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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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

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

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.

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