APEKS-cUTI: A Study of Efficacy and Safety of Intravenous Cefiderocol (S-649266) Versus Imipenem/Cilastatin in Complicated Urinary Tract Infections

• Sponsor: Shionogi (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02321800
• Collaborator: (none)
• Enrollment: 452
• Arms: 2
• Actual Duration (Months): 18.3

Study Details

Study Description

Brief Summary

The purpose of this study was to determine the efficacy and safety of intravenous cefiderocol (S-649266) in hospitalized adults with complicated urinary tract infections caused by Gram-negative pathogens.

Condition or Disease	Intervention/Treatment	Phase
Urinary Tract Infections	Drug: Cefiderocol; Drug: Imipenem/cilastatin	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 452 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Double-blind, Randomized, Clinical Study to Assess the Efficacy and Safety of Intravenous S-649266 in Complicated Urinary Tract Infections With or Without Pyelonephritis or Acute Uncomplicated Pyelonephritis Caused by Gram-Negative Pathogens in Hospitalized Adults in Comparison With Intravenous Imipenem/Cilastatin
• Actual Study Start Date: Feb 5, 2015
• Actual Primary Completion Date: Jul 26, 2016
• Actual Study Completion Date: Aug 16, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cefiderocol Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Drug: Cefiderocol; 2000 mg intravenously every 8 hours for 7 to 14 days; dose adjustments for participants with reduced renal function (estimated CrCl ≤ 70 mL/minute) and/or body weight (< 70 kg) included every 6-hour dosing intervals and/or reduced doses.; Other Names: FETROJA® S-649266
Active Comparator: Imipenem/cilastatin Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.	Drug: Imipenem/cilastatin; 1000 mg of each intravenously every 8 hours for 7 to 14 days; dose adjustments for participants with reduced renal function (estimated CrCl ≤ 70 mL/minute) and/or body weight (< 70 kg) included every 6-hour dosing intervals and/or reduced doses.; Other Names: PRIMAXIN®

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Composite Response of Microbiological Eradication and Clinical Response at Test of Cure [Test of cure (TOC; 7 days after end of treatment [EOT], equivalent to Study Day 14 to 21)]

   The primary efficacy endpoint was the composite outcome of clinical response and microbiological response at the test of cure assessment, defined as 7 days (±2 days) after the end of antibiotic treatment. Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with response defined as resolution or improvement of complicated urinary tract infection symptoms present at study entry and the absence of new symptoms. Microbiological outcome was based on quantitative microbiological urine cultures, with eradication defined as the bacterial pathogen found at study entry at > 1 × 10⁵ CFU/mL reduced to 1 × 10⁴ CFU/mL or less.

Secondary Outcome Measures

1. Percentage of Participants With Composite Response of Microbiological Eradication and Clinical Response at Early Assessment [Early assessment (EA; Day 4)]

   A composite outcome of clinical response and microbiological response at the early assessment, defined as Day 4 of antibiotic treatment. Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with response defined as resolution or improvement of complicated urinary tract infection symptoms present at study entry and the absence of new symptoms. Microbiological outcome was based on quantitative microbiological urine cultures, with eradication defined as the bacterial pathogen found at study entry at > 1 × 10⁵ CFU/mL reduced to 1 × 10⁴ CFU/mL or less.

2. Percentage of Participants With Composite Response of Microbiological Eradication and Clinical Response at End of Treatment [End of treatment (EOT; Day 7 to 14)]

   A composite outcome of clinical response and microbiological response at the end of treatment, defined as the end of the last infusion of antibiotic treatment. Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with response defined as resolution or improvement of complicated urinary tract infection symptoms present at study entry and the absence of new symptoms. Microbiological outcome was based on quantitative microbiological urine cultures, with eradication defined as the bacterial pathogen found at study entry at > 1 × 10⁵ CFU/mL reduced to 1 × 10⁴ CFU/mL or less.

3. Percentage of Participants With Composite Response of Microbiological Eradication and Clinical Response at Follow-up [Follow-up (FUP; 14 days after end of treatment, Day 21 to 28)]

   A composite response of clinical response and microbiological response at the follow-up assessment, defined as 14 days after the end of treatment. Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with sustained response defined as all pre-therapy signs and symptoms of cUTI show no evidence of recurrence after administration of the last dose of study drug. Microbiological outcome was based on quantitative microbiological urine cultures, with sustained eradication defined as a urine culture obtained after documented eradication at the TOC, up to and including the FUP, showed that the bacterial uropathogen(s) identified at baseline at ≥ 10⁵ CFU/mL remained < 10⁴ CFU/mL.

4. Percentage of Participants With Microbiological Eradication at Test of Cure [Test of cure (7 days after end of treatment, Day 14 to 21)]

   Microbiological outcome was based on quantitative microbiological urine cultures, with eradication defined as all bacterial uropathogens found at study entry at > 1 × 10⁵ CFU/mL reduced to 1 × 10⁴ CFU/mL or less.

5. Percentage of Participants With Microbiological Eradication at Early Assessment [Early assessment, Day 4]

   Microbiological outcome was based on quantitative microbiological urine cultures, with eradication defined as all bacterial uropathogens found at study entry at > 1 × 10⁵ CFU/mL reduced to 1 × 10⁴ CFU/mL or less.

6. Percentage of Participants With Microbiological Eradication at End of Treatment [End of treatment, Day 7 to 14]

   Microbiological outcome was based on quantitative microbiological urine cultures, with eradication defined as all bacterial uropathogens found at study entry at > 1 × 10⁵ CFU/mL reduced to 1 × 10⁴ CFU/mL or less.

