Table A3.

Resistance mediated by mutations affecting function/expression of porins and efflux pumps.

Target Genes/Involved Porins/Efflux Pumps	Organism(s)	Findings
ompK35, ompK36, ompK37 (porins)	K. pneumoniae	Based on isogenic mutants: ○ 4-fold higher MIC (0.031→0.125 mg/L) by deletion of ompK35 and 2-fold higher MIC (0.031→0.063 mg/L) by deletion of ompK36 (with or without concurrent deletion of ompK35) [47]. Based on clinical isolates: ○ ompK37 mutations were identified in all n = 7 cefiderocol-resistant K. pneumoniae isolates (in combination with ompK36 mutations in 6) [37] ○ Truncation of ompK35 was detected in two cefiderocol-resistant clinical isolates in combinations with KPC variants known to contribute to cefiderocol resistance [55]. ○ In two cefiderocol-resistant K. pneumoniae isolates, disruption of OmpK35, OmpK36, and OmpK37 was detected in combination with various β-lactamases [53].
ompC, ompF (porins)	Enterobacter spp.	Based on clinical isolates: ○ Alterations in ompC and ompF (in combination with AmpC and ESBLs) were detected in four cefiderocol-resistant Enterobacter spp. isolates [53]. ○ ompC deletions/truncation were found in three of six cefiderocol-resistant Enterobacter spp. in one study [37].
oprD (porin)	P. aeruginosa	Based on isogenic mutants: ○ Mutation in porin oprD was associated with a 2-fold higher MIC (0.125→0.25 mg/L) [47]. Based on clinical isolates: ○ Opr-D truncation was detected in two in vivo emerging (after cefiderocol treatment) cefiderocol-resistant clinical P. aeruginosa isolates (MIC 0.25→4 mg/L in both) [21].
ChrA (heavy metal iron transporter), SugE (efflux pump)	K. pneumoniae	n = 7 cefiderocol-resistant (MIC > 2 mg/L) and CR K. pneumoniae clinical isolates were compared by WGS with n = 8 cefiderocol-susceptible CR K. pneumoniae isolates. ChrA expression was detected in five of seven cefiderocol-resistant isolates but only one of eight cefiderocol-susceptible isolates [37]. SugE expression was detected in two of seven cefiderocol-resistant isolates but none of the cefiderocol-susceptible isolates [37].
mexR or nalD (repressors of MexAB–OprM efflux pump) *	P. aeruginosa *	Based on isogenic mutants: mutations in mexR or nalD leading to overexpression of the MexAB–OprM efflux pump were associated with 2-fold higher cefiderocol MIC (0.125→0.25 mg/L) in P. aeruginosa, while mutations in mexB or oprM (resulting in loss of function of the MexAB–OprM efflux pump) resulted in a 2-fold lower cefiderocol MIC [47].
smeT **	S. maltophilia **	SmeT promoter mutation (resulting in overexpression of the efflux pump smeDEF) was detected in an in vitro derived cefiderocol-resistant mutant [60].
AxyABM (efflux pump) *	A. xylosoxidans *	Overexpression of AxyABM was associated with a 3-fold higher cefiderocol MIC when comparing two isogenic A. xylosoxidans isolates (0.032→0.094 mg/L). Disruption of the efflux pump was associated with 2- to 23.5-fold lower cefiderocol MICs [51].

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 experiments (group 5 studies, see “Eligibility criteria” in Methods). ** Based only on in vitro derived mutants (group 4 studies, see “Eligibility criteria” in Methods).