of mild or moderate cases of IMI is initiated for 18–24 hours while culture results are pending. Intramammary (IMM) antimicrobial treatment is reserved for cows with Gram‐positive pathogens or mixed pathogens identified on microbial milk culture. Multiple research studies have compared the IMM treatment of all cows with mild or moderate IMI to the treatment of only those with Gram‐positive pathogens on milk culture, using outcomes such as bacteriological cure, clinical cure, rate and rapidity of recurrence, and culling. Selective, culture‐based treatment has comparable short‐term and long‐term outcomes to treatment of all clinical cases of IMI. This is because many cases of IMI that yield no growth or Gram‐negative pathogen growth on culture resolve spontaneously and antimicrobial treatment is of no benefit. Decreasing the number of treated cows on farms that have previously treated every case of IMI results in financial benefit, even after the cost of conducting microbial culture of each new case is factored in. In addition, these culture‐based selective treatment programs can reduce the number of cows treated with IMM antimicrobials by 50% or more, thereby decreasing the selection pressure for drug‐resistant bacterial populations. If a culture‐based approach is taken, it is necessary to understand that Gram‐negative IMI can develop into chronic infection or severe systemic illness. In addition, Mycoplasma spp. require special culture media and more stringent incubation conditions than this simple approach provides, so they will not be identified by typical on‐farm culture programs. Retaining milk samples in the freezer for a period of time after the initial treatment is a useful practice. If the treatment outcome is undesirable, the retained sample can be submitted to a diagnostic laboratory for detailed microbiological diagnosis. By saving the pretreatment sample of cows treated with antimicrobials, there is no need to wait for the drugs to be eliminated from the mammary gland prior to sampling for repeat culture. For cows left untreated that do not improve, a repeat culture may be taken at any time to obtain results indicative of their current microbiological status. Culture is also an irreplaceable aid to determining whether a chronic case of IMI might be resolved by extended antimicrobial therapy or if the pathogen causing the IMI is not amenable to therapy and the greatest financial benefit to the farm would be not to treat it again. An example of a culture‐based herd mastitis treatment protocol is given in Figure 30.1. Antimicrobial susceptibility testing is a way of quantifying the interaction between microbes and antimicrobials in the laboratory (see Chapter 2). Validated veterinary breakpoints are used to determine whether a particular laboratory outcome indicates susceptibility for a specific drug, dosing regimen, pathogen, affected species, and disease condition. Currently, validated veterinary breakpoints are available for two US Food and Drug Administration (FDA)‐approved preparations for IMM treatment of lactating cows (ceftiofur, pirlimycin) and one FDA‐approved intramammary preparation for treatment of dry cows (a combination of penicillin and novobiocin). Susceptibility testing appears to have limited value as an aid to therapeutic decision making for bovine IMI. The relationship between susceptibility determined by laboratory susceptibility testing and the outcome of clinical cases of IMI is inconsistent. The issue is further complicated by the use of variable outcomes in trials assessing resolution of clinical IMI; the achievement of a cure may be defined as resolution of clinical signs, one or more negative microbial cultures, or some combination of these outcomes, and the amount of time between treatment and the assessment of treatment outcomes is not standardized. A more practical approach to assessing whether an IMI therapy works is to design farm protocols for treatment of clinical IMI with selected antimicrobials, then periodically evaluate the protocols for the efficacy of the selected drugs in achieving the farm’s therapeutic objectives. Common therapeutic objectives include clinically normal milk and/or a reduction in SCCs. Microbial culture of IMI is a valuable aid in determining whether to initiate drug therapy and if so, what approach to use. Intramammary infections with certain pathogens are likely to respond to antimicrobial therapy, while other pathogens have a more variable response. As mentioned above, some IMI