7. Percentage of Participants With Microbiological Eradication at Follow-up [Follow-up, 14 days after end of treatment, Day 21 to 28]

   Microbiological outcome was based on quantitative microbiological urine cultures, with sustained eradication defined as a urine culture obtained after documented eradication at the TOC, up to and including the FUP, where the bacterial uropathogen(s) identified at baseline at ≥ 10⁵ CFU/mL remained < 10⁴ CFU/mL.

8. Percentage of Participants With Microbiological Eradication at Test of Cure Per Uropathogen [Test of cure; 7 days after end of treatment, Day 14 to 21]

   Microbiological outcome was based on quantitative microbiological urine cultures, with eradication defined as the bacterial pathogen found at study entry at > 1 × 10⁵ CFU/mL reduced to 1 × 10⁴ CFU/mL or less. Results are reported for the 4 most frequent uropathogens, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis.

9. Percentage of Participants With Microbiological Eradication at Early Assessment Per Uropathogen [Early assessment, Day 4]

   Microbiological outcome was based on quantitative microbiological urine cultures, with eradication defined as the bacterial pathogen found at study entry at > 1 × 10⁵ CFU/mL reduced to 1 × 10⁴ CFU/mL or less. Results are reported for the 4 most frequent uropathogens, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis.

10. Percentage of Participants With Microbiological Eradication at End of Treatment Per Uropathogen [End of treatment, Day 7 to 14]

    Microbiological outcome was based on quantitative microbiological urine cultures, with eradication defined as the bacterial pathogen found at study entry at > 1 × 10⁵ CFU/mL reduced to 1 × 10⁴ CFU/mL or less. Results are reported for the 4 most frequent uropathogens, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis.

11. Percentage of Participants With Microbiological Eradication at Follow-up Per Uropathogen [Follow-up, 14 days after the end of treatment, Day 21 to 28]

    Microbiological outcome was based on quantitative microbiological urine cultures, with sustained eradication defined as a urine culture obtained after documented eradication at the TOC, up to and including the FUP, where the bacterial uropathogen identified at baseline at ≥ 10⁵ CFU/mL remained < 10⁴ CFU/mL. Results are reported for the 4 most frequent uropathogens, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis.

12. Percentage of Participants With Clinical Response at Test of Cure [Test of cure, 7 days after end of treatment, Day 14 to 21]

    Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with response defined as resolution or improvement of complicated urinary tract infection symptoms present at study entry and the absence of new symptoms.

13. Percentage of Participants With Clinical Response at Early Assessment [Early assessment, Day 4]

    Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with response defined as resolution or improvement of complicated urinary tract infection symptoms present at study entry and the absence of new symptoms.

14. Percentage of Participants With Clinical Response at End of Treatment [End of treatment, Day 7 to 14]

    Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with response defined as resolution or improvement of complicated urinary tract infection symptoms present at study entry and the absence of new symptoms.

15. Percentage of Participants With Clinical Response at Follow-up [Follow-up, 14 days after end of treatment, Day 21 to 28]

    Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with sustained response defined as all pre-therapy signs and symptoms of cUTI showing no evidence of recurrence after administration of the last dose of study drug.

16. Percentage of Participants With Clinical Response at Test of Cure Per Uropathogen [Test of cure, 7 days after end of treatment, Day 14 to 21]

    Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with response defined as resolution or improvement of complicated urinary tract infection symptoms present at study entry and the absence of new symptoms. Results are reported for the 4 most frequent uropathogens, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis.

17. Percentage of Participants With Clinical Response at Early Assessment Per Uropathogen [Early assessment, Day 4]

    Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with response defined as resolution or improvement of complicated urinary tract infection symptoms present at study entry and the absence of new symptoms. Results are reported for the 4 most frequent uropathogens, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis.

18. Percentage of Participants With Clinical Response at End of Treatment Per Uropathogen [End of treatment, Day 7 to 14]

    Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with response defined as resolution or improvement of complicated urinary tract infection symptoms present at study entry and the absence of new symptoms. Results are reported for the 4 most frequent uropathogens, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis.

19. Percentage of Participants With Clinical Response at Follow-up Per Uropathogen [Follow-up, 14 days after the end of treatment, Day 21 to 28]

    Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with sustained response defined as all pre-therapy signs and symptoms of cUTI show no evidence of recurrence after administration of the last dose of study drug. Results are reported for the 4 most frequent uropathogens, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis.

20. Plasma Concentration of Cefiderocol [On Day 3 of dosing prior to infusion, end of infusion, and at 1 hour post infusion]

21. Urine Concentration of Cefiderocol [Day 3, 2 hours and 6 hours after end of infusion]

22. Number of Participants With Adverse Events [From first dose of study drug until 28 days after end of treatment; Day 35 to 42]

    A serious adverse event was defined by regulation as any adverse event (AE) occurring at any dose 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. The relationship of an event to the study drug was determined by the investigator based on whether the AE could be reasonably explained as being caused by the study drug.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Hospitalized male and female patients ≥ 18 years

• Clinical diagnosis of either complicated urinary tract infections (cUTI) with or without pyelonephritis or acute uncomplicated pyelonephritis

• cUTI diagnosed with a history of ≥ 1 of the following:

• Indwelling urinary catheter or recent instrumentation of the urinary tract

• Urinary retention (caused by benign prostatic hypertrophy)

