Cefiderocol Retains Antibiofilm Activity in Multidrug-Resistant Gram-Negative Pathogens

Abstract

Cefiderocol is a siderophore cephalosporin with potent antibacterial activity against a broad range of Gram-negative pathogens, including multidrug-resistant strains. Siderophore antibiotics bind ferric iron and utilize iron transporters to cross the cell membrane. In the biofilm setting, where antibiotic resistance is high but iron scavenging is important, cefiderocol may have advantageous antimicrobial properties. In this study, we compared the antimicrobial activity of cefiderocol to that of seven commonly used antibiotics in well-characterized multidrug-resistant pathogens and then determined their efficacy in the biofilm setting. MIC₉₀ values for cefiderocol were consistently lower than those of other antibiotics (ceftolozane-tazobactam, ceftazidime-avibactam, ceftazidime, piperacillin-tazobactam, imipenem, and tobramycin) in all strains tested. Cefiderocol treatment displayed a reduction in the levels of Pseudomonas aeruginosa biofilm (93%, P < 0.0001) superior to that seen with the other antibiotics (49% to 82%). Cefiderocol was generally as effective as or superior to the other antibiotics, depending on the pathogen-antibiotic combination, in reducing biofilm in other pathogens. There was a trend toward greater biofilm reduction seen with increased antibiotic dose or with increased frequency of antibiotic treatment. We conclude that cefiderocol effectively reduces biofilm and is a potent inhibitor of planktonic growth across a range of Gram-negative medically important pathogens.

Keywords: Gram negatives; biofilms; cefiderocol; multidrug resistance.

FIG 1

Cefiderocol can reduce existing biofilm in both MHII and ID-CAMHB. Data represent averages of results determined for 4 P. aeruginosa (A) and K. pneumoniae (B) strains in three independent experiments per strain (**, P < 0.001; ***, P < 0.0001). Error bars represent standard deviations from the means.

FIG 2

Cefiderocol reduces biofilm biomass in a dose-dependent fashion in P. aeruginosa. Data represent normalized crystal violet assay results for an average of 5 strains with three independent experiments per strain. Concentrations of antibiotics used in eradication assays are indicated with a clear bar.

FIG 3

Cefiderocol reduces P. aeruginosa biofilm burden to a greater extent than comparator antibiotics. Data represent viability assay results for an average of 5 strains with three independent experiments per strain. The reduction in biofilm burden associated with each antibiotic was compared to that seen with an untreated control by 2-way ANOVA with Tukey’s multiple-comparison test (**, P < 0.001; ***, P < 0.0001). Error bars represent standard deviations from the means.

FIG 4

Cefiderocol reduces biofilm in other MDR Gram-negative pathogens. (A) K. pneumoniae. (B) S. maltophilia. (C) B. cepacia complex. (D) A. baumannii. (E) E. coli. Data represent viability assay results for an average of 4 or 5 strains with three independent experiments per strain. The reduction in biofilm burden associated with each antibiotic was compared to that seen with an untreated control by 2-way ANOVA with Tukey’s multiple-comparison test (*, P < 0.05; **, P < 0.001; ***, P < 0.0001). Error bars represent standard deviations from the means.

FIG 5

P. aeruginosa biofilm eradication analyzed by viability count does not demonstrate dose dependence. Data represent viability assay results for an average of 5 strains with three independent experiments. The reduction in biofilm burden associated with each antibiotic was compared to that seen with an untreated control by 2-way ANOVA with Tukey’s multiple-comparison test (*, P < 0.05; ***, P < 0.0001). Error bars represent standard deviations from the means.

FIG 6

Increasing dosage frequency does not significantly increase biofilm eradication in P. aeruginosa (bottom panel) and K. pneumoniae (top panel). The levels of eradication seen with two MDR isolates for each species were compared by challenging biofilms either every 12 h for 24 h (24q12) or every 8 h for 24 h (24q8). Data represent an average of 3 viability assays. The reductions in biofilm burden seen with the different dosing schedules were compared by 2-way ANOVA with Sidak’s multiple-comparison test, but no significance was found. Error bars represent standard deviations from the means.