Dataset Information

ARGONAUT-I: Activity of Cefiderocol (S-649266), a Siderophore Cephalosporin, against Gram-Negative Bacteria, Including Carbapenem-Resistant Nonfermenters and Enterobacteriaceae with Defined Extended-Spectrum ?-Lactamases and Carbapenemases.

ABSTRACT: The activity of the siderophore cephalosporin cefiderocol is targeted against carbapenem-resistant Gram-negative bacteria. In this study, the activity of cefiderocol against characterized carbapenem-resistant Acinetobacter baumannii complex, Stenotrophomonas maltophilia, Pseudomonas aeruginosa, and Enterobacteriaceae strains was determined by microdilution in iron-depleted Mueller-Hinton broth. The MIC90s against A. baumannii, S. maltophilia, and P. aeruginosa were 1, 0.25, and 0.5?mg/liter, respectively. Against Enterobacteriaceae, the MIC90 was 1?mg/liter for the group harboring OXA-48-like, 2?mg/liter for the group harboring KPC-3, and 8?mg/liter for the group harboring TEM/SHV ESBL, NDM, and KPC-2.

SUBMITTER: Jacobs MR

PROVIDER: S-EPMC6325197 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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ARGONAUT-I: Activity of Cefiderocol (S-649266), a Siderophore Cephalosporin, against Gram-Negative Bacteria, Including Carbapenem-Resistant Nonfermenters and Enterobacteriaceae with Defined Extended-Spectrum β-Lactamases and Carbapenemases.

Jacobs Michael R MR Abdelhamed Ayman M AM Good Caryn E CE Rhoads Daniel D DD Hujer Kristine M KM Hujer Andrea M AM Domitrovic T Nicholas TN Rudin Susan D SD Richter Sandra S SS van Duin David D Kreiswirth Barry N BN Greco Chris C Fouts Derrick E DE Bonomo Robert A RA

Antimicrobial agents and chemotherapy 20181221 1

The activity of the siderophore cephalosporin cefiderocol is targeted against carbapenem-resistant Gram-negative bacteria. In this study, the activity of cefiderocol against characterized carbapenem-resistant Acinetobacter baumannii complex, Stenotrophomonas maltophilia, Pseudomonas aeruginosa, and Enterobacteriaceae strains was determined by microdilution in iron-depleted Mueller-Hinton broth. The MIC90s against A. baumannii, S. maltophilia, ...[more]

PMID: 30323050

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Project description:ObjectivesMany carbapenem-resistant (CR) Gram-negative (GN) pathogens exhibit MDR, meaning few therapeutic options are available for CR-GN infections. Cefiderocol, a siderophore cephalosporin, has demonstrated in vitro efficacy against CR-GN bacteria. In the SIDERO-CR-2014-2016 surveillance study, European clinical isolates comprising carbapenem-non-susceptible (CarbNS) Enterobacterales and MDR non-fermenters were tested against cefiderocol and comparators.MethodsCefiderocol MICs were determined using iron-depleted CAMHB, and comparators using CAMHB, per recommended CLSI methodology. Carbapenemase gene profiles were determined using PCR.ResultsIsolates (N = 870) from 23 European countries comprised CarbNS Enterobacterales (n = 457), MDR Pseudomonas aeruginosa (n = 177) and MDR Acinetobacter baumannii (n = 236). The most common carbapenemases were KPC (52%), OXA-48-like (19%), VIM (14%) and NDM (8%) in Enterobacterales, VIM (41%) in P. aeruginosa and OXA-23-like (57%) and OXA-24/40-like (37%) in A. baumannii. Most carbapenemase-producing isolates (65%) co-carried ESBLs. Approximately half of P. aeruginosa isolates were negative for carbapenemases, compared with 10% of Enterobacterales and 3% of A. baumannii. A similar proportion of Enterobacterales were susceptible to cefiderocol (81.6%; 79.0% of VIM producers; 51.4% of NDM producers; based on EUCAST breakpoint values) compared with comparator antimicrobial agents, including colistin (76.4%; 93.5% of VIM producers; 78.4% of NDM producers) and ceftazidime/avibactam (76.6%; 1.6% of VIM producers; 2.7% of NDM producers). Of P. aeruginosa isolates, 98.3% were susceptible to cefiderocol (100% of VIM producers), similar to colistin (100%). Against A. baumannii, 94.9% had cefiderocol MIC ≤2 mg/L and 93.6% of isolates were susceptible to colistin.ConclusionsCefiderocol demonstrated potent activity against CarbNS and MDR GN bacteria, including non-fermenters and a wide variety of MBL- and serine-β-lactamase-producing strains.

