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Cefiderocol (CFDC) is a parenteral siderophore cephalosporin that is active against Gram-negative bacteria, including carbapenem-resistant isolates. We report the in vitro activity of CFDC and other antibiotics against 1,738 clinical isolates of Gram-negative bacilli (GNB) provided by five medical centers in five provinces of China in 2020 METHODS: : Antibiotic susceptibility testing was performed using the Clinical and Laboratory Standards Institute broth microdilution method.Against Pseudomonas aeruginosa and Acinetobacter spp., the CFDC concentration inhibiting the growth of 90% of the isolates (MICCFDC demonstrated potent in vitro activity against a recent collection of clinical isolates, including meropenem-non-susceptible isolates, obtained from medical centers in mainland China.

Objective Evaluate the in vivo efficacy and resistance prevention of cefiderocol in combination with ceftazidime/avibactam, ampicillin/sulbactam and meropenem using human-simulated regimens (HSR) in the murine infection model. Methods In total, 15 clinical A. baumannii were assessed: cefiderocol MICs, 2 mg/L (previously developed resistance on therapy), n = 3; 8 mg/L, n = 2; ≥32 mg/L, n = 10 (including VEB and PER-harbouring isolates). Mice received inactive control, cefiderocol, cefiderocol + ceftazidime/avibactam (C-CZA), cefiderocol + ampicillin/sulbactam (C-SAM) or cefiderocol + meropenem (C-MEM) HSRs. The mean change in log10 cfu/thigh compared with starting inoculum was assessed. Resistance development on treatment was a >4-fold increase in MIC relative control animals. In vitro activities of combinations were assessed by disc stacking. Results Against cefiderocol-non-susceptible isolates, combinations produced significant kill with C-CZA −3.75 ± 0.37 reduction in log10 cfu/thigh, C-SAM produced −3.55 ± 0.50 and C-MEM produced −2.18 ± 1.75 relative to baseline. Elevated MICs in cefiderocol treated animals occurred in three out of three isolates with MICs of 2 mg/L. Of these isolates, one developed elevated MICs with C-MEM compared with none treated with C-CZA or C-SAM. Disc stacking with C-CZA or C-SAM returned all isolates to at least the CLSI intermediate breakpoint, which may correlate with in vivo efficacy. Conclusions Against cefiderocol-non-susceptible isolates, cefiderocol + ceftazidime/avibactam or ampicillin/sulbactam HSR produced in vivo kill against all 12 cefiderocol-non-susceptible isolates. Cefiderocol with ceftazidime/avibactam or ampicillin/sulbactam prevented the development of resistance during treatment against cefiderocol-high-end-susceptible isolates with a propensity for resistance on therapy. These data support the clinical evaluation of cefiderocol with ceftazidime/avibactam or ampicillin/sulbactam against A. baumannii, including multi-drug-resistant isolates.

Overcoming serious infectious diseases such as malaria, tuberculosis, and other neglected tropical diseases (NTDs) that threaten human life around the world is an important issue in global health. Most of these diseases are concentrated in developing and low-income countries, and in order to reinforce drug discovery activities, pharmaceutical companies are actively promoting industry-academia-government partnerships and utilizing funds to stimulate global health activities. In this presentation, three examples of our drug discovery activities are introduced. The first is participation in the Booster project led by Drugs for Neglected Diseases initiative (DNDi) aimed at creating therapeutic agents for leishmaniasis and Chagas disease, an effort supported by the Global Health Innovative Technology (GHIT) Fund. As domestic and overseas pharmaceutical companies participate in the project and provide their own compounds, it is possible to obtain structure-activity relationship information in a short period of time and improve compound potency. We collaborated with DNDi to create a lead compound from one hit compound, and contributed to further enhancement of its activity. The remaining two are collaborations with academia for the creation of new therapeutic agents or vaccines: a joint research project with Hokkaido University Research Center for Zoonosis Control for emerging viral diseases, and a collaboration with Nagasaki University in malaria. In each case, our researchers were based at the university, establishing close working collaborations with the university researchers. Novel solutions for serious infectious diseases are expected by the combination of the high-level basic research capabilities of academia and the drug discovery know-how and original compound libraries possessed by pharmaceutical companies.

Background Difficult-to-treat resistant (DTR) isolates are defined as resistance to all first-line high-efficacy, low-toxicity antibiotics (penicillins, cephalosporins, carbapenems and quinolones), leaving physicians with limited treatment options. Cefiderocol (CFDC) is a siderophore cephalosporin with activity against a wide variety of Gram-negative bacteria, including carbapenem-resistant Enterobacterales and non-fermenters. We evaluated the in vitro activity of cefiderocol against DTR isolates collected in United States as part of SENTRY surveillance program in 2020 and 2021. In vitro susceptibility of cefiderocol and comparator agents to DTR isolates Methods Susceptibility testing was performed by broth microdilution according to CLSI guidelines. All antibiotics were tested in cation-adjusted Mueller-Hinton broth (CAMHB) except for CFDC, for which iron-depleted CAMHB was used. Susceptibility rate (%) was determined according to CLSI breakpoints, and DTR pathogens were defined as being resistant to cefepime, ceftazidime ceftriaxone (only for Enterobacterales), imipenem, meropenem, ciprofloxacin and levofloxacin according to CLSI/FDA breakpoints. Results Among a total of 8,328 Enterobacterales, 2,241 Pseudomonas aeruginosa, and 586 Acinetobacter calcoaceticus-baumannii complex (ACB) clinical isolates from the United States, 50 Enterobacterales (0.6%), 36 P. aeruginosa (1.6%) and 114 ACB (19.5%) isolates showed a DTR phenotype, respectively. CFDC demonstrated its potent in vitro activity against these DTR isolates with MIC90 of ≤4 μg/mL with a susceptibility rate of ≥92% except for DTR ACB based on FDA breakpoint (75.4%). In contrast, MIC90s of β-lactam/β-lactamase inhibitor combination drugs showed lower activity (Table). Conclusion Cefiderocol demonstrated potent in vitro activity against DTR isolates of Enterobacterales, P. aeruginosa and ACB, indicating cefiderocol has high potential for treating infections caused by these difficult-to-treat strains. Disclosures Yoshinori Yamano, PhD, Shionogi: Employee Miki Takemura, n/a, Shionogi: Employee Dee Shortridge, PhD, AbbVie: Grant/Research Support|JMI Laboratory: Employee|Melinta: Grant/Research Support|Menarini: Grant/Research Support|Shionogi: Grant/Research Support Christine M. Slover, PharmD, Shionogi: Employee Christopher M. Longshaw, PhD, Shionogi: Employee Roger Echols, MD, Shionogi: Advisor/Consultant Roger Echols, MD, Shionogi: Advisor/Consultant Roger Echols, MD, Shionogi: Advisor/Consultant.

Background Cefiderocol (CFDC) is a siderophore-conjugated cephalosporin with broad activity against Gram-negative (GN) bacteria, including multidrug-resistant organisms. GN bacteria such as Enterobacterales (ENT), Pseudomonas aeruginosa (PsA), Acinetobacter baumannii complex (ABC), and Stenotrophomonas maltophilia (StM) can be challenging to treat and are often carbapenem-resistant (CR). Regional susceptibility of CFDC and comparators were investigated against US GN isolates collected in 2020-2021 as part of the SENTRY Antimicrobial Surveillance Program. Methods GN pathogens were consecutively collected from 32 US hospitals between 2020 to 2021. Susceptibility testing was performed using the broth microdilution method. CFDC was tested in iron-depleted cation-adjusted Mueller-Hinton broth. FDA or CLSI breakpoints were used where available. Other agents tested included the beta-lactam/beta-lactamase inhibitor (BL/BLI) combinations ceftazidime-avibactam, ceftolozane-tazobactam, imipenem-relebactam, meropenem-vaborbactam, piperacillin-tazobactam, and ampicillin-sulbactam. CR-PsA, or CRAB was defined as meropenem resistant while CRE was defined as imipenem or meropenem resistant by CLSI breakpoints. Results A total of 8328 ENT, 2241 PsA, 586 ABC, and 404 StM were collected. For ENT and PsA, CFDC susceptibility between the 9 US Census regions remained above 98% susceptible by CLSI or FDA breakpoints in all regions (Table 1). Amongst the BL/BLI combinations, the majority had >90% susceptibility across regions except for piperacillin-tazobactam with 79.7% for ENT and 65.9% for PsA in the MidAtlantic by FDA breakpoints. For ABC and StM, CFDC susceptibility was > 88% across all regions. For CR pathogens, 96 CRE, 327 CR-PsA, and 199 CRAB were collected. CFDC had >87.5% susceptibility in all regions for CRE and CR-PSA. For CRAB, 4 regions were > 87.5% by FDA breakpoints and the lowest was 63.6% in 11 isolates in the Mountain region (Table 2). For CRAB, every BL/BLI had susceptibility ≤27.3% in every region. Ampicillin-sulbactam had 27.3% susceptibility in the Mountain region. Table 1 Susceptibility of Cefiderocol against Enterobacterales, Pseudomonas aeruginosa, Acinetobacter baumannii complex and Stenotrophomonas maltiphilia isolates in the cefiderocol program collected from medical centers in the USA Table 2: Susceptibility of cefiderocol against CRE, CR Pseudomonas aeruginosa, and CR Acinetobacter baumannii complex isolates in the cefiderocol program collected from medical centers in the USA Conclusion US GN isolates, including CR pathogens, had high susceptibilities to CFDC across the US census regions. CFDC remains an important treatment option for GN infections in all US census regions. Disclosures Frank H. Kung, PhD, Shionogi Inc: Employee Sean Nguyen, n/a, Shionogi: Employee Christine M. Slover, PharmD, Shionogi: Employee Dee Shortridge, PhD, AbbVie: Grant/Research Support|JMI Laboratory: Employee|Melinta: Grant/Research Support|Menarini: Grant/Research Support|Shionogi: Grant/Research Support Jennifer M. Streit, BS, MT(ASCP), Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Shionogi: Grant/Research Support Roger Echols, MD, Shionogi: Advisor/Consultant Roger Echols, MD, Shionogi: Advisor/Consultant Roger Echols, MD, Shionogi: Advisor/Consultant Miki Takemura, n/a, Shionogi: Employee Yoshinori Yamano, PhD, Shionogi: Employee.

