This is a Phase 2 randomized open label multicentre three arm comparative study evaluating the efficacy safety tolerability and pharmacokinetics of intravenous ertapenem zidebactam ERT ZID compared with ceftazidime avibactam CAZ AVI in adults with complicated urinary tract infection cUTI or acute pyelonephritis AP. Approximately 279 hospitalized participants aged 18 years and above will be enrolled from approximately 30 study sites in India and Europe and randomized in a 1 to 1 to 1 ratio to receive ERT ZID for 5 to 7 days ERT ZID for 7 to 10 days or CAZ AVI for 7 to 10 days. The primary endpoint is overall success at Test of Cure defined by clinical cure and microbiological eradication. Secondary assessments include clinical response microbiological response by pathogen outcomes pharmacokinetic parameters and plasma protein binding with safety monitored through adverse events laboratory tests vital signs and electrocardiograms.
Fever (oral, tympanic, or rectal temperature >38°C [>100.4°F]), which must be observed and documented by a health care provider
Nausea or vomiting
Dysuria, increased urinary frequency, or urinary urgency
Lower abdominal, suprapubic, or pelvic pain
Perinephric or renal abscess
Uncomplicated lower UTI (e.g., cystitis)
Recent trauma to the pelvis or urinary tract
Polycystic kidney disease
Parallel
Ertapenem-zidebactam
Drug(2 g ERT + 2 g ZID) 4 g intravenously (IV) once daily (q24h) for 5 to 7 days
Ceftazidime-Avibactam
Drug(2 g ceftazidime + 0.5 g avibactam) 2.5 g IV every 8 hours (q8h) for 7 to 10 days
Ertapenam-Zidebactam
Drug(2 g ERT + 2 g ZID) 4 g intravenously (IV) once daily (q24h) for 7 to 10 days
Clinical Outcome at Test of Cure (TOC) - mMITT Analysis Set:
Clinical outcome assessed as Clinical Cure, Clinical Failure, or Clinical Indeterminate using the Daily Symptom Assessment questionnaire and Investigator assessment. Unit of measure: categorical (Clinical Cure/Clinical Failure/Clinical Indeterminate)
Microbiological Outcome at Test of Cure (TOC) - mMITT Analysis Set
Microbiological outcome assessed as Microbiological Eradication, Microbiological Persistence, or Microbiological Indeterminate using urine culture with species-level identification and quantitative assessment of bacterial growth. Unit of measure: categorical (Microbiological Eradication/Microbiological Persistence/Microbiological Indeterminate).
Safety and Tolerability
Incidence of treatment-emergent adverse events (TEAEs), drug-related TEAEs, TEAEs leading to study drug discontinuation, and serious adverse events (SAEs), and incidence of potentially clinically significant changes in laboratory parameters, vital signs, and ECG parameters. Measurement tool: adverse-event reporting, clinical laboratory tests, vital signs, and electrocardiograms. Unit of measure: number and percentage of participants.
Clinical Response at End of Treatment (EOT) - mMITT Analysis Set
Clinical response assessed as Clinical Response, Clinical Non-response, or Clinical Indeterminate using the Daily Symptom Assessment questionnaire and Investigator assessment. Unit of measure: categorical (Clinical Response/Clinical Non-response/Clinical Indeterminate).
Microbiological Outcome at EOT - mMITT Analysis Set
Microbiological outcome assessed as Microbiological Eradication, Microbiological Persistence, or Microbiological Indeterminate using urine culture with species-level identification and quantitative assessment of bacterial growth. Unit of measure: categorical (Microbiological Eradication/Microbiological Persistence/Microbiological Indeterminate)
By-Pathogen Overall Outcome at TOC
Overall outcome for each baseline uropathogen, based on the corresponding clinical and microbiological outcomes. Unit of measure: categorical (Overall Success/Overall Failure/Overall Indeterminate). Measurement tools: Daily Symptom Assessment questionnaire and Investigator assessment, and urine culture.
By-Pathogen Microbiological Outcome at TOC
Microbiological outcome for each baseline uropathogen assessed using urine culture with species-level identification and quantitative assessment of bacterial growth. Unit of measure: categorical (Microbiological Eradication/Microbiological Persistence/Microbiological Indeterminate)
Percentage (%) Plasma Protein Binding of ERT and ZID
Percentage of plasma protein binding of ertapenem and zidebactam determined from blood samples collected from participants receiving ERT-ZID. Unit of measure: percentage (%). Measurement tool: plasma protein binding assessment from collected blood samples.
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