Efficacy of Cefiderocol against Carbapenem-Resistant Gram-Negative Bacilli in Immunocompetent-Rat Respiratory Tract Infection Models Recreating Human Plasma Pharmacokinetics

Abstract

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 isolate, 1 multidrug-resistant P. aeruginosa isolate, 2 multidrug-resistant A. baumannii isolates, and 2 carbapenem-resistant K. pneumoniae isolates) were evaluated. Four-day treatment with a human exposure of 1 g ceftazidime every 8 h as a 0.5-h infusion showed potent efficacy only against a ceftazidime-susceptible isolate, not against five ceftazidime-resistant isolates harboring carbapenemase. With cefiderocol, a human exposure of 2 g every 8 h as a 3-h infusion for 4 days produced a >3 log10 reduction in the number of viable cells of these carbapenem-resistant isolates in the lungs. When the infusion time was 1 h, bactericidal activity was also observed against all isolates tested, although for 2 of 5 carbapenem-resistant isolates, a 3 log10 reduction was not achieved. The difference in efficacy achieved by changing the infusion period from 1 h to 3 h was considered to be due to the higher percentage of the dosing interval during which free-drug concentrations were above the MIC (%fTMIC), as observed for β-lactam antibiotics. These results suggest the potential utility of cefiderocol for the treatment of lung infections caused by carbapenem-resistant P. aeruginosa, A. baumannii, and K. pneumoniae strains.

NDM Metallo-β-Lactamases and Their Bacterial Producers in Health Care Settings

“…Although breakpoints to define susceptibility have not been established, the high MICs suggest that the 5 strains were likely resistant to cefiderocol. Cefiderocol demonstrated bactericidal activity against an NDM-1producing K. pneumoniae strain in a rat lung infection model (the cefiderocol MIC was 8 mg/liter) (291). A phase 2 randomized study demonstrated that cefiderocol was noninferior to imipenem for treating patients with complicated urinary tract infections caused by carbapenem-susceptible Gram-negative bacteria (292).…”

ARGONAUT-I: Activity of Cefiderocol (S-649266), a Siderophore Cephalosporin, against Gram-Negative Bacteria, Including Carbapenem-Resistant Nonfermenters and Enterobacteriaceae with Defined Extended-Spectrum β-Lactamases and Carbapenemases

“…Cefiderocol has been reported to be more stable against ␤-lactamases, such as KPC-3, VIM-2, L1 (the chromosomal metallo-type carbapenemase of Stenotrophomonas maltophilia), and NDM-1 carbapenemases than agents such as cefepime and meropenem (11). The human plasma protein binding of cefiderocol is 58% (12), and pharmacokinetic/pharmacodynamic (PK/PD) studies show that cefiderocol is an agent with time-dependent activity, with the fraction of the free drug concentration in plasma exceeding a MIC (fT MIC ) target of 75% of the dosing interval (13,14). At the proposed dosing regimen for cefiderocol of 2 g infused over 3 h every 8 h, PK/PD modeling showed that this 75% fT MIC target would be attained in Ͼ90% of patients for organisms with MICs of Յ4 mg/liter (15).…”

“…The wide distribution of MIC values for Enterobacteriaceae found here has been observed in other studies and is independent of the medium used, including iron-depleted-cation-adjusted (CA) MH broth OXA-23 and -69 (n ϭ 1); OXA-23 and -71 (n ϭ 2); OXA-23 and -82 (n ϭ 12); OXA-23 and -407 (n ϭ 3); OXA-24/40 and -65 (n ϭ 4); OXA-24/40 and -71 (n ϭ 1); OXA-58 and -66 (n ϭ 1); OXA-58 and -100 (n ϭ 1); OXA-66 (n ϭ 1); OXA-72 and -66 (n ϭ 4); OXA-82 (n ϭ 5); OXA-82 and -167 (n ϭ 1); OXA-172 (n ϭ 2); OXA-223 (n ϭ 1); OXA-223 and -72 (n ϭ 1); and OXA-338-like (n ϭ 1). d (approved by CLSI), iron-depleted medium using the chelator ApoT, and non-irondepleted CA MH broth (11,12). This wide distribution is believed to be due to variations in iron transport channel expression, the primary mechanism for cell entry of siderophore antibiotic conjugates, which varies by species and within species (7,11,15).…”

Cefiderocol: A Novel Agent for the Management of Multidrug-Resistant Gram-Negative Organisms

“…Mean bacterial kill of cefiderocol against cefepime-and meropenem-resistant isolates was 1.5 ± 0.4 log 10 CFU [33]. The efficacy of cefiderocol against carbapenem-resistant Gram-negative bacilli was examined in immunocompetent-rat respiratory tract infection models [34]. Six total isolates were evaluated: 1 cephalosporin-susceptible P. aeruginosa isolate, 1 multidrug-resistant P. aeruginosa isolate, 2 multidrug-resistant A. baumannii isolates, and 2 carbapenem-resistant K. Cefiderocol, administered at humanized exposures of 2 g every 8 h (3 h infusion), was compared to untreated control at 24, 48, and 72 h. Sustained kill with cefiderocol exposure over 72 h was observed in 9 isolates.…”