Trial Outcomes & Findings for A Study of Efficacy and Safety of Intravenous Cefiderocol (S-649266) Versus Imipenem/Cilastatin in Complicated Urinary Tract Infections (NCT NCT02321800)

Last Updated: 2019-12-12

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

452 participants

Primary outcome timeframe

Test of cure (TOC; 7 days after end of treatment [EOT], equivalent to Study Day 14 to 21)

Results posted on

2019-12-12

Participant Flow

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.

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).

Participant milestones

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

Reasons for withdrawal

Reasons for withdrawal
Measure	Cefiderocol Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Imipenem/Cilastatin Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Overall Study Withdrawal by Subject	3	3
Overall Study Death	1	0
Overall Study Protocol Violation	1	0
Overall Study Lost to Follow-up	10	4
Overall Study Adverse Event	2	3
Overall Study Other, Miscellaneous	3	1

Baseline Characteristics

Participants with available data

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cefiderocol n=252 Participants Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Imipenem/Cilastatin n=119 Participants Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.	Total n=371 Participants Total of all reporting groups
Age, Continuous	62.3 years STANDARD_DEVIATION 16.10 • n=252 Participants	61.3 years STANDARD_DEVIATION 18.48 • n=119 Participants	62.0 years STANDARD_DEVIATION 16.88 • n=371 Participants
Age, Customized < 65 years	113 Participants n=252 Participants	54 Participants n=119 Participants	167 Participants n=371 Participants
Age, Customized >= 65 years	139 Participants n=252 Participants	65 Participants n=119 Participants	204 Participants n=371 Participants
Sex: Female, Male Female	133 Participants n=252 Participants	71 Participants n=119 Participants	204 Participants n=371 Participants
Sex: Female, Male Male	119 Participants n=252 Participants	48 Participants n=119 Participants	167 Participants n=371 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	5 Participants n=252 Participants	1 Participants n=119 Participants	6 Participants n=371 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	247 Participants n=252 Participants	118 Participants n=119 Participants	365 Participants n=371 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=252 Participants	0 Participants n=119 Participants	0 Participants n=371 Participants
Race/Ethnicity, Customized White	241 Participants n=252 Participants	115 Participants n=119 Participants	356 Participants n=371 Participants
Race/Ethnicity, Customized Black or African American	1 Participants n=252 Participants	0 Participants n=119 Participants	1 Participants n=371 Participants
Race/Ethnicity, Customized Asian	9 Participants n=252 Participants	4 Participants n=119 Participants	13 Participants n=371 Participants
Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander	1 Participants n=252 Participants	0 Participants n=119 Participants	1 Participants n=371 Participants
Creatinine Clearance Renal Grading Group > 80 mL/min (Normal)	124 Participants n=250 Participants • Participants with available data	51 Participants n=119 Participants • Participants with available data	175 Participants n=369 Participants • Participants with available data
Creatinine Clearance Renal Grading Group > 50 - 80 mL/min (Mild)	78 Participants n=250 Participants • Participants with available data	41 Participants n=119 Participants • Participants with available data	119 Participants n=369 Participants • Participants with available data
Creatinine Clearance Renal Grading Group 30 - 50 mL/min (Moderate)	41 Participants n=250 Participants • Participants with available data	23 Participants n=119 Participants • Participants with available data	64 Participants n=369 Participants • Participants with available data
Creatinine Clearance Renal Grading Group < 30 mL/min (Severe)	7 Participants n=250 Participants • Participants with available data	4 Participants n=119 Participants • Participants with available data	11 Participants n=369 Participants • Participants with available data
Clinical Diagnosis at Baseline cUTI with pyelonephritis	65 Participants n=252 Participants	29 Participants n=119 Participants	94 Participants n=371 Participants
Clinical Diagnosis at Baseline cUTI without pyelonephritis	122 Participants n=252 Participants	55 Participants n=119 Participants	177 Participants n=371 Participants
Clinical Diagnosis at Baseline Acute Uncomplicated Pyelonephritis	65 Participants n=252 Participants	35 Participants n=119 Participants	100 Participants n=371 Participants
Number of Gram-negative Uropathogens > 10⁵ CFU/mL Isolated at Baseline 1 uropathogen	241 Participants n=252 Participants	115 Participants n=119 Participants	356 Participants n=371 Participants
Number of Gram-negative Uropathogens > 10⁵ CFU/mL Isolated at Baseline 2 uropathogens	11 Participants n=252 Participants	4 Participants n=119 Participants	15 Participants n=371 Participants

