Efficacy of Temocillin in Urinary Tract Infection Due to ESBL Producing and AmpC Hyperproducing Enterobacteriaceae (TEMO-ESBL)

The present study aims at demonstrating the efficacy of temocillin in the treatment of UTI requiring parenteral therapy due to a confirmed ESBL producing or AmpC hyperproducing Enterobacteriaceae, resistant to quinolones and Bactrim® in France. In addition, this study will describe and support the use of high dose (6g/day) of temocillin which could be of interest for the treatment urinary tract infection due to multi-resistant bacteria having high MIC (up to 32 mg/L). The investigators will also evaluate the tolerance of the drug by monitoring the adverse event and the incidence of eventual Clostridium difficile associated infection.

Study Overview

• Status: Unknown
• Conditions: Urinary Tract Infections
• Intervention / Treatment: Drug: Temocillin

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Phase 4

Contacts and Locations

Study Locations

• France
  • Ajaccio, France
    • CH Ajaccio
  • Annecy, France
    • CH Annecy Genevois
  • Bobigny, France
    • APHP - Avicenne Hospital
  • Clichy, France
    • APHP - Beaujon Hospital
  • Fort De France, France
    • CHU de Martinique
  • Grenoble, France
    • CHU de Grenoble
  • Kremlin-Bicêtre, France
    • APHP - Bicêtre Hospital
  • Lille, France
    • CHU de LILLE
  • Nantes, France
    • CHU de Nantes
  • Nice, France
    • CHU de Nice
  • Paris, France
    • APHP - Bichat Hospital
  • Paris, France
    • APHP - Cochin Hospital
  • Paris, France
    • APHP - St Louis
  • Perpignan, France
    • CH de Perpignan
  • Pointe À Pitre, France
    • CHU de Pointe à Pitre
  • Poitiers, France
    • CHU de Poitiers
  • Rouen, France
    • CHU de ROUEN
  • Saint Etienne, France
    • Chu de Saint Etienne
  • Tours, France
    • CHU de Tours

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:

• Age of at least 18 year old
• Patient benefits from social security
• Signed informed consent
• A urinary tract infection due to a confirmed ESBL producing strain (detected by the use of a rapid diagnostic test applied on the urine) requiring parenteral antimicrobial therapy
• Hospitalized patient
• For women able to procreate: Use of an acceptable method of birth control throughout the study. Acceptable methods of birth control are: oral contraceptives, intrauterine device (IUD), diaphragm with spermicide and condom. (All forms of hormonal contraception are acceptable

Exclusion Criteria:

• Patient infected with a bacteria which is not an ESBL-producing or AmpC hyperproducing Enterobacteriaceae
• Patients infected with a strain sensible to both fluoroquinolones and trimethoprim/sulfamethoxazole
• Patients infected with a strain resistant to temocillin
• Hospital-acquired urinary tract infection (defined as a urinary infection that occurred at least 48h post admission in the hospital)
• Patients has received any dose of active antimicrobial therapy (an antibiotic to which the infecting bacterium is susceptible) in the last 48h (prior to enrolment) except ≤ 2 dose of gentamicin.
• Patients presenting another site of infection than urinary (except onset of bacteraemia from urinary tract origin) due to Gram negative bacteria.
• Patients needing concomitant antimicrobial therapy.
• Septic shock
• Children (up to 18 years old)
• Women who is pregnant, breastfeeding, or expecting to conceive at any time during the study (pregnancy test will be conducted for woman without menopause)
• Patients with any kind of urinary/bladder catheter (JJ ureteral probe, …)
• Hypersensitivity to the active substance, to penicillins or to any other type of beta-lactam agent
• Chronically dialyzed patients
• Patients having a creatinine clearance < 30 mL/min
• Complete obstruction of the urinary tract
• Perinephretic or intrarenal abscesses
• Tutorship or curatorship patient
• Patient unable to give his consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Temocillin; Treatment duration with a minimum of 5 days administration of the study drug: Temocillin (Negaban®) 6g/day (2g/tid) and as monotherapy. Total antibiotic treatment between 10 and 14 days according to local guidelines (up to 21 days in immunosuppressed patients).	Drug: Temocillin; Treatment duration with a minimum of 5 days administration of the study drug: Temocillin (Negaban®) 6g/day (2g/tid) and as monotherapy.; Other Names: NEGABAN

