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

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

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.

Study Overview

• Status: Completed
• Conditions: Urinary Tract Infections
• Intervention / Treatment: Drug: Cefiderocol; Drug: Imipenem/cilastatin

• Study Type: Interventional
• Enrollment (Actual): 452
• Phase: Phase 2

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Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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: S-649266; FETROJA®
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®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Test of cure (TOC; 7 days after end of treatment [EOT], equivalent to Study Day 14 to 21)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Early assessment (EA; Day 4)
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.	End of treatment (EOT; Day 7 to 14)
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.	Follow-up (FUP; 14 days after end of treatment, Day 21 to 28)
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.	Test of cure (7 days after end of treatment, Day 14 to 21)
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.	Early assessment, Day 4
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.	End of treatment, Day 7 to 14
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.	Follow-up, 14 days after end of treatment, Day 21 to 28
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.	Test of cure; 7 days after end of treatment, Day 14 to 21
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.	Early assessment, Day 4
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.	End of treatment, Day 7 to 14
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.	Follow-up, 14 days after the end of treatment, Day 21 to 28
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.	Test of cure, 7 days after end of treatment, Day 14 to 21
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.	Early assessment, Day 4
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.	End of treatment, Day 7 to 14
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.	Follow-up, 14 days after end of treatment, Day 21 to 28
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.	Test of cure, 7 days after end of treatment, Day 14 to 21
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.	Early assessment, Day 4
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.	End of treatment, Day 7 to 14
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.	Follow-up, 14 days after the end of treatment, Day 21 to 28
Plasma Concentration of Cefiderocol		On Day 3 of dosing prior to infusion, end of infusion, and at 1 hour post infusion
Urine Concentration of Cefiderocol		Day 3, 2 hours and 6 hours after end of infusion
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.	From first dose of study drug until 28 days after end of treatment; Day 35 to 42

Collaborators and Investigators

• Sponsor: Shionogi

Publications and helpful links

General Publications

• Wenzler E, Butler D, Tan X, Katsube T, Wajima T. Pharmacokinetics, Pharmacodynamics, and Dose Optimization of Cefiderocol during Continuous Renal Replacement Therapy. Clin Pharmacokinet. 2022 Apr;61(4):539-552. doi: 10.1007/s40262-021-01086-y. Epub 2021 Nov 18. Erratum In: Clin Pharmacokinet. 2022 Jul;61(7):1069.
• Naseer S, Weinstein EA, Rubin DB, Suvarna K, Wei X, Higgins K, Goodwin A, Jang SH, Iarikov D, Farley J, Nambiar S. US Food and Drug Administration (FDA): Benefit-Risk Considerations for Cefiderocol (Fetroja(R)). Clin Infect Dis. 2021 Jun 15;72(12):e1103-e1111. doi: 10.1093/cid/ciaa1799.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 5, 2015
• Primary Completion (Actual): July 26, 2016
• Study Completion (Actual): August 16, 2016

Study Registration Dates

• First Submitted: November 11, 2014
• First Submitted That Met QC Criteria: December 16, 2014
• First Posted (Estimate): December 22, 2014

Study Record Updates

• Last Update Posted (Actual): December 12, 2019
• Last Update Submitted That Met QC Criteria: November 20, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: S-649266; cefiderocol; Gram-negative pathogens; complicated urinary tract infection; acute uncomplicated pyelonephritis; imipenem/cilastatin
• Additional Relevant MeSH Terms: Pathologic Processes; Kidney Diseases; Urologic Diseases; Disease Attributes; Nephritis; Nephritis, Interstitial; Pyelitis; Infections; Communicable Diseases; Urinary Tract Infections; Pyelonephritis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Protease Inhibitors; Anti-Bacterial Agents; Imipenem; Cilastatin
• Other Study ID Numbers: 1409R2121