Background Difficult-to-treat resistance (DTR) organisms are defined as non-susceptible to all first-line high-efficacy, low-toxicity antibiotics (penicillins, cephalosporins, carbapenems and fluoroquinolones), leaving physicians with limited treatment options. Cefiderocol is a parenteral siderophore cephalosporin with potent activity against aerobic Gram-negative pathogens, including carbapenem-resistant strains. We evaluated the in vitro activity of cefiderocol and comparators against DTR pathogens collected in Europe by the SENTRY surveillance study in 2020 and 2021. Methods A total of 11434 clinical isolates of Gram-negative bacilli were systematically collected from 16 EU countries, Israel and Turkey in 2020 and 2021. Minimum inhibitory concentrations (MICs) were determined by broth microdilution for a panel of twenty-two antibiotics according to CLSI guidelines. All antibiotics were tested in cation-adjusted Mueller-Hinton broth (CAMHB) except for cefiderocol, for which iron-depleted CAMHB was used. Susceptibility was determined according to CLSI breakpoints, and DTR pathogens were defined as being resistant to cefepime, ceftazidime ceftriaxone, imipenem, meropenem, ciprofloxacin and levofloxacin according to CLSI breakpoints. Results Among 11434 Gram-negative isolates collected in 2020 and 2021, 792 (7.0%) were resistant to all 1st line therapy including cephalosporins, carbapenems and fluoroquinolone and could be defined as DTR. DTR was most frequently observed in Acinetobacter spp. (530/931, 56.9%), Enterobacterales (201/7739, 2.6%) and Pseudomonas aeruginosa (61/2440, 2.5. Based on CLSI breakpoints, cefiderocol was the most active antibiotic tested against DTR-Acinetobacter spp. (MIC90= 2mg/L, 97.4% susceptibility). Ampicillin/sulbactam was active in less than 1% of the DTR-Acinetobacter spp isolates. None of the drugs recommended by the IDSA for the treatment of resistant Gram-negative infections were as potent as cefiderocol (Table 1). Conclusion Cefiderocol was the only treatment option with demonstrated in vitro activity against more than 95% of all the tested DTR Gram-negative pathogens with limited treatment options. Disclosures Anne Laurence Santerre Henriksen, PhD, Shionogi: Contractor|UTILITY therapeutics Ltd: Advisor/Consultant Christopher M. Longshaw, PhD, Shionogi: Employee Dee Shortridge, PhD, AbbVie: Grant/Research Support|JMI Laboratory: Employee|Melinta: Grant/Research Support|Menarini: Grant/Research Support|Shionogi: Grant/Research Support Jennifer M. Streit, BS, MT(ASCP), Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Shionogi: Grant/Research Support Miki Takemura, n/a, Shionogi: Employee Yoshinori Yamano, PhD, Shionogi: Employee.

Background Infections caused by Achromobacter spp. and Burkholderia spp. have limited clinical treatment options due to the intrinsic resistance of these non-fermenters to several antimicrobial agents. These pathogens are known to cause severe nosocomial infections such as bloodstream infections and pneumonia in immunocompromised patients. Cefiderocol (CFDC) is a siderophore cephalosporin antibiotic approved in the US and Europe, with potent activity against Gram-negative bacteria including carbapenem-resistant strains. We evaluated the in vitro activity of CFDC and comparator agents against Achromobacter spp. and Burkholderia spp. clinical isolates, collected from hospitalized patients in US medical centers as part of the SENTRY Antimicrobial Surveillance Program. Methods Susceptibility testing for CFDC and comparators were performed by broth microdilution according to the CLSI guidance. CFDC was tested in iron-depleted cation-adjusted Mueller Hinton broth. The susceptibilities of CFDC and comparators against a total of 78 strains of Achromobacter spp. and a total of 99 strains of Burkholderia spp. isolated in the US between 2020 to 2021 were analyzed. CLSI breakpoints were used where available. Isolate identification was provided by the submitting site and confirmed at JMI Laboratories using MALDI-TOF. Results The minimum inhibitory concentration (MIC) range, MIC50/90, and susceptible rate for CFDC and comparators for Achromobacter spp. and Burkholderia spp. are shown in the Table 1 and 2, respectively. CFDC inhibited the growth of all 78 Achromobacter spp. isolates tested at ≤4 µg/mL and showed MIC90 of 0.5 μg/mL. CFDC inhibited the growth of 96% (95/99) of Burkholderia spp. isolates tested at ≤4 µg/mL and showed MIC90 of 1 μg/mL. There were 4 strains with high CFDC MIC (≥16 µg/mL), 3 of which were Burkholderia gladioli and 1 was Burkholderia multivorans. Table 1Activity of cefiderocol and comparator antimicrobial agents tested against 78 Achromobacter spp. isolates collected from medical centers in the US during 2020 and 2021Table 2Activity of cefiderocol and comparator antimicrobial agents tested against 99 Burkholderia spp. isolates collected from medical centers in the US during 2020 and 2021 Conclusion CFDC demonstrated potent in vitro activity against Achromobacter spp. and Burkholderia spp. collected in the US between 2020 and 2021, indicating that CFDC has high potential for treating infections caused by these pathogens. Disclosures Miki Takemura, n/a, Shionogi: Employee Dee Shortridge, PhD, AbbVie: Grant/Research Support|JMI Laboratory: Employee|Melinta: Grant/Research Support|Menarini: Grant/Research Support|Shionogi: Grant/Research Support Christine M. Slover, PharmD, Shionogi: Employee Christopher M. Longshaw, PhD, Shionogi: Employee Roger Echols, MD, Shionogi: Advisor/Consultant Roger Echols, MD, Shionogi: Advisor/Consultant Roger Echols, MD, Shionogi: Advisor/Consultant Yoshinori Yamano, PhD, Shionogi: Employee.

