Back to resultsA Study of Efficacy and Safety of Intravenous Cefiderocol (S-649266) Versus Imipenem/Cilastatin in Complicated Urinary Tract Infections (APEKS-cUTI)
Primary Purpose
Urinary Tract Infections
Status
Completed
Phase
Phase 2
Locations
Study Type
Interventional
Intervention
Cefiderocol
Imipenem/cilastatin
Sponsored by
About this trial
This is an interventional treatment trial for Urinary Tract Infections focused on measuring S-649266, complicated urinary tract infection, cefiderocol, acute uncomplicated pyelonephritis, Gram-negative pathogens, imipenem/cilastatin
Eligibility Criteria
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
Sites / Locations
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Cefiderocol
Imipenem/cilastatin
Arm 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.
Outcomes
Primary Outcome Measures
Percentage of Participants With Composite Response of Microbiological Eradication and Clinical Response at Test of Cure
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
Percentage of Participants With Composite Response of Microbiological Eradication and Clinical Response at Early Assessment
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.
Percentage of Participants With Composite Response of Microbiological Eradication and Clinical Response at End of Treatment
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.
Percentage of Participants With Composite Response of Microbiological Eradication and Clinical Response at Follow-up
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.
Percentage of Participants With Microbiological Eradication at Test of Cure
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.
Percentage of Participants With Microbiological Eradication at Early Assessment
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.
Percentage of Participants With Microbiological Eradication at End of Treatment
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.
Percentage of Participants With Microbiological Eradication at Follow-up
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.
Percentage of Participants With Microbiological Eradication at Test of Cure Per Uropathogen
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.
Percentage of Participants With Microbiological Eradication at Early Assessment Per Uropathogen
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.
Percentage of Participants With Microbiological Eradication at End of Treatment Per Uropathogen
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.
Percentage of Participants With Microbiological Eradication at Follow-up Per Uropathogen
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.
Percentage of Participants With Clinical Response at Test of Cure
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.
Percentage of Participants With Clinical Response at Early Assessment
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.
Percentage of Participants With Clinical Response at End of 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.
Percentage of Participants With Clinical Response at Follow-up
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.
Percentage of Participants With Clinical Response at Test of Cure Per Uropathogen
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.
Percentage of Participants With Clinical Response at Early Assessment Per Uropathogen
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.
Percentage of Participants With Clinical Response at End of Treatment Per Uropathogen
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.
Percentage of Participants With Clinical Response at Follow-up Per Uropathogen
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.
Plasma Concentration of Cefiderocol
Urine Concentration of Cefiderocol
Number of Participants With Adverse Events
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02321800
Brief Title
A Study of Efficacy and Safety of Intravenous Cefiderocol (S-649266) Versus Imipenem/Cilastatin in Complicated Urinary Tract Infections
Acronym
APEKS-cUTI
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
Study Type
Interventional
2. Study Status
Record Verification Date
November 2019
Overall Recruitment Status
Completed
Study Start Date
February 5, 2015 (Actual)
Primary Completion Date
July 26, 2016 (Actual)
Study Completion Date
August 16, 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Shionogi
4. Oversight
Data Monitoring Committee
Yes
5. 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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Urinary Tract Infections
Keywords
S-649266, complicated urinary tract infection, cefiderocol, acute uncomplicated pyelonephritis, Gram-negative pathogens, imipenem/cilastatin
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
452 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Cefiderocol
Arm Type
Experimental
Arm Description
Participants received 2 g cefiderocol by intravenous injection once every 8 hours for 7 to 14 days.
Arm Title
Imipenem/cilastatin
Arm Type
Active Comparator
Arm Description
Participants received 1 g each of imipenem/cilastatin by intravenous injection once every 8 hours for 7 to 14 days.
Intervention Type
Drug
Intervention Name(s)
Cefiderocol
Other Intervention Name(s)
FETROJA®, S-649266
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Imipenem/cilastatin
Other Intervention Name(s)
PRIMAXIN®
Intervention Description
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.
Primary Outcome Measure Information:
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)
Secondary Outcome Measure Information:
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)
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)
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)
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)
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Title
Plasma Concentration of Cefiderocol
Time Frame
On Day 3 of dosing prior to infusion, end of infusion, and at 1 hour post infusion
Title
Urine Concentration of Cefiderocol
Time Frame
Day 3, 2 hours and 6 hours after end of infusion
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
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Shionogi Clinical Trials Administrator Clinical Support Help Line
Organizational Affiliation
Shionogi
Official's Role
Study Director
12. IPD Sharing Statement
Citations:
PubMed Identifier
30509675
Citation
Portsmouth S, van Veenhuyzen D, Echols R, Machida M, Ferreira JCA, Ariyasu M, Tenke P, Nagata TD. Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by Gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2018 Dec;18(12):1319-1328. doi: 10.1016/S1473-3099(18)30554-1. Epub 2018 Oct 25.
Results Reference
result
PubMed Identifier
34868583
Citation
Portsmouth S, Echols R, Toyoizumi K, Tillotson G, Nagata TD. Structured patient interview to assess clinical outcomes in complicated urinary tract infections in the APEKS-cUTI study: pilot investigation. Ther Adv Infect Dis. 2021 Nov 24;8:20499361211058257. doi: 10.1177/20499361211058257. eCollection 2021 Jan-Dec.
Results Reference
derived
PubMed Identifier
34792787
Citation
Wenzler E, Butler D, Tan X, Katsube T, Wajima T. Pharmacokinetics, Pharmacodynamics, and Dose Optimization of Cefiderocol during Continuous Renal Replacement Therapy. Clin Pharmacokinet. 2022 Apr;61(4):539-552. doi: 10.1007/s40262-021-01086-y. Epub 2021 Nov 18. Erratum In: Clin Pharmacokinet. 2022 Jul;61(7):1069.
Results Reference
derived
PubMed Identifier
33393598
Citation
Naseer S, Weinstein EA, Rubin DB, Suvarna K, Wei X, Higgins K, Goodwin A, Jang SH, Iarikov D, Farley J, Nambiar S. US Food and Drug Administration (FDA): Benefit-Risk Considerations for Cefiderocol (Fetroja(R)). Clin Infect Dis. 2021 Jun 15;72(12):e1103-e1111. doi: 10.1093/cid/ciaa1799.
Results Reference
derived
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A Study of Efficacy and Safety of Intravenous Cefiderocol (S-649266) Versus Imipenem/Cilastatin in Complicated Urinary Tract Infections
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