Study of Cefiderocol (S-649266) or Best Available Therapy for the Treatment of Severe Infections Caused by Carbapenem-resistant Gram-negative Pathogens (CREDIBLE - CR)

A Multicenter, Randomized, Open-label Clinical Study of S-649266 or Best Available Therapy for the Treatment of Severe Infections Caused by Carbapenem-resistant Gram-negative Pathogens

This study is designed to provide evidence of efficacy of cefiderocol in the treatment of serious infections in adult patients caused by carbapenem-resistant Gram-negative pathogens.

Study Overview

• Status: Completed
• Conditions: Sepsis; Bloodstream Infections (BSI); Hospital Acquired Pneumonia (HAP); Complicated Urinary Tract Infection (cUTI); Healthcare-associated Pneumonia (HCAP); Ventilator Associated Pneumonia (VAP)
• Intervention / Treatment: Drug: Cefiderocol; Drug: Best Available Therapy

Detailed Description

This study is designed to provide evidence of efficacy of cefiderocol in the treatment of serious infections in adult patients with either hospital-acquired pneumonia (HAP), ventilator-associated pneumonia (VAP), healthcare-associated pneumonia (HCAP), complicated urinary tract infection (cUTI), or bloodstream infections (BSI)/sepsis caused by carbapenem-resistant Gram-negative pathogens.

• Study Type: Interventional
• Enrollment (Actual): 152
• Phase: Phase 3

Expanded Access

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Contacts and Locations

Study Locations

• Brazil
  • Bahia
    • Salvador, Bahia, Brazil, 41810-011
      • Shionogi Research Site
  • Parana
    • Curitiba, Parana, Brazil, 80050
      • Shionogi Research Site
  • RIO Grande DO SUL
    • Passo Fundo, RIO Grande DO SUL, Brazil, 99010-080
      • Shionogi Research Site
    • Porto Alegre, RIO Grande DO SUL, Brazil, 90035-074
      • Shionogi Research Site
    • Porto Alegre, RIO Grande DO SUL, Brazil, 90035-903
      • Shionogi Research Site
    • Santa Maria, RIO Grande DO SUL, Brazil, 97105-900
      • Shionogi Research Site
  • SAO Paulo
    • São José do Rio Preto, SAO Paulo, Brazil, 15090
      • Shionogi Research Site
    • São Paulo, SAO Paulo, Brazil, 04378-000
      • Shionogi Research Site
• Croatia
  • Split, Croatia, 21000
    • Shionogi Research Site
  • Zagreb, Croatia, 10000
    • Shionogi Research Site
  • Primorje-Gorski Kotar
    • Rijeka, Primorje-Gorski Kotar, Croatia, 51000
      • Shionogi Research Site
• France
  • Ile-de-france
    • Paris, Ile-de-france, France, 75018
      • Shionogi Research Site
  • Rhone-alpes
    • La Tronche, Rhone-alpes, France, 38043
      • Shionogi Research Site
• Germany
  • Berlin, Germany, 12351
    • Shionogi Research Site
  • Baden-wuerttemberg
    • Heidelberg, Baden-wuerttemberg, Germany, 69120
      • Shionogi Research Site
  • Nordrhein-westfalen
    • Bonn, Nordrhein-westfalen, Germany, 53105
      • Shionogi Research Site
• Greece
  • Attica
    • Athens, Attica, Greece, 11526
      • Shionogi Research Site
    • Athens, Attica, Greece, 12462
      • Shionogi Research Site
  • Peloponnese
    • Patra, Peloponnese, Greece, 26504
      • Shionogi Research Site
  • Thessaly
    • Larisa, Thessaly, Greece, 41110
      • Shionogi Research Site
    • Larisa, Thessaly, Greece, 41221
      • Shionogi Research Site
• Guatemala
  • Ciudad de Guatemala, Guatemala
    • Shionogi Research Site
• Israel
  • Hadera, Israel, 38100
    • Shionogi Research Site
  • Haifa, Israel, 31048
    • Shionogi Research Site
  • Haifa, Israel, 3109601
    • Shionogi Research Site
  • Holon, Israel, 58100
    • Shionogi Research Site
  • Jerusalem, Israel, 91120
    • Shionogi Research Site
  • Beersheba
    • Beer-Sheva, Beersheba, Israel, 84101
      • Shionogi Research Site
  • Rehoboth
    • Be'er Ya'akov, Rehoboth, Israel, 70300
      • Shionogi Research Site
  • Tel Aviv
    • Tel Hashomer, Tel Aviv, Israel, 52621
      • Shionogi Research Site
    • Tel-Aviv, Tel Aviv, Israel, 64239
      • Shionogi Research Site
  • Zefat
    • Safed, Zefat, Israel, 13100
      • Shionogi Research Site
• Italy
  • Milano, Italy, 20122
    • Shionogi Research Site
  • Milano, Italy, 20132
    • Shionogi Research Site
  • Milano, Italy, 20162
    • Shionogi Research Site
  • Modena, Italy, 41124
    • Shionogi Research Site
  • Udine, Italy, 33100
    • Shionogi Research Site
  • Pisa
    • Cisanello, Pisa, Italy, 56124
      • Shionogi Research Site
• Japan
  • Nagasaki, Japan, 852-8501
    • Shionogi Research Site
  • Aichi
    • Nagakute, Aichi, Japan, 480-1195
      • Shionogi Research Site
  • Tokyo
    • Shinagawa-ku, Tokyo, Japan, 142-8999
      • Shionogi Research Site
• Korea, Republic of
  • Daegu, Korea, Republic of, 41931
    • Shionogi Research Site
  • Daegu, Korea, Republic of, 41944
    • Shionogi Research Site
  • Seoul, Korea, Republic of, 06591
    • Shionogi Research Site
  • Seoul, Korea, Republic of, 06973
    • Shionogi Research Site
  • Seoul, Korea, Republic of, 07441
    • Shionogi Research Site
  • Seoul, Korea, Republic of, 135-710
    • Shionogi Research Site
  • Gangwon-Do
    • Wonju-si, Gangwon-Do, Korea, Republic of, 26426
      • Shionogi Research Site
  • Gwangjin-gu
    • Seoul, Gwangjin-gu, Korea, Republic of, 5030
      • Shionogi Research Site
• Spain
  • Barcelona, Spain, 08003
    • Shionogi Research Site
  • Barcelona, Spain, 08025
    • Shionogi Research Site
  • Barcelona, Spain, 08036
    • Shionogi Research Site
  • Ciudad Real, Spain, 13005
    • Shionogi Research Site
  • Gerona, Spain, 17007
    • Shionogi Research Site
  • Madrid, Spain, 28046
    • Shionogi Research Site
  • Malaga, Spain, 29010
    • Shionogi Research Site
  • Sevilla, Spain, 41009
    • Shionogi Research Site
  • Valencia, Spain, 46015
    • Shionogi Research Site
  • Zaragoza, Spain, 50009
    • Shionogi Research Site
  • Barcelona
    • Terrassa, Barcelona, Spain, 08035
      • Shionogi Research Site
  • Cordoba
    • Córdoba, Cordoba, Spain, 14004
      • Shionogi Research Site
  • Lleida
    • Lérida, Lleida, Spain, 25198
      • Shionogi Research Site
• Taiwan
  • Hualien, Taiwan, 97002
    • Shionogi Research Site
  • Kaohsiung, Taiwan, 81362
    • Shionogi Research Site
  • Taichung, Taiwan, 40447
    • Shionogi Research Site
  • ROC
    • Taichung, ROC, Taiwan, 40705
      • Shionogi Research Site
  • Taipei
    • Taipei City, Taipei, Taiwan, 10002
      • Shionogi Research Site
• Thailand
  • Bangkok, Thailand, 10700
    • Shionogi Research Site
  • Muang, Thailand, 40002
    • Shionogi Research Site
  • Muang Nonthaburi, Thailand, 11000
    • Shionogi Research Site
• Turkey
  • Ankara, Turkey
    • Shionogi Research Site
  • Istanbul, Turkey, 34098
    • Shionogi Research Site
  • Istanbul, Turkey, 34214
    • Shionogi Research Site
  • Trabzon, Turkey
    • Shionogi Research Site
  • Izmir
    • Bornova, Izmir, Turkey, 35100
      • Shionogi Research Site
• United Kingdom
  • England
    • London, England, United Kingdom, SE1 7EH
      • Shionogi Research Site
    • London, England, United Kingdom, W 120NN
      • Shionogi Research Site
    • London, England, United Kingdom, W12 0HS
      • Shionogi Research Site
    • London, England, United Kingdom
      • Shionogi Research Site
• United States
  • Connecticut
    • Hartford, Connecticut, United States, 06102
      • Shionogi Research Site
  • Delaware
    • Newark, Delaware, United States, 19718
      • Shionogi Research Site
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Shionogi Research Site
  • Louisiana
    • New Orleans, Louisiana, United States, 70121
      • Shionogi Research Site
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Shionogi Research Site
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • Shionogi Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients with clinically documented infection (HAP/VAP/HCAP, cUTI, or BSI/sepsis) caused by a Gram-negative pathogen with evidence of carbapenem resistance
• Patients who have been treated previously with an empiric antibiotic regiment and failed treatment, both clinically and microbiologically, are eligible for the study, if they have an identified carbapenem-resistant Gram-negative pathogen which has either been shown to be nonsusceptible in vitro to each of the antibiotic(s) of the empiric antibiotic regimen or been grown from a culture performed after at least 2 days of the empiric antibiotic regimen

