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. 2022 May 27;11(6):723. doi: 10.3390/antibiotics11060723

Table A1.

Role of β-lactamases in cefiderocol resistance.

β-Lactamase Organism(s) Findings
NDM Enterobacterales,
A. baumannii
  • Based on isogenic mutants:
    • ○
      Up to 64-fold increases in cefiderocol MIC have been reported by introduction of NDM MBLs in isogenic E. coli mutants: 8- to 64-fold increase by NDM-1 (0.5→4 mg/L [64]) (≤0.125→1 mg/L [56]) (0.03→1 mg/L [54]) (0.06→4 mg/L [29]) [29,54], 8- to 32-fold by NDM-5 (≤0.125→1 mg/L [56]) (0.125→2 mg/L [64]) (0.03→1 mg/L [54]), ≥8-fold (≤0.125→1 mg/L) by NDM-7 [56], and 16- to 64-fold by NDM-9 (≤0.125→1 mg/L [56]) (0.03→2 mg/L [54]).
    • ○
      In a K. pneumoniae mutant, an 8-fold increase in MIC (0.5→4 mg/L) was demonstrated by NDM-5 [64].
    • ○
      In A. baumannii mutants, a ≥16-fold increase in MIC (≤0.125→2) was demonstrated by NDM-1 and NDM-9, as was a 4-fold increase (≤0.125→0.5 mg/L) by NDM-5 [54].
    • ○
      In P. aeruginosa: 8-fold higher (0.5→4 mg/L) MIC by NDM-1, NDM-7, and NDM-9 and 4-fold higher (0.5→2 mg/L) by NDM-5 [56].
  • Based on clinical isolates:
    • ○
      In SIDERO-WT-2014 42% (5/12) of NDM-positive Enterobacterales were nonsusceptible to cefiderocol (MIC > 4 mg/L) [12].
    • ○
      In a multinational European collection, 49% (18/37) of NDM-positive Enterobacterales were nonsusceptible (MIC > 2 mg/L) to cefiderocol [62].
    • ○
      In a cohort from the United Kingdom, 59% and 28% of n = 61 NDM-positive Enterobacterales had an MIC > 2 mg/dL and >4 mg/dL, respectively [19]. Among n = 11 NDM-positive P. aeruginosa, 54% had MIC > 2 mg/dL, and 27% had MIC > 4 mg/dL) [19]. Among n = 20 NDM-positive A. baumannii, 50% had MIC > 2 mg/dL, and 20% had MIC > 4 mg/dL) [19].
    • ○
      In the case of in vivo emerging cefiderocol resistance (intraabdominal abscesses by NDM-5 producing E. coli being treated with cefiderocol), a >16-fold increase in MIC (2→>32 mg/L) was observed associated with increased copy numbers of blaNDM genes) [25].
    • ○
      NDM-1 was detected in a cefiderocol-resistant K. pneumoniae (in combination with SHV-12 and DHA-1) [64].
    • ○
      NDM-5 was detected in in a cefiderocol-resistant K. pneumoniae (in combination with CirA deficiency) [64].
    • ○
      A combination of NDM-1 and PER-1 was detected in a pandrug-resistant Providencia rettgeri clinical isolate [78].
    • ○
      A combination of NDM-1 and TMB-1 was found in a cefiderocol-resistant (MIC = 32 mg/L) A. baumannii [79].
KPC-variants
(conferring resistance to ceftazidime/avibactam)		 K. pneumoniae,
E. coli *
  • Based on isogenic mutants:
    • ○
      Introduction of KPC-variants in E. coli mutants resulted in multifold increases in cefiderocol MIC: ≥8-fold (≤0.125→1) by KPC-3 [55], ≥32-fold (≤0.125→4) by KPC-41 [55], ≥8-fold (≤0.125→1) by KPC-50 [55], 64-fold (0.06→4 mg/L) by KPC-31 [41], 32-fold (0.06→2 mg/L) by KPC-33 [41], 16-fold (0.06→1 mg/L) by KPC-39 [41], 8-fold (0.06→0.5 mg/L) by KPC-44 and KPC-29 [41], and 4-fold (0.06→0.25 mg/L) by KPC-25 [41].
    • ○
      Introduction of KPC-2 in K. pneumoniae resulted in 4-fold higher cefiderocol MIC (0.5→2 mg/L) [64].
  • Based on clinical isolates:
    • ○
      Cefiderocol resistance (MIC > 2 mg/L) was considerably higher (82.5% vs. 6.7%) in ceftazidime/avibactam-resistant (n = 40) than in ceftazidime/avibactam-susceptible (n = 60) KPC-producing Enterobacterales in one cohort [14].
    • ○
      Among 17 paired (before and after ceftazidime/avibactam treatment) KPC-producing K. pneumoniae isolates, 2- to 512-fold higher cefiderocol MICs were noted (0.25→4, 0.25→8, 16→32, 1→4, 1→16, 0.12→64, 0.25→64, 0.25→32, 0.12→4, 1→32, 1→16, 0.25→0.5, 2→32, 1→16, 0.5→>64, 0.25→4, 0.12→4 mg/L) [14].
    • ○
      Emergence of cross-resistance between ceftazidime/avibactam and cefiderocol was reported in two clinical associates associated with mutations in KPC (KPC-41 and KPC-50). MIC was 2- to 4-fold higher (2→ 4–8 mg/L) in the KPC-41 mutant and 8-fold higher in the KPC-50 mutant (2→16 mg/L). In both strains, truncation of OmpK35 was also detected [55].
    • ○
      Emergence of cross-resistance between ceftazidime/avibactam and cefiderocol was reported in another case associated with KPC-31, resulting in a 4-fold higher cefiderocol MIC (4→16 mg/L) [42].
PER-type ESBL A. baumannii,
P. aeruginosa,
E. coli *
