Applied Pharmacology to Support Clinical Decision Making for Bovine Veterinarians

Summary

1. Antimicrobial Stewardship and Judicious drug use (review)
2. Considerations in Selection and Use of Antimicrobial Drugs (review)
3. Compartmental PK approach (new)
4. NNT (Number Needed to Treat) concept (new)
5. CLSI Breakpoints (new)
6. Assessing Treatment Response (new)

Introduction

A good understanding of pharmacological principles is important to food animal practitioners / bovine practitioners as they serve an important role in working with their clients and their animals in providing guidance and oversight on the selection and use of antimicrobial products to treat and manage disease.  The goal of this chapter is to apply pharmacological principles and concepts in ways that support judicious drug use as part of good antimicrobial stewardship as well as enhance the students knowledge and practical application skills.  

Foundational Knowledge Review

Antimicrobial Stewardship and Judicious Drug Use

Antimicrobial stewardship refers to the actions veterinarians take individually and as a profession to preserve the availability and effectiveness of antimicrobial drugs through conscientious oversight and responsible medical decision making while safe-guarding animal, public and environmental health. Such stewardship involves maintaining animal health and welfare by implementing a variety of preventive and management strategies to prevent common diseases; using an evidence based approach in making decisions to use antimicrobial drugs; and then using antimicrobials judiciously, sparingly and with continual evaluation of the outcomes of therapy, respecting the client’s available resources.  (AABP Guidlines - 2019)

Judicious drug use is a component of stewardship and is focused on how antimicrobials are used when they are needed.  There are a variety of different guidelines available related to judicious drug use.  At the core judicious drug use revolves around using the proper selection and use of antimicrobial drugs as well as the related oversight, training and monitoring of the actual use.

Considerations in selection and use of Antimicrobial Drugs -Judicious Drug Use

Selection of antimicrobials for use in the treatment, control and prevention of diseases in production animals involves the consideration of multiple different aspects that involve the animal/production system,  pathogen/disease and antimicrobial agent.  Below is a summary of considerations for selection and use of antimicrobials focused in production livestock that support judicious drug use.

Microorganism

• Organism known or suspected
• Susceptibility

• Known

• Culture and Sensitivity (In Vitro Susceptibility)

• Historical

• Antibiograms for farm or region
• Accepted in literature

• Extracellular/Intracellular infection
• Clinical Experience with type of infection

• Field experience or clinical efficacy
• Field studies / published literature

(Antimicrobial Therapy in Veterinary Medicine, 5th Edition,2013)

Pharmacodynamic Indices

• Minimum Inhibitory Concentration (MIC)

• In vitro measurement, interpretation is important

• Minimum Bactericidal Concentration (MBC)
• Mutant Prevention Concentration (MPC)

• The drug concentration that prevents generation of first-step resistant mutants within a susceptible population.  The range of concentration between the MIC and MPC is the mutant selection window (MSW).  Optimum dosage regimen minimizes MSW.

(Antimicrobial Therapy in Veterinary Medicine, 5th Edition,2013)

• Time Dependent (typical static activity)

• Time > MIC

• Concentration Dependent

• AUC/MIC ratio
• Cmax/MIC ratio

• Bactericidal vs Bacteriostatic (cidial preferred for:)

• Serious life threatening situations
• Host defenses impaired
• Infections in CNS, Cardiovascular, Bones (host defenses may not be functioning)
• Immunodeficient or immunosuppressed animals

• Post-antibiotic effect (PAE)

• PAE is defined as persistent suppression of bacterial growth after a brief exposure of bacteria to an antibiotic.   Factors that affect the duration of the post antibiotic effect include duration of antibiotic exposure, bacterial species, culture medium and class of antibiotic. It has been suggested that an alteration of DNA function is possibly responsible for post antibiotic effect following the observation that most inhibitors of protein and nucleic acid synthesis (aminoglycosides, fluoroquinolones, tetracyclines, clindamycin, certain newer macrolides/ketolides, and rifampicin and rifabutin) induce long-term PAE against susceptible bacteria. Theoretically, the ability of an antibiotic to induce a PAE is an attractive property of an antibiotic since antibiotic concentrations could fall below the MIC for the bacterium yet retain their effectiveness in their ability to suppress the growth. Therefore, an antibiotic with PAE would require less frequent administration and it could improve patient adherence with regard to pharmacotherapy.

Pharmacokinetic Considerations

• Route of Administration

• IM, SQ, Oral, Local

• Availability of drug of choice in a dosage form that is suitable for administration to species and class
• Formulation and dose depend on the route of administration and will affect absorption and distribution.

• Bioavailability

• Subcategory of absorption is the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered intravenously, its bioavailability is 100%. However, when a medication is administered via other routes (such as orally), its bioavailability generally decreases.  The systemic availability (F) is the fraction of the dose that reaches the systemic circulation. In veterinary medicine, practitioners must be mindful of species differences in gastrointestinal anatomy and physiology, as these factors can impact drug absorption.