• Patient is male (no contraception required) or female and meets one of the following criteria:

  • Surgically sterile by hysterectomy and/or bilateral oophorectomy or bilateral salpingectomy or tubal ligation for the purpose of contraception for at least 6 weeks with appropriate documentation of such surgery
  • Postmenopausal (defined as older than 45 years of age with cessation of regular menstrual periods for 6 months and confirmed by a follicle-stimulating hormone level of > 40 mIU/mL, or amenorrhea for at least 12 months)
  • Of childbearing potential and using combined (estrogen and progestogen) or progestogen-only hormonal contraception associated with inhibition of ovulation (including oral, intravaginal, injectable, implantable, and transdermal contraceptives), or an intrauterine device (IUD), or intrauterine hormone-releasing system (IUS) for the entire duration of the study
  • Of childbearing potential and practice abstinence as a preferred and usual lifestyle, and agrees to continue practicing abstinence from Screening and for the entire duration of the study
  • Of childbearing potential, whose sole heterosexual partner has been successfully vasectomized and agrees to not have other heterosexual partners for the entire duration of the study
• Patients meeting specific criteria for each infection site

Exclusion Criteria:

1. Patients who have a history of any moderate or severe hypersensitivity or allergic reaction to any β-lactam (Note: for β-lactams, a history of a mild rash followed by uneventful re-exposure is not a contraindication to enrollment)
2. Patients who need more than 3 systemic antibiotics as part of best available therapy (BAT) for the treatment of the Gram-negative infection (patients with mixed Gram-positive or anaerobic infections may receive appropriate concomitant narrow spectrum antibiotics [eg, vancomycin, linezolid, metronidazole, clindamycin])
3. Patients with coinfection caused by invasive aspergillosis, mucormycosis or other highly lethal mold
4. Patients who have central nervous system (CNS) infection (eg, meningitis, brain abscess, shunt infection)
5. Patients with infection requiring > 3 weeks of antibiotic treatment (eg, bone and joint infection, endocarditis)
6. Patients with cystic fibrosis or moderate to severe bronchiectasis
7. Patients in refractory septic shock defined as persistent hypotension despite adequate fluid resuscitation or despite vasopressive therapy at the time of Randomization
8. Patients with severe neutropenia, ie, polymorphonuclear neutrophils (PMNs) < 100 cells/μL
9. Female patients who have a positive pregnancy test at Screening or who are lactating
10. Patients with Acute Physiology and Chronic Health Evaluation II (APACHE II) score > 30
11. Patients who have received a potentially effective antibiotic regimen for the carbapenem-resistant Gram-negative infection for a continuous duration of more than 24 hours in cUTI, or 36 hours in HAP/VAP/HCAP or BSI/sepsis during the 72 hours leading to Randomization
12. Patients with any condition or circumstance that, in the opinion of the investigator, would compromise the safety of the patient or the quality of the study data
13. Patients who have received another investigational drug or device within 30 days prior to study entry
14. Patients who have previously been randomized in this study or received S-649266
15. Patients receiving peritoneal dialysis
16. Patients meeting specific exclusion criteria for each infection site

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cefiderocol; Participants will receive cefiderocol 2 g administered intravenously over 3 hours, every 8 hours for 7-14 days. Treatment could be extended to 21 days at the discretion of the investigator.	Drug: Cefiderocol; 2 g intravenously over 3 hours every 8 hours for a period of 7 to 14 days, or 2 g every 6 hours for participants with creatinine clearance >120 mL/min.; Other Names: S-649266; Fetroja ®
Active Comparator: Best Available Therapy (BAT); Best available therapy (BAT) will be chosen by the investigator and may include up to three antibacterial agents for carbapenem resistant Gram-negative bacteria, intravenously administered per country-specific guidelines for 7-14 days. Treatment could be extended to 21 days at the discretion of the investigator.	Drug: Best Available Therapy; Standard of care with either a polymyxin-based or non-polymyxin-based regimen as determined by the investigator and consisting of one to three marketed antibacterial agent(s).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Clinical Cure at Test of Cure (TOC) in Participants With HAP/VAP/HCAP or BSI/Sepsis	Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms and was defined for each diagnosis. HAP/VAP/HCAP: Clinical cure was defined as resolution or substantial improvement of Baseline signs and symptoms of pneumonia including a reduction in SOFA and CPIS scores, and improvement or lack of progression of chest radiographic abnormalities such that no antibacterial therapy was required for the treatment of the current infection. BSI/Sepsis: Clinical cure was defined as resolution or substantial improvement of Baseline signs and symptoms including a reduction in SOFA score, such that no antibacterial therapy was required for the treatment of BSI/sepsis. Participants with bacteremia must have eradication of bacteremia caused by the Gram-negative pathogen. Participants with missing data were considered as non-responders.	Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21
Percentage of Participants With Microbiologic Eradication at TOC in Participants With cUTI	Microbiological outcome per Baseline pathogen was determined by the sponsor as defined for each infection site. For cUTI eradication was defined as a urine culture that showed that the Gram-negative uropathogen identified at Baseline at ≥ 10⁵ colony-forming units (CFU)/mL was reduced to < 10³ CFU/mL. Overall per-participant eradication was defined as eradication of all Baseline Gram-negative pathogens.	Test of cure, defined as 7 days after the end of treatment, equivalent to Study Days 14 to 21

