Temocillin vs Meropenem for the Targeted Treatment of Bacteraemia Resistant to Third Gen Cephalosporins

Study Overview
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Brief Summary
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A Phase 3, Multicenter, Randomised, Controlled, Open-Label Study to demonstrate noninferiority of temocillin (unauthorized investigational medicinal product IMP in Spain, but authorized in Belgium and UK) vs a carbapenem antibiotic (meropenem) in adults with bacteraemia due to third-generation cephalosporin-resistant Enterobacteriaceae. The duration of treatment will be between 7 and 14 days. From the 5th day of intravenous treatment, the sequential oral treatment is permitted if the patient meets appropriate conditions.

Detailed Description
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The objective of the trial is to demonstrate the non-inferiority of temocillin (2g each 8 hours, intravenous) to carbapenems (meropenem 1g each 8 hours, intravenous) in terms of efficacy and safety in the targeted treatment of bacteraemia due to Enterobacteriaceae resistant to third-generation cephalosporins, and therefore provide evidence for the use of temocillin in these infections. The duration of treatment will be between 7 and 14 days. From the 5th day of intravenous treatment, the sequential oral treatment is permitted if the patient meets appropriate conditions.

Official Title
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Randomised Controlled Trial of Temocillin vs Meropenem for the Targeted Treatment of Bacteraemia Due to Enterobacteriaceae Showing Resistance to Third Generation Cephalosporins

Conditions
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Bacteremia

Intervention / Treatment
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* Drug: Temocillin
* Drug: Meropenem


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients with monomicrobial bacteremia due to Enterobacteriaceae showing resistance to cefotaxime, ceftriaxone (MIC >2 mg/L) and/or ceftazidime (MIC >4 mg/L), and sensible to temocillin (MIC ≤8 mg/L, except in bacteremia only of urinary origin, for which the criterion is MIC ≤16 mg/L ) and meropenem (MIC ≤2 mg/L). Duration of intravenous treatment is planned to be at least 4 days. The patient signed informed consent form. Exclusion Criteria: <18 years Pregnancy Breastfeeding Palliative care Allergy to betalactams Polymicrobial bacteraemia Infections typically needing prolonged >14 days of therapy (e.g., endocarditis, prosthetic joint infection, vascular graft infection, empyema, chronic prostatitis) or meningitis Active empirical treatment> 96 hours after initial blood culture extraction Delay in inclusion> 48 h Recruited in another clinical trial with active treatment Peritoneal dialysis or continuous hemofiltration extreme gravity or imminent death

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized 1.1 to temocillin: meropenem
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Temocillin<br>Patients enrolled in this arm, will receive 2g each 8 hours of intravenous temocillin. | Drug: Temocillin<br>* The intervention of experimental arm will be Intravenous administration of temocillin.<br>|
| Active Comparator: Meropenem<br>Patients enrolled in this arm, will receive 1g each 8 hours of intravenous meropenem. | Drug: Meropenem<br>* The intervention of comparator arm will be intravenous administration of meropenem.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with a success at the test of cure (TOC) | A success at the test of cure is the resolution of infection symptoms | Up to 7-10 days after the last day of antibiotic therapy | 
| Survival at day 28 | Number of patients who are alive | At day 28. | 
| Number of patients who do not need to stop or change the assigned drug | Reasons for not change can be no adverse event, no perceived failure during treatment or no occurrence of a superimposed infection. Participants who stop or change the assigned drug will not meet the primary outcome. | Up to 7-14 days after the last day of antibiotic therapy | 
| Number of patients who do not need to prolong therapy beyond 14 days | Assigned treatment to be administered for less than 14 days | Up to 7-14 days after the last day of antibiotic therapy | 
| Not recurrence until day 28 | Recurrence is reappearance of symptoms with positive blood culture for the same microorganism. Participants with recurrence will not meet the primary outcome. | At day 28. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 28-day mortality | Number of patients dead up to day 28. | Up to day 28. | 
| Length of hospital stay (days) | Number of days patients has been in-hospital | Through study completion, an average of 28 days | 
| Length of intravenous therapy (days) | Number of days patients has been under intravenous antibiotic treatment | From day 1 of intravenous antibiotic treatment administration to last intravenous administration, average 14 days | 
| Length of total administration of therapy (days) | Number of days patients has been under intravenous or oral antibiotic treatment | From day 1 of intravenous or oral antibiotic treatment administration to last intravenous or oral administration, average 14 days | 
| Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 | Up to day 28 | 
| Number of subjects with resistance development during therapy | Resistance development will be measured in a positive blood culture | Up to day 28 | 
| Recurrence rate | Percentage of subjects with recurrence | Up to day 28. | 
| Changes in Sequential Organ failure (SOFA) score | Sequential Organ failure (SOFA) score changes | At days 1, 3, end of treatment (days 7-14) and visit 4 | 
| Changes in Barthel Index for Activities of Daily Living (ADL) for patients older than 70 years old | Barthel Index for Activities of Daily Living (ADL) score changes; score from 0, completely dependent patient to 100, completely independent for activities of daily living | At days 1, 3, end of treatment (days 7-14) and visit 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Bacteraemia, Enterobacteriaceae, Temocillin, Third-generation cephalosporin-resistant Enterobacteriaceae.