  • Based on isogenic mutants:
    • ○
      Introduction of PER-1 in isogenic E. coli mutants was reported to result in 8- to 16-fold higher cefiderocol MICs (0.063–0.125→1 mg/L [29]).
    • ○
      In another study [56], introduction of PER-1, PER-6, and PER-7 in isogenic E. coli resulted in ≥32-fold (≤0.125→4 mg/L) higher MIC, while PER-2 resulted in ≥8-fold (≤0.125→1 mg/L) [56]. In P. aeruginosa: 32-fold higher (0.5→16 mg/L) MIC by PER-1, 16-fold higher (0.5→8 mg/L) by PER-6 and -7, and 2-fold higher (0.5→1 mg/L) by PER-2.
    • ○
      Similarly, a 64-fold increase in MIC (0.03→2 mg/L) was demonstrated by introduction of PER-1 in isogenic A. baumannii mutants [54].
  • Based on clinical isolates:
    • ○
      PER ESBLs were detected in 25 of 28 cefiderocol-nonsusceptible A. baumannii in one study (all PER-1) [29], in all 8 nonsusceptible A. baumannii isolates in another study (either PER-1 or PER-7) [54], in 5 of 24 cefiderocol nonsusceptible A. baumannii in another study [27], but only in 1 of 21 cefiderocol-resistant A. baumannii isolates in another single-centre cohort [30].
    • ○
      In a cohort from the United Kingdom, 33% (5 of 15) and 27% (4 of 15) of PER-producing P. aeruginosa isolates had a cefiderocol MIC >2 mg/dL and >4 mg/L, respectively [19].
SHV-type ESBL K. pneumoniae,
A. baumannii,
E. coli *
  • Based on isogenic mutants:
    • ○
      Introduction in E. coli: 8-fold higher (0.03→0.25 mg/L) MIC by SHV-2 [54]; ≥2-fold higher (≤0.125→0.25 mg/L) by SHV-2a [56]; 2- to 4-fold higher (0.063–0.125→0.25 mg/L) by SHV-1 [29]; 4- to 8-fold higher (0.063–0.125→0.5 mg/L) by SHV-4, SHV-12, and SHV-5 [29]; and ≥32-fold (≤0.125→4 mg/L) by SHV-12 in another study [56]. Up to 2-fold higher (0.063–0.125→0.125 mg/L) by SHV-3, SHV-11, SHV-26, and SHV-28 [29].
    • ○
      Introduction in P. aeruginosa: 8-fold (0.5→4 mg/L) higher MIC by SHV-2a, 16-fold (0.5→8 mg/L) higher MIC by SHV-12 [29].
  • Based on clinical isolates:
    • ○
      Iregui et al. [17] showed that K. pneumoniae and A. baumannii isolates expressing the SHV extended-spectrum β-lactamase (ESBL) had significantly higher MICs than isolates lacking SHV ESBL.
    • ○
      Coexpression of NDM-1 and SHV was detected in four of five cefiderocol nonsusceptible K. pneumoniae in one cohort [29].
AmpC variants Enterobacter spp.
P. aeruginosa *
E. coli *
  • Based on isogenic mutants:
    • ○
      32-fold increase in cefiderocol MIC (0.06→2 mg/L) by introduction of A292_L293del AmpC in E. coli [43].
    • ○
      4-fold increase (0.5→2 mg/L) by introduction of A294_P295del AmpC in E. coli [43].
    • ○
      4-fold increase (0.25→1 mg/L) by overexpression of AmpC in E. cloacae [48].
    • ○
      2-fold increase (0.125→0.25 mg/L) by introduction of ACT-17-like (A313P) in E. coli [32].
  • Based on clinical isolates:
    • ○
      In vivo emerging cefiderocol cross-resistance attributable to AmpC mutations was reported in two patients with E. cloacae infections being treated with ceftazidime/avibactam [43].
    • ○
      AmpC E247K (emerging during treatment with ceftolozane/tazobactam) was detected in two ceftolozane/tazobactam-resistant P. aeruginosa isolates and was associated with 32-fold (0.25→8 mg/L) and 8-fold (0.12→1 mg/L) higher cefiderocol MIC [16].
    • ○
      AmpC L147F (emerging during treatment with ceftolozane/tazobactam) in combination with mutations in piuA and pirR was detected in a ceftolozane/tazobactam-resistant P. aeruginosa isolates and was associated with a 4-fold (2→8 mg/L) higher cefiderocol MIC [44].
    • ○
      ACT-17-like (A313P) was detected in an in vivo emerging cefiderocol-resistant E. cloacae (MIC1→4 mg/L) [21,32].
OXA-427 Enterobacterales
  • Based on isogenic mutants:
    • ○
      Introduction of OXA-427 in E. coli resulted in only a 2-fold increase in (MIC ≤0.125→0.25 mg/L) [56].
  • Based on clinical isolates:
    • ○
      Uniform cefiderocol nonsusceptibility (based on disk diffusion) was reported among n = 26 OXA-427-producing Enterobacterales from Belgium [15].
SPM-1, VIM-2, AIM-1, GIM-1 (MBLs) E. coli *,
P. aeruginosa *
  • Based on isogenic mutants:
    • ○
      In E. coli: ≥16-fold higher MIC (≤0.125→2 mg/L) by SPM-1; no change by VIM-2, AIM-1, or GIM-1 [56].
    • ○
      In P. aeruginosa: 16-fold higher MIC (0.5→8 mg/L) by SPM-1, 2-fold higher (0.5→1 mg/L) by VIM-2, and 4-fold higher (0.5→2 mg/L) by AIM-1 and GIM-1 [56].
GES-6 P. aeruginosa *