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With Clinical Cure at End of Treatment (EOT) in Participants With HAP/VAP/HCAP or BSI/Sepsis	Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms and was defined for each diagnosis. HAP/VAP/HCAP: Clinical cure was defined as resolution or substantial improvement of Baseline signs and symptoms of pneumonia including a reduction in SOFA and CPIS scores, and improvement or lack of progression of chest radiographic abnormalities such that no antibacterial therapy was required for the treatment of the current infection. BSI/Sepsis: Clinical cure was defined as resolution or substantial improvement of Baseline signs and symptoms including a reduction in SOFA score, such that no antibacterial therapy was required for the treatment of BSI/sepsis. Participants with bacteremia must have eradication of bacteremia caused by the Gram-negative pathogen.	End of treatment, Day 7 to 14
Percentage of Participants With Sustained Clinical Cure at Follow-up (FU) in Participants With HAP/VAP/HCAP or BSI/Sepsis	Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms and was defined for each diagnosis. Sustained clinical cure for HAP/VAP/HCAP: Continued resolution or substantial improvement of Baseline signs and symptoms of pneumonia, such that no antibacterial therapy was required for the treatment of pneumonia in a participant assessed as cured at TOC. BSI/Sepsis: Continued resolution or substantial improvement of Baseline signs and symptoms associated with reduction in SOFA score, such that no antibacterial therapy was required for the treatment of the original BSI/sepsis in a participant assessed as cured at TOC.	Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28
Percentage of Participants With Clinical Cure at Test of Cure in Participants With cUTI	Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms and was defined for each diagnosis. cUTI: Resolution or substantial improvement of Baseline signs and symptoms of cUTI, or return to pre-infection Baseline if known, such that no antibacterial therapy is required for the treatment of the current infection.	Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21
Percentage of Participants With Clinical Cure at End of Treatment (EOT) in Participants With cUTI	Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms and was defined for each diagnosis. cUTI: Resolution or substantial improvement of Baseline signs and symptoms of cUTI, or return to pre-infection Baseline if known, such that no antibacterial therapy is required for the treatment of the current infection.	End of treatment, Day 7 to 14
Percentage of Participants With Sustained Clinical Cure at Follow-up in Participants With cUTI	Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms and was defined for each diagnosis. Sustained clinical cure for cUTI: Continued resolution or improvement of Baseline signs and symptoms of cUTI, or return to pre-infection Baseline if known, in a participant assessed as cured at TOC.	Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28
Percentage of Participants With Clinical Cure at End of Treatment in Participants With HAP/VAP/HCAP + BSI/Sepsis, and Overall	Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms and was defined for each diagnosis. HAP/VAP/HCAP: Resolution or substantial improvement of Baseline signs and symptoms of pneumonia including a reduction in SOFA and CPIS scores, and improvement or lack of progression of chest radiographic abnormalities such that no antibacterial therapy was required for the treatment of the current infection. BSI/Sepsis: Resolution or substantial improvement of Baseline signs and symptoms including a reduction in SOFA score, such that no antibacterial therapy was required for the treatment of BSI/sepsis. Participants with bacteremia must have eradication of bacteremia caused by the Gram-negative pathogen. cUTI: Resolution or substantial improvement of Baseline signs and symptoms of cUTI, or return to pre-infection Baseline if known, such that no antibacterial therapy is required for the treatment of the current infection.	End of treatment, Day 7 to 14
Percentage of Participants With Clinical Cure at Test of Cure in Participants With HAP/VAP/HCAP + BSI/Sepsis, and Overall	Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms and was defined for each diagnosis. HAP/VAP/HCAP: Resolution or substantial improvement of Baseline signs and symptoms of pneumonia including a reduction in SOFA and CPIS scores, and improvement or lack of progression of chest radiographic abnormalities such that no antibacterial therapy was required for the treatment of the current infection. BSI/Sepsis: Resolution or substantial improvement of Baseline signs and symptoms including a reduction in SOFA score, such that no antibacterial therapy was required for the treatment of BSI/sepsis. Participants with bacteremia must have eradication of bacteremia caused by the Gram-negative pathogen. cUTI: Resolution or substantial improvement of Baseline signs and symptoms of cUTI, or return to pre-infection Baseline if known, such that no antibacterial therapy is required for the treatment of the current infection.	Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21
Percentage of Participants With Sustained Clinical Cure at Follow-up in Participants With HAP/VAP/HCAP + BSI/Sepsis, and Overall	Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms and was defined for each diagnosis. Sustained clinical cure for HAP/VAP/HCAP: Continued resolution or substantial improvement of Baseline signs and symptoms of pneumonia, such that no antibacterial therapy is required for the treatment of pneumonia in a participant assessed as cured at TOC. BSI/Sepsis: Continued resolution or substantial improvement of Baseline signs and symptoms associated with reduction in SOFA score, such that no antibacterial therapy is required for the treatment of the original BSI/sepsis in a participant assessed as cured at TOC. cUTI: Continued resolution or improvement of Baseline signs and symptoms of cUTI, or return to pre-infection Baseline if known, in a participant assessed as cured at TOC.	Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28
