In Vitro Activity and In Vivo Efficacy of Cefiderocol against Stenotrophomonas maltophilia

Abstract

Cefiderocol is a novel siderophore cephalosporin antibiotic with broad coverage against difficult-to-treat Gram-negative bacteria, including those resistant to carbapenems. Its activity against Stenotrophomonas maltophilia was investigated in vitro against clinical isolates and in lung infection models using strains either resistant (SR202006) or susceptible (SR201934, SR200614) to trimethoprim/sulfamethoxazole. Cefiderocol demonstrated potent in vitro activity against all 217 S. maltophilia clinical isolates tested (MIC50: 0.063 μg/mL, MIC90: 0.25 μg/mL). Cefiderocol also demonstrated low MICs against the trimethoprim/sulfamethoxazole-resistant S. maltophilia strains (i.e. SR202006: MIC=0.125 μg/mL). In a neutropenic mouse lung infection model, cefiderocol (30 mg/kg and 100 mg/kg) demonstrated a significant, dose-dependent reduction in the lung viable bacteria cell count compared with untreated controls in S. maltophilia infection and was the only antibiotic tested to show a similar significant effect in a trimethoprim/sulfamethoxazole-resistant S. maltophilia infection. In immunocompetent rat lung infection models of S. maltophilia, humanized dosing of cefiderocol (2 g every 8 hours) and meropenem (1 g every 8 hours) revealed pharmacokinetic profiles similar to those in human subjects and the humanized cefiderocol dosing significantly reduced the lung viable bacteria cell count compared with baseline controls, which received no intervention. Together, the results from these studies suggest that cefiderocol could provide an effective alternative treatment option for S. maltophilia infections in the lower respiratory tract, particularly strains resistant to empiric antibiotics, such as trimethoprim/sulfamethoxazole or minocycline.

Cefiderocol for the Treatment of Multidrug-Resistant Gram-Negative Bacteria: A Systematic Review of Currently Available Evidence

“…Twenty-five studies investigated the characteristics of PK and/or PD of cefiderocol ( Katsube et al, 2016 ; Katsube et al, 2017 ; Matsumoto et al, 2017 ; Monogue et al, 2017 ; Ghazi et al, 2018a ; Ghazi et al, 2018b ; Katsube et al, 2018 ; Kawaguchi et al, 2018 ; Saisho et al, 2018 ; Katsube et al, 2019a ; Kidd et al, 2019a ; Katsube et al, 2019b ; Kidd et al, 2019b ; Chen et al, 2019 ; Miyazaki et al, 2019 ; Nakamura et al, 2019 ; Stainton et al, 2019 ; Matsumoto et al, 2020 ; Ota et al, 2020 ; Gill et al, 2021 ; Katsube et al, 2021 ; Kawaguchi et al, 2021 ; Kobic et al, 2021 ; König et al, 2021 ; Nakamura et al, 2021 ). A phase I study including healthy Japanese and Caucasian volunteers showed exhibit linear PK at doses of up to 2,000 mg, with low to moderate interindividual variability ( Saisho et al, 2018 ).…”

“…An in vitro PK/PD study showed that the standard dose could completely kill meropenem-resistant gram-negative isolates showing cefiderocol MICs of 0.5–4 g/ml within 24 h ( Matsumoto et al, 2020 ). Nine animal studies using neutropenic murine thigh models or respiratory tract infection models mimicking humanized exposures (2g q8h with a 3-h infusion) showed a >1 log 10 reduction in bacterial colony forming units (CFU) of most Gram-negative bacteria with MICs ≤4 g/ml, but not for the isolates with MICs ≥ 8 mg/L ( Supplementary Table S1 ) ( Matsumoto et al, 2017 ; Monogue et al, 2017 ; Ghazi et al, 2018b ; Kidd et al, 2019b ; Chen et al, 2019 ; Stainton et al, 2019 ; Ota et al, 2020 ; Gill et al, 2021 ; Nakamura et al, 2021 ).…”

Phenotypic and Molecular Characteristics of the MDR Efflux Pump Gene-Carrying Stenotrophomonas maltophilia Strains Isolated in Warsaw, Poland

“…All 94 isolates tested in our study were susceptible to minocycline. Recently, the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved a new drug, cefiderocol, which also presents high activity against S. maltophilia strains [ 36 ].…”

Overcoming Stenotrophomonas maltophilia Resistance for a More Rational Therapeutic Approach

“…Although all 3 isolates had cefiderocol MICs of 0.25 mg/L, bactericidal activity achieved by 8 hours and sustained through 24 hours was subsequently lost as regrowth and the development of resistant mutants (MIC >64 mg/L) was observed by 72 hours against all strains. Despite this relatively poor in vitro activity in static and dynamic PK/PD models, cefiderocol has demonstrated excellent in vivo activity against S maltophilia in neutropenic and immunocompetent mouse and rat thigh and lung infection models [ 28 , 48 , 49 ]. Importantly, the efficacy of cefiderocol was equal to or better than that of comparator agents such as ceftazidime, levofloxacin, and minocycline and was not impacted by resistance to these agents.…”