Background Beta-lactam resistance is a major worldwide concern. Metallo-β-lactamases (MBLs) are a group of enzymes that can inactivate most commonly used β-lactam antibiotics including carbapenems and are not affected by new β-lactamase inhibitors. Therefore, treating infections caused by MBL producing strains is difficult. Imipenemase (IMP) type MBL is a rare family of acquired carbapenemases detected from Enterobacterales globally, however, it has been detected and become a major therapeutic concern in clinical settings mainly in East Asia including Japan [1]. Cefiderocol (CFDC) is a novel injectable siderophore cephalosporin antibiotic with potent activity against a wide variety of carbapenem resistant strains including both serine- and metallo-type carbapenemase-producers. We evaluated in vitro activity of CFDC and comparator agents against IMP-producing Enterobacterales isolated in Japan. Methods A total of 150 IMP-producing strains consisting of 48 Escherichia coli, 34 Klebsiella pneumoniae, 29 Klebsiella oxytoca, 21 Enterobacter cloacae, 7 Citrobacter freundii, 7 Serratia marcescens, 2 Providencia rettgeri, 1 Klebsiella aerogenes, and 1 Morganella morganii were tested. The minimum inhibitory concentrations (MICs) were determined for CFDC, ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C/T), imipenem-relebactam (I-R), meropenem (MEM), and amikacin (AMK) by broth microdilution according to CLSI guidelines. CFDC was tested in iron-depleted cation-adjusted Mueller-Hinton broth. Results MIC50 and MIC90 of CFDC were 0.25 and 1 µg/mL, respectively. MICs of CFDC for all tested strains ranged from ≤ 0.03 to 4 µg/mL, which showed all strains were susceptible to CFDC based on the CLSI breakpoint (≤ 4 µg/mL). On the other hand, MIC90s of CZA, C/T, I-R, MEM, and AMK were > 32/4, > 32/4, 8/4, > 32, and 4 µg/mL, respectively. The susceptibilities were 98.0% for AMK, 66.0% for I-R, and < 10% for CZA, C/T and MEM. Conclusion CFDC had potent in vitro activity against IMP-producing Enterobacterales collected from Japan, indicating CFDC has high potential for treating infections caused by these difficult-to-treat strains. Reference: 1. Logan, LK. et al., J Infect Dis. 2017 Feb 15;215(suppl 1):S28-S36. Disclosures Hidenori Yamashiro, Shionogi & Co., Ltd.: Employee Ryuichiro Nakai, n/a, Shionogi TechnoAdvance Research CO., LTD.: Employee Miki Takemura, n/a, Shionogi: Employee Yoshinori Yamano, PhD, Shionogi: Employee.

Background Acinetobacter baumannii continues to challenge clinicians as multi-drug resistance limits therapeutic options. CFDC possesses potent in vitro and in vivo activity however combination therapy has been recommended for A. baumannii due to its propensity for multiple resistance mechanisms. The present study utilized clinically relevant exposures of CFDC (2 g IV q8h 3 h infusion) in combination with CZA (2.5 g IV q8h 2 h infusion) or MEM (2 g IV q8h 3h infusion) to evaluate the bactericidal activity and resistance prevention. Methods 15 clinical A. baumannii with the following FDC MICs were assessed: 2 mg/L, n = 3; 8 mg/L, n = 2; ≥ 32 mg/L, n = 10). CZA MICs ranged from 16 - >64 mg/L while MEM MICs ranged from 4 - >64 mg/L. Groups of 6 mice received sham control, CFDC HSR, CFDC + CZA HSR, or CFDC + MEM HSR for 72 h. 1 thigh per mouse was harvested to elucidated bacterial burden at 0 h (baseline) and at 72 h (or when the animal succumbed to infection). Efficacy of the combinations was assessed as change in log10 CFU/thigh relative to CFDC HSR. Development of resistance was defined as > 4 fold increase in MIC relative to that from control animals. Results Untreated controls resulted in robust growth (3.48±0.67). Against isolates with CFDC MICs of 2 mg/L, 2/3 reached 1-log10 kill with CFDC HSR relative to baseline compared with 1/2 and 0/10 isolates with FDC MICs of 8 mg/L and ≥ 32 mg/L, respectively. Against all 15 isolates, CFDC + CZA HSR produced significant kill with a mean -4.77±1.93 reduction in log10 CFU/thigh relative to CFDC treated mice (15/15 ≥1-log10 kill relative to baseline). Similarly, CFDC + MEM HSR produced a mean reduction of -4.13±2.50 relative to CFDC treated mice (12/15 ≥1-log10 kill relative to baseline). Elevated MICs in CFDC treated animals occurred in 3/3 isolates with baseline MICs of 2 mg/L. Of these isolates, 1 developed elevated MICs with CFDC + CZA HSR compared with no isolates with CFDC + MEM HSR. Figure 1. Change in log10 CFU/thigh relative to 0 h control after treatment with cefiderocol HSR, cefiderocol + ceftazidime/avibactam HSR, or cefiderocol + meropenem HSR in the 72 h murine thigh infection model. Cefiderocol MICs are displayed in parentheses. Conclusion The present study using clinical exposures of CFDC, CZA, and MEM suggest the enhanced microbiologic activity of these combinations relative to CFDC alone. Combinations also prevented the development of elevated MICs against 2/3 and 3/3 susceptible isolates with CFDC + CZA and CFDC + MEM, respectively. These data support the clinical evaluation of such combinations against A. baumannii with high CFDC MICs. Disclosures Christian M. Gill, PharmD, Shionogi: Grant/Research Support Miki Takemura, n/a, Shionogi: Employee Christopher M. Longshaw, PhD, Shionogi: Employee Yoshinori Yamano, PhD, Shionogi: Employee Roger Echols, MD, Shionogi: Advisor/Consultant Roger Echols, MD, Shionogi: Advisor/Consultant Roger Echols, MD, Shionogi: Advisor/Consultant David P. Nicolau, PharmD, Shionogi: Grant/Research Support.

Stenotrophomonas maltophilia is an important cause of pneumonia in immunocompromised patients. Cefiderocol is a parenteral siderophore cephalosporin with potent in vitro activity against S. maltophilia .

Modern medicine is threatened by the rising tide of antimicrobial resistance, especially among Gram-negative bacteria, where resistance to β-lactams is most often mediated by β-lactamases. The penicillin and cephalosporin ascendancies were, in their turn, ended by the proliferation of TEM penicillinases and CTX-M extended-spectrum β-lactamases. These class A β-lactamases have long been considered the most important. For carbapenems, however, the threat is increasingly from the insidious rise of a class D carbapenemase, OXA-48, and its close relatives. Over the past 20 years, OXA-48 and “OXA-48-like” enzymes have proliferated to become the most prevalent enterobacterial carbapenemases across much of Europe, Northern Africa, and the Middle East. OXA-48-like enzymes are notoriously difficult to detect because they often cause only low-level in vitro resistance to carbapenems, meaning that the true burden is likely underestimated. Despite this, they are associated with carbapenem treatment failures. A highly conserved incompatibility complex IncL plasmid scaffold often carries bla(OXA-48) and may carry other antimicrobial resistance genes, leaving limited treatment options. High conjugation efficiency means that this plasmid is sometimes carried by multiple Enterobacterales in a single patient. Producers evade most β-lactam–β-lactamase inhibitor combinations, though promising agents have recently been licensed, notably ceftazidime-avibactam and cefiderocol. The molecular machinery enabling global spread, current treatment options, and the development pipeline of potential new therapies for Enterobacterales that produce OXA-48-like β-lactamases form the focus of this review.

Objectives This study evaluated the sustained kill and potential for resistance development of Acinetobacter baumannii exposed to human-simulated exposure of cefiderocol over 72 h in in vitro and in vivo infection models. Methods Seven A. baumannii isolates with cefiderocol MICs of 0.12–2 mg/L were tested. The sustained bactericidal activity compared with the initial inoculum and the resistance appearance over 72 h treatment were evaluated in both an in vitro chemostat and an in vivo murine thigh infection model under the human-simulated exposure of cefiderocol (2 g every 8 h as 3 h infusion). Results In the in vitro model, regrowth was observed against all seven tested isolates and resistance emergence (>2 dilution MIC increase) was observed in five test isolates. Conversely, sustained killing over 72 h and no resistance emergence were observed in six of seven tested isolates in vivo. The mechanism of one resistant isolate that appeared only in the in vitro chemostat studies was a mutation in the tonB-exbB-exbD region, which contributes to the energy transduction on the iron transporters. The resistance acquisition mechanisms of other isolates have not been identified. Conclusions The discrepancy in the sustained efficacy and resistance emergence between in vitro and in vivo models was observed for A. baumannii. Although the resistance mechanisms in vitro have not been fully identified, sustained efficacy without resistance emergence was observed in vivo for six of seven isolates. These studies reveal the in vivo bactericidal activity and the low potential for development of resistance among A. baumannii evaluated under human-simulated exposures.

We report in vitro susceptibility data from five consecutive annual SIDERO-WT surveillance studies (2014-2019) 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 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 99.6-100%/year; Europe, range 99.3-99.9%/year) and P. aeruginosa (99.8-100%; 99.9-100%) were unchanged from 2014 to 2019. Annual percent susceptible rates for A. baumannii complex demonstrated sporadic, non-directional differences (97.5-100%; 90.4-97.5%); the wider range for Europe (∼7%) was due to isolates from Russia. Annual percent susceptible rates for S. maltophilia showed minor, non-directional differences (96.4-100%; 95.6-100%). 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.

