Meccanismi di resistenza al Cefiderocol in isolati clinici di Enterobacter spp. produttori di carbapenemasi VIM

Abstract

Antimicrobial resistance is currently one of the greatest threats to public health. Among the most worrying microorganisms are the so-called ESKAPE pathogens. In recent years, there has been an increasing spread of carbapenem-resistant Enterobacter spp. strains due to the production of carbapenemases. This study evaluated the in vitro activity of cefiderocol (FDC) against 78 VIM-positive isolates. The results showed a high rate of resistance to FDC. To investigate the mechanisms of resistance to FDC, 38/78 isolates underwent molecular characterization through WGS sequencing. Sequence analysis confirmed the ubiquitous presence of VIM-1. The blaSHV-12 gene was detected only in FDC-resistant isolates or those classified as ATU. By evaluating the coverage ratio of the blaSHV-12/blaACT genes, 13 isolates with a probable increased gene dosage of blaSHV-12 gene, were identified and selected to test the in vitro activity of the FDC–avibactam combination. The results showed recovery of susceptibility to FDC in 53.8% of the strains tested; however, in some isolates, the inhibitory activity of AVI against SHV-12 was limited or absent. The in vitro activity of the FDC-EDTA combination was subsequently evaluated on 10 isolates. The results showed that inhibition of VIM-1 led to a recovery of sensitivity to FDC in 100% of the strains tested. The data obtained from this study indicate that the synergistic interaction between the metallo-β-lactamase VIM-1 and SHV-12 contributes significantly to determining various levels of resistance to FDC; the recovery of susceptibility to FDC obtained by inhibiting VIM-1 is indicative of the fact that this enzyme is a critical determinant for the evolution of resistance to cefiderocol.

L’antimicrobico-resistenza, risulta attualmente una delle più grandi minacce alla Salute Pubblica. Tra i microrganismi più preoccupanti, rientrano i cosiddetti patogeni ESKAPE. Negli ultimi anni è stata osservata una sempre più grande diffusione di ceppi di E

Antimicrobial resistance is currently one of the greatest threats to public health. Among the most worrying microorganisms are the so-called ESKAPE pathogens. In recent years, there has been an increasing spread of carbapenem-resistant Enterobacter spp. strains due to the production of carbapenemases. This study evaluated the in vitro activity of cefiderocol (FDC) against 78 VIM-positive isolates. The results showed a high rate of resistance to FDC. To investigate the mechanisms of resistance to FDC, 38/78 isolates underwent molecular characterization through WGS sequencing. Sequence analysis confirmed the ubiquitous presence of VIM-1. The blaSHV-12 gene was detected only in FDC-resistant isolates or those classified as ATU. By evaluating the coverage ratio of the blaSHV-12/blaACT genes, 13 isolates with a probable increased gene dosage of blaSHV-12 gene, were identified and selected to test the in vitro activity of the FDC–avibactam combination. The results showed recovery of susceptibility to FDC in 53.8% of the strains tested; however, in some isolates, the inhibitory activity of AVI against SHV-12 was limited or absent. The in vitro activity of the FDC-EDTA combination was subsequently evaluated on 10 isolates. The results showed that inhibition of VIM-1 led to a recovery of sensitivity to FDC in 100% of the strains tested. The data obtained from this study indicate that the synergistic interaction between the metallo-β-lactamase VIM-1 and SHV-12 contributes significantly to determining various levels of resistance to FDC; the recovery of susceptibility to FDC obtained by inhibiting VIM-1 is indicative of the fact that this enzyme is a critical determinant for the evolution of resistance to cefiderocol.