PRIMARY outcome

Timeframe: Test of cure (TOC; 7 days after end of treatment [EOT], equivalent to Study Day 14 to 21)

Population: Modified intent-to-treat population

Outcome measures

Outcome measures
Measure	Cefiderocol n=252 Participants Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Imipenem/Cilastatin n=119 Participants Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Percentage of Participants With Composite Response of Microbiological Eradication and Clinical Response at Test of Cure	72.6 percentage of participants	54.6 percentage of participants

SECONDARY outcome

Timeframe: Early assessment (EA; Day 4)

Population: Modified intent-to-treat population

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.

Outcome measures

Outcome measures
Measure	Cefiderocol n=252 Participants Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Imipenem/Cilastatin n=119 Participants Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Percentage of Participants With Composite Response of Microbiological Eradication and Clinical Response at Early Assessment	88.1 percentage of participants	87.4 percentage of participants

SECONDARY outcome

Timeframe: End of treatment (EOT; Day 7 to 14)

Population: Modified intent-to-treat population

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.

Outcome measures

Outcome measures
Measure	Cefiderocol n=252 Participants Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Imipenem/Cilastatin n=119 Participants Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Percentage of Participants With Composite Response of Microbiological Eradication and Clinical Response at End of Treatment	96.4 percentage of participants	95.8 percentage of participants

SECONDARY outcome

Timeframe: Follow-up (FUP; 14 days after end of treatment, Day 21 to 28)

Population: Modified intent-to-treat population

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.

Outcome measures

Outcome measures
Measure	Cefiderocol n=252 Participants Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Imipenem/Cilastatin n=119 Participants Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Percentage of Participants With Composite Response of Microbiological Eradication and Clinical Response at Follow-up	54.4 percentage of participants	39.5 percentage of participants

SECONDARY outcome

Timeframe: Test of cure (7 days after end of treatment, Day 14 to 21)

Population: Modified intent-to-treat population

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.

Outcome measures

Outcome measures
Measure	Cefiderocol n=252 Participants Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Imipenem/Cilastatin n=119 Participants Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Percentage of Participants With Microbiological Eradication at Test of Cure	73.0 percentage of participants	56.3 percentage of participants

SECONDARY outcome

Timeframe: Early assessment, Day 4

Population: Modified intent-to-treat population

Outcome measures

Outcome measures
Measure	Cefiderocol n=252 Participants Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Imipenem/Cilastatin n=119 Participants Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Percentage of Participants With Microbiological Eradication at Early Assessment	92.1 percentage of participants	90.8 percentage of participants

SECONDARY outcome

Timeframe: End of treatment, Day 7 to 14

Population: Modified intent-to-treat population

Outcome measures

Outcome measures
Measure	Cefiderocol n=252 Participants Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Imipenem/Cilastatin n=119 Participants Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Percentage of Participants With Microbiological Eradication at End of Treatment	96.8 percentage of participants	95.8 percentage of participants

SECONDARY outcome

Timeframe: Follow-up, 14 days after end of treatment, Day 21 to 28

Population: Modified intent-to-treat population

Outcome measures

Outcome measures
Measure	Cefiderocol n=252 Participants Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Imipenem/Cilastatin n=119 Participants Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Percentage of Participants With Microbiological Eradication at Follow-up	57.1 percentage of participants	43.7 percentage of participants

SECONDARY outcome

Timeframe: Test of cure; 7 days after end of treatment, Day 14 to 21

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

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.