The objective of this study was to characterize isolates with reduced susceptibility to cefiderocol in patients receiving cefiderocol for nosocomial pneumonia or carbapenem-resistant infections in the Phase 3 APEKS-NP and CREDIBLE-CR studies. Susceptibility testing of isolates was conducted at a central laboratory, and post-treatment changes were evaluated according to available breakpoints for cefiderocol. Whole-genome sequencing and multilocus sequence typing were performed for isolates to confirm their origin and identify mutations. Five (APEKS-NP) and nine (CREDIBLE-CR) isolates demonstrated a ≥ 4-fold minimum inhibitory concentration (MIC) increase compared with genetically related baseline isolates; most remained susceptible to cefiderocol despite the ≥4-fold MIC increase. Mutations in β-lactamases or penicillin-binding protein (PBP) were identified in 4/14 isolates: one

Objectives The reproducibility of cefiderocol MIC determination using broth microdilution (BMD) in iron-depleted CAMHB (ID-CAMHB) was investigated, and the EUCAST disc diffusion (DD) method for cefiderocol susceptibility testing was developed and validated against reference BMD. Methods Cefiderocol values were determined for wild-type (WT) and non-WT isolates using BMD plates with ID-CAMHB (Thermo Scientific, Oakwood, USA) per EUCAST guidelines. DD was performed using standard EUCAST methodology on unsupplemented Mueller–Hinton agar with cefiderocol 30 μg discs. Control agents were included in all tests. MICs were correlated with zone diameters (ZD), and ZD breakpoints (BP) best corresponding to the MIC BPs were determined. Areas of technical uncertainty (ATU) were included where appropriate. External laboratory validation of cefiderocol DD was performed per the EUCAST SOP 9.2. Results MIC and ZD distributions for cefiderocol against WT isolates were established. Cefiderocol ZD BPs were set at susceptible ≥22 mm, resistant Conclusions DD is a robust and easy-to-perform method for cefiderocol susceptibility testing. For isolates with results in the ATU, an MIC test should be performed to confirm the results.

This study evaluated the sustained kill and potential for resistance development ofSevenIn theThe discrepancy in the sustained efficacy and resistance emergence between

The β-site amyloid precursor protein cleaving enzyme 1 (BACE1, also known as β-secretase) is a promising target for the treatment of Alzheimer's disease. A pKa lowering approach over the initial leads was adopted to mitigate hERG inhibition and P-gp efflux, leading to the design of 6-CF3 dihydrothiazine 8 (N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-5-cyanopicolinamide). Optimization of 8 led to the discovery of 15 (N-(3-((4S,6S)-2-amino-4-methyl-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-thiazin-4-yl)-4-fluorophenyl)-5-(fluoromethoxy)pyrazine-2-carboxamide) with an excellent balance of potency, hERG inhibition, P-gp efflux, and metabolic stability. Oral administration of 8 elicited robust Aβ reduction in dog even at 0.16 mg/kg. Reflecting the reduced hERG inhibitory activity, no QTc prolongation was observed at high doses. The potential for reactive metabolite formation of 15 was realized in a nucleophile trapping assay using [14 C]-KCN in human liver microsomes. Utilizing covalent binding (CVB) in human hepatocytes and the maximum projected human dosage, the daily CVB burden of 15 was calculated to be at an acceptable value of below 1 mg/day. However, hepatotoxicity was observed when 15 was subjected to a two-week tolerance study in dog, which prevented further evaluation of this compound.

In 2017, the Clinical and Laboratory Standards Institute (CLSI) Subcommittee on Antimicrobial Susceptibility Testing approved the use of iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB) prepared with Chelex® 100 resin (Bio-Rad Laboratories, Hercules, CA) to determine MICs for cefiderocol. The current study examined the reproducibility of cefiderocol MICs generated for 19 clinical isolates of Gram-negative bacilli, with CAMHB produced by three manufacturers; each of the 19 isolates was tested for 10 replicates in ID-CAMHB from each manufacturer. When analyzed by individual media lot, greater than 95% of MIC results were within ± one doubling-dilution of the mode for each of the 19 isolates tested. The remaining 5.0% of MIC results were within ± two doubling-dilutions of the modal MIC. For all media lots combined, 92.2% of MIC results were within ± one doubling-dilution of the modal MIC for each isolate, 99.8% were within ± two doubling-dilutions and 100% were within three doubling-dilutions.

Cefiderocol (S-649266) is a parenteral siderophore cephalosporin in phase III of clinical development. In this study, we determined the in vitro susceptibility to cefiderocol and comparators of a 2015-2016 collection of 8954 clinical isolates of Gram-negative bacilli (GNB), provided by 100 clinical laboratories in North America and Europe, using the Clinical and Laboratory Standards Institute broth microdilution method. Iron-depleted cation-adjusted Mueller-Hinton broth was used to test cefiderocol. The concentration of cefiderocol inhibiting 90% of isolates (MIC90) was 0.5 mg/L (North America; n=2470) and 1 mg/L (Europe; n=3,543) for Enterobacteriaceae, 0.5 mg/L (North America; n=619) and 0.5 mg/L (Europe; n=921) for Pseudomonas aeruginosa, 1 mg/L (North America; n=308) and 2 mg/L (Europe; n=664) for Acinetobacter spp., 0.5 mg/L (North America; n=165) and 0.25 mg/L (Europe; n=175) for Stenotrophomonas maltophilia, and 0.12 mg/L (North America; n=40) and 0.5 mg/L (Europe; n=49) for Burkholderia cepacia complex spp. Cefiderocol MICs were ≤4 mg/L for 99.9% (6005/6013) of Enterobacteriaceae, 99.9% (1539/1540) of P. aeruginosa, 96.4% (937/972) of Acinetobacter spp., 99.4% (338/340) of S. maltophilia, and 94.4% (84/89) of Burkholderia cepacia complex spp. isolates tested. Against meropenem-non-susceptible isolates, MICs to cefiderocol were ≤4 mg/L for 99.6% (245/246) of Enterobacteriaceae, 99.7% (394/395) of P. aeruginosa, 96.1% (540/562) of Acinetobacter spp., and 87.1% (27/31) of B. cepacia complex spp. We conclude that cefiderocol demonstrated potent in vitro activity (MIC ≤4 mg/L) against the majority (99.4%, 8903/8954) of clinical isolates of GNB in a recent (2015-2016), multi-continent collection, including carbapenem-non-susceptible isolates.

Background Achromobacter spp. is intrinsically resistant to multiple antibiotics, and the treatment options are limited. Cefiderocol (CFDC), a siderophore cephalosporin approved in US and EU, is active against a wide variety of aerobic Gram-negative bacteria, including carbapenem-resistant strains. In this study, in vitro and in vivo antibacterial activity of CFDC against Achromobacter spp. was evaluated. Methods A total of 334 global isolates collected by IHMA from 39 countries in 2015-2019 were used. Minimum inhibitory concentrations (MICs) of CFDC and comparators were determined by broth microdilution method using iron-depleted CAMHB or CAMHB, respectively, as recommended by CLSI guidelines. In vivo efficacy of CFDC was compared with meropenem (MEM), piperacillin-tazobactam (PIP/TAZ), ceftazidime (CAZ), and ciprofloxacin (CIP) in a neutropenic murine lung infection model (n=5), and compared with MEM in a immunocompetent rat lung infection model (n=3-7) caused by 2 A. xylosoxydans. In the murine model, treatment was given 2, 5, and 8 hours post-infection, and the numbers of viable cfu in lungs were determined 24 hours post-infection. In the rat model, the humanized PK in plasma resulting from CFDC 2 g every 8 h (3-h infusion) or meropenem 1 g every 8 h (0.5-h infusion) were recreated via continuous intravenous infusion for 4 days, following which cfu in lungs were determined. Results CFDC showed in vitro activity with MIC50/90 of 0.06/0.5 µg/mL against 334 Achromobacter spp. Only 7 isolates (2.1%) had MICs > 4 µg/mL. These were the lowest values among all compound tested (Table). In the murine model, CFDC caused > 1.5 log10 decrease of viable cfu in lungs at 100 mg/kg dose (%fT >MIC: < 50%) from baseline control against both of strains (CFDC MIC: 0.5 and 2 µg/mL) (P< 0.05). No decrease of cfu in lungs was observed for the comparators at 100 mg/kg (MEM, PIP/TAZ, CAZ, and CIP MICs were >16, >64, >32, and >8 µg/mL, respectively). In the rat model, humanized CFDC dosing reduced the viable cfu by >1 log10 CFU/lung compared with baseline controls (P< 0.05). MEM showed no significant activity. In vitro activity of CFDC and comparator agents against Achromobacter spp. 334 Achromobacter spp. isolates collected from 2015 and 2019. The majority of isolates tested were A. xylosoxidans (312/334; 93.4%), followed by A. insolitus (11/334; 3.3%), Achromobacter sp. (8/334; 2.4%), A. denitrificans (2/334; 0.6%), and A. piechaudii (1/334; 0.3%). Conclusion CFDC showed potent in vivo efficacy reflecting in vitro activity against A. xylosoxidans. The results suggested that CFDC has the potential to be an effective therapeutic option for Achromobacter spp. infections. Disclosures Ryuichiro Nakai, MSc, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Ayaka makino, BSc, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Toriko Yoshitomi, -, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Rio Nakamura, BSc, Shionogi TechnoAdvance Research & Co., Ltd. (Employee) Meredith Hackel, PhD MPH, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Miki Takemura, MS, SHIONOGI & CO., LTD. (Employee) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Yoshinori Yamano, PhD, Shionogi (Employee)

