In Vitro Susceptibility of Gram-Negative Pathogens to Cefiderocol in Five Consecutive Annual Multinational SIDERO-WT Surveillance Studies, 2014 to 2019

ABSTRACT We report in vitro susceptibility data from five consecutive annual SIDERO-WT surveillance studies (2014 to 2019) for cefiderocol and comparators tested against Gram-negative clinical isolates from North America and Europe. CLSI broth microdilution was used to determine MICs for Enterobacterales (n = 31,896), Pseudomonas aeruginosa (n = 7,700), Acinetobacter baumannii complex (n = 5,225), Stenotrophomonas maltophilia (n = 2,030), and Burkholderia cepacia complex (n = 425). MICs were interpreted by CLSI-approved clinical breakpoints (February 2021). Cefiderocol inhibited 99.8, 96.7, 91.6, and 97.7% of all Enterobacterales, meropenem-nonsusceptible, ceftazidime-avibactam-nonsusceptible, and ceftolozane-tazobactam-nonsusceptible isolates, respectively, at ≤4 μg/mL (susceptible breakpoint). Cefiderocol inhibited 99.9, 99.8, 100, and 99.8% of all P. aeruginosa, meropenem-nonsusceptible, ceftazidime-avibactam-nonsusceptible, and ceftolozane-tazobactam-nonsusceptible isolates, respectively, at ≤4 μg/mL (susceptible breakpoint). Cefiderocol inhibited 96.0% of all A. baumannii complex isolates and 94.2% of meropenem-nonsusceptible isolates at ≤4 μg/mL (susceptible breakpoint) and 98.6% of S. maltophilia isolates at ≤1 μg/mL (susceptible breakpoint). B. cepacia complex isolates were tested with a MIC50 of ≤0.03 μg/mL and MIC90 of 0.5 μg/mL. Annual cefiderocol percent susceptible rates for Enterobacterales (North America range, 99.6 to 100%/year; Europe range, 99.3 to 99.9%/year) and P. aeruginosa (North America range, 99.8 to 100%; Europe range, 99.9 to 100%) were unchanged from 2014 to 2019. Annual percent susceptible rates for A. baumannii complex demonstrated sporadic, nondirectional differences (North America range, 97.5 to 100%; Europe range, 90.4 to 97.5%); the wider range for Europe (∼7%) was due to isolates from Russia. Annual percent susceptible rates for S. maltophilia showed minor, nondirectional differences (North America range, 96.4 to 100%; Europe range, 95.6 to 100%). We conclude that clinical isolates of Enterobacterales (99.8% susceptible), P. aeruginosa (99.9%), A. baumannii (96.0%), and S. maltophilia (98.6%) collected in North America and Europe from 2014 to 2019 were highly susceptible to cefiderocol.

carbapenem-resistant Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii as pathogens of the highest (critical) priority for development of new antibacterial agents (2). Cefiderocol, a parenteral siderophore cephalosporin, was approved by the United States Food and Drug Administration (FDA) in November 2019 for the treatment of adults with complicated urinary tract infections, including pyelonephritis, caused by susceptible Gram-negative bacilli (Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae complex, and P. aeruginosa) when limited or no other treatment options exist (4). In April 2020, the European Medicines Agency (EMA) licensed cefiderocol for the treatment of infections due to aerobic Gram-negative organisms in adults with limited treatment options (5). In September 2020, the FDA approved cefiderocol for a new indication, the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia caused by Enterobacterales (E. coli, K. pneumoniae, E. cloacae complex, and Serratia marcescens), P. aeruginosa, and Acinetobacter baumannii complex. Clinical development of cefiderocol continues for the treatment of serious infections attributable to resistant Gram-negative bacilli, including infections caused by carbapenem-resistant Gramnegative bacilli (6).
Cefiderocol possesses a unique mechanism of bacterial cell entry, making it an important addition to the antimicrobial armamentarium. The optimized chloro-catechol moiety within the C-3 side chain of cefiderocol facilitates formation of chelated complexes with ferric iron and expedites its transport across the outer membrane of Gramnegative bacilli using constitutive iron transport systems (7). Following its delivery to the periplasmic space, cefiderocol binds primarily to penicillin binding protein 3 (PBP 3), similarly to other cephalosporins, and impedes peptidoglycan synthesis (7). Cefiderocol has been shown to be stable to hydrolysis by most clinically important b-lactamases, including both serine b-lactamases of Ambler classes A (e.g., KPC and, extended-spectrum lactamase [ESBL; e.g., CTX type, SHV type, and TEM type]), C (i.e., AmpC), and D (e.g., OXA) carbapenemases and metallo-b-lactamases of Ambler class B (e.g., IMP, NDM, and VIM) and to be minimally affected by porin deletions and effluxmediated resistance mechanisms (2-to 4-fold increases in cefiderocol MIC) (7)(8)(9)(10)(11)(12)(13)(14).