Project description:Cefiderocol (formerly S-649266) is an investigational siderophore cephalosporin. Iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB) was prepared according to the Clinical and Laboratory Standards Institute (CLSI) protocol and used to perform broth microdilution testing of cefiderocol against a 2014-2015 collection of clinical isolates of Gram-negative bacilli from North America (n = 4,239) and Europe (n = 4,966). The concentrations of cefiderocol inhibiting 90% of isolates tested (MIC90s) were 0.5 ?g/ml (North America; n = 3,007) and 1 ?g/ml (Europe; n = 3,080) for all isolates of Enterobacteriaceae; 1 ?g/ml (North America; n = 30) and 4 ?g/ml (Europe; n = 139) for meropenem-nonsusceptible (MIC ? 2 ?g/ml) isolates of Enterobacteriaceae; 0.5 ?g/ml for both North American (n = 765) and European (n = 765) isolates of Pseudomonas aeruginosa; 0.5 ?g/ml (North America; n = 151) and 1 ?g/ml (Europe; n = 202) for meropenem-nonsusceptible (MIC ? 4 ?g/ml) isolates of P. aeruginosa; 1 ?g/ml for both North American (n = 309) and European (n = 839) isolates of all Acinetobacter baumannii strains as well as for both North American (n = 173) and European (n = 595) isolates of meropenem-nonsusceptible A. baumannii; and 0.5?g/ml (North America; n = 152) and 0.25 ?g/ml (Europe; n = 276) for isolates of Stenotrophomonas maltophilia MICs of cefiderocol were ?4 ?g/ml for 99.9% (6,078/6,087) of all Enterobacteriaceae, 97.0% (164/169) of meropenem-nonsusceptible Enterobacteriaceae, 99.9% (1,529/1,530) of all P. aeruginosa isolates, 100% (353/353) of meropenem-nonsusceptible P. aeruginosa isolates, 97.6% (1,120/1,148) of all A. baumannii isolates, 96.9% (744/768) of meropenem-nonsusceptible A. baumannii isolates, 100% of isolates of S. maltophilia (428/428) and 93.8% of isolates of Burkholderia cepecia (11/12). We conclude that cefiderocol demonstrated potent in vitro activity against a recent collection of clinical isolates of commonly encountered Gram-negative bacilli, including carbapenem-nonsusceptible isolates.

Project description:Abstract Background Cefiderocol (CFDC) is the first siderophore cephalosporin approved (US and EU) for a broad range of infections caused by Gram-negative (GN) bacteria, including carbapenem-resistant Enterobacterales (ENT) and non-fermenters (NFs). Bacteremia is a serious manifestation of GN infection and understanding how well an antibiotic works to clear the bacteremia is an important part of drug evaluation. Methods All completed clinical studies for CFDC development were used to identify patients with GN bacteremia. Information collected included the primary infection site, species identification and antibiotic susceptibility, post randomization blood cultures and clinical and bacteremia outcome. In patients with missing data (blood cultures) clinical response of cure was used to impute microbiological eradication. Indeterminate responses resulted from a combination of missing data and clinical failure, including death prior to test of cure (TOC). Results Three clinical studies randomized 900 patients (CFDC 552; comparators 348) of whom 84 (CFDC 52; comparators 32) had GN bacteremia at baseline (Table). Bacteremia rate by study was CREDIBLE-CR 25.3%, APEKS-cUTI 6.2%, APEKS-NP 6.0%. Escherichia coli (29), Klebsiella pneumoniae (23) and Acinetobacter spp (21) were most frequent species. Sources included urinary tract (31), lung (22), unknown (10), IV line (8), intraabdominal (6), or other (7). Persistence of bacteremia at TOC was seen in 2/52 (3.8%) CFDC and 2/32 (6.2%) control patients (Table), usually due to lack of source control. Clinical outcomes varied by study and infection source and were often confounded (indeterminate response). Eradication in patients with ENT at TOC was determined for 27/39 (69%) for CFDC and 16/23 (70%) for controls, and for 9/16 (56%) for CFDC and 10/11 (91%) for controls in patients with NFs, respectively. Table. Clinical and bacteremia microbiological outcomes per patient at TOC. Conclusion Post-treatment negative blood cultures were inconsistently collected, especially in APEKS-NP and -cUTI, however, negative blood cultures on therapy without recurrence was seen in 96% of CFDC patients with sufficient information. A dedicated clinical trial in GN bacteremia (GAME CHANGER; NCT03869437) is ongoing and will better delineate microbiological outcomes. Disclosures David Paterson, Accelerate (Speaker’s Bureau)BioMerieux (Speaker’s Bureau)BioMerieux (Advisor or Review Panel member)Entasis (Advisor or Review Panel member)Merck (Advisor or Review Panel member)Merck (Grant/Research Support)Merck (Speaker’s Bureau)Pfizer (Speaker’s Bureau)Shionogi & Co., Ltd. (Grant/Research Support)VenatoRx (Advisor or Review Panel member) Masahiro Kinoshita, MPharm, Shionogi & Co., Ltd. (Employee) Kiichiro Toyoizumi, PhD, Shionogi & Co., Ltd. (Employee) Yuko Matsunaga, MD, Shionogi Inc. (Employee) Roger Echols, MD, Shionogi Inc. (Consultant)

Dataset Information

ARGONAUT-I: Activity of Cefiderocol (S-649266), a Siderophore Cephalosporin, against Gram-Negative Bacteria, Including Carbapenem-Resistant Nonfermenters and Enterobacteriaceae with Defined Extended-Spectrum ?-Lactamases and Carbapenemases.

Publications

ARGONAUT-I: Activity of Cefiderocol (S-649266), a Siderophore Cephalosporin, against Gram-Negative Bacteria, Including Carbapenem-Resistant Nonfermenters and <i>Enterobacteriaceae</i> with Defined Extended-Spectrum β-Lactamases and Carbapenemases.

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