Efficacy of Cefiderocol against Carbapenem-resistant Gram-negative bacilli in Immunocompetent Rat Respiratory Tract Infection Models Recreating Human Plasma pharmacokinetics.

Research paper by Shuhei S Matsumoto, Christine M CM Singley, Jennifer J Hoover, Rio R Nakamura, Roger R Echols, Stephen S Rittenhouse, Masakatsu M Tsuji, Yoshinori Y Yamano

Indexed on: 21 Jun '17Published on: 21 Jun '17Published in: Antimicrobial agents and chemotherapy


Cefiderocol (S-649266), a novel siderophore cephalosporin, shows potent activity against carbapenem-resistant Gram-negative bacilli. In this study, we evaluated the efficacy of cefiderocol against carbapenem-resistant Gram-negative bacilli (Pseudomonas aeruginosa,Acinetobacter baumannii and Klebsiella pneumoniae) in immunocompetent rat respiratory tract infection models recreating plasma pharmacokinetics (PK) profiles in healthy human subjects. A total of 6 clinical isolates (1 cephalosporin-susceptible P. aeruginosa, 1 multidrug-resistant P. aeruginosa, 2 multidrug-resistant A. baumannii and 2 carbapenem-resistant K. pneumoniae) were evaluated. Four-day treatment under human exposure of ceftazidime 1 g every 8-h as a 0.5-h infusion showed potent efficacy only against a ceftazidime-susceptible isolate, but did not against other five ceftazidime-resistant isolates harboring carbapenemase. In the case of cefiderocol, human exposure of 2 g every 8-h as a 3-h infusion for 4 days produced more than 3-log10 reduction of the viable bacterial cells in lungs against these carbapenem-resistant isolates. When the infusion time was 1-h, the bactericidal activity was also observed against all isolates tested, although 3-log10 reduction was not achieved against 2 of 5 carbapenem-resistant isolates. The differences of the efficacy by changing the infusion period from 1-h to 3-h was considered to be due to the prolonged %fT>MIC values as observed for β-lactam antibiotics. These results suggest the potential utility of cefiderocol for treatment of lung infections caused by carbapenem-resistant P. aeruginosa, A. baumannii and K. pneumoniae.