Clinical and Laboratory Standards Institute guideline VET02—Development of Quality Control Ranges, Breakpoints, and Interpretive Categories for Antimicrobial Agents Used in Veterinary Medicine provides recommendations for developing QC ranges, agar disk diffusion zones of inhibition breakpoints, and dilution minimal inhibitory concentration breakpoints for antimicrobial susceptibility tests for aerobic bacteria isolated from animals and performed by CLSI antimicrobial susceptibility testing standards. It describes the data used by the Subcommittee on Veterinary Antimicrobial Susceptibility Testing to establish these QC ranges, breakpoints, and interpretive categories for antimicrobial agents intended for veterinary use. Host-specific pharmacokinetics, in vitro drug characteristics, distributions of microorganisms, and correlation of test results with outcome statistics are described for interpretation of test results. As antimicrobial agents are used in practice, additional experience accrued may be used to reassess QC ranges, breakpoints, or interpretive categories. Users of this guideline should understand that susceptibility test results cannot predict clinical outcomes with absolute certainty. Susceptibility test results should be used along with experienced clinical judgment and laboratory support to reach conclusions resulting in the best possible outcome for the patient.

This guideline replaces the previous edition of the approved guideline, VET02-A3, published in 2008. Several changes were made in this edition, including:

• General:

– Updated guideline title

– Updated pharmacokinetic/pharmacodynamic (PK/PD) targets

– Changed "PK/PD parameter(s)" to "PK/PD index (indices)" throughout

– Improved guidance for sponsors on clinical cutoff (COCL) determination

– Included guidance for determining breakpoints using the three cutoff values (wild-type cutoff [COWT], pharmacodynamic cutoff [COPD], and COCL)

• Subchapter 1.2, Background:

– Added new subchapter for background information

– Updated the reference to the new table format in CLSI document VET01S2

– Clarified the role of the Generic Drug Working Group

• Subchapter 1.3.1, Definitions:

– Updated definitions and terms approved for consistent use in all CLSI VAST documents

– Removed "Pharmacokinetics/Pharmacodynamics" and "Pharmacodynamics" as subheadings

– Added Subchapter 1.3.1.3, Epidemiological Cutoff Values and Interpretive Categories

– Added Subchapter 1.3.1.4, Components of Breakpoint Determination

– Added Subchapter 1.3.1.5, Pharmacokinetic and Pharmacodynamic Indices

• Subchapter 2.1, Sponsor Presentation Requirements:

– Changed title from "Subcommittee Requirements"

• Subchapter 2.4, Development of Breakpoints for Generic or Unsponsored Compounds:

– Changed title from "Development of Interpretive Categories for Generic or Older Compounds"

• Chapter 3, Quality Control:

– Changed title from "Data Generation and Establishment of QC Limits"

– Added citations for CLSI reference methods

• Chapter 4, Data to Provide to Establish Breakpoints:

– Moved information previously found in Appendix C, section V

– Removed redundant information throughout the chapter

• Subchapter 4.2, Wild-Type Cutoff (Epidemiological Cutoff Value):

– Clarified that the COWT is also known as the epidemiological cutoff value

• Subchapter 4.3, Clinical Cutoff:

– Moved COCL information from Appendix C, section III

– Extensively revised the COCL subchapter to provide guidance to sponsors

• This guideline provides more than one approach for sponsors to determine COCL based on evaluation of clinical response in relation to susceptibility data.

• Subchapter 4.4, Pharmacodynamic Cutoff:

– Moved COPD information from Appendix C, section IV

– Added perspectives to consider when a COPD is established

– Revised and updated Subchapter 4.4.1 on determining COPD

– Added veterinary-specific references on the use of Monte Carlo simulation for obtaining COPD for veterinary use in Subchapter 4.4.4

• The use of PK/PD indices is defined, with examples provided to guide sponsors.

• Chapter 5, Establishing Breakpoints:

– Removed redundant information throughout the chapter

– Clarified that at least two cutoff values must be considered when establishing a clinical breakpoint and that COPD cannot be used as the sole basis for a breakpoint determination

• Subchapter 5.1, General Points to Consider for Setting Susceptible Breakpoints:

– Added new subchapter on considerations for setting susceptible breakpoints

– Moved information previously found in Appendix C, sections II and III, and removed redundant information

• Subchapter 5.2, Strategies for Establishing Breakpoints:

– Changed title from "Decision Tree for Setting Breakpoints"

– Changed "decision tree" to "decision table" and revised the basis for consideration

– Removed Table 1, Example of the Application of the Decision Tree in Figure 1

– Removed Figure 1, Susceptibility Breakpoint (SBPT) Decision Tree

– Added new Table 10, Decision Table With Three Cutoff Values Available, Including COCL as a Pivotal Parameter, showing breakpoint assessment when COCL is considered pivotal

– Added new Table 11, Decision Table With Three Cutoff Values Available, Including COCL as a Supportive Parameter, showing breakpoint assessment when COCL is considered supportive

– Added new Table 12, Decision Table With Two Cutoff Values Available (COWT and COPD or COCL), showing breakpoint assessment when only two of three cutoff values are available

• Appendixes:

– Added Appendix B, Data Requirements to Establish Clinical Breakpoints for Antimicrobial Agents Used for Treating Bovine Mastitis

– Added Appendix C, Pharmacokinetic/Pharmacodynamic Targets Associated With Clinical Success

• Included new Table C1, Examples of Reported PK/PD Targets Associated With Clinical Success

– Deleted former Appendix C, The Use of PK and PD Relationships in the Setting of Susceptibility Breakpoints for Veterinary Antimicrobial Agents

This guideline provides direction for determining QC ranges, breakpoints, and interpretive categories for veterinary antimicrobial agents that have a direct action on microorganisms. This guideline applies to therapeutic antimicrobial agents intended to treat or control systemic or organ-specific infectious diseases processes in nonhuman, animal species (terrestrial or aquatic). The intended audience includes sponsors (eg, antimicrobial agent manufacturers) planning to submit data to establish or revise antimicrobial susceptibility testing (AST) QC ranges, breakpoints, and interpretive categories for inclusion in CLSI AST documents. Guidance presented in VET02 applies only to CLSI procedures and documents. The methods described in this guideline do not apply to:

• Antimicrobial agents used for growth promotion or prophylaxis (disease prevention)

– See CLSI document VET011 for details.

• Antimicrobial agents formulated for direct administration to skin or mucous membranes (eg, topical antimicrobial agents such as lotions, creams, ointments, or eye drops) or for inhalation