Percentage of Participants With Clinical Cure at End of Treatment By Baseline Pathogen	Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms and was defined for each diagnosis: HAP/VAP/HCAP: Resolution or substantial improvement of Baseline signs and symptoms of pneumonia including a reduction in SOFA and CPIS scores, and improvement or lack of progression of chest radiographic abnormalities such that no antibacterial therapy was required for the treatment of the current infection. BSI/Sepsis: Resolution or substantial improvement of Baseline signs and symptoms including a reduction in SOFA score, such that no antibacterial therapy was required for the treatment of BSI/sepsis. Participants with bacteremia must have eradication of bacteremia caused by the Gram-negative pathogen. cUTI: Resolution or substantial improvement of Baseline signs and symptoms of cUTI, or return to pre-infection Baseline if known, such that no antibacterial therapy is required for the treatment of the current infection.	End of treatment, Day 7 to 14
Percentage of Participants With Clinical Cure at Test of Cure By Baseline Pathogen	Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms and was defined for each diagnosis. HAP/VAP/HCAP: Resolution or substantial improvement of Baseline signs and symptoms of pneumonia including a reduction in SOFA and CPIS scores, and improvement or lack of progression of chest radiographic abnormalities such that no antibacterial therapy was required for the treatment of the current infection. BSI/Sepsis: Resolution or substantial improvement of Baseline signs and symptoms including a reduction in SOFA score, such that no antibacterial therapy was required for the treatment of BSI/sepsis. Participants with bacteremia must have eradication of bacteremia caused by the Gram-negative pathogen. cUTI: Resolution or substantial improvement of Baseline signs and symptoms of cUTI, or return to pre-infection Baseline if known, such that no antibacterial therapy is required for the treatment of the current infection.	Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21
Percentage of Participants With Sustained Clinical Cure at Follow-up By Baseline Pathogen	Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms and was defined for each diagnosis. Sustained clinical cure for HAP/VAP/HCAP: Continued resolution or substantial improvement of Baseline signs and symptoms of pneumonia, such that no antibacterial therapy was required for the treatment of pneumonia in a participant assessed as cured at TOC. BSI/Sepsis: Continued resolution or substantial improvement of Baseline signs and symptoms associated with reduction in SOFA score, such that no antibacterial therapy was required for the treatment of the original BSI/sepsis in a participant assessed as cured at TOC. cUTI: Continued resolution or improvement of Baseline signs and symptoms of cUTI, or return to pre-infection Baseline if known, in a participant assessed as cured at TOC.	Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28
Percentage of Participants With Clinical Cure at EOT By Baseline Carbapenem-resistant Pathogen	Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms and was defined for each diagnosis: HAP/VAP/HCAP: Resolution or substantial improvement of Baseline signs and symptoms of pneumonia including a reduction in SOFA and CPIS scores, and improvement or lack of progression of chest radiographic abnormalities such that no antibacterial therapy was required for the treatment of the current infection. BSI/Sepsis: Resolution or substantial improvement of Baseline signs and symptoms including a reduction in SOFA score, such that no antibacterial therapy was required for the treatment of BSI/sepsis. Participants with bacteremia must have eradication of bacteremia caused by the Gram-negative pathogen. cUTI: Resolution or substantial improvement of Baseline signs and symptoms of cUTI, or return to pre-infection Baseline if known, such that no antibacterial therapy is required for the treatment of the current infection.	End of treatment, Day 7 to 14
Percentage of Participants With Clinical Cure at TOC By Baseline Carbapenem-resistant Pathogen	Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms and was defined for each diagnosis: HAP/VAP/HCAP: Resolution or substantial improvement of Baseline signs and symptoms of pneumonia including a reduction in SOFA and CPIS scores, and improvement or lack of progression of chest radiographic abnormalities such that no antibacterial therapy was required for the treatment of the current infection. BSI/Sepsis: Resolution or substantial improvement of Baseline signs and symptoms including a reduction in SOFA score, such that no antibacterial therapy was required for the treatment of BSI/sepsis. Participants with bacteremia must have eradication of bacteremia caused by the Gram-negative pathogen. cUTI: Resolution or substantial improvement of Baseline signs and symptoms of cUTI, or return to pre-infection Baseline if known, such that no antibacterial therapy is required for the treatment of the current infection.	Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21
Percentage of Participants With Sustained Clinical Cure at Follow-up By Baseline Carbapenem-resistant Pathogen	Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms and was defined for each diagnosis. Sustained clinical cure for HAP/VAP/HCAP: Continued resolution or substantial improvement of Baseline signs and symptoms of pneumonia, such that no antibacterial therapy was required for the treatment of pneumonia in a participant assessed as cured at TOC. BSI/Sepsis: Continued resolution or substantial improvement of Baseline signs and symptoms associated with reduction in SOFA score, such that no antibacterial therapy was required for the treatment of the original BSI/sepsis in a participant assessed as cured at TOC. cUTI: Continued resolution or improvement of Baseline signs and symptoms of cUTI, or return to pre-infection Baseline if known, in a participant assessed as cured at TOC.	Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28
Percentage of Participants With Microbiologic Eradication at EOT in Participants With HAP/VAP/HCAP or BSI/Sepsis	Microbiological outcomes per Baseline pathogen were determined by the sponsor according to the following criteria established for each infection site: HAP/VAP/HCAP: Eradication was defined as the absence of the Baseline Gram-negative pathogen from an appropriate clinical specimen (sputum, tracheal aspirate, bronchoalveolar lavage (BAL) fluid, protected specimen brush, pleural fluid, or lung biopsy). If it was not possible to obtain an appropriate clinical culture and the participant had a successful clinical outcome, the response was presumed to be eradication. BSI/Sepsis: Absence of the Baseline Gram-negative pathogen from a blood culture and/or other primary source as applicable. In the case of sepsis, if the participant had a successful clinical outcome and it was not possible to obtain an appropriate clinical culture, the response was presumed to be eradication. Overall per-participant eradication was defined as eradication of all Baseline Gram-negative pathogens.	End of treatment, Day 7 to 14
