In recent years there have been important changes in antimicrobial therapy based on availability of new antimicrobials, a greater database of species‐specific pharmacokinetic (PK) and pharmacodynamic (PD) information available for antimicrobials used in veterinary medicine and refinement of practices based on PK/PD information, principles of antimicrobial therapy, and antimicrobial stewardship efforts. These have allowed more accurate drug dosing, aiming to maximize antimicrobial efficacy while minimizing adverse effects. Concerns over drug residues in food animals and the continued development of bacterial resistance to antimicrobials have heightened the awareness of rational use of antimicrobials. In many countries, antimicrobial stewardship efforts have resulted in increasing veterinary oversight of antimicrobial use in animals and veterinarians are expected to document an evidence‐based need before using or prescribing antimicrobials.

For good antimicrobial stewardship, numerous considerations need to be taken in to account prior to antimicrobial use (Figure 6.1).

Does the Diagnosis Warrant Antimicrobial Therapy?

A substantial amount of antimicrobial use is likely directed at nonbacterial infections or infections where specific treatment is unnecessary (e.g., self‐limiting infections). Antimicrobials are often used in the absence of a definitive diagnosis, and that is often justifiable. However, a reasonable diagnosis and justification for treatment must be established before administering or prescribing antimicrobial therapy. Using antimicrobials to treat minor infections or purely viral or inflammatory diseases is irrational and expensive, can be hazardous to the patient and promotes antimicrobial resistance. Clients/producers may expect antimicrobials for trivial infections or “just in case” an infection may develop. Veterinary practitioners must resist such pressure to use or prescribe unnecessary antimicrobials. Clinicians may similarly use a “just in case” approach in situations where they know infection is unlikely to be present or at high risk of developing, or where prophylaxis is not likely to be indicated. However, use remains common as a form of defensive medicine, whereby the clinician is prescribing antimicrobials more for themselves than their patient.

What Organism(s) is/are Likely to be Involved?

It is not always necessary to culture samples from all patients with infectious diseases in order to identify the organism involved. Even when specimens can be submitted for culture, treatment is usually started prior to results being available, necessitating an empirical decision. Often, the practitioner can use clinical experience from similar cases to identify the likely bacterium and typically effective treatments. The signs of some infectious diseases are so obvious and the susceptibility of the causative agent is predictable (e.g., “strangles” in horses from Streptococcus equi subsp. equi) that the need for microbiological identification is minimal from the standpoint of making an antimicrobial selection.

However, for those infectious diseases of unknown cause or for those attributable to organisms with unpredictable antimicrobial susceptibility, there is no substitute for isolation and identification of the causative pathogen, if proper specimens can be collected. For these organisms, initial empirical therapy while waiting for culture results may include an antimicrobial with a broad spectrum of activity that is expected to be effective against the most common pathogens. However, broad‐spectrum drugs are usually more toxic and more expensive, so antimicrobial deescalation to more selective therapy should be done once culture results are obtained. The severity of disease, likelihood of resistance, and likely outcome if the initial antimicrobial selection is incorrect needs to be considered. In life‐threatening infections, broader spectrum treatment that covers all reasonable causes is indicated because of the potential serious (or fatal) outcome if effective treatment is not started.

What is the Antimicrobial Susceptibility of the Organism(s)?

While clinical experience may aid the clinician in suspecting a given pathogen, it is optimal to obtain specimens for culture and susceptibility testing in order to select the most appropriate drug and dosage regimen. Preferably, samples for bacteriological culture should be collected before administering an antimicrobial drug. Cytology of an appropriately collected sample may provide insight as to the etiological agent and aid in interpretation of culture results. Susceptibility testing can provide values for minimal inhibitory concentration (MIC), minimal bactericidal concentration (MBC), and/or mutant prevention concentration (MPC) (Chapter 2). Other important pharmacodynamic (Chapter 5) considerations include whether the antimicrobial shows time‐ or concentration‐dependent activity and other microbial effects including postantibiotic effect (PAE) and postantibiotic leukocyte enhancement.

Will the Antimicrobial Reach the Site of Infection? Will It Be Active in the Infection Environment?

