The role of pharmacokinetics/pharmacodynamics in setting clinical MIC breakpoints: the EUCAST approach

Abstract

Clinical breakpoints are used in clinical microbiology laboratories to categorize microorganisms as clinically susceptible (S), intermediate (I) or resistant (R) dependent on the quantitative antimicrobial susceptibility as indicated by the MIC value determined in a well-defined standard test system. The laboratory report, with the designations of S, I or R for each antimicrobial agent, provides guidance to clinicians with respect to the potential use of agents in the treatment of patients, and clinical breakpoints should therefore distinguish between patients that are likely or unlikely to respond to antimicrobial treatment. In Europe, clinical breakpoints are set by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), following a defined procedure. This includes evaluation of efficacy in experimental settings and clinical studies to derive pharmacodynamic targets such as the fAUC/MIC ratio or %fT > MIC required for efficacy, the pharmacokinetic properties of the agent, Monte Carlo simulations to estimate exposures of the antimicrobial agent in the target patient population and commonly used dosing regimens. The probability of target attainment is subsequently determined for a range of pharmacodynamic targets and the results from the Monte Carlo simulations. The breakpoints derived are subsequently evaluated with respect to the wild-type population of the target microorganisms, specific resistance mechanisms and other relevant data. In this paper, we provide an overview of the EUCAST process and considerations for setting pharmacokinetic/pharmacodynamic breakpoints. These are the breakpoints that in the EUCAST breakpoint tables are referred to as 'non-species-related breakpoints'.

Exposure to Ceftobiprole Is Associated with Microbiological Eradication and Clinical Cure in Patients with Nosocomial Pneumonia

“…A %fTϾMIC of 60 to 65% of the dosing interval has been identified in mouse infection models as the target of near-maximal bacterial killing, and a %fTϾMIC of 40% best predicted bacteriostasis at 24 h for cephalosporins in general (2)(3)(4). These %fTϾMIC values are often regarded as PD targets for drug exposure and as the values on which to base clinical breakpoints, and in general as targets to reach during therapy (5). Whereas data to support the use of these targets in clinical infections in humans for quinolones and glycopeptides have appeared over the last decade (6)(7)(8), the clinical evidence for beta-lactams was limited until recently, when a correlation between exposure to ceftazidime and microbiological eradication as well as clinical cure was demonstrated in patients with nosocomial pneumonia.…”

Proposed Pharmacokinetic-Pharmacodynamic Breakpoint of Garenoxacin and Other Quinolones

“…In Europe, clinical BPs are set by the EUCAST, according to a defined procedure. This includes an evaluation of efficacy in experimental settings and clinical studies to derive PD targets such as the fAUC MIC ratio or fT ＞ MIC required for efficacy, the PK properties of the agent, MCSs to estimate exposure of the antibacterial agent in the target patient population, and commonly used regimens (27). In the present study, we calculated the BP of GRNX along with other quinolones based on PK-PD information using the MCS.…”

Pharmacokinetic/pharmacodynamic based dosing of ciprofloxacin in complicated urinary tract infections

“…Microorganisms listed as susceptible can have wide range of actual MIC values, and since MIC are reported in multiplication factors of two, with each level of decreased susceptibility a two-fold increase in pharmacokinetic component of pharmacokinetic/pharmacodynamic is necessary to maintain the target ratio (Schentag, 2000). Clinical breakpoints are used in clinical microbiology laboratories to categorize microorganisms as clinically susceptible, intermediate or resistant depending on the quantitative antimicrobial susceptibility as indicated by the MIC value determined in a well-defined standard test system (Mouton et al,2012). However, whether the results of the in vitro (Chen et al, 2013).…”