are likely to resolve without any treatment. Common IMI pathogens that are unlikely to be responsive to antimicrobial therapy are listed in Table 30.2. A brief overview of some other commonly encountered pathogens follows. Streptococcus agalactiae is a contagious IMI pathogen. It is typically responsive to therapy with antimicrobials with activity against Gram‐positive pathogens, such as beta‐lactams and lincosamides. Staphylococcus aureus is also a contagious IMI pathogen. Chronicity decreases the responsiveness of S. aureus infection to antimicrobial therapy. A new case in one quarter of a young cow, caused by a S. aureus strain that is susceptible to penicillin, is more likely to respond to appropriate therapy than one or more quarters chronically infecting an older cow, particularly with a penicillin‐resistant strain. Extending the duration of therapy improves the likelihood of therapeutic success when treating IMI caused by S. aureus. If treatment duration is extended beyond the label dosage, additional withdrawal time is required and milk testing for drug residues is recommended. Figure 30.1 Example herd mastitis treatment protocol incorporating on‐farm culture. Streptococci other than S. agalactiae and staphylococci other than S. aureus are the most commonly isolated Gram‐positive pathogens found on microbial milk culture. IMM treatment with amoxicillin or ceftiofur resulted in similar outcomes including clinical cure (return to normal milk and udder appearance) and bacterial cure (no growth on milk culture) rates among cows affected with mild or moderate mastitis due to a variety of Gram‐positive pathogens, with clinical cure rates higher than bacterial cure rates (Tomazi et al., 2021). Both types of cure were less common in cows affected with Streptococcus uberis than other pathogens. Cows with Trueperella pyogenes or S. aureus infections were excluded from the study because these pathogens are not responsive to treatment, and no cows had a positive culture for S. agalactiae. Table 30.2 Mastitis pathogens unlikely to respond to antimicrobial drug treatment. For IMI with Gram‐negative pathogens that do not spontaneously resolve or that recur, treatment with antimicrobials may be warranted. Multiple studies have failed to produce solid evidence that treatment of a new case of IMI caused by a Gram‐negative pathogen will improve clinical or bacteriological outcomes when compared with no treatment. Unfortunately, what to do with Gram‐negative IMI that does not resolve without treatment or that recurs has not been established. If treatment of such cases is undertaken, selection of a drug with an appropriate spectrum of activity (an aminopenicillin or cephalosporin, not a lincosamide) is indicated, and an extended duration of therapy should be considered. Unlike other mastitis pathogens, Mycoplasma bovis cannot be grown using typical on‐farm culture methods (i.e., blood agar in an aerobic culture environment), and it is associated with diseases other than IMI, such as otitis media and joint infections. Mastitis caused by Mycoplasma may occasionally resolve without treatment, but antimicrobial therapy does not affect the outcome (Gelgie et al., 2022). After cow factors, culture results, and pathogen factors have been weighed up and the decision has been made to treat IMI, a suitable therapeutic regimen must be designed. Components of a therapeutic regimen include the drug to be used, drug dose, route of administration, frequency of administration, duration of use, and meat and milk withdrawal times. For mild to moderate IMI, antimicrobial therapy is usually administered by the IMM route. There are eight antimicrobials approved by the US FDA for IMM use in lactating cows: amoxicillin, ceftiofur, cephapirin, cloxacillin, erythromycin, hetacillin, penicillin, and pirlimycin. Although they remain approved, products containing erythromycin, cloxacillin or pirlimycin are no longer marketed in the US. In Canada, only ceftiofur and cephapirin are available for IMM treatment in lactating cows. In the European Union (EU) and other countries, available IMM formulations include amoxicillin/clavulanic acid, cephalexin/kanamycin, novobiocin/dihydrostreptomycin/neomycin, neomycin/streptomycin/penicillin G, cephalexin/kanamycin, cefquinome, dihydrostreptomycin/framycetin/penethamate, tetracycline/neomycin/bacitracin, rifaximin, lincomycin/neomycin, cefuroxime, cefoperazone, and cloxacillin/neomycin. Intramammary use of drug preparations not specifically manufactured