Abstract Background Appropriate in vitro susceptibility testing interpretive criteria (STIC) are crucial to ensure optimal patient care. Pharmacometric analyses for aminoglycosides were undertaken to provide recommendations for dosing regimens adjusted for renal function and to support the original 2019 and 2023 reassessments of STIC for Enterobacterales and Pseudomonas aeruginosa. Methods Using simulation, traditional and extended-interval aminoglycoside dosing regimens adjusted for renal function that match drug exposures for patients with normal renal function were constructed. Using in vitro surveillance, nonclinical pharmacokinetic–pharmacodynamic (PK-PD), population pharmacokinetic (PK) model data, and simulation, PK-PD target attainment analyses were carried out to assess aminoglycoside STIC for Enterobacterales and P. aeruginosa. Susceptible breakpoints identified represented the highest minimum inhibitory concentration (MIC) values at which percent probabilities of PK-PD target attainment approached or were ≥90% based upon area under the concentration-time curve (AUC):MIC ratio targets associated with a 1-log10 colony-forming unit reduction from baseline at 24 hours, and extended-interval dosing regimens. Susceptible breakpoints based on therapeutic drug monitoring (S-TDM) were also considered as such data can be used to adjust dose to achieve targeted AUC values for efficacy, in addition to monitoring for safety. Results Aminoglycoside dosing regimens adjusted for renal function were successfully identified. For Enterobacterales and P. aeruginosa, recommended susceptible, S-TDM, and resistance breakpoints were ≤2, 4, and ≥8 µg/mL, respectively, for amikacin and ≤0.5, 1, and ≥2 µg/mL, respectively, for gentamicin and tobramycin, based on the evaluation of extended-interval dosing regimens. Conclusions Use of dosing recommendations adjusted for renal function and United States Committee on Antimicrobial Susceptibility Testing–recommended STIC will allow clinicians to optimally use aminoglycosides.
Bhavnani et al. (Sat,) studied this question.