Background Cefiderocol (CFDC), a siderophore cephalosporin, has broad coverage of Gram-negative bacteria and has been approved for clinical use in USA and Europe. The SIDERO-WT surveillance studies showed that CFDC shows >95% susceptibility against Acinetobacter baumannii. Against many of CFDC non-susceptible isolates, most of which had blaPER gene, the combination use of avibactam significantly decreased the MIC by broth microdilution (BMD). In this study, we evaluated the appropriate methodology to evaluate the synergistic effect by disk diffusion studies. Methods The susceptibility testing was conducted as recommended by the CLSI using CFDC non-susceptible isolates (MIC of >4 µg/mL based on CLSI breakpoint). The MIC by BMD was determined using iron-depleted cation-adjusted Mueller-Hinton broth, in the presence or absence of 4 µg/mL of avibactam. The disk diffusion was evaluated using Mueller-Hinton agar, and the synergy was evaluated by using disk stacking methods. For disk stacking methods, CFDC disk was placed on agar on which bacterial suspension of 0.5 McFarland units was spread, then the ceftazidime-avibactam (CZA) disks was stacked on the top, followed by adding a drop (30 µL) of saline on the stacked disks. As an alternative method, CZA was immersed in saline for 1 second instead of adding a drop of saline, followed by the stacking on the top. The disk zone size was determined after 24-hour incubation at 37°C. Results Against blaPER-positive A. baumannii which showed >64 µg/mL MIC of CFDC and CZA, CFDC MIC decreased to 0.25 µg/mL in the presence of avibactam. The disk diffusion methods also showed isolates resistant to CFDC and CZA and showed susceptiblilty disk zone to CFDC by stacking both disks. On the other hand, against blaNDM-positive A. baumannii which showed 64 µg/mL MIC of CFDC and CZA, the disk diffusion methods showed resistance even when stacking both disks. Against multiple isolates, the MIC of CFDC without or with avibactam was correlated well with the disk zone produced by CFDC disk alone or stacked with CZA disks, respectively (Figure). Conclusion The synergistic effect between CFDC and avibactam by BMD methods could be detected by disk stacking methodology using CFDC and CZA disks. Disclosures Yoshinori Yamano, PhD, Shionogi (Employee) Miki Takemura, MS, SHIONOGI & CO., LTD. (Employee) Roger Echols, MD, Shionogi (Consultant) Christopher Longshaw, PhD, Shionogi (Employee)

Objectives The present study evaluated the sustained kill and the potential for resistance development of Stenotrophomonas maltophilia exposed to a human-simulated exposure of cefiderocol over 72 h in in vitro and in vivo infection models. Methods A total of seven S. maltophilia isolates with cefiderocol MICs of 0.03–0.5 mg/L were utilized. The sustained bactericidal activity compared with the initial inoculum and the appearance of resistance after the 72 h treatment were evaluated in both an in vitro chemostat model (four strains) and an in vivo murine thigh infection model (six strains) under the human-simulated exposure of cefiderocol (2 g every 8 h as a 3 h infusion). Results In the in vitro model, regrowth was observed for three of four tested isolates and resistance emergence (>2-dilution MIC increase) was observed for all of the four test isolates. Conversely, sustained killing over 72 h and no resistance emergence were observed for all of the six tested isolates in the in vivo models. The mechanism of all resistant isolates that appeared only in the in vitro chemostat studies was a mutation in the tonB-exbB-exbD region, which contributes to the energy transduction on the iron transporters. Conclusions The discrepancy in the sustained efficacy and resistance emergence between in vivo and in vitro models appears to be due to the resistance acquisition mechanism caused by mutation in the tonB-exbB-exbD region developing in the enriched media utilized in vitro. These studies reveal the in vivo bactericidal activity and the low potential for development of resistance among Stenotrophomonas evaluated under human-simulated exposures.

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 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 body weight 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 h) and meropenem (1 g every 8 h) 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 empirical antibiotics, such as trimethoprim-sulfamethoxazole or minocycline.

Activities of cefiderocol under simulated human plasma concentrations at the recommended dosing regimen of 2 g every 8 h with a 3-h infusion were evaluated using an in vitro chemostat model. Against a total of 6 meropenem-resistant Gram-negative strains with cefiderocol MICs of 0.5 to 4 μg/ml, including metallo-β-lactamase producers and carbapenem-resistant Acinetobacter baumannii, cefiderocol treatment showed a bactericidal effect within 8 h and sustained efficacy with no marked bacterial regrowth over 24 h.

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.

Objective To investigate possible mechanistic factors to explain cefiderocol (CFDC) non-susceptibility, we characterized 38 clinical isolates with a CFDC minimum inhibitory concentration (MIC) of >4 μg/mL from a multi-national surveillance study. Methods The MIC measurement in the presence of β-lactamase inhibitors and whole genome sequencing were performed. Results The MIC decrease of CFDC by β-lactamase inhibitors was observed against all of the test isolates. Among the 38 isolates, NDM and PER genes were observed in 5 and 25 isolates, respectively. No other β-lactamases responsible for high MIC were identified in the other eight isolates. The MIC of CDFC against Escherichia coli isogenic strains introduced with NDM and PER β-lactamase increased by ≥16-fold, suggesting the contribution of NDM and PER to the non-susceptibility to CFDC. Against NDM producers, a ≥8-fold MIC increase was observed only when both serine- and metallo-type β-lactamase inhibitors were added. In addition, many of the PER or NDM producers remained susceptible to CFDC. These results suggested that the presence of only NDM or PER would not lead to non-susceptibility to CFDC and that multiple factors would be related to CFDC resistance. Conclusion Multiple factors including NDM and PER could be related to reduced susceptibility to CFDC.

OBJECTIVES We assessed the activity of the novel siderophore cephalosporin, cefiderocol and selected other antibacterial agents against Gram-negative bacterial isolates in Europe. METHODS Isolates were obtained between 2013 and 2018 from European countries participating in the SIDERO-WT and SIDERO-Proteeae multinational surveillance studies. Isolates were categorised by infection site, focusing on bloodstream infections, hospital-acquired/ventilator-associated bacterial pneumonia (HABP/VABP), complicated intra-abdominal infections and complicated urinary tract infections. Cefiderocol activity was compared with ceftazidime-avibactam, ceftolozane-tazobactam, colistin and meropenem using standard susceptibility testing methods. European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints were used to interpret susceptibility data. RESULTS Isolates (n = 20 911) were collected from 145 sites in 24 countries in Europe, the highest proportion (34%) being from patients with HABP/VABP. Enterobacterales (66.6% of isolates) were more frequent than glucose non-fermenting species (33.4%) overall, with some differences between infection sites. Across all infection sites, the MIC50/MIC90 for cefiderocol was ≤0.5/≤2 mg/L for Enterobacter spp., ≤0.25/

Objectives The siderophore cephalosporin cefiderocol possesses in vitro activity against MDR Gram-negative bacteria. The stability of cefiderocol against serine- and metallo-type carbapenemases has been reported previously, but little is known about how cefiderocol interacts with chromosomal AmpC β-lactamases. We investigated a number of features of cefiderocol, namely antibacterial activity against AmpC overproducers, stability against AmpC β-lactamases and propensity for AmpC induction using Pseudomonas aeruginosa and Enterobacter cloacae. Methods MICs were determined by broth microdilution according to CLSI guidelines. The MIC of cefiderocol was determined in iron-depleted CAMHB. Hydrolysis of the antibiotics was determined by monitoring the changes in the absorbance in the presence of AmpC β-lactamase, and AmpC induction was evaluated by double disc diffusion and nitrocefin degradation assays. Results The MICs of ceftazidime and cefepime for PAO1 increased 4- to 16-fold with inactivation of either ampD or dacB, whereas cefiderocol MICs were little affected by these inactivations (

β-Secretase (BACE1) has an essential role in the production of amyloid β peptides that accumulate in patients with Alzheimer's disease (AD). Thus, inhibition of BACE1 is considered to be a disease-modifying approach for the treatment of AD. Our hit-to-lead efforts led to a cellular potent 1,3-dihydro-oxazine 6, which however inhibited hERG and showed high P-gp efflux. The close analogue of 5-fluoro-oxazine 8 reduced P-gp efflux; further introduction of electron withdrawing groups at the 6-position improved potency and also mitigated P-gp efflux and hERG inhibition. Changing to a pyrazine followed by optimization of substituents on both the oxazine and the pyrazine culminated in 24 with robust Aβ reduction in vivo at low doses as well as reduced CYP2D6 inhibition. On the basis of the X-ray analysis and the QM calculation of given dihydro-oxazines, we reasoned that the substituents at the 6-position as well as the 5-fluorine on the oxazine would stabilize a bioactive conformation to increase potency.