The pharmacokinetics of the antimicrobial (absorption, distribution, metabolism, excretion) will determine if the it will reach the site of infection in effective concentrations for the necessary amount of time (Chapter 4). An antimicrobial’s physiochemical properties (e.g., lipid solubility, ionization, degree of protein binding) and the route of administration both impact an antimicrobial’s pharmacokinetic profile. Treatment of sequestered infections such as prostatitis, mastitis or meningitis requires antimicrobials that readily cross biological barriers. Antimicrobials characterized by low values for volume of distribution due to their physiochemical properties are unlikely to reach therapeutic concentrations in such sites. For some antimicrobials, the local infection environment reduces their efficacy. Sulfonamides are ineffective in purulent debris, since paraamino benzoic acid (PABA) released from decaying neutrophils serves as a PABA source for bacteria and reduces the competitive effect of the sulfonamide. Aminoglycosides are ineffective in an abscess due to the acidic, anaerobic environment along with the presence of nucleic acid material from decaying cells which inactivates the aminoglycosides.

What Dosage Regimen will Maintain the Appropriate Antimicrobial Concentration for the Proper Duration of Time?

Dosage regimens are calculated from PK/PD integration (Chapter 5) and may need to be adjusted for physiological variation (e.g., neonates, geriatrics) or pathophysiology (e.g., hepatic and/or renal insufficiency). In some cases, combinations of antimicrobials may be synergistic or additive in their antimicrobial activity. Use of multiple antimicrobial drugs should be limited to:

• known synergism against specific organisms (e.g., beta‐lactams plus aminoglycosides in the treatment of enterococcal endocarditis) (Goldstein et al., 2003)
  
• prevention of the rapid development of bacterial resistance (e.g., trimethoprim combined with a sulfonamide) (Worthington and Melander, 2013)
  
• extending the antimicrobial spectrum of initial empirical therapy of life‐threatening conditions (e.g., beta‐lactams plus aminoglycosides in the treatment of septic foals) (Magdesian, 2017)
  
• treating mixed bacterial infections (e.g., a penicillin or cephalosporin plus enrofloxacin in the treatment of aspiration pneumonia in dogs) (Sherman and Karagiannis, 2017).

Known antagonistic combinations of antimicrobials should be avoided, such as penicillin with tetracycline (penicillin acts on actively dividing cell walls while tetracyclines are bacteriostatic in action) (Gal, 1965). In addition to increased costs, there is usually also an increased risk of adverse effects from the administration of multiple antimicrobials (e.g., antimicrobial‐associated diarrhea) (Wilson et al., 1996). For any antimicrobial dosage regimen, patient acceptance, client compliance with dosing, and the cost of the treatment relative to the value of the animal must be considered.

The availability of evidence‐based appropriate dosage data must also be considered. Quality of evidence can range from randomized controlled trials for the species diseases and animal species, to pharmacokinetic studies of a small number of healthy animals to extrapolation from other species. Interspecies differences can be substantial so species‐specific clinical efficacy or pharmacokinetic study data should be used whenever available, and limitations in available dosing data should be considered when determining whether to use an antimicrobial. This book attempts to incorporate the latest recommendations on dosages and to point out any current uncertainties about such dosages. Dosing recommendations can also change over time based on new information about the use of that drug in the individual animal species or broader understanding of use of the drug (e.g., the change to once‐daily administration of aminoglycosides from older q8h recommendations). Clinicians should ensure that up‐to‐date treatment recommendations are used.

Duration of therapy is a key aspect of the treatment regimen and is typically accompanied by the least (or lowest quality) evidence. Inadequate durations reduce the likelihood of clinical resolution while excessive durations add cost, inconvenience for the person administering treatments, adverse drug reaction risks, and enhanced antimicrobial resistance selection pressure. As opposed to human medicine, where large trials have compared durations for a range of clinical conditions, data are very limited in veterinary medicine. This likely results in the use of excessively long durations either largely for historical reasons or because of a precautionary or defensive approach, particularly as avoiding treatment failure is a more obvious and motivating concern than most of the potential negative effects of treatment.

There is increasing movement to using shorter treatment durations in both human and veterinary medicine. Some veterinary treatment guidelines have reduced the recommended durations, albeit based more on expert opinion and extrapolation from human medicine than species‐specific data (Hillier et al., 2014; Lappin et al., 2017

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