Percentage of Participants With Microbiologic Eradication at TOC in Participants With HAP/VAP/HCAP or BSI/Sepsis	Microbiological outcomes per Baseline pathogen were determined by the sponsor according to the following criteria established for each infection site: HAP/VAP/HCAP: Eradication was defined as the absence of the Baseline Gram-negative pathogen from an appropriate clinical specimen (sputum, tracheal aspirate, bronchoalveolar lavage (BAL) fluid, protected specimen brush, pleural fluid, or lung biopsy). If it was not possible to obtain an appropriate clinical culture and the participant had a successful clinical outcome, the response was presumed to be eradication. BSI/Sepsis: Absence of the Baseline Gram-negative pathogen from a blood culture and/or other primary source as applicable. In the case of sepsis, if the participant had a successful clinical outcome and it was not possible to obtain an appropriate clinical culture, the response was presumed to be eradication. Overall per-participant eradication was defined as eradication of all Baseline Gram-negative pathogens.	Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21
Percentage of Participants With Sustained Microbiologic Eradication at Follow-up in Participants With HAP/VAP/HCAP or BSI/Sepsis	Microbiological outcomes per Baseline pathogen at FU were determined according to the following criteria for each diagnosis: HAP/VAP/HCAP: Sustained eradication was defined as the absence of the Baseline Gram-negative pathogen from an appropriate clinical specimen after TOC. If an appropriate clinical culture could not be obtained and the participant had a successful clinical response after TOC, the response was presumed sustained eradication. BSI/Sepsis: Absence of the Baseline Gram-negative pathogen from a blood culture or other primary source after TOC as applicable. For sepsis, if the participant has a successful clinical outcome after TOC and an appropriate clinical culture could not be obtained, the response was presumed sustained eradication. Overall per-participant response was defined as sustained eradication of all Baseline Gram-negative pathogens after documented eradication at TOC.	Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28
Percentage of Participants With Microbiologic Eradication at EOT in Participants With cUTI	Microbiological outcome per Baseline pathogen was determined by the sponsor as defined for each infection site. For cUTI eradication was defined as a urine culture that showed that the Gram-negative uropathogen identified at Baseline at ≥ 10⁵ CFU/mL was reduced to < 10³ CFU/mL. Overall per-participant eradication was defined as eradication of all Baseline Gram-negative pathogens.	End of treatment, Day 7 to 14
Percentage of Participants With Sustained Microbiologic Eradication at Follow-up in Participants With cUTI	Microbiological outcome per Baseline pathogen at follow-up was determined by the sponsor as defined for each infection site. For cUTI sustained eradication was defined as a culture taken any time after documented eradication at TOC and a urine culture obtained at FU showed that the Baseline uropathogen found at entry at ≥10⁵ CFU/mL remained <10³ CFU/mL. Overall per-participant sustained eradication was defined as sustained eradication of all Baseline Gram-negative pathogens.	Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28
Percentage of Participants With Microbiologic Eradication at EOT in Participants With HAP/VAP/HCAP + BSI/Sepsis, and Overall	Microbiological outcomes per Baseline pathogen were determined by the sponsor according to the following criteria for each diagnosis: HAP/VAP/HCAP: Eradication was defined as the absence of the Baseline Gram-negative pathogen from an appropriate clinical specimen. If it was not possible to obtain an appropriate clinical culture and the participant had a successful clinical outcome, the response was presumed to be eradication. BSI/Sepsis: Absence of the Baseline Gram-negative pathogen from a blood culture and/or other primary source as applicable. In the case of sepsis, if the participant had a successful clinical outcome and it was not possible to obtain an appropriate clinical culture, the response was presumed to be eradication. cUTI: a urine culture that showed that the Gram-negative uropathogen identified at Baseline at ≥ 10⁵ CFU/mL was reduced to < 10³ CFU/mL. Overall per-participant eradication was defined as eradication of all Baseline Gram-negative pathogens.	End of treatment, Day 7 to 14
Percentage of Participants With Microbiologic Eradication at TOC in Participants With HAP/VAP/HCAP + BSI/Sepsis, and Overall	Microbiological outcomes per Baseline pathogen were determined by the sponsor according to the following criteria for each diagnosis: HAP/VAP/HCAP: Eradication was defined as the absence of the Baseline Gram-negative pathogen from an appropriate clinical specimen. If it was not possible to obtain an appropriate clinical culture and the participant had a successful clinical outcome, the response was presumed to be eradication. BSI/Sepsis: Absence of the Baseline Gram-negative pathogen from a blood culture and/or other primary source as applicable. In the case of sepsis, if the participant had a successful clinical outcome and it was not possible to obtain an appropriate clinical culture, the response was presumed to be eradication. cUTI: a urine culture that showed that the Gram-negative uropathogen identified at Baseline at ≥ 10⁵ CFU/mL was reduced to < 10³ CFU/mL. Overall per-participant eradication was defined as eradication of all Baseline Gram-negative pathogens.	Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21
