Temocillin Versus a Carbapenem as Initial Intravenous Treatment for ESBL Related Urinary Tract Infections

Study Overview
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Brief Summary
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TEMO-CARB is a phase 3, randomized, controlled, multicentre, open-label pragmatic clinical trial to test the non-inferiority of temocillin versus carbapenem as initial intravenous treatment of Urinary Tract Infection (UTI) due to extended-spectrum beta-lactamase (ESBL) producing enterobacteriaceae.

Detailed Description
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Urinary tract infections are among the most common bacterial infections that are treated in the community by an empirical antibiotic treatment regimen. Enterobacteriaceae are the most common bacteria involved in urinary tract infection. Since 2006, extended-spectrum beta-lactamase (ESBL) producing enterobacteriaceae have spread in France, as elsewhere. Finding therapeutic alternatives to carbapenems in infections caused by ESBL producing enterobacteriaceae is imperative. Although temocillin, 6-α-methoxy derivative of ticarcillin has been suggested as a potential alternative to carbapenem therapy for ESBL related infections, it was not investigated in accordance with current standard. The hypothesis to test in this study is that temocillin is not inferior to a carbapenem as initial intravenous treatment of urinary tract infections caused by ESBL producing enterobacteriaceae.

Official Title
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Temocillin Versus a Carbapenem as Initial Intravenous Treatment for Extended-spectrum Beta-lactamase Related Urinary Tract Infections, a Non-inferiority Study

Conditions
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Urinary Tract Infections

Intervention / Treatment
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* Drug: Temocillin
* Drug: meropenem or imipenem


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult (≥ 18 years) Hospitalized patient with clinically significant monomicrobial UTI Complicated UTI due to ESBL producing enterobacteriaceae (pyelonephritis, prostatitis or renal abscess) requiring parenteral antimicrobial therapy Susceptibility to temocillin and carbapenem as evidenced by testing results For woman able to procreate: negative pregnancy test and use of an effective method of contraception (abstinence, oral contraceptives, intra-uterine device, diaphragm with spermicide and condom). All forms of hormonal contraception are acceptable Signed informed consent by patient himself (able or under curatorship) or his legal representative (patient unable to give his consent or under tutorship) Patient affiliated to the social security system Exclusion Criteria: Patient infected with a bacteria which is not an ESBL-producing enterobacteriaceae. Polymicrobial infection. Hypersensitivity and/or previous intolerance to carbapenem or temocillin, or penicillins or any other beta-lactam. Patient with a contraindication to any of the drugs to be used in research Patient presenting another site of infection than urinary (except onset of bacteraemia from urinary tract origin due to Gram negative bacteria). Woman who is pregnant, breastfeeding, or expecting to conceive at any time during the study (pregnancy test will be conducted for woman without menopause). Palliative care of life expectancy < 90 days. Ongoing empirical treatment of the urinary tract infections with carbapenem or temocillin > 24 hours before randomization Delay in randomization > 48 hours after identification of ESBL producing enterobacteriaceae in urinary and/or blood culture. Participation in other clinical trial for the infection.

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intravenous temocillin<br>Intravenous temocillin 2g/intravenously/8h or renally adjusted equivalent (ORAE) in 30-40 min infusion or continuous intravenous (6g/24h) | Drug: Temocillin<br>* Intravenous temocillin disodium 2g intravenously/8h Or Renally Adjusted Equivalent (ORAE) in 30-40 min infusion or continuous intravenous (6g/24h) .<br>|
| Active Comparator: Intravenous meropenem or imipenem<br>Intravenous meropenem or imipenem 1g/Intravenously /8h ORAE in 15-30 min infusion. Then switch to oral therapy | Drug: meropenem or imipenem<br>* Intravenous carbapenem (meropenem 1g intravenously/8h Or Renally Adjusted Equivalent (ORAE) or imipenem 1g intravenously/8h ORAE)<br>* Other names: Carbapenems;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical and microbiological cure | The primary endpoint, was defined as achieving both clinical cure and microbiological eradication of all baseline pathogens 5-7 days after completion of treatment. Clinical cure is defined as complete resolution, substantial improvement or return to pre-infections signs and symptoms of complicated lower urinary tract infections or pyelonephritis without the need for additional antibiotic therapy Microbiological efficacy will be assessed by quantitative urine culture and defined as follows < 10^3 Colony Forming Unit (CFU)/mL of the baseline pathogens | 5-7 days after end of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Early microbiological eradication | Microbiological eradication will be assessed by quantitative urine culture and defined as follows < 10^3 colony forming unit Colony Forming Unit (CFU)/mL of the baseline pathogens | 3-4 days after randomization | 
| Frequency of oral antibiotic switch in both arms (temocillin vs. carbapenem) |  | 60 days after randomization | 
| Length of hospital stay | Time from randomization to hospital discharge | 60 days after randomization | 
| Persistent cure rate | Clinical cure is defined as complete resolution, substantial improvement or return to pre-infections signs and symptoms of complicated lower urinary tract infections or pyelonephritis without the need for additional antibiotic therapy | 60 days after randomization | 
| Clinical recurrences | Relapse: new symptoms of urinary tract infection in a patient previously considered as clinically or microbiologically cured in the visit 5-7 days after treatment completion plus positive urine ± blood culture grows the same microorganism isolated that in the initial culture. Re-infection: same definition but with different strain in urinary culture | 60 days after randomization | 
| Mortality | Death for any reason or for infectious events | 60 days after randomization | 
| Pharmacokinetic of temocillin according to kidney function | Description of the temocillin plasma concentration and its variability among patients | 3 days after treatment initiation | 
| Microbiota impact study | Study treatment impact in the gut colonization with multidrug Gram negative bacilli) and temocillin resistant Gram negative bacilli | Time Frame : 5-7 days after treatment completion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-inferiority study, Temocillin, Carbapenem, ESBL infection, Urinary tract infection