Background Cefiderocol (CFDC) has been developed for the treatment of serious infections caused by drug-resistant aerobic Gram-negative pathogens, including carbapenem-resistant (CR) Pseudomonas aeruginosa (CRPA). The current CFDC susceptibility breakpoints for P. aeruginosa differ between US Food and Drug Administration (FDA) and Clinical and Laboratory Standards Institute (CLSI) (Table). Data characterizing the impact of CFDC minimum inhibitory concentrations (MICs) on the clinical responses of patients treated with CFDC for CRPA are sparse. Methods We reviewed patients treated with compassionate-use CFDC (2 g, q8h or renally adjusted dosages) for infections caused by CRPA with no alternative treatment options. CFDC minimum inhibitory concentrations (MICs) were evaluated according to CLSI guidelines in iron-depleted cation-adjusted Müller–Hinton broth for available CRPA isolates. We then assessed physician-reported clinical responses to CFDC therapy and stratified results by CFDC MIC. Results There were 71 patients overall with CRPA treated with CFDC. Treatment duration ranged from 1 to 132 days. For the subset of 33 patients for whom CFDC MIC values were available, the most common infection sites were the respiratory tract (n=15), blood (n=12), and urinary tract (n=4). Patients could have had an infection at ≥1 sites and in other locations. CFDC MIC range was ≤0.03– >64 µg/mL. The modal MIC value was 2 µg/mL (n=13; Table). CRPA isolates were susceptible to CFDC in 13/33 patients (39.4%) based on the FDA breakpoint (MIC ≤1 µg/mL) and in 31/33 patients (93.9%) based on the CLSI breakpoint (MIC ≤4 µg/mL). Clinical response was reported for 15/18 patients (83.3%) who had infections with CFDC MICs of 2–4 µg/mL, organisms that are considered susceptible by CLSI but not by FDA breakpoints (Table). Clinical response was reported in 6/13 patients (46.1%) with infections with CFDC MIC ≤1 µg/mL and in 1 of 2 patients (50.0%) with CFDC MIC ≥8 µg/mL (Table). 21 (63.6%) patients survived to Day 28 and there were no trends in mortality by CFDC MIC. Conclusion Clinical response rate was high for CRPA infections with CFDC MICs of 2–4 µg/mL, supporting the higher CLSI susceptibility breakpoint. Disclosures Michael J. Satlin, MD, MS, Achaogen (Consultant)Allergan (Research Grant or Support)BioFire Diagnostics (Research Grant or Support)Merck (Research Grant or Support)Shionogi (Consultant) David Fam, PharmD, Shionogi (Employee) Roger Echols, MD, Shionogi (Consultant) Christopher Longshaw, PhD, Shionogi (Employee) Miki Takemura, MS, SHIONOGI & CO., LTD. (Employee) Yoshinori Yamano, PhD, Shionogi (Employee)

Background Multidrug-resistant (MDR) phenotypes are frequently observed among P. aeruginosa (PsA) isolated from hospitalized patients. This study describes the in vitro activities of cefiderocol (CFDC) and comparator agents against various non-susceptible (NS) phenotypic subsets of MDR PsA isolates from the SIDERO-WT multi-national surveillance program. Methods Clinical PsA isolates were collected from North America (NA) and Europe in 2014-2019 and tested for susceptibility at a central laboratory. MICs (μg/ml) were determined for CFDC, ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C/T), colistin, cefepime, meropenem (MEM), and ciprofloxacin by broth microdilution according to CLSI guidelines. Aztreonam-avibactam (avibactam fixed concentration of 4 µg/ml) and imipenem/relebactam (I/R) were only tested during SIDERO-WT Year 5 (i.e. 2019). Susceptibility was interpreted according to current FDA and 2021 CLSI breakpoints. Results The different phenotypic subsets and susceptibility of tested compounds are shown in the table. Among 7700 PsA isolates, 47.7% and 23% were from respiratory and gastrointestinal sources of infection. CFDC inhibited 97.5% and 99.9% of all PsA at its FDA-S and CLSI-S MIC breakpoint of ≤1 and ≤4, respectively. CFDC had the lowest MIC90 of all tested agents and >99% S at an MIC ≤4 for all phenotypic subsets. At a MIC ≤1, CFDC displayed high susceptibility rates against all subsets including ≥88% S against CZA-NS, C/T-NS, I/R-NS, and MEM+I/R-NS isolates. Against MDR subsets, comparator agents consistently demonstrated lower activity than CFDC; 88% of MEM+C/T-NS and MEM+CZA-NS isolates had a CFDC MIC≤1 while 15.6% and 20.3% were S to I/R, respectively. 86% of MEM+CZA+C/T-NS and 80.4% CZA+C/T+I/R-NS isolates were S to CFDC. CFDC inhibited 98.1% and 99.4% of PsA isolates from NA (n = 3548) at a MIC of ≤1 and ≤4, respectively. In NA isolates that were MEM+C/T-NS; 85.7% of PsA isolates had a MIC ≤1 to CFDC and 33.3% and 28.6% were S to CZA and I/R, respectively. MEM: Meropenem; NS: Non-susceptible; CZA: Ceftazidime/avibactam; C/T: Ceftolozane/tazobactam; I/R: Imipenem/relebactam Conclusion CFDC demonstrated potent in vitro activity against a variety of phenotypic subsets of MDR P. aeruginosa isolates as compared to agents that are commonly used to treat MDR PsA infections including strains NS to other agents. These data support the use of CFDC as an important treatment option for MDR PsA. Disclosures Sean Nguyen, PharmD, Shionogi Inc (Employee) David Fam, PharmD, Shionogi (Employee) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Meredith Hackel, PhD MPH, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Roger Echols, MD, Shionogi (Consultant) Yoshinori Yamano, PhD, Shionogi (Employee)

Background Cefiderocol (CFDC) is a novel siderophore cephalosporin with efficacy against Gram-negative (GN) bacteria, including carbapenem-resistant Enterobacterales and non-glucose-fermenters such as Pseudomonas aeruginosa and Acinetobacter baumannii. In consecutive multinational surveillance (SIDERO-WT) studies (2014–2017), CFDC demonstrated activity with minimum inhibitory concentrations (MICs) of ≤4 mg/mL against 99.4% of 28,629 GN clinical isolates. We conducted molecular characterization of 161 isolates with CFDC MICs >4 mg/mL from the SIDERO-WT studies. Methods A total of 161 isolates underwent whole genome sequencing by Illumina Hiseq. Analyses were done using the CLC genomics workbench (Qiagen) for possible resistance-related genes (e.g. β-lactamases, porin channels or penicillin-binding protein genes) and some TonB-dependent siderophore uptake receptor genes (fiu, cir, piu, pir). Fiu and Cir in Escherichia coli and Piu in P. aeruginosa are the iron transporters involved in CFDC transport. Results Of 161 isolates with CFDC MIC >4 mg/mL, 128 were A. baumannii, 22 Enterobacterales, 7 Burkholderia multivorans, 2 P. aeruginosa, and 2 Stenotrophomonas maltophilia. Genes encoding PER/VEB extended-spectrum β-lactamases and NDM-type metallo-β-lactamases were detected in some isolates, but other β-lactamase genes (bla) were not shown to be linked to high CFDC MICs. blaPER/blaVEB were found only in A. baumannii and blaNDM was found in A. baumannii and Klebsiella pneumoniae. In 128 A. baumannii isolates, 103 harbored PER or VEB, including PER positive isolates from Russia (n=87) and Turkey (n=6) and 4 VEB positive isolates from USA. Nine NDM-positive isolates (7 K. pneumoniae, 2 A. baumannii) were found. Disruption of iron transport genes was also detected in some isolates, including piuA (11 A. baumannii, 1 P. aeruginosa), pirA (2 A. baumannii), and fiuA (4 B. multivorans, 1 Proteus mirabilis). No cir homologs were found in 2 B. multivorans. Conclusion PER and NDM could reduce susceptibility to CFDC, as such isolates have been seen in some countries. Iron transporter disruption was also observed in some isolates with high CFDC MICs; the contribution of these deficiencies in A. baumannii and B. multivorans requires further study. Disclosures Yoshinori Yamano, PhD, Shionogi & Co., Ltd. (Employee) Miki Takemura, MSc, Shionogi & Co., Ltd. (Employee) Krystyna Kazmierczak, PhD, Shionogi & Co., Ltd. (Independent Contractor) Mark G G. Wise, PhD, Shionogi & Co., Ltd. (Independent Contractor) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Consultant)Shionogi & Co., Ltd. (Independent Contractor) Roger Echols, MD, Shionogi Inc. (Consultant)