Percentage of Participants With Sustained Microbiologic Eradication at Follow-up in Participants With HAP/VAP/HCAP + BSI/Sepsis, and Overall	Microbiological outcomes per Baseline pathogen at FU were determined according to the following criteria for each diagnosis: HAP/VAP/HCAP: Sustained eradication was defined as the absence of the Baseline Gram-negative pathogen from an appropriate clinical specimen after TOC. BSI/Sepsis: Absence of the Baseline Gram-negative pathogen from a blood culture or other primary source after TOC as applicable. For HAP/VAP/HCAP and sepsis if an appropriate clinical culture could not be obtained and the participant had a successful clinical response after TOC, the response was presumed sustained eradication. cUTI: a culture taken any time after documented eradication at TOC, and a urine culture obtained at FU showed that the Baseline uropathogen found at entry at ≥10⁵ CFU/mL remained < 10³ CFU/mL. Overall per-participant response was defined as sustained eradication of all Baseline Gram-negative pathogens after documented eradication at TOC.	Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28
Percentage of Participants With Microbiologic Eradication at EOT By Baseline Pathogen	Microbiological outcomes per Baseline pathogen were determined by the sponsor according to the following criteria for each diagnosis: HAP/VAP/HCAP: Eradication was defined as the absence of the Baseline Gram-negative pathogen from an appropriate clinical specimen. If it was not possible to obtain an appropriate clinical culture and the participant had a successful clinical outcome, the response was presumed to be eradication. BSI/Sepsis: Absence of the Baseline Gram-negative pathogen from a blood culture and/or other primary source as applicable. In the case of sepsis, if the participant had a successful clinical outcome and it was not possible to obtain an appropriate clinical culture, the response was presumed to be eradication. cUTI: a urine culture that showed that the Gram-negative uropathogen identified at Baseline at ≥ 10⁵ CFU/mL was reduced to < 10³ CFU/mL. Overall per-participant eradication was defined as eradication of all Baseline Gram-negative pathogens.	End of treatment, Day 7 to 14
Percentage of Participants With Microbiologic Eradication at TOC By Baseline Pathogen	Microbiological outcomes per Baseline pathogen were determined by the sponsor according to the following criteria for each diagnosis: HAP/VAP/HCAP: Eradication was defined as the absence of the Baseline Gram-negative pathogen from an appropriate clinical specimen. If it was not possible to obtain an appropriate clinical culture and the participant had a successful clinical outcome, the response was presumed to be eradication. BSI/Sepsis: Absence of the Baseline Gram-negative pathogen from a blood culture and/or other primary source as applicable. In the case of sepsis, if the participant had a successful clinical outcome and it was not possible to obtain an appropriate clinical culture, the response was presumed to be eradication. cUTI: a urine culture that showed that the Gram-negative uropathogen identified at Baseline at ≥ 10⁵ CFU/mL was reduced to < 10³ CFU/mL. Overall per-participant eradication was defined as eradication of all Baseline Gram-negative pathogens.	Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21
Percentage of Participants With Sustained Microbiologic Eradication at Follow-up By Baseline Pathogen	Microbiological outcomes per Baseline pathogen at FU were determined according to the following criteria for each diagnosis: HAP/VAP/HCAP: Sustained eradication was defined as the absence of the Baseline Gram-negative pathogen from an appropriate clinical specimen after TOC. BSI/Sepsis: Absence of the Baseline Gram-negative pathogen from a blood culture or other primary source after TOC as applicable. For HAP/VAP/HCAP and sepsis if an appropriate clinical culture could not be obtained and the participant had a successful clinical response after TOC, the response was presumed sustained eradication. cUTI: a culture taken any time after documented eradication at TOC, and a urine culture obtained at FU showed that the Baseline uropathogen found at entry at ≥10⁵ CFU/mL remained < 10³ CFU/mL. Overall per-participant response was defined as sustained eradication of all Baseline Gram-negative pathogens after documented eradication at TOC.	Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28
Percentage of Participants With Microbiologic Eradication at EOT By Baseline Carbapenem-resistant Pathogen	Microbiological outcome per Baseline carbapenem-resistant pathogen were determined according to the following criteria for each diagnosis: HAP/VAP/HCAP: Eradication was defined as the absence of the Baseline Gram-negative pathogen from an appropriate clinical specimen. If it was not possible to obtain an appropriate clinical culture and the participant had a successful clinical outcome, the response was presumed to be eradication. BSI/Sepsis: Absence of the Baseline Gram-negative pathogen from a blood culture and/or other primary source as applicable. In the case of sepsis, if the participant had a successful clinical outcome and it was not possible to obtain an appropriate clinical culture, the response was presumed to be eradication. cUTI: a urine culture that showed that the Gram-negative uropathogen identified at Baseline at ≥ 10⁵ CFU/mL was reduced to < 10³ CFU/mL. Overall per-participant eradication was defined as eradication of all Baseline Gram-negative pathogens.	End of treatment, Day 7 to 14
Percentage of Participants With Microbiologic Eradication at TOC By Baseline Carbapenem-resistant Pathogen	Microbiological outcome per Baseline carbapenem-resistant pathogen were determined according to the following criteria for each diagnosis: HAP/VAP/HCAP: Eradication was defined as the absence of the Baseline Gram-negative pathogen from an appropriate clinical specimen. If it was not possible to obtain an appropriate clinical culture and the participant had a successful clinical outcome, the response was presumed to be eradication. BSI/Sepsis: Absence of the Baseline Gram-negative pathogen from a blood culture and/or other primary source as applicable. In the case of sepsis, if the participant had a successful clinical outcome and it was not possible to obtain an appropriate clinical culture, the response was presumed to be eradication. cUTI: a urine culture that showed that the Gram-negative uropathogen identified at Baseline at ≥ 10⁵ CFU/mL was reduced to < 10³ CFU/mL. Overall per-participant eradication was defined as eradication of all Baseline Gram-negative pathogens.	Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21
