Cefiderocol-Xeruborbactam Active Against Carbapenem-Resistant Bacteria

Cefiderocol-xeruborbactam (Shionogi/Qpex Biopharma) inhibited nearly all Enterobacterales and Pseudomonas aeruginosa, and 98.5% of carbapenem-nonsusceptible Acinetobacter baumannii-calcoaceticus complex isolates, in 2024 global surveillance data.^1-3 A fourth poster showed the combination restored bactericidal activity in a mouse urinary tract infection model.⁴ Investigators from Element Iowa City (JMI Laboratories) and Shionogi presented the 4 posters at IDWeek 2026, held October 21-24 in Washington, DC.

The investigational combination pairs cefiderocol (Fetroja; Shionogi), a siderophore-conjugated cephalosporin, with xeruborbactam, a boronate β-lactamase inhibitor active against serine and metallo-β-lactamases (MBLs).^1,4 The program targets antimicrobial resistance driven by New Delhi metallo-β-lactamase (NDM) and other carbapenemases, which reduce susceptibility to cefiderocol alone.⁴

Cefiderocol-Xeruborbactam Activity Against Enterobacterales and Pseudomonas aeruginosa

Investigators tested 7995 Enterobacterales from 69 hospitals in 20 countries through the SENTRY Surveillance Program.¹ All isolates, including extensively drug-resistant (XDR) and carbapenem-nonsusceptible strains, had cefiderocol-xeruborbactam MICs of 4 mg/L or lower (MIC50/90, ≤0.015/0.12 mg/L). Comparator susceptibility ranged from 83.1% to 99.9%.¹

Gaps appeared among resistant subsets for most comparators. Against XDR Enterobacterales, comparators reached only 38.2% to 67.2% susceptibility, except cefiderocol (96.3%) and aztreonam-avibactam (99.2%).¹ Against MBL producers, most comparators were active against 0% to 13.5% of isolates.¹

KPC and MBL producers came from both US and European centers, while OXA-48-like producers and isolates carrying more than 1 carbapenemase appeared only in Europe.¹ Against isolates with multiple carbapenemases, comparators reached 0% to 55.6% susceptibility, except cefiderocol (92.1%) and aztreonam-avibactam (100%).¹

European Enterobacterales were less susceptible than US isolates to imipenem-relebactam, meropenem-vaborbactam, and ceftazidime-avibactam.¹ Most comparators remained active against carbapenemase-negative isolates, with susceptibility of 88.1% to 100%, except colistin.¹

Among 2185 P aeruginosa isolates, 99.6% had cefiderocol-xeruborbactam MICs of 4 mg/L or lower (MIC50/90, ≤0.06/0.25 mg/L).² Against carbapenemase producers, ceftolozane-tazobactam, imipenem-relebactam, meropenem-vaborbactam, and ceftazidime-avibactam showed 2.4% to 4.8% susceptibility, compared with 76.2% for cefiderocol. Cefiderocol-xeruborbactam inhibited 92.9% to 99.2% of resistant subsets, including XDR and ceftolozane-tazobactam-nonsusceptible isolates.²

Carbapenemase-positive P aeruginosa came mostly from Europe, with a single carbapenemase producer identified among US isolates.² European isolates were less susceptible than US isolates to cefiderocol-xeruborbactam, cefiderocol, and ceftazidime-avibactam, but more susceptible to ceftolozane-tazobactam, imipenem-relebactam, and meropenem-vaborbactam.²

Activity Against Carbapenem-Resistant Acinetobacter and Mouse UTI Model Results

Of 1307 A baumannii-calcoaceticus isolates from 93 medical centers in 20 countries, 41.2% were carbapenem nonsusceptible, with higher rates in Europe (50.5%) than North America (28.8%).³ Cefiderocol-xeruborbactam inhibited 98.5% of carbapenem-nonsusceptible isolates, compared with 0.2% for meropenem and 92.8% for colistin. Activity reached 98.9% against OXA-23-like producers and 93.1% against NDM producers.³

Xeruborbactam restored cefiderocol activity against PER-producing isolates, inhibiting 100% vs 4.8% with cefiderocol alone.³ The combination also inhibited 84.0% of cefiderocol-nonsusceptible and 90.2% of sulbactam-durlobactam-nonsusceptible isolates. Against sequence type 2, which accounted for 69.7% of carbapenem-nonsusceptible isolates, cefiderocol-xeruborbactam inhibited 98.7% vs 87.7% for cefiderocol and 92.8% for sulbactam-durlobactam.³

Nonsusceptibility to cefiderocol (5.7%) and sulbactam-durlobactam (3.9%) was far less common than carbapenem nonsusceptibility.³ Only 23 isolates (1.8%) had cefiderocol-xeruborbactam MICs above 4 mg/L.³

In the mouse model, investigators infected neutropenic mice with 4 Enterobacterales isolates with cefiderocol MICs of 4 mg/L or higher, including an NDM producer.⁴ Adding xeruborbactam lowered cefiderocol MICs against all 4 isolates in vitro, and bacterial burdens in untreated controls rose by about 2 to 3 log10 colony-forming units per kidney.⁴

Cefiderocol alone, given at a humanized regimen, did not achieve a reduction of more than 1 log10 in kidney bacterial counts, and xeruborbactam alone showed no efficacy.⁴ The combination produced more than a 1-log10 reduction against all 4 strains.⁴

For the combination, MICs in the mouse model study were also determined in cation-adjusted Mueller-Hinton broth, consistent with the susceptibility testing methodology approved by CLSI and EUCAST in 2026.⁴

References

1. Papp-Wallace KM, Kimbrough JH, Maher JM, Mendes RE, Sader HS, Castanheira M. Activity of cefiderocol-xeruborbactam and comparator agents against Enterobacterales, including molecularly characterized isolates recovered globally in 2024. Presented at: IDWeek 2026; October 21-24, 2026; Washington, DC. Poster P-166.

2. Papp-Wallace KM, Kimbrough JH, Maher JM, Mendes RE, Sader HS, Castanheira M. Activity of cefiderocol-xeruborbactam and comparator agents against Pseudomonas aeruginosa, including molecularly characterized isolates recovered globally in 2024. Presented at: IDWeek 2026; October 21-24, 2026; Washington, DC. Poster P-168.

3. Kimbrough JH, Papp-Wallace KM, Castanheira M. Activity of cefiderocol-xeruborbactam and comparator agents against global Acinetobacter baumannii-calcoaceticus species complex isolates. Presented at: IDWeek 2026; October 21-24, 2026; Washington, DC. Poster P-167.

4. Mizusawa E, Toba S, Takagi F, et al. Bactericidal activity of cefiderocol/xeruborbactam in a murine urinary tract infection model. Presented at: IDWeek 2026; October 21-24, 2026; Washington, DC. Poster P-163.