Preventing resistance development in infections by OXA β-lactamase-producing Pseudomonas aeruginosa : correlating clinical outcomes with hollow-fibre model input
Year: 2025
Type: article
Abstract: BACKGROUND: Infections caused by XDR Pseudomonas aeruginosa significantly limit treatment options. Although ceftolozane/tazobactam and ceftazidime/avibactam have emerged as promising alternatives, increasing resistance has been reported. This study describes three critically ill patients with ventilator-associated pneumonia caused by OXA-producing XDR P. aeruginosa that developed resistance to both agents during therapy. METHODS: Antibiotic exposure and resistance were monitored clinically and in a hollow-fibre infection model (HFIM) to evaluate different ceftazidime/avibactam and ceftolozane/tazobactam regimens. Drug concentrations, bacterial burden and resistant mutants were assessed. Whole-genome sequencing and resistance profiling were performed on both clinical and HFIM-derived isolates. RESULTS: Initial patient isolates were susceptible to both antibiotics. One belonged to ST179 (OXA-10 producer), while two were ST235 (OXA-2 or OXA-2 + OXA-10 producers). Resistance emerged during therapy in all cases. In the HFIM, continuous infusion of ceftolozane/tazobactam plus meropenem achieved bacterial eradication for ST179 within 8 h. For ST235 isolates, high-exposure ceftazidime/avibactam regimens (4-h or continuous infusion) achieved bacterial eradication and prevented regrowth. In contrast, low-exposure 2-h infusions allowed bacterial rebound and resistance selection. Mechanisms of resistance were similar across clinical and HFIM isolates, involving overexpression or structural modification of OXA enzymes, except in one ST235 HFIM derived-isolate, in which resistance development was caused by an AmpC Ω-loop mutation. Pharmacokinetic validation confirmed accurate drug exposure in the model. CONCLUSIONS: These findings underscore the importance of optimized dosing strategies, particularly high-concentration and prolonged infusions, in eradicating and preventing resistance development in OXA-producing P. aeruginosa infections.
DOI: 10.1093/jac/dkaf464
Institutions: Universitat Pompeu Fabra, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red, Hospital Del Mar, Municipal Institute for Medical Research, Hospital del Mar Research Institute, Centro de Investigación Biomédica en Red Enfermedades Infecciosas, Health Research Institute of the Balearic Islands, Hospital Universitario Son Espases, Generalitat de Catalunya
Language: English
Subfield: Molecular Medicine
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,784
Awards: G1603461899, Evaluación in vitro de la apotransferrina como terapia innovadora en las infecciones por Pseudomonas aeruginosa extremadamente resistente mediante un modelo dinámico PK/PD., G4508625590, Optimización del diagnóstico, tratamiento y control de las infecciones por Pseudomonas aeruginosa a través de la monitorización de la dinámica del resistoma a escala de paciente y de nación completa., Estudio PseudoNOVA2. Diseño de pautas optimizadas de tratamiento antimicrobiano de infecciones respiratorias por Pseudomonas aeruginosa. Estudio clínico observacional, microbiológico y farmacodinámico mediante el modelo in vitro hollow fiber.
OpenAlex ID: W4417409640