Effect of biofilm formation on the antimicrobial activity of tigecycline against Mycobacterium abscessus in the hollow fiber infection model

Abstract

Introduction Due to the inherent drug-resistance mechanisms and biofilm formation of Mycobacterium abscessus (Mab) that attenuate drug sensitivity, characterizing the impact of these factors on the pharmacological profile of antibiotics is critical to improve therapeutic outcomes.Methods This study aimed to define the exposure-response relationship of tigecycline in Mab therapy and to simultaneously evaluate the effects of biofilm and resistance development on bacterial killing activity of tigecycline using a Transwell system and a Hollow Fiber Infection Model combined with pharmacokinetic/pharmacodynamic (PK/PD) modeling.Results Dynamic time-kill assays conducted using the hollow fiber system, which mimicked tigecycline lung exposure under diverse intrapulmonary aerosol administration scenarios, demonstrated that high exposure to tigecycline effectively killed Mab. However, the pattern and timing of bacterial resistance development varied depending on the dosing regimen when exposure was insufficient for complete bacterial killing. Transwell-based in vitro tigecycline permeability study results revealed that the biofilm played a crucial role as a barrier to prevent molecular transfer of drug, eventually reducing the extent of exposure to Mab in biofilm by generating concentration gradients. The PK/PD model, integrating data from the in vitro dynamic time-kill assay and biofilm permeability study, adequately captured multiple factors, including dose-dependent bacterial killing, transition of Mab to less susceptible populations, biofilm formation, and biofilm-associated changes in permeability, all of which can influence the antibacterial activity of tigecycline.Discussion A quantitative assessment of the impact of these factors modulating the bacterial pathophysiology provides insights into how Mab undermines the antibacterial efficacy of tigecycline, thereby ultimately contributing to the development of more efficacious tigecycline treatment strategies.