About_editors 1..1 - Free

Applying Pharmacodynamics for Susceptibility Breakpoint Selection 39infections with those organisms that would provide the most useful data indetermining the true susceptibility breakpoint.As clinical data are unlikely to provide the answer, CLSI depends onmicrobiologic data, animal modeling data, and PK–PD modeling data to determinethe likely susceptibility breakpoint. The clinical data are then utilizedprimarily as a means of confirming or fine tuning the susceptibility breakpoint.The microbiologic data consist of distributions of organisms and their MIC values,including a broad representation of organisms against which the antimicrobialagent is likely to be used, strains with known resistance mechanisms, and strainsgathered from clinical studies. Animal modeling, which has been correlated withclinical outcomes, allows one to determine the PK–PD target that would bepredictive of clinical outcomes. Once PK data are available and the targetsidentified, one can utilize PD modeling to predict a susceptibility breakpoint.The Current Approach of EUCASTEUCAST has defined a procedure for determining breakpoints for new antimicrobials,which is also used for harmonizing and/or revising breakpoints for existingantimicrobials.1. Define dose or dosages. Consider an “intermediately susceptible” categoryonly for drugs with more than one dose.2. Define target microorganisms.3. Define WT MIC distributions for target microorganisms and their ECOFFvalues.4. Evaluate the PK properties of the drug and define a PK profile.5. Evaluate the PD properties of the drug and define a PD profile.6. Perform PK/PD modeling, including MCSs, to determine tentativebreakpoints.7. Evaluate the tentative breakpoints in relation to known clinical efficacy andWTs of target microorganisms. When necessary, to avoid dividing WT MICdistributions, adjust the breakpoint one MIC concentration up or down andexplain in footnote.8. Consult national breakpoint committees in Europe on EUCAST tentativebreakpoints.9. For new drugs, consult EMEA rapporteur and experts; for existing drugs,consult EUCAST General Committee (one representative per Europeancountry), expert groups, and pharmaceutical and AST industry.10. Get final decision on EUCAST breakpoints from the EUCAST SteeringCommittee.11. Finalize a rationale document for the antimicrobial drug or group of drugs:(i) for new drugs, send to EMEA for formal decision; and (ii) for existingdrugs, get EUCAST steering committee decision.12. Look up breakpoint table and rationale document on EUCAST website andEUCAST Technical Note in CMI.CONCLUDING REMARKSIn this chapter, we discussed the methods and approaches currently used to establishclinical breakpoints of antimicrobials. From a historical perspective, the methods and