In vitro activity of the siderophore cephalosporin, cefiderocol, against molecularly characterized, carbapenem-non-susceptible Gram-negative bacteria from Europe

Abstract

Objectives: Many carbapenem-resistant (CR) Gram-negative (GN) pathogens exhibit MDR, meaning few therapeutic options are available for CR-GN infections. Cefiderocol, a siderophore cephalosporin, has demonstrated in vitro efficacy against CR-GN bacteria. In the SIDERO-CR-2014-2016 surveillance study, European clinical isolates comprising carbapenem-non-susceptible (CarbNS) Enterobacterales and MDR non-fermenters were tested against cefiderocol and comparators.

Methods: Cefiderocol MICs were determined using iron-depleted CAMHB, and comparators using CAMHB, per recommended CLSI methodology. Carbapenemase gene profiles were determined using PCR.

Results: Isolates (N = 870) from 23 European countries comprised CarbNS Enterobacterales (n = 457), MDR Pseudomonas aeruginosa (n = 177) and MDR Acinetobacter baumannii (n = 236). The most common carbapenemases were KPC (52%), OXA-48-like (19%), VIM (14%) and NDM (8%) in Enterobacterales, VIM (41%) in P. aeruginosa and OXA-23-like (57%) and OXA-24/40-like (37%) in A. baumannii. Most carbapenemase-producing isolates (65%) co-carried ESBLs. Approximately half of P. aeruginosa isolates were negative for carbapenemases, compared with 10% of Enterobacterales and 3% of A. baumannii. A similar proportion of Enterobacterales were susceptible to cefiderocol (81.6%; 79.0% of VIM producers; 51.4% of NDM producers; based on EUCAST breakpoint values) compared with comparator antimicrobial agents, including colistin (76.4%; 93.5% of VIM producers; 78.4% of NDM producers) and ceftazidime/avibactam (76.6%; 1.6% of VIM producers; 2.7% of NDM producers). Of P. aeruginosa isolates, 98.3% were susceptible to cefiderocol (100% of VIM producers), similar to colistin (100%). Against A. baumannii, 94.9% had cefiderocol MIC ≤2 mg/L and 93.6% of isolates were susceptible to colistin.

Conclusions: Cefiderocol demonstrated potent activity against CarbNS and MDR GN bacteria, including non-fermenters and a wide variety of MBL- and serine-β-lactamase-producing strains.

Figure 1.

Cefiderocol MIC distribution against (a) ceftazidime/avibactam-resistant Enterobacterales, (b) ceftolozane/tazobactam-resistant P. aeruginosa and (c) colistin-resistant European SIDERO-CR-2014–2016 isolates. Based on EUCAST breakpoints for susceptibility (ceftazidime/avibactam: 8 mg/L; ceftolozane/tazobactam: 4 mg/L; colistin: 2 mg/L).

Figure 2.

Carbapenemases identified in European SIDERO-CR-2014–2016 isolates, by country, for (a) CarbNS Enterobacterales, (b) MDR P. aeruginosa and (c) MDR A. baumannii. (a) Includes two isolates co-carrying KPC and VIM carbapenemases (Greece) and eight isolates co-carrying OXA-48 and NDM carbapenemases (six in Romania and two in Turkey). (b) Includes one isolate co-carrying GES and VIM carbapenemases (Russia) and one isolate co-carrying GES and NDM carbapenemases (Serbia). (c) Includes two isolates co-carrying OXA-24/40-like, OXA-58 and NDM carbapenemases (Serbia) and one isolate co-carrying OXA-23-like and NDM carbapenemases (Denmark).

Figure 3.

Cefiderocol MIC distribution for all carbapenemase subclasses identified in European SIDERO-CR-2014–2016 isolates, by pathogen: (a) CarbNS Enterobacterales, (b) MDR P. aeruginosa and (c) MDR A. baumannii.