In vitro synergy of ceftolozane/tazobactam in combination with fosfomycin or aztreonam against MDR Pseudomonas aeruginosa. (2nd April 2020)

• Record Type: Journal Article
• Authors: Cuba, Gabriel T; Rocha-Santos, Gerlan; Cayô, Rodrigo; Streling, Ana Paula; Nodari, Carolina S; Gales, Ana C; Pignatari, Antonio C C; Nicolau, David P; Kiffer, Carlos R V
• Is Part Of: Journal of antimicrobial chemotherapy. Volume 75:Number 7(2020)
• Page Start: 1874
• Page End: 1878
• Publication Date: 2020-04-02
• Subjects: Anti-infective agents -- Periodicals; Chemotherapy -- Periodicals; 615.58
• DOI: 10.1093/jac/dkaa095
• Languages: English
• ISSNs: 0305-7453

Abstract

Abstract: Objectives: Carbapenem-resistant Pseudomonas aeruginosa (CR-PSA) imposes great limitations on empirical therapeutic choices, which are further complicated by metallo-β-lactamase production. This study evaluated in vitro antimicrobial synergy of ceftolozane/tazobactam in combination with aztreonam and fosfomycin against MDR PSA. Methods: MICs were determined by broth microdilution and gradient strips. The effect of ceftolozane/tazobactam+aztreonam and ceftolozane/tazobactam+fosfomycin combinations were tested against 27 MDR PSA isolates carrying bla SPM-1 ( n = 13), bla IMP ( n = 4), bla VIM ( n = 3), bla GES-1 ( n = 2) and bla CTX-M -like ( n = 2), and 3 isolates with no acquired β-lactamase production detected by gradient diffusion strip crossing (GDSC). Six genetically unrelated SPM-1-producing isolates were also evaluated by time–kill analysis (TKA). Results: All CR-PSA isolates harbouring bla SPM-1, bla GES-1 and bla IMP-1 were categorized as resistant to ceftolozane/tazobactam, meropenem and fosfomycin, with 70% being susceptible to aztreonam. Synergism for ceftolozane/tazobactam+fosfomycin and ceftolozane/tazobactam+aztreonam combinations was observed for 88.9% (24/27) and 18.5% (5/27) of the isolates by GDSC, respectively. A 3- to 9-fold reduction in ceftolozane/tazobactam MICs was observed, depending on the combination. Ceftolozane/tazobactam+fosfomycin was synergistic by TKA against one of six SPM-1-producing isolates, with additional non-synergistic bacterial density reduction for another isolate. Aztreonam peak concentrations alone demonstrated a ≥3 log10 cfu/mL reduction against all six isolates, but all strains were within the susceptible range for the drug. No antagonism was observed. Conclusions: In the context of increasing CR-PSA and the genetic diversity of resistance mechanisms, new combinations and stewardship strategies may need to be explored in the face of increasingly difficult to treat pathogens.