Activity of cefepime/taniborbactam and comparators against whole genome sequenced ertapenem-non-susceptible Enterobacterales clinical isolates: CANWARD 2007–19

Abstract

Objectives This study assessed in vitro activities of cefepime/taniborbactam and comparator antimicrobial agents against ertapenem-non-susceptible Enterobacterales (ENSE) clinical isolates collected from the CANWARD study 2007–19, and associations between MIC and various mechanisms of β-lactam resistance identified using WGS. Methods A total of 179 ENSE (MIC ≥ 1 mg/L) isolates underwent susceptibility testing using reference CLSI broth microdilution. WGS was performed using the Illumina NextSeq platform. Carbapenemases, ESBLs and other β-lactamases were identified using ResFinder 4.0. Alterations in ompC/F and ftsI (PBP3) were identified by comparing extracted sequences to the appropriate NCBI reference gene. Porin alterations were analysed with Provean v1.1.3. Specific alterations of interest in PBP3 included a YRIN or YRIK insertion after P333. Results Cefepime/taniborbactam was highly active (MIC50/MIC90, 0.5/2 mg/L; 177/179 isolates inhibited at ≤ 8 mg/L) against ENSE with various antimicrobial resistance phenotypes. Thirteen (7.3%) of the 179 ENSE isolates demonstrated cefepime/taniborbactam MIC values ≥ 4 mg/L and possessed combinations of β-lactam resistance mechanisms, including a carbapenemase and/or ESBL and/or other β-lactamase genes, as well as alterations in OmpC and/or OmpF and/or PBP3. Of the two Escherichia coli isolates that demonstrated a cefepime/taniborbactam MIC of 32 mg/L, one possessed NDM-5, OXA-181 and TEM-1B, an OmpC alteration and P333_Y334insYRIN in PBP3, while the second contained CTX-M-71, a truncated OmpF and a large alteration in OmpC (F182_R195delinsMTTNGRDDVFE). Conclusions Cefepime/taniborbactam was highly active against ENSE with various antimicrobial resistance phenotypes/genotypes. ENSE isolates with cefepime/taniborbactam MIC values ≥ 4 mg/L possessed combinations of β-lactam resistance mechanisms, including β-lactamase genes, as well as alterations in OmpC and/or OmpF and/or PBP3.

In Vitro Activity of Cefepime-Taniborbactam and Comparators against Clinical Isolates of Gram-Negative Bacilli from 2018 to 2020: Results from the Global Evaluation of Antimicrobial Resistance via Surveillance (GEARS) Program

“…The potent activity of cefepime-taniborbactam against KPC-, OXA-48-like-, ESBL-, and AmpC-positive Enterobacterales was observed in earlier, limited studies focusing on challenge sets of isolates ( 9 – 11 , 15 , 16 ). A study of 247 carbapenemase-producing Enterobacterales from Spain reported cefepime-taniborbactam MICs of ≤16 μg/mL for 98.5% (199/202) of serine carbapenemase-positive and 93.3% (42/45) of MBL-positive isolates ( 12 ).…”

“…In that study, bla NDM-5 -positive E. coli (76.1%, 35/46) were the majority of the isolates with elevated cefepime-taniborbactam MICs, and almost all isolates of this subset had a YRIN or INYR insertion in PBP3, suggesting that PBP3 insertions were associated with elevated cefepime-taniborbactam MICs, as taniborbactam is known to inhibit NDM-5 (9). Canadian investigators identified two isolates of E. coli with cefepime-taniborbactam MICs of >16 μg/mL (32 μg/mL) among a set of 179 ertapenem-nonsusceptible isolates from over a decade of nationwide resistance surveillance; 1 possessed NDM-5, OXA-181 and TEM-1B, an OmpC alteration and a YRIN insertion in PBP3, while the second contained CTX-M-71, a truncated OmpF and a large alteration in OmpC ( 11 ). A study of Enterobacterales with cefepime-taniborbactam MICs of >8 μg/mL noted no universal resistance mechanism across the isolates tested but, rather, combinations of carbapenemases (e.g., NDM-5, NDM-7) with PBP3 insertions and/or porin changes ( 10 ).…”

In Vitro Activity of Two Cefepime-Based Novel Combinations, Cefepime/Taniborbactam and Cefepime/Zidebactam, against Carbapenemase-Expressing Enterobacterales Collected in India

“…Even though taniborbactam has been reported to possess potent inhibitory activity (50% inhibitory concentration [IC 50 ]) against the purified NDM variants and many ESBLs ( 28 ), higher MICs obtained against E. coli producing NDM and OXA-48-like or NDM alone led us to undertake an additional investigation. Based on previous publications ( 29 – 31 ), we analyzed PBP3 for the presence of 4-amino-acid insertions among E. coli isolates and found that an overwhelming proportion of isolates (97%) harbored the inserts regardless of the carbapenemase type. It has been reported previously that those β-lactams that heavily rely on the PBP3 engagement for their antibacterial action are adversely impacted by the presence of amino acid inserts in PBP3 of E. coli ( 32 , 33 ).…”

Can fosfomycin be an alternative therapy for infections caused byE. coliharbouring dual resistance: NDM and four-amino acid insertion in PBP3?

“…In a recent publication by Golden et al ., 1 resistance to cefepime/taniborbactam was observed in an NDM-expressing Escherichia coli harbouring a four-amino acid insertion in PBP3. This particular combination of resistance mechanisms seems to be an emerging threat.…”

“…Very disturbingly, published studies as well as our laboratory studies (unpublished) hint that even cefiderocol and cefepime/taniborbactam would have limited activity against E. coli with these dual resistance mechanisms. 1 , 6 Plazomicin has been shown to exhibit inconsistent activity against NDM producers. 7 Cefepime/zidebactam is highly active against these organisms but is in clinical development.…”