Simulated lung exposure in pneumonia patients to evaluate the antibacterial capacity and resistance suppression of clinical tigecycline regimens against carbapenem-resistant Acinetobacter baumannii

Abstract

Background: Tigecycline is increasingly used off-label for hospital-acquired pneumonia caused by carbapenem-resistant Acinetobacter baumannii (CRAB). While the standard-dose regimen (100 mg loading dose followed by 50 mg q12h) yields suboptimal outcomes, a high-dose regimen (200 mg loading dose followed by 100 mg q12h) has been proposed to improve efficacy, but its clinical benefits remain controversial. This study aimed to compare microbiological responses of standard- and high-dose tigecycline regimens under simulated lung exposure.

Methods: Two clinical CRAB isolates (CRAB21824 and CRAB21849) were characterized by tigecycline susceptibility testing and carbapenemase phenotypic/genotypic analysis. A hollow-fibre infection model (HFIM) along with semi-mechanistic PK/PD modelling was employed to simulate tigecycline pharmacokinetics in epithelial lining fluid of pneumonia patients and assess the antibacterial activity and resistance development under both dosing regimens. Tigecycline resistance mechanisms were investigated using whole-genome resequencing and molecular docking.

Results: Tigecycline MICs were 1 and 0.25 mg/L for CRAB21824 and CRAB21849, respectively. Both strains carried blaOXA-66 and blaOXA-23, encoding Class D carbapenemase, but lacked Class A and B carbapenemases. HFIM-driven semi-mechanistic PK/PD modelling revealed strain- and dose-dependent antibacterial activity of tigecycline. The high-dose regimen exhibited prolonged antimicrobial effects compared to standard dosing. However, it ultimately led to bacterial regrowth for CRAB21849, despite achieving the pharmacodynamic target of AUC0-24h/MIC >4.5. A missense mutation in adeB (c.218T > G, p.Val73Gly) enhancing tigecycline efflux was identified as the resistance mechanism.

Conclusion: While high-dose tigecycline enhanced antibacterial efficacy, its failure to prevent efflux-mediated resistance in specific strains highlights the inherent limitations of dose escalation for CRAB pneumonia treatment.