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

Ryan K Shields; Ellen G Kline; Kevin M Squires; Daria Van Tyne; Yohei Doi

doi:10.1093/jacamr/dlad107

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

JAC Antimicrob Resist. 2023 Oct 3;5(5):dlad107. doi: 10.1093/jacamr/dlad107. eCollection 2023 Oct.

Authors

Ryan K Shields^{1

2

3}, Ellen G Kline¹, Kevin M Squires¹, Daria Van Tyne^{1

2

4}, Yohei Doi^{1

2

5}

Affiliations

¹ Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
² Center for Innovative Antimicrobial Therapy, University of Pittsburgh, Pittsburgh, PA, USA.
³ Antibiotic Management Program, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
⁴ Center for Evolutionary Biology and Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
⁵ Departments of Microbiology and Infectious Diseases, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.

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.

Abstract

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