• Urinary retention of at least 100 mL or more of residual urine after voiding (neurogenic bladder)

• Obstructive uropathy

• Azotemia caused by intrinsic renal disease (blood urea nitrogen and creatinine values greater than normal laboratory values) OR Pyelonephritis and normal urinary tract anatomy, ie, acute uncomplicated pyelonephritis AND

At least 2 of the following signs or symptoms:

• Chills or rigors or warmth associated with fever (temperature greater than or equal to 38 degrees Celsius)

• Flank pain (pyelonephritis) or suprapubic/pelvic pain (cUTI)

• Nausea or vomiting

• Dysuria, urinary frequency, or urinary urgency

• Costo-vertebral angle tenderness on physical examination AND

All subjects had to have urinalysis evidence of pyuria demonstrated by 1 of the following:

• Dipstick analysis positive for leukocyte esterase

• ≥ 10 white blood cells (WBCs) per μL in unspun urine, or ≥ 10 WBCs per high power field in spun urine

• Positive urine culture within 48 hours prior to randomization containing ≥10^5 colony forming unit (CFU)/mL of a Gram-negative uropathogen likely to be susceptible to imipenem (IPM)

• Patients who were treated previously with an empiric antibiotic other than the study drugs but failed treatment, both clinically and microbiologically, were eligible for the study if they had an identified Gram-negative uropathogen that was not susceptible to the previously used empiric treatment and likely to be susceptible to IPM

• Subjects receiving antibiotic prophylaxis for UTI who present with signs and symptoms consistent with an active new UTI

Exclusion Criteria:

• Urine culture identifies only a Gram-positive pathogen and/or a Gram-negative uropathogen resistant to IPM

• Urine culture at study entry isolates more than 2 uropathogens or patient has a confirmed fungal UTI

• Asymptomatic bacteriuria, the presence of >10^5 CFU/mL of a uropathogen and pyuria but without local or systemic symptoms

• Patient is receiving hemodialysis or peritoneal dialysis

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Shionogi

Investigators

• Study Director: Shionogi Clinical Trials Administrator Clinical Support Help Line, Shionogi

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Shionogi
• ClinicalTrials.gov Identifier: NCT02321800
• Other Study ID Numbers: 1409R2121
• First Posted: Dec 22, 2014
• Last Update Posted: Dec 12, 2019
• Last Verified: Nov 1, 2019

• Keywords provided by Shionogi: S-649266; complicated urinary tract infection; cefiderocol; acute uncomplicated pyelonephritis; Gram-negative pathogens; imipenem/cilastatin
• Additional relevant MeSH terms: Infections; Communicable Diseases; Urinary Tract Infections; Pyelonephritis; Imipenem; Cilastatin

Study Results

Participant Flow

Recruitment Details	This study was conducted at 67 hospitals in 15 countries. Participants diagnosed with complicated urinary tract infections (cUTIs) with or without pyelonephritis or acute uncomplicated pyelonephritis were enrolled from February 5, 2015 to August 16, 2016.
Pre-assignment Detail	Participants were randomly assigned (2:1) to receive either cefiderocol or imipenem-cilastatin. Randomization was stratified by clinical diagnosis (complicated urinary tract infection with or without pyelonephritis or with acute uncomplicated pyelonephritis) and region (North America, Europe, Russia, and Japan).

Arm/Group Title	Cefiderocol	Imipenem/Cilastatin
Arm/Group Description	Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Period Title: Overall Study
STARTED	303	149
Received Study Drug	300	148
COMPLETED	283	138
NOT COMPLETED	20	11

Baseline Characteristics

Arm/Group Title	Cefiderocol	Imipenem/Cilastatin	Total
Arm/Group Description	Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.	Total of all reporting groups
Overall Participants	252	119	371
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.3 (16.10)	61.3 (18.48)	62.0 (16.88)
Age, Customized (Count of Participants)
< 65 years	113 44.8%	54 45.4%	167 45%
>= 65 years	139 55.2%	65 54.6%	204 55%
Sex: Female, Male (Count of Participants)
Female	133 52.8%	71 59.7%	204 55%
Male	119 47.2%	48 40.3%	167 45%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 2%	1 0.8%	6 1.6%
Not Hispanic or Latino	247 98%	118 99.2%	365 98.4%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	241 95.6%	115 96.6%	356 96%
Black or African American	1 0.4%	0 0%	1 0.3%
Asian	9 3.6%	4 3.4%	13 3.5%
Native Hawaiian or Other Pacific Islander	1 0.4%	0 0%	1 0.3%
Creatinine Clearance Renal Grading Group (Count of Participants)
> 80 mL/min (Normal)	124 49.2%	51 42.9%	175 47.2%
> 50 - 80 mL/min (Mild)	78 31%	41 34.5%	119 32.1%
30 - 50 mL/min (Moderate)	41 16.3%	23 19.3%	64 17.3%
< 30 mL/min (Severe)	7 2.8%	4 3.4%	11 3%
Clinical Diagnosis at Baseline (Count of Participants)
cUTI with pyelonephritis	65 25.8%	29 24.4%	94 25.3%
cUTI without pyelonephritis	122 48.4%	55 46.2%	177 47.7%
Acute Uncomplicated Pyelonephritis	65 25.8%	35 29.4%	100 27%
Number of Gram-negative Uropathogens > 10⁵ CFU/mL Isolated at Baseline (Count of Participants)
1 uropathogen	241 95.6%	115 96.6%	356 96%
2 uropathogens	11 4.4%	4 3.4%	15 4%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Composite Response of Microbiological Eradication and Clinical Response at Test of Cure
Description	The primary efficacy endpoint was the composite outcome of clinical response and microbiological response at the test of cure assessment, defined as 7 days (±2 days) after the end of antibiotic treatment. Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with response defined as resolution or improvement of complicated urinary tract infection symptoms present at study entry and the absence of new symptoms. Microbiological outcome was based on quantitative microbiological urine cultures, with eradication defined as the bacterial pathogen found at study entry at > 1 × 10⁵ CFU/mL reduced to 1 × 10⁴ CFU/mL or less.
Time Frame	Test of cure (TOC; 7 days after end of treatment [EOT], equivalent to Study Day 14 to 21)

