In vitro PK/PD modeling and simulation to accurately assess the antimicrobial activity of tigecycline against Mycobacterium abscessus

Abstract

Conventional in vitro susceptibility testing methods may underestimate the bactericidal activity of antibiotics that are chemically unstable in aqueous media, thereby limiting their clinical translatability. Tigecycline is considered a representative example of such compounds, exhibiting notable therapeutic efficacy against a broad range of pathogens despite poor in vitro susceptibility profiles, as reflected by elevated MIC values. This discrepancy is likely attributable, at least in part, to the chemical instability of TGC under standard MIC assay conditions. In this manuscript, we propose a mechanism-based PK/PD modeling approach as a framework to overcome the limitations of traditional MIC assessments and to address potential discrepancies between intrinsic and experimentally measured apparent antibacterial activity. Dynamic time-kill curves for single and multiple dose scenarios of TGC against Mycobacterium abscessus (Mab) were experimentally simulated in 24-well plates, leveraging the chemical instability of TGC. Based on the resulting in vitro data, a mechanism-based model was developed to perform simulations for characterizing intrinsic efficacy and potency of TGC. While the in vitro MIC of TGC determined under standard conditions was determined as 3.125 mg/L, an intrinsic MIC simulated based on model predicted bacterial time-time kill curves was 0.5 mg/L. Model-based analysis also revealed that MIC under standard conditions was stemming from drug instability and bacterial growth rate in the utilized media. In conclusion, the PK/PD modeling and simulation-based MIC determination indicated that clinically achievable exposure levels of TGC are sufficient to kill Mab, underlining the therapeutic potential of TGC against Mab infections.