Combating Metallo-β-Lactamase-Producing Pseudomonas aeruginosa: The Fractional Inhibitory Concentration Index as a Tool to Evaluate Antibiotic Synergy
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Background: Multi-drug-resistant Gram negative bacteria producing metallo-β-lactamase are an increasing concern. Here we describe three cases of infection due to difficult to treat resistant P. aeruginosa producing metallo-β-lactamases, successfully treated with antibiotic combination of cefiderocol plus imipenem-relebactam and report on the molecular and epidemiological features of the isolates and the in vitro synergistic effects of different antibiotic combinations to guide the antibiotic treatment.Patients and methods: Three P. aeruginosa strains were isolated from respiratory or blood cultures of three different patients. Minimum inhibitory concentrations breackpoints were interpreted according to EUCAST recommendations. Next Generation Sequencing data were used for in silico identifying resistance genes, 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 (isolates named Pse-1 and Pse-3) and blaVIM-2 carbapenemases (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). Conclusion: 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.