By Charles H. Nightingale, Paul G. Ambrose, George L. Drusano, Takeo Murakawa
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Extra info for Antimicrobial Pharmacodynamics in Theory and Clinical Practice, 2nd Edition
In this chapter, we will discuss the meaning of S, I, and R in a historical context as well as provide the current view, based on PK–PD 21 22 Mouton et al. relationships. Both the European Committee on Antimicrobial Susceptibility Testing (EUCAST) (3) and the Clinical and Laboratory Standards Institute [CLSI, formally known as the National Committee for Clinical Laboratory Standards (NCCLS)] consider PK–PD data in the selection of susceptibility breakpoints (4). HISTORY Initially, isolates were categorized as S or R largely based on MIC frequency distributions.
The table shows the AUC values of several fluoroquinolones based on dosing regimens commonly used. Importantly, the protein binding of the drug is indicated as well, since it is only the free fraction of the drug that is active (see below) (42,43). Using these figures, Table 2 shows the PD susceptibility breakpoints of these fluoroquinolones based on the assumption that the AUC:MIC ratio should be at least approximately 100 and the Cmax:MIC ratio at least 8 to 12. For comparison, the CLSI susceptibility breakpoints are included as well (44).
USE OF PK–PD IN THE DEVELOPMENT OF ANTIMICROBIALS AND SETTING OF TENTATIVE SUSCEPTIBILITY BREAKPOINTS Since the importance of concentration–effect relationships is increasingly appreciated, antimicrobials are now being developed using these relationships in two ways. The first is in the early phase to determine the PK–PD index that best correlates with effect in in vitro PK models and in animal models of infection, and whether the values obtained to ensure a maximum effect are possibly achieved in humans for those microorganisms that therapy is directed at, based on the frequency distributions for those microorganisms.
Antimicrobial Pharmacodynamics in Theory and Clinical Practice, 2nd Edition by Charles H. Nightingale, Paul G. Ambrose, George L. Drusano, Takeo Murakawa