Retrospective analysis of the transmission of difficult-to-treat resistant Pseudomonas aeruginosa – genotype beats phenotype

Background Difficult-to-treat resistant Pseudomonas aeruginosa (DTRPA) represents a challenging resistance phenotype with carbapenem-resistant P. aeruginosa playing a major role. However, carbapenemase-negative DTRPA (CN-DTRPA) are more susceptible to reserve antibiotics and rarely reported in outbreaks, differing from frequently outbreak-associated carbapenemase-producing DTRPA (CP-DTRPA) with limited therapeutic options. Despite, international guidelines recommend equal infection prevention and control (IPC) measures. Here, we analysed the transmission of CP-DTRPA and CN-DTRPA using epidemiology and whole-genome sequencing (WGS). Methods Clinical DTRPA isolates collected between 2019 and 2024 were subjected to WGS. Genetic clusters were defined using cgMLST thresholds of ≤ 11 and ≤ 3 allelic differences. Epidemiological relatedness was estimated on hospital stay, interpatient contact and environmental exposures. For possibly epidemiologically linked cases, precolonisation with carbapenem-susceptible P. aeruginosa (CSPA) and antibiotic exposure during hospitalisation were assessed. Results Among 190 DTRPA isolates, CN-DTRPA (79.5%) was predominant compared to 20.5% CP-DTRPA, mainly carrying bla VIM−2 . Twelve genetic clusters involving 39 patients were identified. Seven clusters (CP-DTRPA n = 4; CN-DTRPA n = 2, CP-DTRPA/CN-DTRPA-mixed n = 1) showed possible epidemiological relatedness. CP-DTRPA isolates were frequently associated with clusters (OR 17.47, 95% CI 7.43–41.08) and environmental transmission. Diverse CN-DTRPA were rather linked to interpatient CSPA-transmission following CN-DTRPA emergence after prolonged antibiotic exposure. Conclusion CN-DTRPA predominated and displayed high diversity, consistent with possible antibiotic-driven resistance development in precolonised patients. In contrast, less frequent and less diverse CP-DTRPA were associated to outbreaks. These findings highlight the need to evaluate differentiated IPC strategies, including targeted screening and environmental interventions for CP-DTRPA, while further investigating the potential role of antimicrobial stewardship in preventing the emergence of CN-DTRPA. Multicentre studies are required for evidence-based IPC strategies.