Preclinical Pharmacokinetics and Pharmacodynamics of Antibiotic Adjuvants

Antimicrobial resistance (AMR) is a significant global health challenge, undermining the effectiveness of existing therapies and driving substantial mortality and economic burdens worldwide. In the development of novel antimicrobials, pharmacokinetic/pharmacodynamic (PK/PD) analysis provides a critical bridge between preclinical studies and clinical application, guiding the design of optimal dosing regimens for clinical trials. The use of antibiotic adjuvants that can restore or enhance the antimicrobial activity of clinically employed antibiotics against AMR-associated pathogens presents a promising strategy to combat AMR. Although β-lactamase inhibitors are the only antibiotic adjuvant class that are currently clinically employed, emerging adjuvant therapies have shown promise in preclinical and clinical development studies. PK/PD relationships of antibiotic adjuvants in combination with antibiotics require thorough investigation in mouse infection models as a prerequisite for progression into clinical trials. As exemplified by β-lactamase inhibitors, conventional MIC-based approaches are not appropriate for the characterization of adjuvant PK/PD relationships, due to the lack of intrinsic antimicrobial activity of the adjuvant. Modified PK/PD parameters using threshold concentrations (C_T) or instantaneous MIC (MIC_i) values are discussed as potentially more suitable approaches.