Using current standardized reference testing methods and reliable, predictable, evidence-driven MIC and disk diffusion zone size interpretative criteria to determine in vitro activities for recently approved and investigational agents is critical to establishing and supporting treatment decisions and expanding the role of these agents in patient care, particularly for patients where unmet medical need exists (2). Investigational MIC and disk diffusion zone diameter interpretative criteria for cefiderocol were published by the Clinical and Laboratory Standards Institute (CLSI) in 2019 based on in vitro activity and preclinical in vivo pharmacokinetic/pharmacodynamics data prior to FDA approval of cefiderocol (15,16). In February 2021, CLSI approved MIC clinical breakpoints for Enterobacterales, P. aeruginosa, and Acinetobacter species of #4 mg/mL (susceptible), 8 mg/mL (intermediate), and $16 mg/mL (resistant) and for Stenotrophomonas maltophilia of #1 mg/mL (susceptible) and .1 mg/mL (nonsusceptible) (17). The updated MIC clinical breakpoints for cefiderocol will be published in early 2022 with the release of the 32nd edition of the CLSI M100 document. Clinical breakpoints for cefiderocol are also available from the United States Food and Drug Administration (FDA) (18) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) (19) (see Table S1 in the supplemental material) but were not used for MIC interpretation in this article.
The intent of the current study was to evaluate the in vitro susceptibility to cefiderocol of Gram-negative pathogens (Enterobacterales, P. aeruginosa, A. baumannii complex, S. maltophilia, and Burkholderia cepacia complex) collected over five consecutive annual SIDERO-WT surveillance studies (from November 2014 to December 2019) conducted in North America and Europe using the recently approved (February 2021) CLSI MIC clinical breakpoints (17). In addition, we performed cefiderocol susceptibility subset analysis that included isolates with meropenem-, ceftazidime-avibactam-, and ceftolozane-tazobactam-nonsusceptible phenotypes, as it is in patients infected with these nonsusceptible isolates where cefiderocol use most directly addresses an unmet medical need, and reviewed the cefiderocol percent susceptible rates and isolate MIC distributions by year to identify trends in cefiderocol in vitro activity over time.
Annual cefiderocol percent susceptible rates for isolates of Enterobacterales from North America (99.6 to 100% susceptible) and Europe (99.3 to 99.9% susceptible) varied over very narrow ranges (0.4 to 0.6%) ( Table 2). Even less variation (0.1 to 0.2%) in annual cefiderocol percent susceptible rates was observed for P. aeruginosa. Annual cefiderocol percent susceptible rates for isolates of P. aeruginosa from North America ranged from 99.8% to 100%, and those for isolates from Europe ranged from 99.9% to 100%. Annual percent susceptible rates for A. baumannii demonstrated sporadic, nondirectional differences. The annual cefiderocol percent susceptible rate range was narrower for isolates of A. baumannii from North America (97.5 to 100%) than for isolates from Europe (90.4 to 97.5%). In total, there were 171 isolates of A. baumannii with Annual percent susceptible rates for ceftazidime-avibactam for isolates of Enterobacterales from North America (99.7 to 100%) and Europe (98.2 to 98.8%) were similar (,2% annual variation), while annual percent susceptible rates for ceftolozanetazobactam were higher in isolates from North America (93.8 to 94.9%) than in those from Europe (87.3 to 90.6%) ( Table 2). Annual percent susceptible rates for isolates of P. aeruginosa from North America were higher for both ceftazidime-avibactam (96.0 to 99.6%) and ceftolozane-tazobactam (96.7 to 99.6%) than for isolates from Europe (ceftazidime-avibactam, 90.3 to 93.1%; ceftolozane-tazobactam, 90.2 to 91.5%).
Isolates of Enterobacterales, P. aeruginosa, A. baumannii complex, S. maltophilia, and B. cepacia complex collected in 2019 were also tested against meropenem-vaborbactam and   imipenem-relebactam (see Table S7 in the supplemental material
Single, specific mechanisms conferring resistance to cefiderocol in Enterobacterales, P. aeruginosa, and A. baumannii have not been identified, although the addition of avibactam, a b-lactamase inhibitor, to cefiderocol has been shown to lower the MICs for some cefiderocol-resistant isolates, primarily A. baumannii possessing various ESBLs. (15,25,26). In addition, in some isolates of Gram-negative bacilli with cefiderocol MICs ranging from 2 to 256 mg/mL, the addition of a b-lactamase inhibitor (e.g., clavulanic acid, avibactam, or dipicolinic acid) was shown to lower cefiderocol MICs (4). Cross-resistance between cefiderocol and other antibacterial classes has not been identified; generally, isolates of Gram-negative bacilli resistant to other antibacterial agents are reliably