P2798 In vitro synergy of ceftolozane/tazobactam (C/T) plus fosfomycin and C/T plus aztreonam against Pseudomonas aeruginosa strains carrying distinct beta- lactamase encoding genes Gabriel Cuba*1, Gerlan Santos1, Rodrigo Cayô Da Silva2, Ana Streling2, Carolina Silva Nodari2, Ana Gales2, Antônio Pignatari1, David Nicolau3, Carlos Kiffer1

1 Laboratorio Especial de Microbiologia Clinica, Universidade Federal de São Paulo, São Paulo, Brazil, 2 Laboratório Alerta, Universidade Federal de São Paulo, São Paulo, Brazil, 3 Hartford Hospital, Center for Anti-Infective Research and Development, Hartford, United States Background: PSA infections represent a significant challenge for hospital epidemiologists and clinicians worldwide. The multidrug resistance phenotype commonly observed in carbapenem-resistant PSA (CR-PSA) imposes great limitations on therapeutic choices. In Brazil, local dissemination of a particular metallo-β-lactamase (MβL) SPM-1 requires a specific therapeutic strategy. This study aimed to examine the potential role of in vitro antimicrobial synergy of the new cephalosporin and beta-lactamase inhibitor combination of C/T with ATM, FOS, polymyxin B (PO), and meropenem (MER). Materials/methods: Initially, the minimum inhibitory concentrations (MICs) were determined by EUCAST broth microdilution. Subsequently, E-test® strips of C/T+ATM, C/T+FOS, C/T+PO, and C/T+MER were tested in combination using the gradient diffusion strip crossing methodology (crossed at a 90º degree angle at respective MIC for each agent) against six representative SPM-1-producing PSA clinical strains. The best combinations were further tested against another 14 representative CR-PSA clinical strains carrying the beta-lactamase encoding genes: blaSPM-1 (n=9), blaIMP-1 (n=2), blaGES-1 (n=2), and blaCTX-M-2 (n=1). Fraction inhibitory concentration index (FICI) was calculated and interactions were defined as: synergy (≤0.5), additive (0.5-1), no effect (1-4) and antagonism (≥4), respectively. Results: Among the six representative SPM-1-producing CR-PSA strains, synergy was observed with C/T+FOS combinations in all six isolates, and in half of C/T+ATM combinations, an additive effect was also observed. No effect was observed in all PSA isolates with C/T+PO and C/T+MER combinations. Further testing confirmed synergistic and additive effect with C/T+FOS combination among 85% (n=17/20) and 10% (n=2/20) of PSA isolates, respectively; C/T+ATM combination provided synergistic effect among 25% (n=5/20) and additive effect in 40% (n=8/20) of PSA strains Conclusions: C/T+FOS combination showed the best synergistic activity against most of CR-PSA strains tested, being most of them carbapenemase producers, and this combination should be further evaluated. Thus, these findings could improve our knowledge on new therapeutic strategies to overcome the clinical challenge imposed by CR-PSA in general, and particularly against MβL-producing PSA infections in endemic areas as occurred in Brazil with SPM-1.

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