Outcome measures

Outcome measures
Measure	Cefiderocol n=231 Participants Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Imipenem/Cilastatin n=110 Participants Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Percentage of Participants With Microbiological Eradication at Test of Cure Per Uropathogen Escherichia coli	75.0 percentage of participants	58.2 percentage of participants
Percentage of Participants With Microbiological Eradication at Test of Cure Per Uropathogen Klebsiella pneumoniae	75.0 percentage of participants	52.0 percentage of participants
Percentage of Participants With Microbiological Eradication at Test of Cure Per Uropathogen Pseudomonas aeruginosa	44.4 percentage of participants	60.0 percentage of participants
Percentage of Participants With Microbiological Eradication at Test of Cure Per Uropathogen Proteus mirabilis	76.5 percentage of participants	50.0 percentage of participants

SECONDARY outcome

Timeframe: Early assessment, Day 4

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

Outcome measures

Outcome measures
Measure	Cefiderocol n=231 Participants Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Imipenem/Cilastatin n=110 Participants Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Percentage of Participants With Microbiological Eradication at Early Assessment Per Uropathogen Escherichia coli	92.8 percentage of participants	94.9 percentage of participants
Percentage of Participants With Microbiological Eradication at Early Assessment Per Uropathogen Klebsiella pneumoniae	89.6 percentage of participants	88.0 percentage of participants
Percentage of Participants With Microbiological Eradication at Early Assessment Per Uropathogen Pseudomonas aeruginosa	94.4 percentage of participants	80.0 percentage of participants
Percentage of Participants With Microbiological Eradication at Early Assessment Per Uropathogen Proteus mirabilis	88.2 percentage of participants	100.0 percentage of participants

SECONDARY outcome

Timeframe: End of treatment, Day 7 to 14

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

Outcome measures

Outcome measures
Measure	Cefiderocol n=231 Participants Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Imipenem/Cilastatin n=110 Participants Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Percentage of Participants With Microbiological Eradication at End of Treatment Per Uropathogen Escherichia coli	98.7 percentage of participants	97.5 percentage of participants
Percentage of Participants With Microbiological Eradication at End of Treatment Per Uropathogen Klebsiella pneumoniae	97.9 percentage of participants	92.0 percentage of participants
Percentage of Participants With Microbiological Eradication at End of Treatment Per Uropathogen Pseudomonas aeruginosa	88.9 percentage of participants	100.0 percentage of participants
Percentage of Participants With Microbiological Eradication at End of Treatment Per Uropathogen Proteus mirabilis	94.1 percentage of participants	100.0 percentage of participants

SECONDARY outcome

Timeframe: Follow-up, 14 days after the end of treatment, Day 21 to 28

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

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.

Outcome measures

Outcome measures
Measure	Cefiderocol n=231 Participants Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Imipenem/Cilastatin n=110 Participants Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Percentage of Participants With Microbiological Eradication at Follow-up Per Uropathogen Escherichia coli	59.9 percentage of participants	41.8 percentage of participants
Percentage of Participants With Microbiological Eradication at Follow-up Per Uropathogen Klebsiella pneumoniae	58.3 percentage of participants	52.0 percentage of participants
Percentage of Participants With Microbiological Eradication at Follow-up Per Uropathogen Pseudomonas aeruginosa	27.8 percentage of participants	20.0 percentage of participants
Percentage of Participants With Microbiological Eradication at Follow-up Per Uropathogen Proteus mirabilis	64.7 percentage of participants	0 percentage of participants

SECONDARY outcome

Timeframe: Test of cure, 7 days after end of treatment, Day 14 to 21

Population: Modified intent-to-treat population

Outcome measures

Outcome measures
Measure	Cefiderocol n=252 Participants Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Imipenem/Cilastatin n=119 Participants Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Percentage of Participants With Clinical Response at Test of Cure	89.7 percentage of participants	87.4 percentage of participants