• Physicochemical properties

• Concentration in Phagocytic Cells

• Potent weak bases that become ion-trapped in acidic intracellular compartments phagosomes and lysosomes (macrolides and azalides).
• Plasma concentrations of these drugs decrease (below MIC) while the high intracellular concentrations and slow release maintain drug level in the pulmonary epithelial lining fluid (PELF) and Bronchoalveolar cells.

• Distribution Characteristics

• Protein Binding

• A drug's efficiency may be affected by the degree to which it binds to the proteins within blood plasma. The less bound a drug is, the more efficiently it can traverse cell membranes or diffuse.  It is the unbound fraction which exhibits pharmacologic effects. It is also the fraction that may be metabolized and/or excreted

• Volume of Distribution (Vd)

• The VD of a drug represents the degree to which a drug is distributed in body tissue rather than the plasma. VD is directly correlated with the amount of drug distributed into tissue; a higher VD indicates a greater amount of tissue distribution. 

• Patterns of distribution can only be measured for specific drugs by looking at tissues.

• Lipid-solubility (Lipophilic)

• Lipophilic antimicrobials readily penetrate cellular barriers (exception of the blood-brain).  These are well absorbed by the GI and become widely distributed in body fluids and tissues.  Generally have a high Vd.

• Half-life (T1/2)

• Elimination t½ is the time (usually in hr) at which the plasma concentration decreases to 50% of its Cmax.  Only directly applies for IV administration.

• Barriers to Penetration

• CSF and blood-brain barrier

• Penetration depends on transcellular transport and lipid solubility. Lipid-soluble, non-ionized drug molecules that are free (not bound to plasma proteins) may enter the brain and CSF by passive diffusion.

• Passage into Milk

• Majority of Antimicrobial agents cross the blood-milk barrier (more restrictive functionally than anatomically) by passive diffusion.
• Both non-polar and polar lipid-soluble compounds that possess sufficient lipid solubility passively diffuse through the predominantly lipoidal barrier.
• Rate of transfer is proportional to the concentration gradient and lipid-solubility of the non-bound drug available.

• Compartmental PK

• Compartmental modeling of pharmacokinetics is the description of a drug in the body divided into compartments.  By describing the events observed and giving an explanation of the underlying mechanisms, compartmental modeling allows predictions regarding the pharmacokinetics of a drug, and potentially related treatment choices and regimens.

• Cattle Antibiotic PK/PD Chart

• Summary of major antimicrobials used in bovine medicine PK/PD indices, developed by Dr. Dee Griffin.

Risks

• Risk considerations can be complicated and include risks to the individual being treated, the person administering the antimicrobial, long term risks related to the use, and risks to the food system from residues and regulatory aspects of antimicrobial use.  Detailed aspects include:

• Direct host Toxicity / Adverse Drug Reactions / Risk to Fetus or Neonate
• Destruction of Microflora

• Chose narrow spectrum over broad spectrum
• Excretion (bile excretion impacts intestinal MF more than kidney excretion)
• Macrolides accumulate into rumen?

• Antimicrobial Resistance (AMR)
• Tissue Injection Damage
• Drug Residues in Meat / Milk
• ELDU / AMDUCA / VCPR / Legal Requirements

Cost

• Cost considerations can be complex and are not simply based on minimizing cost, but may be more about optimization and return on investment.  Non monetary considerations can revolve around risk tolerance and management of antimicrobial use risks. Key Factors:

• Cost of Treatment
• Risk management costs
• Value of Product / Animal
• ROI

Animal Factors

• Animal factors are a key consideration and represent the production system / environment,  disease status of the individual being treated, people skills,and the recognition of compliance and ability to get the drug into the animal.  Key considerations:

• Physiological and psychological status

• Immune status of the host
• Disease state (dehydration, fever, fasting, etc)

• Facilities/animal access/husbandry skills

Monitoring/ Oversight

• The monitoring of antimicrobial drug use should be done periodically to assure compliance and effectiveness.  Monitoring requires records and can be a valuable tool in guiding the refinement of management and treatment protocols.  Monitoring can include:

• Pathogens associated with clinical disease

• including antimicrobial susceptibility patterns, or evaluating

• Treatment outcomes

• treatment failure / retreatment
• culling
• case fatality rates

• Protocol Development and Compliance

• Actual use vs. Protocol
• Drug budgets

• Training and education

Additional Resources

• https://aabp.org/resources/AABP_Guidelines/AntimicrobialStewardship-7.27.17.pdf (AABP member only)
• https://aabp.org/Resources/AABP_Guidelines/AABP-AVC_Joint_Judicious_Therapeutic_Use_of_Antimicrobials_Guideline-2019.pdf  (AABP member only)

Acknowledgments

Antimicrobial Therapy in Veterinary Medicine, 5th Edition, 2013

Dr. Dee Griffin

Dr. Mike Apley