Personalised bactericidal combination regimens against carbapenem-resistant Pseudomonas aeruginosa

Limited treatment options are available for carbapenem-resistant Pseudomonas aeruginosa (CRPA), especially those harbouring carbapenemases. Given the variability in effectiveness of antibiotic combinations, in vitro test-guided antibiotic therapies have been suggested to improve the outcomes of patients receiving combination therapy. We investigated the in vitro bactericidal activities of various combinations against CRPA and described our experience of using a personalised test-guided approach in managing these difficult-to-treat infections.

In vitro antibiotic combination tests (iACTs) comprising up to 180 unique combinations at clinically relevant unbound concentrations were performed for CRPA isolates collected for a monocentric prospective cohort study conducted between 2017 and 2022.

In vitro activities of antibiotic combinations are highly strain-specific. Polymyxin-containing combinations exhibit the highest bactericidal activity [454/497 (91%) isolate-combination pairs] against 66 isolates tested. Most of the CRPA produce carbapenemases (73%). Polymyxin-sparing combinations exhibiting >60% bactericidal activity include fosfomycin + aztreonam (40/58) and fosfomycin + cefepime (37/58). We show good outcomes in the 42 patients who eventually received at least 72 h of personalised iACT-guided therapy [end-of-treatment clinical response rate: 93%; 30-day all-cause mortality: 2%]. We observe microbiological eradication for all bloodstream infections, but 13% of patients get reinfected with CRPA subsequently.

Polymyxin-containing combinations exhibit the highest bactericidal activity against CRPA, while fosfomycin +  aztreonam or fosfomycin + cefepime represent promising polymyxin-sparing options. A personalised in vitro test-guided treatment approach may be feasible for managing P. aeruginosa infections, particularly those involving carbapenemase production and/or difficult-to-treat phenotypes.