SECONDARY outcome

Timeframe: Early assessment, Day 4

Population: Modified intent-to-treat population

Outcome measures

Outcome measures
Measure	Cefiderocol n=252 Participants Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Imipenem/Cilastatin n=119 Participants Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Percentage of Participants With Clinical Response at Early Assessment	90.5 percentage of participants	90.8 percentage of participants

SECONDARY outcome

Timeframe: End of treatment, Day 7 to 14

Population: Modified intent-to-treat population

Outcome measures

Outcome measures
Measure	Cefiderocol n=252 Participants Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Imipenem/Cilastatin n=119 Participants Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Percentage of Participants With Clinical Response at End of Treatment	98.0 percentage of participants	99.2 percentage of participants

SECONDARY outcome

Timeframe: Follow-up, 14 days after end of treatment, Day 21 to 28

Population: Modified intent-to-treat population

Outcome measures

Outcome measures
Measure	Cefiderocol n=252 Participants Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Imipenem/Cilastatin n=119 Participants Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Percentage of Participants With Clinical Response at Follow-up	81.3 percentage of participants	72.3 percentage of participants

SECONDARY outcome

Timeframe: Test of cure, 7 days after end of treatment, Day 14 to 21

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

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.

Outcome measures

Outcome measures
Measure	Cefiderocol n=220 Participants Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Imipenem/Cilastatin n=107 Participants Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Percentage of Participants With Clinical Response at Test of Cure Per Uropathogen Escherichia coli	89.7 percentage of participants	88.3 percentage of participants
Percentage of Participants With Clinical Response at Test of Cure Per Uropathogen Klebsiella pneumoniae	89.1 percentage of participants	84.0 percentage of participants
Percentage of Participants With Clinical Response at Test of Cure Per Uropathogen Pseudomonas aeruginosa	73.3 percentage of participants	75.0 percentage of participants
Percentage of Participants With Clinical Response at Test of Cure Per Uropathogen Proteus mirabilis	100.0 percentage of participants	100.0 percentage of participants

SECONDARY outcome

Timeframe: Early assessment, Day 4

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

Outcome measures

Outcome measures
Measure	Cefiderocol n=220 Participants Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Imipenem/Cilastatin n=107 Participants Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Percentage of Participants With Clinical Response at Early Assessment Per Uropathogen Escherichia coli	91.8 percentage of participants	96.1 percentage of participants
Percentage of Participants With Clinical Response at Early Assessment Per Uropathogen Klebsiella pneumoniae	82.6 percentage of participants	88.0 percentage of participants
Percentage of Participants With Clinical Response at Early Assessment Per Uropathogen Pseudomonas aeruginosa	93.3 percentage of participants	75.0 percentage of participants
Percentage of Participants With Clinical Response at Early Assessment Per Uropathogen Proteus mirabilis	84.6 percentage of participants	100.0 percentage of participants

SECONDARY outcome

Timeframe: End of treatment, Day 7 to 14

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

Outcome measures

Outcome measures
Measure	Cefiderocol n=220 Participants Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Imipenem/Cilastatin n=107 Participants Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Percentage of Participants With Clinical Response at End of Treatment Per Uropathogen Escherichia coli	97.9 percentage of participants	98.7 percentage of participants
Percentage of Participants With Clinical Response at End of Treatment Per Uropathogen Klebsiella pneumoniae	100.0 percentage of participants	100.0 percentage of participants
Percentage of Participants With Clinical Response at End of Treatment Per Uropathogen Pseudomonas aeruginosa	93.3 percentage of participants	100.0 percentage of participants
Percentage of Participants With Clinical Response at End of Treatment Per Uropathogen Proteus mirabilis	100.0 percentage of participants	100.0 percentage of participants

SECONDARY outcome

Timeframe: Follow-up, 14 days after the end of treatment, Day 21 to 28

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

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.

