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- ItemSomente MetadadadosTestes conceituais relativos ao conhecimento terapêutico em Pseudomonas aeruginosa produtoras de São Paulo metalo-beta-lactamase (SPM-1)(Universidade Federal de São Paulo (UNIFESP), 2021) Cuba, Gabriel Trova [UNIFESP]; Kiffer, Carlos Roberto Veiga [UNIFESP]; Universidade Federal de São PauloObjective: Carbapenem-resistant Pseudomonas aeruginosa (CR-PSA) imposes great limitations on empirical therapeutic choices, which are further complicated by metallo-beta-lactamase production. In Brazil, local dissemination of São Paulo metallo-beta-lactamase last decade was detected. In this context, this study evaluated new therapeutical strategies of antimicrobial combination therapy against multidrug resistant P. aeruginosa Methods: Minimum Inhibitory Concentrations (MICs) were determined by broth microdilution and gradient strips. A total of 6 unrelated and representative carbapenem resistant strains carrying blaSPM-1, which were previously characterized by whole genome sequencing (WGS), were selected. First, synergy assessment by gradient diffusion strip crossing was performed between ceftolozane/tazobactam and aztreonam, Fosfomycin and ticarcillin/clavulanate; ticarcillin/clavulanate and aztreonam combination was also tested. Then, the most successful combinations were tested against 27 MDR PSA isolates carrying blaSPM-1 (n= 13), blaIMP (n= 4), blaVIM (n= 3), blaGES-1 (n=2) and blaCTX-M-like (n= 2), and 3 isolates with no acquired beta-lactamase production detected by gradient diffusion strip crossing. Finally, those combinations were also tested against six genetically unrelated SPM-1-producing isolates were also evaluated by time–kill analysis. Results: All carbapenem resistant P. aeruginosa isolates harbouring blaSPM-1, blaGES- 1 and blaIMP-1 were categorized as resistant to ceftolozane/tazobactam, meropenem and fosfomycin, with 70% being susceptible to aztreonam. No synergism between ceftolozane/tazobactam and meropenem, polymyxin or ticarcillin/clavulanate was reported. Synergism for ceftolozane/tazobactam and fosfomycin and ceftolozane/tazobactam and aztreonam combinations was observed for 88.9% (24/27) and 18.5% (5/27) of the isolates by gradient diffusion strip crossing, respectively. A 3- to 9-fold reduction in ceftolozane/ tazobactam MICs was observed, depending on the combination. Ceftolozane/tazobactam and fosfomycin was synergistic by TKA against one of six SPM-1-producing isolates, with additional nonsynergistic bacterial density reduction for another isolate. Aztreonam peak concentrations alone demonstrated a more than 3 log10 cfu/mL reduction against all six isolates, but all strains were within the susceptible range for the drug.xi Ticarcillin/clavulanate and aztreonam against SPM-1 producers showed a synergistic (n = 3) and additive (n = 2) effects. Conclusions: In the context of increasing carbapenem resistance among P. aeruginosa isolates worldwide, new combinations and stewardship strategies may need to be explored in the face of increasingly difficult to treat Gram-negative pathogens. Ceftolozane/tazobactam plus fosfomycin combination were synergistic when tested by gradient diffusion strip crossing and time kill analysis and ticarcillun/clavulanate plus aztreonam was synergistic against SPM-1 producing P. aeruginosa. These results, although limited, may be promising for guiding further in vivo studies. Combining biochemical properties with knowledge of resistance mechanisms might lead to innovative therapeutic approaches.