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Microbiological efficacy at Test of Cure in patients microbiologically evaluable	The microbiological efficacy will be assessed by quantitative urine culture and defined as follows: Eradication : < 10^3 CFU/mL of the baseline pathogen; Persistence : ≥ 10^3 CFU/ml of the baseline pathogen; Superinfection : ≥ 10^5 CFU/ml of another uropathogen during therapy; New infection : ≥ 10^5 CFU/ml of another uropathogen after therapy; Relapse : eradication at TOC but ≥ 10^3 CFU/mL of the baseline pathogen at FU Overall microbiological response will be determined as "unfavorable" if persistence or superinfection or new infection or relapse.	7 days post end of Temocillin Treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical efficacy in clinical evaluable group	Each patient's response will be categorized as cure (resolution of all clinical symptoms), improvement (normalization of body temperature but persistence of either urinary syndrome or flank pain) or failure (persistence of baseline clinical symptoms or emergence of new symptoms related to UTI).	3 weeks for end of Temocillin Treatment
Microbiological efficacy	The microbiological efficacy will be assessed by quantitative urine culture and defined as follows: Eradication : < 10^3 CFU/mL of the baseline pathogen; Persistence : ≥ 10^3 CFU/ml of the baseline pathogen; Superinfection : ≥ 10^5 CFU/ml of another uropathogen during therapy; New infection : ≥ 10^5 CFU/ml of another uropathogen after therapy; Relapse : eradication at TOC but ≥ 10^3 CFU/mL of the baseline pathogen at FU	3 weeks for end of Temocillin Treatment
Development of resistance to temocillin during treatment	The acquisition of resistance will be monitored in the central laboratory and is defined as an increase in MIC of at least 4 dilutions.	3 weeks for end of Temocillin Treatment

Collaborators and Investigators

• Sponsor: University Hospital, Grenoble
• Collaborators: French National Network of Clinical Research in Infectious Diseases (RENARCI)
• Investigators: Study Chair: Jean Paul STAHL, PU-PH, University Hospital, Grenoble

Publications and helpful links

General Publications

• Laterre PF, Wittebole X, Van de Velde S, Muller AE, Mouton JW, Carryn S, Tulkens PM, Dugernier T. Temocillin (6 g daily) in critically ill patients: continuous infusion versus three times daily administration. J Antimicrob Chemother. 2015 Mar;70(3):891-8. doi: 10.1093/jac/dku465. Epub 2014 Nov 27.
• Balakrishnan I, Awad-El-Kariem FM, Aali A, Kumari P, Mulla R, Tan B, Brudney D, Ladenheim D, Ghazy A, Khan I, Virgincar N, Iyer S, Carryn S, Van de Velde S. Temocillin use in England: clinical and microbiological efficacies in infections caused by extended-spectrum and/or derepressed AmpC beta-lactamase-producing Enterobacteriaceae. J Antimicrob Chemother. 2011 Nov;66(11):2628-31. doi: 10.1093/jac/dkr317. Epub 2011 Aug 2.
• Fournier D, Chirouze C, Leroy J, Cholley P, Talon D, Plesiat P, Bertrand X. Alternatives to carbapenems in ESBL-producing Escherichia coli infections. Med Mal Infect. 2013 Feb;43(2):62-6. doi: 10.1016/j.medmal.2013.01.006. Epub 2013 Feb 19.
• Schulze B, Heilmann HD. Treatment of severe infections with temocillin. Clinical and bacteriological evaluation. Drugs. 1985;29 Suppl 5:207-9. doi: 10.2165/00003495-198500295-00046.
• De Jongh R, Hens R, Basma V, Mouton JW, Tulkens PM, Carryn S. Continuous versus intermittent infusion of temocillin, a directed spectrum penicillin for intensive care patients with nosocomial pneumonia: stability, compatibility, population pharmacokinetic studies and breakpoint selection. J Antimicrob Chemother. 2008 Feb;61(2):382-8. doi: 10.1093/jac/dkm467. Epub 2007 Dec 10.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2016
• Primary Completion (Actual): April 1, 2018
• Study Completion (Anticipated): September 1, 2018

Study Registration Dates

• First Submitted: November 27, 2015
• First Submitted That Met QC Criteria: February 9, 2016
• First Posted (Estimate): February 12, 2016

Study Record Updates

• Last Update Posted (Actual): June 6, 2018
• Last Update Submitted That Met QC Criteria: June 1, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Urologic Diseases; Disease Attributes; Infections; Communicable Diseases; Urinary Tract Infections; Anti-Infective Agents; Anti-Bacterial Agents; Temocillin
• Other Study ID Numbers: 38RC15.213; 2015-004178-14 (EudraCT Number)