Outcome measures

Outcome measures
Measure	Cefiderocol n=220 Participants Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Imipenem/Cilastatin n=107 Participants Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Percentage of Participants With Clinical Response at Follow-up Per Uropathogen Escherichia coli	82.9 percentage of participants	72.7 percentage of participants
Percentage of Participants With Clinical Response at Follow-up Per Uropathogen Klebsiella pneumoniae	82.6 percentage of participants	68.0 percentage of participants
Percentage of Participants With Clinical Response at Follow-up Per Uropathogen Pseudomonas aeruginosa	53.3 percentage of participants	75.0 percentage of participants
Percentage of Participants With Clinical Response at Follow-up Per Uropathogen Proteus mirabilis	84.6 percentage of participants	100.0 percentage of participants

SECONDARY outcome

Timeframe: On Day 3 of dosing prior to infusion, end of infusion, and at 1 hour post infusion

Population: 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

Outcome measures

Outcome measures
Measure	Cefiderocol n=293 Participants Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Imipenem/Cilastatin Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Plasma Concentration of Cefiderocol Pre-infusion	18.0 µg/mL Standard Deviation 18.3	—
Plasma Concentration of Cefiderocol End of infusion	141 µg/mL Standard Deviation 220	—
Plasma Concentration of Cefiderocol 1 hour after end of infusion	70.2 µg/mL Standard Deviation 30.4	—

SECONDARY outcome

Timeframe: Day 3, 2 hours and 6 hours after end of infusion

Population: Pharmacokinetic concentration population with available urine concentration data

Outcome measures

Outcome measures
Measure	Cefiderocol n=8 Participants Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Imipenem/Cilastatin Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Urine Concentration of Cefiderocol 2 hours after end of infusion	2710 µg/mL Standard Deviation 1520	—
Urine Concentration of Cefiderocol 6 hours after end of infusion	1520 µg/mL Standard Deviation 1370	—

SECONDARY outcome

Timeframe: From first dose of study drug until 28 days after end of treatment; Day 35 to 42

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

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.

Outcome measures

Outcome measures
Measure	Cefiderocol n=300 Participants Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.	Imipenem/Cilastatin n=148 Participants Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Number of Participants With Adverse Events All adverse events	122 Participants	76 Participants
Number of Participants With Adverse Events Drug-related adverse events	27 Participants	17 Participants
Number of Participants With Adverse Events Deaths	1 Participants	0 Participants
Number of Participants With Adverse Events Serious adverse events	14 Participants	12 Participants
Number of Participants With Adverse Events Drug-related serious adverse events	1 Participants	1 Participants
Number of Participants With Adverse Events Discontinuation of study drug due to AE	5 Participants	3 Participants
Number of Participants With Adverse Events Discontinuation due to drug-related AE	3 Participants	0 Participants

Adverse Events

S-649266

Serious events: 14 serious events

Other events: 60 other events

Deaths: 1 deaths

Imipenem/Cilastatin

Serious events: 12 serious events

Other events: 48 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Shionogi Clinical Trials Administrator

Shionogi Inc.

