Table 1.

Antibacterial activity of cefiderocol against diverse Gram-negative bacteria and resistance or reduced susceptibility identified in these studies.

Bacteria	Susceptibility		Resistance
Achromobacter spp.	Cefiderocol appeared as a promising therapeutic alternative for managing Achromobacter infections in patients with cystic fibrosis.	[53,54,55,56,57]	Overexpression of AxyABM efflux pump in A. xylosoxidans was associated with a threefold higher cefiderocol MIC.	[58]
Acinetobacter baumannii Complex	SIDERO-WT study 2014 reports 100% of susceptibility of 158 A. baumannii complex isolates. SIDERO-WT studies from 2015 to 2019 report percentages of susceptibility to cefiderocol ranging 97.6% to 99.1%.	[59,60]	Twenty-one cefiderocol-non-susceptible carbapenem-resistant A. baumannii isolates were characterized, highlighting the contribution β-lactamases, including the presence of an ESBL (PER-1), and deficiency of the iron siderophore transporter PiuA in several isolates. In the second study, by investigating a series of A. baumannii clinical isolates with elevated MICs of cefiderocol, the authors showed that PER-like β-lactamases and, to a lesser extent, NDM-like β-lactamases, significantly contributed to reduced susceptibility to cefiderocol. Thirdly, cefiderocol resistance was associated with reduced expression of the siderophore receptor gene pirA in A. baumannii isolates.	[61,62,63]
Burkholderia cepacia Complex	Cefiderocol was more potent in vitro than cefepime, ceftazidime-avibactam, ceftolozane-tazobactam, ciprofloxacin, and colistin.	[54,59,64,65]	Only 1 of the 4, 1 of the 12, and 5 of the 89 isolates tested had a cefiderocol MICs of 16, 8, and ≥8 μg/mL, respectively.	[59,64,65]
Citrobacter freundii Complex	All the isolates tested in the SIDERO-WT study 2014 (n = 303) were susceptible to cefiderocol.	[59,66]	Only 1 of the 32 and 1 of the 252 isolates tested had a cefiderocol MIC of 8 μg/mL.	[64,65]
Citrobacter koseri	SIDERO-WT study 2014 involving 73 isolates of C. koseri with MICs ranging from 0.006 to 4 μg/mL.	[59]	Study involving 73 isolates of C. koseri with MICs ranging from 0.008 to 4 μg/mL. In the second study, 1 of 169 isolates had a MIC of 8 μg/mL.	[59,65]
Escherichia coli	SIDERO-WT study 2014 involving 1529 isolates of E. coli with MICs ranging from ≤0.002 to 4 μg/mL. The MIC90 value of cefiderocol against E. coli isolates was 0.5 and 1 μg/mL in the second and third study, respectively.	[59,65,66]	In total, 10 out of 142 E. coli isolates were resistant to cefiderocol. In 26 of 1158 E. coli isolates harboring NDM-5 high levels of cefiderocol resistance was reported, in the second study. In the third study, a multidrug-resistant ST167 Escherichia coli clinical isolate recovered from a patient hospitalized in Switzerland produced NDM-35 showing ca. 10-fold increased hydrolytic activity toward cefiderocol compared to NDM-1.	[49,67,68]
Enterobacter cloacae Complex	In SIDERO-WT-2014 study and in another study involving 514 and 103 isolates of E. cloacae, respectively, the MIC90 value was 1 μg/mL.	[59,66]	In the first study, the authors report 2 cefiderocol-resistant ECC isolates in a collection of 10 isolates collected from diabetic patients. In the second study, the potential role of the VIM-1 carbapenemase in cefiderocol resistance in the ECC was highlighted. This effect is probably enhanced due to combination with additional mechanisms, such as ESBL production and siderophore inactivation. The presence of the NDM β-lactamase facilitates the emergence of resistance via nonsynonymous mutations of the cirA catecholate siderophore receptor in the third study.	[67,69,70]
Klebsiella (Enterobacter) aerogenes	The MIC90 value of cefiderocol against E. aerogenes isolates in was 0.5 μg/mL in both studies with 238 and 100 isolates.	[59,66]	In this study, 1158 cefiderocol resistant isolates were identified, of which 20 (1.7%) were K. aerogenes.	[49]
Klebsiella pneumoniae	The MIC90 value of cefiderocol against 765 and 100 K. pneumoniae isolates was 0.5 and 0.125 μg/mL, in the first and in the second study, respectively. In the second study MIC values ranged between ≤0.063–2 μg/mL.	[59,66]	In the first study, 7 out of 91 K. pneumoniae were resistant to cefiderocol. In the second study, 1158 cefiderocol-resistant isolates were identified, of which 798 (68.9%) were K. pneumoniae. In the third study, the authors characterized four cefiderocol-non-susceptible K. pneumoniae strains (4/86, 4.7%).	[49,50,67]
Klebsiella oxytoca	In the SIDERO-WT-2014 (505 isolates) and 2015 (349 isolates) the MIC values of cefiderocol ranged between ≤0.002 and 2 μg/mL and MIC90 value was 0.25 and 0.5 μg/mL, respectively.	[59,65]	In this study, 1158 cefiderocol resistant isolates were identified, of which 23 (2%) were K. oxytoca.	[49]
Morganella morganii	All of 37 and 32 isolates tested were classified as susceptible to cefiderocol, respectively, in two studies.	[71,72]	Only 1 out of 1158 isolates of M. morganii was classified as cefiderocol-resistant in this study.	[49]
Proteus spp.	All of 89 isolates tested were classified as susceptible to cefiderocol.	[71]	Only 2 out of 52 isolates were resistant to cefiderocol. In a second study, 1 of 10 isolates resistant to carbapenems was resistant to cefiderocol.	[67,72]
Providencia rettgeri	Treatment of complicated urinary tract infections (cUTI), due to Gram-negative bacteria in patients with limited or no alternative treatment options	[16]	One strain was obtained from the blood of a patient and it was resistant to all antimicrobials tested including the cefiderocol	[16,73]
Pseudomonas aeruginosa	In both studies all the collection of 120 and 33 isolates, respectively, were susceptible to cefiderocol. Five consecutive annual SIDERO-WT Studies reports a 99.9% of susceptibility to cefiderocol in a total of 7700 isolates.	[54,60,74]	Whole genome sequencing of P. aeruginosa non-susceptible to cefiderocol identified mutations in major iron transport pathways. The second study reports in vivo development of cefiderocol resistance among four sequential P. aeruginosa clinical isolates ST244 recovered from a single patient, without exposure to cefiderocol.	[75,76]
Serratia spp./Serratia marcescens	In SIDERO-WT-2014 study, in 503 isolates of Serratia spp. MIC90 value was 0.25 μg/mL and in another study involving 103 isolates of S. marcescens the MIC90 value was ≤0.0063 μg/mL.	[59,66]	In total, 14 out of 1158 isolates of S. marcescens were classified as cefiderocol-resistant in this study.	[49]
Stenotrophomonas maltophilia	Twenty-five meropenem-resistant S. maltophilia were susceptible to cefiderocol. In the second study, all the 7 isolates tested were also susceptible. SIDERO WT studies of 2014 and 2017 reports 100% of susceptibility to cefiderocol in 21 and 187 isolates of S. maltophilia, respectively.	[54,60,74]	S. maltophilia strains evolved cefiderocol resistance through different genetic pathways, but often involved iron transport.	[77]