Aminoglycoside Susceptibility Testing Breakpoint Re-evaluations: Updates Based on the Application of Pharmacokinetics-Pharmacodynamics and Contemporary Microbiology Surveillance Data

Abstract

Background. In this current era of antimicrobial chemotherapy, resistance to aminoglycosides (AMG) and numerous other classes has emerged. To ensure that susceptibility is accurately characterized and that clinicians have reliable data to select effective agents at contemporary doses, in vitro susceptibility testing interpretive criteria [susceptible breakpoints (BKPTs)] are paramount. To give a USA voice to the EUCAST/ EMA (the dominant international BKPT organization) process, USCAST was formed in this country. The evaluation of BKPTs for the three most commonly used AMG [gentamicin (GEN), tobramycin (TOB) and amikacin (AMI), representing >95% of use] was undertaken. Methods. Multiple data sources were considered, including longitudinal USA reference MIC surveillance distributions using data collected over 18 years (SENTRY Antimicrobial Surveillance Program, TEST, etc.), QC parameters (MIC, disk diffusion), population pharmacokinetics (PK), and clinical and/or animal pharmacokinetic-pharmacodynamic (PK-PD) models. Using population PK models, AUC:MIC ratio targets for AMG efficacy and Monte Carlo simulation, probabilities of PK-PD target attainment by MIC value for the safer once-daily AMG dosing regimens (5 and 7.5 mg/kg for GEN and TOB; 20 and 30 mg/kg for AMI) were evaluated. Epidemiological cut-off, PK-PD and clinical BKPTs were determined and considered when recommending BKPTs for AMG-pathogen pairs. Results. A subset of recommended AMG BKPTs for three pathogens is shown in Table 1. These USCAST BKPTs, which were based on the application of population PK and PK-PD models, simulation techniques and contemporary MIC distribution statistics, were generally lower than those of EUCAST/EMA, USA-FDA and CLSI. Adequate probabilities of PK-PD target attainment were not achieved for some AMGpathogen pairs, even when the highest AMG dosing regimens were evaluated (examples: GEN versus P. aeruginosa; AMI versus S. aureus). Conclusion. Data evaluated to make AMG BKPT recommendations will be made freely available to the EUCAST-Steering Committee, USA-FDA and CLSI and will be finalized after considering comments from interested stakeholders worldwide. This process will be followed in an effort to bring global harmonization to BKPTs for this class. (Table Presented) .