Percentage of Participants With Sustained Microbiologic Eradication at Follow-up By Baseline Carbapenem-resistant Pathogen	Microbiological outcomes per Baseline pathogen at FU were determined according to the following criteria for each diagnosis: HAP/VAP/HCAP: Sustained eradication was defined as the absence of the Baseline Gram-negative pathogen from an appropriate clinical specimen after TOC. BSI/Sepsis: Absence of the Baseline Gram-negative pathogen from a blood culture or other primary source after TOC as applicable. For HAP/VAP/HCAP and sepsis if an appropriate clinical culture could not be obtained and the participant had a successful clinical response after TOC, the response was presumed sustained eradication. cUTI: a culture taken any time after documented eradication at TOC, and a urine culture obtained at FU showed that the Baseline uropathogen found at entry at ≥10⁵ CFU/mL remained < 10³ CFU/mL. Overall per-participant response was defined as sustained eradication of all Baseline Gram-negative pathogens after documented eradication at TOC.	Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28
Percentage of Participants With Microbiologic Eradication at EOT in Participants With Documented Carbapenem-resistant Gram-negative Bacteremia	The percentage of participants who experienced eradication of the Baseline documented carbapenem-resistant Gram-negative bacteremia, defined as absence of the Baseline Gram-negative pathogen from a blood culture.	End of treatment, Day 7 to 14
Percentage of Participants With Microbiologic Eradication at TOC in Participants With Documented Carbapenem-resistant Gram-negative Bacteremia	The percentage of participants who experienced eradication of the Baseline documented carbapenem-resistant Gram-negative bacteremia, defined as absence of the Baseline Gram-negative pathogen from a blood culture.	Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21
Percentage of Participants With Sustained Microbiologic Eradication at Follow-up in Participants With Documented Carbapenem-resistant Gram-negative Bacteremia	The percentage of participants who experienced sustained eradication of the Baseline documented carbapenem-resistant Gram-negative bacteremia, defined as absence of the Baseline Gram-negative pathogen from a blood culture after TOC.	Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28
Percentage of Participants With a Composite Clinical and Microbiological Response at EOT	The composite clinical and microbiological response rate is defined as the percentage of participants with both clinical cure and microbiologic eradication, as defined above for each site of infection.	End of treatment, Day 7 to 14
Percentage of Participants With a Composite Clinical and Microbiological Response at TOC	The composite clinical and microbiological response rate is defined as the percentage of participants with both clinical cure and microbiologic eradication, as defined above for each site of infection.	Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21
Percentage of Participants With a Composite Clinical and Microbiological Response at Follow-up	The composite clinical and microbiological response rate is defined as the percentage of participants with both sustained clinical cure and sustained microbiologic eradication, as defined above for each site of infection.	Follow-up, defined as 14 days after the end of treatment, equivalent to Study Day 21 to 28
All-cause Mortality at Day 14 and Day 28	The all-cause mortality rate at Day 14 and Day 28 was calculated as the percentage of participants who experienced mortality regardless of the cause at or before Day 14 and Day 28, respectively.	Day 14 and Day 28
Percentage of Participants Alive and With No Change in Antibiotic Treatment Due to Either Lack of Therapeutic Benefit or Drug-related Toxicity at TOC		Test of cure, defined as 7 days after end of treatment, equivalent to Study Day 14 to 21
Survival Time	Survival time was analyzed by Kaplan-Meier survival curve. The table below presents deaths that occurred in10-day time intervals through the end of study	Days 1 to 10, 11 to 20, 21 to 30, 31 to 40, 41-50, and 51 to 60.
Change From Baseline in Clinical Pulmonary Infection Score (CPIS) in Participants With Pneumonia (HAP/VAP/HCAP)	Clinical pulmonary infection score (CPIS) is a surrogate for diagnosis and treatment response. Points (0, 1, or 2) are assigned for observed findings for 5 variables including body temperature, white blood cell count, tracheal secretions, ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2), and chest radiograph infiltrates. The total score ranges from 0 to 10, where higher scores may indicate a higher likelihood of mortality; a negative change from Baseline indicates improvement	Baseline, end of treatment (Day 7-14), test of cure (7 days after end of treatment, equivalent to Study Day 14 to 21) and follow-up (14 days after end of treatment, equivalent to Study Day 21 to 28)
Change From Baseline in Sequential Organ Failure Assessment (SOFA)	The SOFA score is a scoring system to determine the extent of a patient's organ function or rate of failure. The score is based on six different scores, one each for the respiratory, cardiovascular, hepatic, coagulation, renal, and neurological systems. Each score is from 0 to 4, and the total score ranges from 0 to 24, where higher scores indicate a higher likelihood of mortality. A negative change from Baseline score indicates improvement.	Baseline, end of treatment (Day 7 to 14), test of cure (7 days after end of treatment, equivalent to Study Day 14 to 21) and follow-up (14 days after end of treatment, equivalent to Study Day 21 to 28)
Number of Participants With Adverse Events	The severity of each adverse event (AE) was graded by the investigator according to the following definitions: Mild: Symptom or finding is minor and does not interfere with usual daily activities; Moderate: The event causes discomfort and interferes with usual daily activity or affects clinical status; Severe: The event causes interruption of usual daily activities or has a clinically significant effect The relationship of AEs to study treatment was determined by the investigator according to the following definition: ● Related: An AE which can be reasonably explained as having been caused by the study treatment. A serious AE is defined as any AE that resulted in any of the following outcomes: Death; Life-threatening condition; Hospitalization or prolongation of existing hospitalization; Persistent or significant disability/incapacity; Congenital anomaly/birth defect; Other medically important condition	From first dose of study drug up to 28 days after last dose; maximum treatment duration was 29 days in the cefiderocol group and 22 days in the BAT group.

