Pharmacodynamic interaction of apotransferrin and anti-pseudomonal antibiotics against extensively drug-resistant Pseudomonas aeruginosa in a dynamic PK/PD model

Abstract

Objectives: The rise of antibiotic resistance in clinical settings poses a major challenge. Apotransferrin has emerged as a potential non-traditional therapy for combating infections, potentially preventing resistance development while enhancing bactericidal effects. This study evaluated the efficacy of apotransferrin combined with antipseudomonal antibiotics against extensively drug-resistant (XDR) Pseudomonas aeruginosa isolates. Methods: Twenty XDR P. aeruginosa clinical isolates were evaluated. Different apotransferrin concentrations were tested to determine the optimal in vitro concentration. Time-kill assays assessed the combined effects of apotransferrin with meropenem or ceftolozane/tazobactam (C/T). A chemostat model using four selected isolates validated the most effective combinations and monitored resistance emergence. Results: Apotransferrin monotherapy did not reduce bacterial load, but its combination with antipseudomonal antibiotics enhanced efficacy. Meropenem activity improved in 10/20 isolates, and C/T activity in 13/20 compared to antibiotic monotherapy. The chemostat model confirmed synergistic interactions between apotransferrin and C/T in two isolates, with additive effects in two others. This combination outperformed the most effective monotherapy in all isolates, with no emergence of new C/T-resistant strains. Conclusions: In conclusion, the combination of apotransferrin with C/T demonstrated superior in vitro efficacy against XDR P. aeruginosa isolates compared to either treatment alone. These findings suggest that apotransferrin could be a valuable adjunctive therapy, enhancing the antimicrobial effects of existing antibiotics and potentially extending their clinical utility.