Phone: 800-849-9707

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER

Measure	S-649266 n=300 participants at risk	Imipenem/Cilastatin n=148 participants at risk
Blood and lymphatic system disorders Anaemia	0.33% 1/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	0.00% 0/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Blood and lymphatic system disorders Haemorrhagic anaemia	0.33% 1/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	0.00% 0/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Cardiac disorders Cardiac failure	0.33% 1/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	0.68% 1/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Cardiac disorders Cardiac failure acute	0.33% 1/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	0.00% 0/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Cardiac disorders Cardio-respiratory arrest	0.33% 1/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	0.00% 0/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Cardiac disorders Myocardial ischaemia	0.33% 1/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	0.00% 0/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Congenital, familial and genetic disorders Congenital ureteric anomaly	0.00% 0/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	0.68% 1/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Gastrointestinal disorders Diarrhoea	0.33% 1/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	0.68% 1/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Gastrointestinal disorders Duodenal ulcer	0.33% 1/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	0.00% 0/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Gastrointestinal disorders Lower gastrointestinal haemorrhage	0.00% 0/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	0.68% 1/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Gastrointestinal disorders Upper gastrointestinal haemorrhage	0.33% 1/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	0.00% 0/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
General disorders Pyrexia	0.33% 1/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	0.00% 0/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Hepatobiliary disorders Gallbladder pain	0.33% 1/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	0.00% 0/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Infections and infestations Abscess	0.00% 0/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	0.68% 1/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Infections and infestations Ascariasis	0.33% 1/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	0.00% 0/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Infections and infestations Cellulitis	0.33% 1/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	0.00% 0/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Infections and infestations Clostridium difficile colitis	0.33% 1/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	1.4% 2/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Infections and infestations Device related infection	0.00% 0/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	0.68% 1/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Infections and infestations Pneumonia	0.33% 1/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	0.00% 0/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Infections and infestations Prostatic abscess	0.00% 0/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	0.68% 1/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Infections and infestations Pyelonephritis	0.00% 0/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	0.68% 1/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Infections and infestations Renal abscess	0.33% 1/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	0.00% 0/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Infections and infestations Urinary tract infection	0.33% 1/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	0.00% 0/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Injury, poisoning and procedural complications Alcohol poisoning	0.00% 0/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	0.68% 1/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Injury, poisoning and procedural complications Gastrointestinal injury	0.00% 0/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	0.68% 1/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Investigations Blood creatine phosphokinase increased	0.33% 1/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	0.00% 0/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Investigations Haematocrit decreased	0.00% 0/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	0.68% 1/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Nervous system disorders Ischaemic stroke	0.00% 0/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	0.68% 1/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Renal and urinary disorders Acute kidney injury	0.00% 0/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	0.68% 1/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Renal and urinary disorders Hydronephrosis	0.00% 0/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	0.68% 1/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Renal and urinary disorders Obstructive nephropathy	0.33% 1/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	0.00% 0/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Renal and urinary disorders Ureterolithiasis	0.33% 1/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	0.00% 0/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Renal and urinary disorders Urinary tract obstruction	0.33% 1/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	0.00% 0/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Surgical and medical procedures Urethrotomy	0.33% 1/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	0.00% 0/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Vascular disorders Deep vein thrombosis	0.00% 0/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	0.68% 1/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42

Measure	S-649266 n=300 participants at risk	Imipenem/Cilastatin n=148 participants at risk
Gastrointestinal disorders Abdominal pain upper	0.67% 2/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	3.4% 5/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Gastrointestinal disorders Constipation	3.3% 10/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	4.1% 6/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Gastrointestinal disorders Diarrhoea	4.0% 12/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	5.4% 8/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Gastrointestinal disorders Nausea	2.3% 7/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	4.1% 6/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Gastrointestinal disorders Vomiting	2.0% 6/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	1.4% 2/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
General disorders Infusion site erythema	1.0% 3/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	2.0% 3/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
General disorders Infusion site pain	3.0% 9/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	3.4% 5/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Infections and infestations Clostridium difficile colitis	0.00% 0/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	2.0% 3/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Infections and infestations Vaginal infection	0.33% 1/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	2.0% 3/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Metabolism and nutrition disorders Hypokalaemia	1.7% 5/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	2.7% 4/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Nervous system disorders Headache	2.3% 7/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	5.4% 8/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Psychiatric disorders Insomnia	1.3% 4/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	2.0% 3/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Renal and urinary disorders Renal cyst	1.3% 4/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	3.4% 5/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Respiratory, thoracic and mediastinal disorders Cough	2.3% 7/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	0.68% 1/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42
Vascular disorders Hypertension	4.3% 13/300 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42	5.4% 8/148 • From first dose of study drug until 28 days after end of treatment; Day 35 to 42