Combating Metallo-β-Lactamase-Producing Pseudomonas aeruginosa: The Fractional Inhibitory Concentration Index as a Tool to Evaluate Antibiotic Synergy.

Background: Multi-drug-resistant Gram-negative bacteria producing metallo-β-lactamase are an increasing concern. Here, we described three cases of infection due to difficult-to-treat and drug-resistant P. aeruginosa producing metallo-β-lactamases, which were successfully treated with antibiotic combination of cefiderocol plus imipenem-relebactam, and reported on the molecular and epidemiological features of the isolates and the in vitro synergistic effects of different antibiotic combinations guiding antibiotic treatment. Patients and methods: Three P. aeruginosa strains were isolated from respiratory or blood cultures of three different patients. Minimum inhibitory concentrations breakpoints were interpreted according to EUCAST recommendations. Next-generation sequencing data were used for in silico identification of resistance genes and sequence types and for core genome multi-locus sequence typing analysis. The fractional inhibitory concentration index was performed as a measure of synergy of cefiderocol plus imipenem and imipenem-relebactam. Results: The three isolates exhibited different multi-drug-resistant and molecular profiles carrying blaIMP-13 (imipenemase metallo-β-lactamase-13) (isolates named Pse-1 and Pse-3) and blaVIM-2 (Verona integron-encoded metallo-β-lactamase-2) (isolate Pse-2). Typing showed that the isolates did not cluster and belonged to different sequence types. The E-test method showed the presence of synergy of cefiderocol in combination with imipenem-relebactam in the two P. aeruginosa isolates producing IMP-13 (Pse-1 and Pse-3). No synergy was observed in the isolate producing VIM-2 (Pse-2). Conclusions: Cefiderocol in association with imipenem-relebactam exhibited a synergistic effect against IMP-producing P. aeruginosa isolates. Further studies with a range of drugs and an expanded number of isolates are required to ascertain potential novel synergistic associations and the clinical utility of the fractional inhibitory concentration index.