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat population

Arm/Group Title	Cefiderocol	Imipenem/Cilastatin
Arm/Group Description	Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Measure Participants	252	119
Number [percentage of participants]	72.6 28.8%	54.6 45.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cefiderocol, Imipenem/Cilastatin
	Comments	Adjusted estimates of the difference between the two treatment groups are based on a stratified analysis using Cochran-Mantel-Haenszel weights, with clinical diagnosis (complicated urinary tract infection with or without pyelonephritis vs acute uncomplicated pyelonephritis) as the stratification factor.
	Type of Statistical Test	Non-Inferiority
	Comments	The margin of noninferiority was 20%. Noninferiority was concluded if the lower bound of a 2-sided 95% CI for the difference in response rates between the 2 treatment groups was greater than -20%. If the noninferiority inference based on the 20% margin was concluded successfully, noninferiority inference based on the 15% margin was performed.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	18.58
	Confidence Interval	(2-Sided) 95%; 8.23 to 28.92
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Percentage of Participants With Composite Response of Microbiological Eradication and Clinical Response at Early Assessment
Description	A composite outcome of clinical response and microbiological response at the early assessment, defined as Day 4 of antibiotic treatment. Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with response defined as resolution or improvement of complicated urinary tract infection symptoms present at study entry and the absence of new symptoms. Microbiological outcome was based on quantitative microbiological urine cultures, with eradication defined as the bacterial pathogen found at study entry at > 1 × 10⁵ CFU/mL reduced to 1 × 10⁴ CFU/mL or less.
Time Frame	Early assessment (EA; Day 4)

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat population

Arm/Group Title	Cefiderocol	Imipenem/Cilastatin
Arm/Group Description	Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Measure Participants	252	119
Number [percentage of participants]	88.1 35%	87.4 73.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cefiderocol, Imipenem/Cilastatin
	Comments	Adjusted estimates of the difference between the two treatment groups are based on a stratified analysis using Cochran-Mantel-Haenszel weights, with clinical diagnosis (complicated urinary tract infection with or without pyelonephritis vs acute uncomplicated pyelonephritis) as the stratification factor.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	0.66
	Confidence Interval	(2-Sided) 95%; -6.48 to 7.79
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percentage of Participants With Composite Response of Microbiological Eradication and Clinical Response at End of Treatment
Description	A composite outcome of clinical response and microbiological response at the end of treatment, defined as the end of the last infusion of antibiotic treatment. Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with response defined as resolution or improvement of complicated urinary tract infection symptoms present at study entry and the absence of new symptoms. Microbiological outcome was based on quantitative microbiological urine cultures, with eradication defined as the bacterial pathogen found at study entry at > 1 × 10⁵ CFU/mL reduced to 1 × 10⁴ CFU/mL or less.
Time Frame	End of treatment (EOT; Day 7 to 14)

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat population

Arm/Group Title	Cefiderocol	Imipenem/Cilastatin
Arm/Group Description	Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Measure Participants	252	119
Number [percentage of participants]	96.4 38.3%	95.8 80.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cefiderocol, Imipenem/Cilastatin
	Comments	Adjusted estimates of the difference between the two treatment groups are based on a stratified analysis using Cochran-Mantel-Haenszel weights, with clinical diagnosis (complicated urinary tract infection with or without pyelonephritis vs acute uncomplicated pyelonephritis) as the stratification factor.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	0.72
	Confidence Interval	(2-Sided) 95%; -3.48 to 4.92
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Percentage of Participants With Composite Response of Microbiological Eradication and Clinical Response at Follow-up
Description	A composite response of clinical response and microbiological response at the follow-up assessment, defined as 14 days after the end of treatment. Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with sustained response defined as all pre-therapy signs and symptoms of cUTI show no evidence of recurrence after administration of the last dose of study drug. Microbiological outcome was based on quantitative microbiological urine cultures, with sustained eradication defined as a urine culture obtained after documented eradication at the TOC, up to and including the FUP, showed that the bacterial uropathogen(s) identified at baseline at ≥ 10⁵ CFU/mL remained < 10⁴ CFU/mL.
Time Frame	Follow-up (FUP; 14 days after end of treatment, Day 21 to 28)

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat population

Arm/Group Title	Cefiderocol	Imipenem/Cilastatin
Arm/Group Description	Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Measure Participants	252	119
Number [percentage of participants]	54.4 21.6%	39.5 33.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cefiderocol, Imipenem/Cilastatin
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	15.31
	Confidence Interval	(2-Sided) 95%; 4.69 to 25.92
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Percentage of Participants With Microbiological Eradication at Test of Cure
Description	Microbiological outcome was based on quantitative microbiological urine cultures, with eradication defined as all bacterial uropathogens found at study entry at > 1 × 10⁵ CFU/mL reduced to 1 × 10⁴ CFU/mL or less.
Time Frame	Test of cure (7 days after end of treatment, Day 14 to 21)