Background Metallo-β-lactamases (MBLs; eg, NDM, VIM, and IMP) can inactivate most commonly-used β-lactam antibiotics, including carbapenems. Infections caused by MBL producers are difficult to treat due to their resistance to many antibiotics. Cefiderocol (CFDC) is a siderophore cephalosporin antibiotic approved in the USA in 2019, with potent activity against carbapenem-resistant Gram-negative bacteria (GNB), including both serine- and metallo-carbapenemase positive strains. We evaluated the in vitro activity of CFDC and comparator agents against MBL-producing strains of GNB from North America and Europe in 3 years’ of consecutive surveillance studies (SIDERO-WT-2014–2016). Methods Susceptibility testing for CFDC, ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C/T), meropenem (MEM), cefepime (FEP), ciprofloxacin (CIP), and colistin (CST) was performed by broth microdilution according to CLSI guidance. CFDC was tested in iron-depleted medium. A total of 275 MBL-producing strains, consisting of 120 Enterobacterales (45 NDM; 75 VIM), 5 NDM-producing Acinetobacter baumannii, and 150 Pseudomonas aeruginosa (134 VIM; 16 IMP), identified among 4985 (654 Enterobacterales and 4331 non-fermenters) MEM non-susceptible (based on CLSI breakpoints) strains were used for the current analysis. Results The minimum inhibitory concentration (MIC) range and MIC90 for CFDC and comparators for each MBL-producing organism group are shown in the Table. Against NDM-producing Enterobacterales, of which 42% and 33% were isolated in Turkey and Russia, respectively, CFDC inhibited the growth of 84% of isolates tested at ≤4 µg/mL. CFDC MIC90 was 4 μg/mL for VIM-producing Enterobacterales (41% and 31% isolated in Greece and Italy, respectively), 1 μg/mL for VIM-producing P. aeruginosa (50% isolated in Russia), and 4 μg/mL for IMP-producing P. aeruginosa (88% isolated in Czech Republic). Other comparators (except for CST) were not active against these MBL producers. Table. MIC range and MIC90 (μg/mL) for CFDC and comparators of MBL-producing organisms Conclusion CFDC inhibited the growth of 100% of MBL-positive GNB at ≤8 mg/mL and showed MIC90 of 4 μg/mL against all 275 MBL producers, indicating that CFDC has high potential for treating infections caused by these difficult-to-treat strains. Disclosures Miki Takemura, MSc, Shionogi & Co., Ltd. (Employee) Krystyna Kazmierczak, PhD, Shionogi & Co., Ltd. (Independent Contractor) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Consultant)Shionogi & Co., Ltd. (Independent Contractor) Roger Echols, MD, Shionogi Inc. (Consultant) Yoshinori Yamano, PhD, Shionogi & Co., Ltd. (Employee)

Background Non-fermenting Gram-negative bacilli (NFGNB), such as Pseudomonas aeruginosa, Acinetobacter baumannii-complex (ABC), Stenotrophomonas maltophilia, and Burkholderia cepacia-complex (BCC), are recognized as difficult-to-treat organisms due to acquired and intrinsic antimicrobial resistance. This study evaluated the in vitro activity of cefiderocol (CFDC), a novel parenteral siderophore cephalosporin, and comparator agents against NFGNB clinical isolates collected in 2014–2018 as part of the multinational SIDERO-WT surveillance program. Methods 12,293 non-fermenter clinical isolates, including 5310 from North America and 6983 from Europe, were tested for antimicrobial susceptibility. Minimum inhibitory concentrations (MICs) were determined for CFDC, cefepime (FEP), ceftazidime-avibactam (CZA), ceftolozane-tazobactam (C/T), meropenem-vaborbactam (MVB), meropenem (MEM), ciprofloxacin (CIP), colistin (CST), and trimethoprim-sulfamethoxazole (SXT) by broth microdilution according to Clinical Laboratory and Standards Institute (CLSI) guidelines. MICs for aztreonam-avibactam (ATM/AVI; ATM in the presence of 4 μg/mL AVI), MVB, and SXT were determined only for SIDERO-WT 2018 strains. As per CLSI guidelines, CFDC was tested in iron-depleted media, and carbapenem-non-susceptible (CarbNS) isolates were defined as non-susceptible to MEM. Results CFDC demonstrated in vitro activity with MIC90s of 0.25–2 µg/mL against clinical isolates of P. aeruginosa, ABC, S. maltophilia, and BCC, including CarbNS subsets. MIC90s of CFDC against CarbNS P. aeruginosa (N=1416), CarbNS ABC (N=2274), S. maltophilia (N=1565), and CarbNS BCC (N=80) were 1, 2, 0.5, and 2 μg/mL, respectively, which were the lowest among the tested compounds (Table). The MIC90 differences between all isolates and CarbNS subsets were ≤2-fold for P. aeruginosa and ABC, showing that CFDC is active against CarbNS subsets as well as carbapenem-susceptible isolates. However, an 8-fold MIC90 difference between all isolates and CarbNS subsets was observed for BCC. Conclusion In 4 years of consecutive multinational surveillance studies, CFDC was the most active agent among antimicrobials tested against a wide range of NFGNB, including CarbNS strains. Disclosures Yuuta Ukai, MSc, Shionogi & Co., Ltd. (Employee) Rio Nakamura, BSc, Shionogi & Co., Ltd. (Employee) Merime Oota, BSc, Shionogi & Co., Ltd. (Employee) Roger Echols, MD, Shionogi Inc. (Consultant) Miki Takemura, MSc, Shionogi & Co., Ltd. (Employee) Yoshinori Yamano, PhD, Shionogi & Co., Ltd. (Employee) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Consultant)Shionogi & Co., Ltd. (Independent Contractor)

Background Cefiderocol (CFDC) is a novel siderophore cephalosporin developed to treat serious carbapenem-resistant (CR) Gram-negative (GN) infections. Methods In CREDIBLE-CR (NCT02714595), adults with serious infections caused by CR GN pathogens received CFDC 2 g, q8h, 3-h infusion, or best available therapy (BAT). In APEKS-NP (NCT03032380), adults with nosocomial pneumonia received CFDC or high-dose, extended-infusion meropenem (each 2 g, q8h, 3-h infusion). All treatments were given for 7‒14 days (extendable to 21 days). Biospecimens were collected before the first dose of study drug and at subsequent visits for assessments, and minimum inhibitory concentrations (MIC) to various antibiotics, including CFDC and carbapenems, were determined. Isolates with an increased MIC were evaluated by RT-PCR or whole genome sequencing (WGS) for CFDC resistance-related genes or mutations. Results for genetically related isolates with an elevated MIC during therapy are shown. Results On-therapy ≥4-fold CFDC MIC increase was found in 12 out of 106 (CREDIBLE-CR; Table 1) and 7 out of 159 (APEKS-NP; Table 2) isolates, respectively. For most isolates, CFDC MIC increased by 4–8-fold but remained ≤4 µg/mL. Specific mutations which could explain CFDC MIC increases were found in only 3 isolates. Mutations in iron-transport related genes were not identified. Mutation in CFDC target gene PBP-3 was identified in 1 A. baumannii isolate. Class-C enzyme mutation was observed in 2 isolates (CREDIBLE-CR: PDC-30 in P. aeruginosa; APEKS-NP: ACT-17 in E. cloacae), although the contribution to CFDC MIC increase has not been confirmed. In the BAT arm in CREDIBLE-CR, 6 out of 46 isolates had ≥4-fold MIC increase; all post-treatment isolates were resistant to BAT agents (Table 1), although WGS was not conducted for these isolates. In the meropenem arm in APEKS-NP, 5 out of 164 isolates had ≥4-fold MIC increase (Table 2). Table 1. MIC changes in CREDIBLE-CR Table 2. MIC changes in APEKS-NP Conclusion Among isolates with ≥4-fold MIC increase during CFDC treatment, actual CFDC MIC values remained relatively low for most isolates. Frequency of MIC increase in BAT or meropenem arms was similar to that of CFDC, but the magnitude was greater. Acquisition of contributory mechanism has not been identified except for the mutation in PBP 3 and some β-lactamases. Disclosures Miki Takemura, MSc, Shionogi & Co., Ltd. (Employee) Yoshinori Yamano, PhD, Shionogi & Co., Ltd. (Employee) Yuko Matsunaga, MD, Shionogi Inc. (Employee) Mari Ariyasu, BPharm, Shionogi & Co., Ltd. (Employee) Roger Echols, MD, Shionogi Inc. (Consultant) Tsutae Den Nagata, MD, Shionogi & Co., Ltd. (Employee)