Collaborators and Investigators

• Sponsor: Shionogi

Publications and helpful links

General Publications

• Nordmann P, Shields RK, Doi Y, Takemura M, Echols R, Matsunaga Y, Yamano Y. Mechanisms of Reduced Susceptibility to Cefiderocol Among Isolates from the CREDIBLE-CR and APEKS-NP Clinical Trials. Microb Drug Resist. 2022 Apr;28(4):398-407. doi: 10.1089/mdr.2021.0180. Epub 2022 Jan 24.
• Wenzler E, Butler D, Tan X, Katsube T, Wajima T. Pharmacokinetics, Pharmacodynamics, and Dose Optimization of Cefiderocol during Continuous Renal Replacement Therapy. Clin Pharmacokinet. 2022 Apr;61(4):539-552. doi: 10.1007/s40262-021-01086-y. Epub 2021 Nov 18. Erratum In: Clin Pharmacokinet. 2022 Jul;61(7):1069.
• Naseer S, Weinstein EA, Rubin DB, Suvarna K, Wei X, Higgins K, Goodwin A, Jang SH, Iarikov D, Farley J, Nambiar S. US Food and Drug Administration (FDA): Benefit-Risk Considerations for Cefiderocol (Fetroja(R)). Clin Infect Dis. 2021 Jun 15;72(12):e1103-e1111. doi: 10.1093/cid/ciaa1799.
• Bassetti M, Echols R, Matsunaga Y, Ariyasu M, Doi Y, Ferrer R, Lodise TP, Naas T, Niki Y, Paterson DL, Portsmouth S, Torre-Cisneros J, Toyoizumi K, Wunderink RG, Nagata TD. Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant Gram-negative bacteria (CREDIBLE-CR): a randomised, open-label, multicentre, pathogen-focused, descriptive, phase 3 trial. Lancet Infect Dis. 2021 Feb;21(2):226-240. doi: 10.1016/S1473-3099(20)30796-9. Epub 2020 Oct 12.
• Bassetti M, Ariyasu M, Binkowitz B, Nagata TD, Echols RM, Matsunaga Y, Toyoizumi K, Doi Y. Designing A Pathogen-Focused Study To Address The High Unmet Medical Need Represented By Carbapenem-Resistant Gram-Negative Pathogens - The International, Multicenter, Randomized, Open-Label, Phase 3 CREDIBLE-CR Study. Infect Drug Resist. 2019 Nov 21;12:3607-3623. doi: 10.2147/IDR.S225553. eCollection 2019.

Study record dates

Study Major Dates

• Study Start (Actual): September 7, 2016
• Primary Completion (Actual): April 1, 2019
• Study Completion (Actual): April 22, 2019

Study Registration Dates

• First Submitted: February 26, 2016
• First Submitted That Met QC Criteria: March 15, 2016
• First Posted (Estimate): March 21, 2016

Study Record Updates

• Last Update Posted (Actual): January 12, 2021
• Last Update Submitted That Met QC Criteria: December 18, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: Sepsis; S-649266; cefiderocol; Bloodstream infections (BSI); Complicated urinary tract infection (cUTI); Ventilator associated pneumonia (VAP); Hospital acquired pneumonia (HAP); multi-drug resistant pathogens; Gram-negative pathogens; Healthcare-associated pneumonia (HCAP); carbapenem resistant pathogens
• Additional Relevant MeSH Terms: Pathologic Processes; Respiratory Tract Infections; Respiratory Tract Diseases; Lung Diseases; Urologic Diseases; Systemic Inflammatory Response Syndrome; Inflammation; Disease Attributes; Cross Infection; Iatrogenic Disease; Sepsis; Infections; Communicable Diseases; Healthcare-Associated Pneumonia; Pneumonia; Urinary Tract Infections; Pneumonia, Ventilator-Associated
• Other Study ID Numbers: 1424R2131; 2015-004703-23 (EudraCT Number)