Activity of cefiderocol (S-649266) against carbapenem-resistant Gram-negative bacteria collected from inpatients in Greek hospitals

Abstract

Cefiderocol exhibited greater antimicrobial activity in vitro against carbapenem-resistant Gram-negative bacteria than comparator antibiotics.

Burkholderia pseudomalleiclinical isolates are highly susceptiblein vitroto cefiderocol, a novel siderophore cephalosporin

“…Cefiderocol has great potential as antimicrobial therapy for multi-drug resistant B. pseudomallei infections. This is supported by the findings of this study, in combination with the efficacy of cefiderocol being unaffected by resistance to other antimicrobials in vitro 32 , the antimicrobial being well tolerated by patients 5,8 and found to be safe in clinical trials to date 8 . However, this study also suggests that cefiderocol may lose efficacy in vitro against B. pseudomallei isolates derived from individuals with significant underlying co-morbidities and prolonged antibiotic exposure.…”

“…In this study isolates with MIC values ≥2 mg/L were considered to have elevated cefiderocol MICs, yet few were identified in this collection ( n =13). This finding is expected, with previous in vitro studies identifying very few resistant isolates for several Gram-negative bacilli species, for example only 24/753 isolates showed MICs ≥8 mg/L from a global dataset 31 , 54/8954 isolates had MICs ≥4 mg/L 13 and no resistant isolates were identified among 189 isolates from Greece 32 . In vitro MIC 90 values of the 250 primary B. pseudomallei isolates was 1 mg/L in this study, higher than the previously described MIC 90 of 0.25 mg/L obtained from a pilot study of 30 B. pseudomallei isolates 14 .…”

“…Subsequent isolate C5 exhibited a multidrug resistant profile with resistance to meropenem, amoxicillin-clavulanic acid, trimethoprim-sulfamethoxazole, doxycycline, non-susceptibility to ceftazidime and a cefiderocol MIC of 8 mg/L. Previous studies have highlighted that cefiderocol activity is not generally impacted by resistance to other antimicrobials 5–7,13,32 . In this study, amoxicillin-clavulanic acid resistance does not appear to impact cefiderocol or ceftazidime MICs.…”

“…In vitro MIC 90 values of the 250 primary B. pseudomallei isolates was 1 mg/L in this study, higher than the previously described MIC 90 of 0.25 mg/L obtained from a pilot study of 30 B. pseudomallei isolates 14 . The increase in MIC may be influenced by the increase in sample size, however larger samples sizes have not substantially increased the MIC 90 of cefiderocol in other pathogens such as P. aeruginosa, A. baumannii, K. pneumoniae and E. coli 13,31,32 . Moreover, sister species B. mallei has an MIC 90 of 4 mg/L from 30 isolates, significantly higher than that observed in B. pseudomallei 14 , whereas isolates from the closely related B. cepacia complex also exhibit a consistently low MIC 90 of 0.016 and 0.12 mg/L, despite small sample sizes in ID-CAMHB media 5,13 .…”

Multiple substitutions lead to increased loop flexibility and expanded specificity in Acinetobacter baumannii carbapenemase OXA-239

“…Given the on-going efforts to develop novel therapeutic agents that target A. baumannii , these observations may also serve a clinically-relevant harbinger role. While cephalosporins and monobactams are not currently used against A. baumannii , novel agents such as the cephalosporin cefiderocol and monobactam BAL30072 show great potential against carbapenem-resistant strains of that species [42–44]. Enhanced activity against advanced generation cephalosporins and aztreonam has now been observed for at least five unique variants of the OXA-23, OXA-24/40 and OXA-51/66 subfamilies of class D β-lactamases [9, 10, 20, 21].…”