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat population

Arm/Group Title	Cefiderocol	Imipenem/Cilastatin
Arm/Group Description	Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Measure Participants	252	119
Number [percentage of participants]	73.0 29%	56.3 47.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cefiderocol, Imipenem/Cilastatin
	Comments	Adjusted estimates of the difference between the two treatment groups are based on a stratified analysis using Cochran-Mantel-Haenszel weights, with clinical diagnosis (complicated urinary tract infection with or without pyelonephritis vs acute uncomplicated pyelonephritis) as the stratification factor.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	17.25
	Confidence Interval	(2-Sided) 95%; 6.92 to 27.58
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Percentage of Participants With Microbiological Eradication at Early Assessment
Description	Microbiological outcome was based on quantitative microbiological urine cultures, with eradication defined as all bacterial uropathogens found at study entry at > 1 × 10⁵ CFU/mL reduced to 1 × 10⁴ CFU/mL or less.
Time Frame	Early assessment, Day 4

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat population

Arm/Group Title	Cefiderocol	Imipenem/Cilastatin
Arm/Group Description	Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Measure Participants	252	119
Number [percentage of participants]	92.1 36.5%	90.8 76.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cefiderocol, Imipenem/Cilastatin
	Comments	Adjusted estimates of the difference between the two treatment groups are based on a stratified analysis using Cochran-Mantel-Haenszel weights, with clinical diagnosis (complicated urinary tract infection with or without pyelonephritis vs acute uncomplicated pyelonephritis) as the stratification factor.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	1.28
	Confidence Interval	(2-Sided) 95%; -4.83 to 7.39
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Percentage of Participants With Microbiological Eradication at End of Treatment
Description	Microbiological outcome was based on quantitative microbiological urine cultures, with eradication defined as all bacterial uropathogens found at study entry at > 1 × 10⁵ CFU/mL reduced to 1 × 10⁴ CFU/mL or less.
Time Frame	End of treatment, Day 7 to 14

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat population

Arm/Group Title	Cefiderocol	Imipenem/Cilastatin
Arm/Group Description	Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Measure Participants	252	119
Number [percentage of participants]	96.8 38.4%	95.8 80.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cefiderocol, Imipenem/Cilastatin
	Comments	Adjusted estimates of the difference between the two treatment groups are based on a stratified analysis using Cochran-Mantel-Haenszel weights, with clinical diagnosis (complicated urinary tract infection with or without pyelonephritis vs acute uncomplicated pyelonephritis) as the stratification factor.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	1.10
	Confidence Interval	(2-Sided) 95%; -3.04 to 5.25
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Percentage of Participants With Microbiological Eradication at Follow-up
Description	Microbiological outcome was based on quantitative microbiological urine cultures, with sustained eradication defined as a urine culture obtained after documented eradication at the TOC, up to and including the FUP, where the bacterial uropathogen(s) identified at baseline at ≥ 10⁵ CFU/mL remained < 10⁴ CFU/mL.
Time Frame	Follow-up, 14 days after end of treatment, Day 21 to 28

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat population

Arm/Group Title	Cefiderocol	Imipenem/Cilastatin
Arm/Group Description	Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Measure Participants	252	119
Number [percentage of participants]	57.1 22.7%	43.7 36.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cefiderocol, Imipenem/Cilastatin
	Comments	Adjusted estimates of the difference between the two treatment groups are based on a stratified analysis using Cochran-Mantel-Haenszel weights, with clinical diagnosis (complicated urinary tract infection with or without pyelonephritis vs acute uncomplicated pyelonephritis) as the stratification factor.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	13.92
	Confidence Interval	(2-Sided) 95%; 3.21 to 24.63
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Percentage of Participants With Microbiological Eradication at Test of Cure Per Uropathogen
Description	Microbiological outcome was based on quantitative microbiological urine cultures, with eradication defined as the bacterial pathogen found at study entry at > 1 × 10⁵ CFU/mL reduced to 1 × 10⁴ CFU/mL or less. Results are reported for the 4 most frequent uropathogens, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis.
Time Frame	Test of cure; 7 days after end of treatment, Day 14 to 21

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat population with the relevant pathogen at Baseline

Arm/Group Title	Cefiderocol	Imipenem/Cilastatin
Arm/Group Description	Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Measure Participants	231	110
Escherichia coli	75.0 29.8%	58.2 48.9%
Klebsiella pneumoniae	75.0 29.8%	52.0 43.7%
Pseudomonas aeruginosa	44.4 17.6%	60.0 50.4%
Proteus mirabilis	76.5 30.4%	50.0 42%

10. Secondary Outcome

Title	Percentage of Participants With Microbiological Eradication at Early Assessment Per Uropathogen
Description	Microbiological outcome was based on quantitative microbiological urine cultures, with eradication defined as the bacterial pathogen found at study entry at > 1 × 10⁵ CFU/mL reduced to 1 × 10⁴ CFU/mL or less. Results are reported for the 4 most frequent uropathogens, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis.
Time Frame	Early assessment, Day 4

Outcome Measure Data

Analysis Population Description

Intent-to-treat population with the relevant pathogen at Baseline

Arm/Group Title	Cefiderocol	Imipenem/Cilastatin
Arm/Group Description	Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Measure Participants	231	110
Escherichia coli	92.8 36.8%	94.9 79.7%
Klebsiella pneumoniae	89.6 35.6%	88.0 73.9%
Pseudomonas aeruginosa	94.4 37.5%	80.0 67.2%
Proteus mirabilis	88.2 35%	100.0 84%