for IMM administration is not recommended; such substances may be irritating to udder tissues and promote inflammation. In addition, compounded preparations are at risk for contamination with infectious pathogens, and milk and meat withdrawal times recommended for other routes of administration are likely to be inaccurate. Different antimicrobial preparations should not be used simultaneously in one quarter, since interactions between the two drug formulations may decrease efficacy. Antimicrobial spectrum of activity is a key consideration when selecting an antimicrobial for IMM therapy of mastitis. One of the earliest beta‐lactam drugs to be developed, penicillin G, is available for IMM administration alone or in combination formulations. Penethamate is the diethylaminoethyl ester of penicillin G. Penicillin is active against many streptococci and nonpenicillinase‐producing staphylococci. The drug is inactive against the Enterobacterales, and staphylococcal resistance is common. Amoxicillin and hetacillin are aminopenicillins that share similar spectra of activity. The aminopenicillins are active against bacteria susceptible to penicillin G, as well as some Enterobacterales such as E. coli. Many E. coli isolates are now resistant to the aminopenicillins through beta‐lactamase production. Amoxicillin in combination with the beta‐lactamase inhibitor clavulanic acid is available for IMM administration in the EU; this combination is more effective than aminopenicillins alone against beta‐lactamase‐producing bacterial strains. Cloxacillin is a penicillinase‐resistant penicillin active against penicillinase‐producing S. aureus strains that are resistant to the natural penicillins and aminopenicillins. It is less active against other penicillin‐sensitive organisms. Cephapirin and cephalexin are first‐generation cephalosporin drugs generally active against staphylococci and streptococci and sometimes active against coliforms such as E. coli and Klebsiella spp. All Enterococcus spp. are inherently resistant to cephalosporins. Cefuroxime is a second‐generation cephalosporin with increased activity against coliforms. The third‐generation cephalosporins ceftiofur and cefoperazone and fourth‐generation cephalosporin cefquinome have further increased activity against coliforms. Dihydrostreptomycin, streptomycin, neomycin, kanamycin, and framycetin are aminoglycosides available in combination IMM formulations in the EU and other countries. These antimicrobials have activity against aerobic, Gram‐negative bacteria and against Staphylococcus spp. Pirlimycin, a lincosamide, was the only drug available as an IMM preparation in the US and Canada that was not a member of the beta‐lactam drug class. Lincosamide is available in IMM formulations in some countries. Lincosamides have a primarily Gram‐positive antimicrobial spectrum and are not active against coliform IMI pathogens. A recent metaanalysis evaluated 30 clinical trials of IMI treatment in cows using various drugs against various pathogens, comparing outcomes based on classifications of drug importance in human medicine (third‐ and fourth‐generation cephalosporins, highest priority; penicillins, high priority; and first‐ and second‐generation cephalosporins, highly important) (Nobrega et al., 2020). For nonsevere IMI, treatment of infection due to E. coli showed no benefit over nontreatment, and among the other most common pathogens, using an WHO critically important antimicrobial (CIA) (e.g., ceftiofur, cefquinome) did not improve outcomes compared to using noncritically important antimicrobials. In the interests of antimicrobial stewardship, these findings should be considered when selecting an antimicrobial for the treatment of IMI. When possible, preference should be given to the use of antimicrobials of least importance to human medicine.
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Antimicrobial Therapy in Dairy Cattle
Dairy Animal Use Considerations
Intramammary Infection
Cow Factors
Herd‐based Therapeutic Protocols
Question
Relevant information
On‐farm/Rapid Result Microbial Culture and Treatment
Pathogen Identification and Antimicrobial Susceptibility Testing
Pathogen Factors
Bacillus spp.
Mycobacterium spp.
Mycoplasma bovis
Nocardia spp.
Pasteurella spp.
Proteus spp.
Prototheca spp. (algae)
Pseudomonas spp.
Serratia spp.
Trueperella pyogenes
Yeasts (e.g., Candida spp.; IMM treatment will delay spontaneous cure)
Intramammary Antimicrobial Use
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