Carbapenem-resistant gram-negative bacteria including Enterobacteriaceae as well as nonfermenters, such as Pseudomonas aeruginosa and Acinetobacter baumannii, have emerged as significant global clinical threats. Although new agents have recently been approved, none are active across the entire range of resistance mechanisms presented by carbapenem-resistant gram-negative bacteria. Cefiderocol, a novel siderophore cephalosporin, has been shown in large surveillance programs and independent in vitro studies to be highly active against all key gram-negative causative pathogens isolated from patients with hospital-acquired or ventilator-associated pneumonia, bloodstream infections, or complicated urinary tract infections. The improved structure, the novel mode of entry into bacteria, and its stability against carbapenemases enables cefiderocol to exhibit high potency against isolates that produce carbapenemases of all classes or are resistant due to porin channel mutations and/or efflux pump overexpression. Resistance to cefiderocol is uncommon and appears to be multifactorial.

Genetic evidence points to deposition of amyloid-β (Aβ) as a causal factor for Alzheimer's disease. Aβ generation is initiated when β-secretase (BACE1) cleaves the amyloid precursor protein. Starting with an oxazine lead 1, we describe the discovery of a thiazine-based BACE1 inhibitor 5 with robust Aβ reduction in vivo at low concentrations, leading to a low projected human dose of 14 mg/day where 5 achieved sustained Aβ reduction of 80% at trough level.

The pharmacokinetic (PK) and pharmacodynamic (PD) parameters which correlated with the in vivo efficacy of cefiderocol were evaluated using neutropenic murine thigh and lung infection models in which the infections were caused by a variety of Gram-negative bacilli., The pharmacokinetic (PK) and pharmacodynamic (PD) parameters which correlated with the in vivo efficacy of cefiderocol were evaluated using neutropenic murine thigh and lung infection models in which the infections were caused by a variety of Gram-negative bacilli. The dose fractionation study using the thigh infection model in which the infection was caused by Pseudomonas aeruginosa showed that the cumulative percentage of a 24-h period that the free drug concentration in plasma exceeds the MIC (%fT>MIC) rather than the free peak level divided by the MIC (fCmax/MIC) and the area under the free concentration-time curve over 24 h divided by the MIC (fAUC/MIC) was the PK/PD parameter that best correlated with efficacy. The study with multiple carbapenem-resistant strains revealed that the %fT>MIC determined in iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB) better reflected the in vivo efficacy of cefiderocol than the %fT>MIC determined in cation-adjusted Mueller-Hinton broth (CAMHB). The mean %fT>MIC of cefiderocol required for a 1-log10 reduction against 10 strains of Enterobacteriaceae and 3 strains of Pseudomonas aeruginosa in the thigh infection models were 73.3% and 77.2%, respectively. The mean %fT>MIC for Enterobacteriaceae, P. aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia in the lung infection model were 64.4%, 70.3%, 88.1%, and 53.9%, respectively. These results indicate that cefiderocol has potent efficacy against Gram-negative bacilli, including carbapenem-resistant strains, irrespective of the bacterial species, in neutropenic thigh and lung infection models and that the in vivo efficacy correlated with the in vitro MIC under iron-deficient conditions.

Herein, we evaluated sustainability of humanized exposures of cefiderocol in vivo over 72 h against pathogens with cefiderocol MICs of 0.5 to 16 μg/ml in the neutropenic murine thigh model. In Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae displaying MICs of 0.5 to 8 μg/ml (n = 11), sustained kill was observed at 72 h among 9 isolates., Herein, we evaluated sustainability of humanized exposures of cefiderocol in vivo over 72 h against pathogens with cefiderocol MICs of 0.5 to 16 μg/ml in the neutropenic murine thigh model. In Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae displaying MICs of 0.5 to 8 μg/ml (n = 11), sustained kill was observed at 72 h among 9 isolates. Postexposure MICs revealed a single 2-dilution increase in one animal compared with controls (1/54 samples, 1.8%) at 72 h. Adaptive resistance during therapy was not observed.

Cefiderocol (S-649266) is a novel parenteral siderophore cephalosporin conjugated with a catechol moiety at the third-position side chain. The in vitro activity of cefiderocol against Pseudomonas aeruginosa was enhanced under iron-depleted conditions, whereas that of ceftazidime was not affected. The monitoring of [thiazole- 14 C]cefiderocol revealed the increased intracellular accumulation of cefiderocol in P. aeruginosa cells incubated under iron-depleted conditions compared with those incubated under iron-sufficient conditions. Cefiderocol was shown to have potent chelating activity with ferric iron, and extracellular iron was efficiently transported into P. aeruginosa cells in the presence of cefiderocol as well as siderophores, while enhanced transport of extracellular ferric iron was not observed when one of the hydroxyl groups of the catechol moiety of cefiderocol was replaced with a methoxy group. We conclude that cefiderocol forms a chelating complex with iron, which is actively transported into P. aeruginosa cells via iron transporters, resulting in potent antibacterial activity of cefiderocol against P. aeruginosa .

A series of novel 7β-[2-(2-aminothiazole-4-yl)-2-(Z)-(alkoxyimino)acetamido]-cephalosporins having pyridinium-linked acyl cyanamide at the C-3 position were prepared and their antibacterial activities and pharmacokinetics profiles were evaluated. Most of the compounds exhibited potent antibacterial activities against penicillin-resistant Streptococcus pneumoniae (PRSP) and β-lactamase non-producing penicillin-resistant Haemophilus influenzae (BLNAR). Introduction of a propenyl group between the cephalospoin core and the side chains at the C-3 position improved the pharmacokinetics profile. Among these compounds, 7β-[2-(2-aminothiazole-4-yl)-2-(Z)- (alkoxyimino)acetamido]-3-(pyridin-1-ium-1-yl)prop-1-en-1-yl)cephalosporins (32j) showed well-balanced antibacterial activity against S. pneumoniae and H. influenzae which included resistant strains and also other Gram-positive or Gram-negative pathogens. Furthermore, 32j showed a long half-life comparable to that of Ceftriaxone in mice and monkeys.

S-649266 is a novel siderophore cephalosporin antibiotic with a catechol moiety on the 3-position side chain. Two sets of clinical isolate collections were used to evaluate the antimicrobial activity of S-649266 against Enterobacteriaceae . These sets included 617 global isolates collected between 2009 and 2011 and 233 β-lactamase-identified isolates, including 47 KPC-, 49 NDM-, 12 VIM-, and 8 IMP-producers. The MIC 90 values of S-649266 against the first set of Escherichia coli , Klebsiella pneumoniae , Serratia marcescens , Citrobacter freundii , Enterobacter aerogenes , and Enterobacter cloacae isolates were all ≤1 μg/ml, and there were only 8 isolates (1.3%) among these 617 clinical isolates with MIC values of ≥8 μg/ml. In the second set, the MIC values of S-649266 were ≤4 μg/ml against 109 strains among 116 KPC-producing and class B (metallo) carbapenemase-producing strains. In addition, S-649266 showed MIC values of ≤2 μg/ml against each of the 13 strains that produced other types of carbapenemases such as SME, NMC, and OXA-48. The mechanisms of the decreased susceptibility of 7 class B carbapenemase-producing strains with MIC values of ≥16 μg/ml are uncertain. This is the first report to demonstrate that S-649266, a novel siderophore cephalosporin, has significant antimicrobial activity against Enterobacteriaceae , including strains that produce carbapenemases such as KPC and NDM-1.