11. Secondary Outcome

Title	Percentage of Participants With Microbiological Eradication at End of Treatment Per Uropathogen
Description	Microbiological outcome was based on quantitative microbiological urine cultures, with eradication defined as the bacterial pathogen found at study entry at > 1 × 10⁵ CFU/mL reduced to 1 × 10⁴ CFU/mL or less. Results are reported for the 4 most frequent uropathogens, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis.
Time Frame	End of treatment, Day 7 to 14

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat population with the relevant pathogen at Baseline

Arm/Group Title	Cefiderocol	Imipenem/Cilastatin
Arm/Group Description	Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Measure Participants	231	110
Escherichia coli	98.7 39.2%	97.5 81.9%
Klebsiella pneumoniae	97.9 38.8%	92.0 77.3%
Pseudomonas aeruginosa	88.9 35.3%	100.0 84%
Proteus mirabilis	94.1 37.3%	100.0 84%

12. Secondary Outcome

Title	Percentage of Participants With Microbiological Eradication at Follow-up Per Uropathogen
Description	Microbiological outcome was based on quantitative microbiological urine cultures, with sustained eradication defined as a urine culture obtained after documented eradication at the TOC, up to and including the FUP, where the bacterial uropathogen identified at baseline at ≥ 10⁵ CFU/mL remained < 10⁴ CFU/mL. Results are reported for the 4 most frequent uropathogens, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis.
Time Frame	Follow-up, 14 days after the end of treatment, Day 21 to 28

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat population with the relevant pathogen at Baseline

Arm/Group Title	Cefiderocol	Imipenem/Cilastatin
Arm/Group Description	Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Measure Participants	231	110
Escherichia coli	59.9 23.8%	41.8 35.1%
Klebsiella pneumoniae	58.3 23.1%	52.0 43.7%
Pseudomonas aeruginosa	27.8 11%	20.0 16.8%
Proteus mirabilis	64.7 25.7%	0 0%

13. Secondary Outcome

Title	Percentage of Participants With Clinical Response at Test of Cure
Description	Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with response defined as resolution or improvement of complicated urinary tract infection symptoms present at study entry and the absence of new symptoms.
Time Frame	Test of cure, 7 days after end of treatment, Day 14 to 21

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat population

Arm/Group Title	Cefiderocol	Imipenem/Cilastatin
Arm/Group Description	Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Measure Participants	252	119
Number [percentage of participants]	89.7 35.6%	87.4 73.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cefiderocol, Imipenem/Cilastatin
	Comments	Adjusted estimates of the difference between the two treatment groups are based on a stratified analysis using Cochran-Mantel-Haenszel weights, with clinical diagnosis (complicated urinary tract infection with or without pyelonephritis vs acute uncomplicated pyelonephritis) as the stratification factor.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	2.39
	Confidence Interval	(2-Sided) 95%; -4.66 to 9.44
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Percentage of Participants With Clinical Response at Early Assessment
Description	Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with response defined as resolution or improvement of complicated urinary tract infection symptoms present at study entry and the absence of new symptoms.
Time Frame	Early assessment, Day 4

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat population

Arm/Group Title	Cefiderocol	Imipenem/Cilastatin
Arm/Group Description	Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Measure Participants	252	119
Number [percentage of participants]	90.5 35.9%	90.8 76.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cefiderocol, Imipenem/Cilastatin
	Comments	Adjusted estimates of the difference between the two treatment groups are based on a stratified analysis using Cochran-Mantel-Haenszel weights, with clinical diagnosis (complicated urinary tract infection with or without pyelonephritis vs acute uncomplicated pyelonephritis) as the stratification factor.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	-0.26
	Confidence Interval	(2-Sided) 95%; -6.57 to 6.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Secondary Outcome

Title	Percentage of Participants With Clinical Response at End of Treatment
Description	Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with response defined as resolution or improvement of complicated urinary tract infection symptoms present at study entry and the absence of new symptoms.
Time Frame	End of treatment, Day 7 to 14

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat population

Arm/Group Title	Cefiderocol	Imipenem/Cilastatin
Arm/Group Description	Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Measure Participants	252	119
Number [percentage of participants]	98.0 38.9%	99.2 83.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cefiderocol, Imipenem/Cilastatin
	Comments	Adjusted estimates of the difference between the two treatment groups are based on a stratified analysis using Cochran-Mantel-Haenszel weights, with clinical diagnosis (complicated urinary tract infection with or without pyelonephritis vs acute uncomplicated pyelonephritis) as the stratification factor.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	-1.07
	Confidence Interval	(2-Sided) 95%; -3.42 to 1.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. Secondary Outcome

Title	Percentage of Participants With Clinical Response at Follow-up
Description	Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with sustained response defined as all pre-therapy signs and symptoms of cUTI showing no evidence of recurrence after administration of the last dose of study drug.
Time Frame	Follow-up, 14 days after end of treatment, Day 21 to 28

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat population

Arm/Group Title	Cefiderocol	Imipenem/Cilastatin
Arm/Group Description	Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Measure Participants	252	119
Number [percentage of participants]	81.3 32.3%	72.3 60.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Cefiderocol, Imipenem/Cilastatin
	Comments	Adjusted estimates of the difference between the two treatment groups are based on a stratified analysis using Cochran-Mantel-Haenszel weights, with clinical diagnosis (complicated urinary tract infection with or without pyelonephritis vs acute uncomplicated pyelonephritis) as the stratification factor.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Treatment Difference
	Estimated Value	9.02
	Confidence Interval	(2-Sided) 95%; -0.37 to 18.41
	Parameter Dispersion	Type: Value:
	Estimation Comments

