600. β-Lactam Resistance Mechanisms in Pseudomonas aeruginosa Isolates Analyzed Using Whole-Genome Sequencing (WGS) and Transcriptions Analysis and Their Impact in Resistance to New β-Lactam/β-Lactamase Inhibitors

BACKGROUND: Ceftazidime–avibactam (CAZ-AVI) and ceftolozane-tazobactam (C-T) display excellent antipseudomonal activity, but Pseudomonas aeruginosa (PSA) susceptibility against these agents can be affected by acquired resistance genes and mutations. We evaluated resistance mechanisms against these agents among 109 PSA isolates using WGS and messenger (m)RNA-sequencing. METHODS: PSA clinical isolates from Europe (n = 62), Asia-Pacific (n = 22), and Latin America (n = 25) in 2017 were susceptibility tested using reference methods and 109 were randomly selected for WGS and total mRNA-sequencing. Data were analyzed using custom software and logistic regression. RESULTS: Isolates carrying metallo-β-lactamases (MBLs) (n = 24) were resistant to all β-lactams, including CAZ-AVI and C-T. The only compound inhibiting >50% of the isolates was colistin. ESBL genes (bla(VEB-1) or bla(VEB-9)), some oxacillinases, and PDC variants caused resistance to CAZ-AVI and C-T, but the presence of bla(PER-1), bla(GES-6), and PDC-97 led to resistance to C-T, but not to CAZ-AVI. Disruptions of ampR (PDC regulator) and glnD (nitrogen metabolism) were associated with resistance to CAZ-AVI and C-T, but armZ (anti-repressor of mexZ) disruption was only associated with C-T resistance. The combination of wild-type sequences of various genes was negatively associated with resistance to CAZ-AVI and C-T, but alterations in dnaJ (chaperone) and oprM were only related to C-T resistance. mRNA-sequencing data did not show strong correlations with CAZ-AVI or C-T resistance or with expression of genes involved in β-lactam resistance, but further analyses will expand the genes analyzed. Interestingly, among 14 isolates overexpressing MexAB-OprM that extrude CAZ, only 6 had CAZ-AVI MICs >8 mg/L. CONCLUSION: Resistance mechanisms against CAZ-AVI and C-T remain poorly understood beyond MBL acquisition. In this study, resistance mechanisms statistically associated with CAZ-AVI resistance in PSA were noted among C-T-resistant isolates, but some mechanisms were only observed among C-T-resistant isolates. The richness of results employing these 2 methodologies requires further investigations that are being performed to evaluate sequences and expression alterations. DISCLOSURES: All authors: No reported disclosures.