  • Introduction of GES-6 in P. aeruginosa resulted in 4-fold (0.5→2 mg/L) higher cefiderocol MICs [56].
PDC-30
(P. aeruginosa cephalosporinase)		 P. aeruginosa
  • Based on isogenic mutants:
    • ○
      8-fold increase (0.125→1 mg/L) by introduction of PDC-30 in E. coli [32]
  • Based on clinical isolates:
    • ○
      PDC-30 was detected in an in vivo emerging cefiderocol-resistant P. aeruginosa (MIC1→4 mg/L) [32]
    • ○
      PDC-30 mutation was in a P. aeruginosa clinical isolate after treatment with cefiderocol and was associated with an 8-fold higher cefiderocol MIC [21]
ADC variants (cephalosporinase), OXA-66, (OXA 23) A. baumannii
  • Based on clinical isolates:
    • ○
      Acquired ADC variants and OXA-23 were detected in all six cefiderocol resistant isolates [63].
    • ○
      ADC variants were detected in all 28 cefiderocol resistant isolates, OXA-23 in 15 isolates, and OXA-66 in 24 [29].
    • ○
      ADC-30 homologues, OXA-23, and OXA-66 were detected in all 20 cefiderocol-resistant clinical isolates [30].

Note: Based on isogenic mutants, introduction of OXA-23 in A. baumannii and E. coli was not shown to affect cefiderocol MIC [29,32,54,66]. Furthermore, cefiderocol has been shown to be stable against OXA-23 [66].
BEL * E. coli *,
P. aeruginosa *
  • Based on isogenic E. coli mutants:
    • ○
      16-fold MIC (0.03→0.5 mg/L) by BEL-2 [54], ≥4-fold-higher (≤0.125→0.5 mg/L) by BEL-2 in another study [56], and ≥2-fold-higher (≤0.125→0.25 mg/L) by BEL-1 [56].
  • Based on isogenic P. aeruginosa mutants:
    • ○
      4-fold (0.5→2 mg/L) higher MIC by BEL-1 and 8-fold (0.5→4 mg/L) by BEL-2 [56].
CTX-M-27 * E. coli * Introduction of CTX-M-27 in E. coli was associated with a 4- to 8-fold higher cefiderocol MIC (0.063–0.125→0.5) [29].

In bold are mechanisms of resistance of which the role has been confirmed in isogenic mutant experiments (group 5 studies, see “Eligibility criteria” in Methods) and that have been detected in cefiderocol-resistant clinical isolates (group 1–3 studies, see “Eligibility criteria” in Methods). * Based only on in vitro isogenic mutant experiment (group 5 studies, see “Eligibility criteria” in Methods).