17. Secondary Outcome

Title	Percentage of Participants With Clinical Response at Test of Cure Per Uropathogen
Description	Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with response defined as resolution or improvement of complicated urinary tract infection symptoms present at study entry and the absence of new symptoms. Results are reported for the 4 most frequent uropathogens, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis.
Time Frame	Test of cure, 7 days after end of treatment, Day 14 to 21

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat population with the relevant pathogen at Baseline and available clinical outcome data

Arm/Group Title	Cefiderocol	Imipenem/Cilastatin
Arm/Group Description	Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Measure Participants	220	107
Escherichia coli	89.7 35.6%	88.3 74.2%
Klebsiella pneumoniae	89.1 35.4%	84.0 70.6%
Pseudomonas aeruginosa	73.3 29.1%	75.0 63%
Proteus mirabilis	100.0 39.7%	100.0 84%

18. Secondary Outcome

Title	Percentage of Participants With Clinical Response at Early Assessment Per Uropathogen
Description	Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with response defined as resolution or improvement of complicated urinary tract infection symptoms present at study entry and the absence of new symptoms. Results are reported for the 4 most frequent uropathogens, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis.
Time Frame	Early assessment, Day 4

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat population with the relevant pathogen at Baseline and with available clinical outcome data

Arm/Group Title	Cefiderocol	Imipenem/Cilastatin
Arm/Group Description	Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Measure Participants	220	107
Escherichia coli	91.8 36.4%	96.1 80.8%
Klebsiella pneumoniae	82.6 32.8%	88.0 73.9%
Pseudomonas aeruginosa	93.3 37%	75.0 63%
Proteus mirabilis	84.6 33.6%	100.0 84%

19. Secondary Outcome

Title	Percentage of Participants With Clinical Response at End of Treatment Per Uropathogen
Description	Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with response defined as resolution or improvement of complicated urinary tract infection symptoms present at study entry and the absence of new symptoms. Results are reported for the 4 most frequent uropathogens, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis.
Time Frame	End of treatment, Day 7 to 14

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat population with the relevant pathogen at Baseline and with available clinical outcome data

Arm/Group Title	Cefiderocol	Imipenem/Cilastatin
Arm/Group Description	Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Measure Participants	220	107
Escherichia coli	97.9 38.8%	98.7 82.9%
Klebsiella pneumoniae	100.0 39.7%	100.0 84%
Pseudomonas aeruginosa	93.3 37%	100.0 84%
Proteus mirabilis	100.0 39.7%	100.0 84%

20. Secondary Outcome

Title	Percentage of Participants With Clinical Response at Follow-up Per Uropathogen
Description	Clinical response was based on the investigator's evaluation of the participant's clinical signs and symptoms, with sustained response defined as all pre-therapy signs and symptoms of cUTI show no evidence of recurrence after administration of the last dose of study drug. Results are reported for the 4 most frequent uropathogens, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Proteus mirabilis.
Time Frame	Follow-up, 14 days after the end of treatment, Day 21 to 28

Outcome Measure Data

Analysis Population Description

Modified intent-to-treat population with the relevant pathogen at Baseline and with available clinical outcome data

Arm/Group Title	Cefiderocol	Imipenem/Cilastatin
Arm/Group Description	Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Measure Participants	220	107
Escherichia coli	82.9 32.9%	72.7 61.1%
Klebsiella pneumoniae	82.6 32.8%	68.0 57.1%
Pseudomonas aeruginosa	53.3 21.2%	75.0 63%
Proteus mirabilis	84.6 33.6%	100.0 84%

21. Secondary Outcome

Title	Plasma Concentration of Cefiderocol
Time Frame	On Day 3 of dosing prior to infusion, end of infusion, and at 1 hour post infusion

Outcome Measure Data

Analysis Population Description

The pharmacokinetic (PK) concentration population included all participants who underwent plasma or urine PK sampling and had at least 1 evaluable PK assay result for cefiderocol

Arm/Group Title	Cefiderocol
Arm/Group Description	Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.
Measure Participants	293
Pre-infusion	18.0 (18.3)
End of infusion	141 (220)
1 hour after end of infusion	70.2 (30.4)

22. Secondary Outcome

Title	Urine Concentration of Cefiderocol
Time Frame	Day 3, 2 hours and 6 hours after end of infusion

Outcome Measure Data

Analysis Population Description

Pharmacokinetic concentration population with available urine concentration data

Arm/Group Title	Cefiderocol
Arm/Group Description	Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.
Measure Participants	8
2 hours after end of infusion	2710 (1520)
6 hours after end of infusion	1520 (1370)

23. Secondary Outcome

Title	Number of Participants With Adverse Events
Description	A serious adverse event was defined by regulation as any adverse event (AE) occurring at any dose 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. The relationship of an event to the study drug was determined by the investigator based on whether the AE could be reasonably explained as being caused by the study drug.
Time Frame	From first dose of study drug until 28 days after end of treatment; Day 35 to 42

Outcome Measure Data

Analysis Population Description

The safety population included all randomized participants who received at least 1 dose of the study drug

