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In vitro activity of cefiderocol against Pseudomonas aeruginosa demonstrating evolved resistance to novel β-lactam/β-lactamase inhibitors.

ABSTRACT:

Background

Cefiderocol demonstrates excellent activity against MDR Pseudomonas aeruginosa; however, the activity against isolates from patients previously treated with β-lactam agents is unknown. We aimed to determine the activity of cefiderocol against P. aeruginosa collected before and after treatment with traditional β-lactams and new β-lactam/β-lactamase inhibitors.

Methods

Cefiderocol MICs were determined in triplicate in iron-depleted cation-adjusted Mueller-Hinton broth and compared with β-lactam MICs tested by standard methods. All isolates underwent WGS analysis to identify mutations associated with resistance.

Results

One hundred and seventy-eight P. aeruginosa isolates were evaluated; 48% (86/178) were non-susceptible to ceftazidime/avibactam, ceftolozane/tazobactam and/or imipenem/relebactam. The cefiderocol MIC₅₀ and MIC₉₀ were 0.12 and 1 mg/L, respectively. Median cefiderocol MICs did not vary against isolates classified as MDR, XDR, or those non-susceptible to ceftazidime/avibactam, ceftolozane/tazobactam and/or imipenem/relebactam when compared with non-MDR isolates. Against isolates collected from patients previously treated with ceftolozane/tazobactam, cefiderocol MICs were increased 4-fold compared with baseline. Cross-resistance to cefiderocol was identified in 21% (3/14) of patients who developed treatment-emergent resistance to ceftolozane/tazobactam. Overall, 6% (11/178) of isolates demonstrated cefiderocol MICs ≥2 mg/L, which were disproportionately collected from patients previously treated with ceftolozane/tazobactam (73%; 8/11). Isolates with reduced cefiderocol susceptibility harboured mutations in ampC, tonB-dependent receptors, the response regulator pirR and ftsI.

Conclusions

Cefiderocol demonstrates excellent in vitro activity against P. aeruginosa isolates exposed to other novel β-lactam agents; however, some exceptions were identified. Cross-resistance between cefiderocol and ceftolozane/tazobactam was evident, but not with ceftazidime/avibactam or imipenem/relebactam. Reduced cefiderocol susceptibility was mediated by mutations in ampC and tonB-dependent receptors.

SUBMITTER: Shields RK

PROVIDER: S-EPMC10546814 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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<i>In vitro</i> activity of cefiderocol against <i>Pseudomonas aeruginosa</i> demonstrating evolved resistance to novel β-lactam/β-lactamase inhibitors.

Shields Ryan K RK Kline Ellen G EG Squires Kevin M KM Van Tyne Daria D Doi Yohei Y

JAC-antimicrobial resistance 20231003 5

<h4>Background</h4>Cefiderocol demonstrates excellent activity against MDR <i>Pseudomonas aeruginosa</i>; however, the activity against isolates from patients previously treated with β-lactam agents is unknown. We aimed to determine the activity of cefiderocol against <i>P. aeruginosa</i> collected before and after treatment with traditional β-lactams and new β-lactam/β-lactamase inhibitors.<h4>Methods</h4>Cefiderocol MICs were determined in triplicate in iron-depleted cation-adjusted Mueller-Hi ...[more]

PMID: 37795425

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