Arm/Group Title	Cefiderocol	Imipenem/Cilastatin
Arm/Group Description	Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Measure Participants	300	148
All adverse events	122 48.4%	76 63.9%
Drug-related adverse events	27 10.7%	17 14.3%
Deaths	1 0.4%	0 0%
Serious adverse events	14 5.6%	12 10.1%
Drug-related serious adverse events	1 0.4%	1 0.8%
Discontinuation of study drug due to AE	5 2%	3 2.5%
Discontinuation due to drug-related AE	3 1.2%	0 0%

Adverse Events

Time Frame	From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Arm/Group Title	S-649266		Imipenem/Cilastatin
Arm/Group Description
All Cause Mortality
	S-649266		Imipenem/Cilastatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/300 (0.3%)		0/148 (0%)
Serious Adverse Events
	S-649266		Imipenem/Cilastatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/300 (4.7%)		12/148 (8.1%)
Blood and lymphatic system disorders
Anaemia	1/300 (0.3%)		0/148 (0%)
Haemorrhagic anaemia	1/300 (0.3%)		0/148 (0%)
Cardiac disorders
Cardiac failure	1/300 (0.3%)		1/148 (0.7%)
Cardiac failure acute	1/300 (0.3%)		0/148 (0%)
Cardio-respiratory arrest	1/300 (0.3%)		0/148 (0%)
Myocardial ischaemia	1/300 (0.3%)		0/148 (0%)
Congenital, familial and genetic disorders
Congenital ureteric anomaly	0/300 (0%)		1/148 (0.7%)
Gastrointestinal disorders
Diarrhoea	1/300 (0.3%)		1/148 (0.7%)
Duodenal ulcer	1/300 (0.3%)		0/148 (0%)
Lower gastrointestinal haemorrhage	0/300 (0%)		1/148 (0.7%)
Upper gastrointestinal haemorrhage	1/300 (0.3%)		0/148 (0%)
General disorders
Pyrexia	1/300 (0.3%)		0/148 (0%)
Hepatobiliary disorders
Gallbladder pain	1/300 (0.3%)		0/148 (0%)
Infections and infestations
Abscess	0/300 (0%)		1/148 (0.7%)
Ascariasis	1/300 (0.3%)		0/148 (0%)
Cellulitis	1/300 (0.3%)		0/148 (0%)
Clostridium difficile colitis	1/300 (0.3%)		2/148 (1.4%)
Device related infection	0/300 (0%)		1/148 (0.7%)
Pneumonia	1/300 (0.3%)		0/148 (0%)
Prostatic abscess	0/300 (0%)		1/148 (0.7%)
Pyelonephritis	0/300 (0%)		1/148 (0.7%)
Renal abscess	1/300 (0.3%)		0/148 (0%)
Urinary tract infection	1/300 (0.3%)		0/148 (0%)
Injury, poisoning and procedural complications
Alcohol poisoning	0/300 (0%)		1/148 (0.7%)
Gastrointestinal injury	0/300 (0%)		1/148 (0.7%)
Investigations
Blood creatine phosphokinase increased	1/300 (0.3%)		0/148 (0%)
Haematocrit decreased	0/300 (0%)		1/148 (0.7%)
Nervous system disorders
Ischaemic stroke	0/300 (0%)		1/148 (0.7%)
Renal and urinary disorders
Acute kidney injury	0/300 (0%)		1/148 (0.7%)
Hydronephrosis	0/300 (0%)		1/148 (0.7%)
Obstructive nephropathy	1/300 (0.3%)		0/148 (0%)
Ureterolithiasis	1/300 (0.3%)		0/148 (0%)
Urinary tract obstruction	1/300 (0.3%)		0/148 (0%)
Surgical and medical procedures
Urethrotomy	1/300 (0.3%)		0/148 (0%)
Vascular disorders
Deep vein thrombosis	0/300 (0%)		1/148 (0.7%)
Other (Not Including Serious) Adverse Events
	S-649266		Imipenem/Cilastatin
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	60/300 (20%)		48/148 (32.4%)
Gastrointestinal disorders
Abdominal pain upper	2/300 (0.7%)		5/148 (3.4%)
Constipation	10/300 (3.3%)		6/148 (4.1%)
Diarrhoea	12/300 (4%)		8/148 (5.4%)
Nausea	7/300 (2.3%)		6/148 (4.1%)
Vomiting	6/300 (2%)		2/148 (1.4%)
General disorders
Infusion site erythema	3/300 (1%)		3/148 (2%)
Infusion site pain	9/300 (3%)		5/148 (3.4%)
Infections and infestations
Clostridium difficile colitis	0/300 (0%)		3/148 (2%)
Vaginal infection	1/300 (0.3%)		3/148 (2%)
Metabolism and nutrition disorders
Hypokalaemia	5/300 (1.7%)		4/148 (2.7%)
Nervous system disorders
Headache	7/300 (2.3%)		8/148 (5.4%)
Psychiatric disorders
Insomnia	4/300 (1.3%)		3/148 (2%)
Renal and urinary disorders
Renal cyst	4/300 (1.3%)		5/148 (3.4%)
Respiratory, thoracic and mediastinal disorders
Cough	7/300 (2.3%)		1/148 (0.7%)
Vascular disorders
Hypertension	13/300 (4.3%)		8/148 (5.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The sponsor can embargo results from a PI's center until the combined results from the completed study have been published in full or the sponsor confirms there will be no multicenter study publication. Results communications must be provided to the sponsor for review at least 60 days before submission for publication. By written request, the sponsor can extend the embargo up to an additional 60 days. The sponsor cannot require changes to scientific content and cannot further extend the embargo.