Efficacy and Pharmacokinetic/Pharmacodynamic Parameters of Cefoxitin in Women With Acute Uncomplicated Pyelonephritis Due to Extended-spectrum β-lactamase Producing Escherichia Coli (FOXICOLI)
Escherichia coli is the primary cause of urinary tract infections and Gram-negative bacteremia worldwide. Since the early years of the 21st century, E.coli has acquired a new mechanism of resistance to antibiotics: extended spectrum β-lactamase (ESBL), type CTX-M. These ESBL inactivate most β-lactams, the preferred class of antibiotics for the treatment of severe E.coli infections. Moreover, the strains that produce these ESBL are often resistant to other classes of antibiotics. Their rapid spread constitutes a major public health concern because of a serious risk of therapeutic impasse. Treatment options in cases of infection with ESBL-producing E.coli are often limited to carbapenems, a class of more recently developed β-lactams. Carbapenems have a very wide spectrum of activity but their effectiveness is threatened by the emergence of strains producing carbapenemases. The development of therapeutic alternatives to treat ESBL-producing E.coli infections is therefore essential. Cephamycins, including cefoxitin, are β-lactams marketed in the seventies but their use was practically abandoned when wide spectrum antibiotics became available. They are distinguished by the presence of an α-methoxy group in position 7 which interferes with the action of the extended-spectrum β-lactamase and renders it ineffective against cephamycins. Cefoxitin is therefore active in vitro against ESBL-producing E.coli and offers the advantage of a narrower antibacterial spectrum, thus reducing the selection pressure and the emergence of resistance. However, the in vivo activity of cefoxitin for the treatment of ESBL-producing E.coli infections has never been measured. Furthermore, available pharmacokinetic and pharmacodynamic (PK/PD) data for cefoxitin are dated and incomplete, which raises many questions concerning the optimal dosage regimen. We have shown in a mouse model of ESBL-producing E. coli CTX-M pyelonephritis that cefoxitin efficacy is comparable to that of carbapenems without selecting resistant mutants. Cefoxitin could thus constitute an alternative to carbapenems for the treatment of pyelonephritis caused by ESBL-producing E.coli.
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Efficacy and Pharmacokinetic/Pharmacodynamic Parameters of Cefoxitin in Women With Acute Uncomplicated Pyelonephritis Due to Extended-spectrum β-lactamase Producing Escherichia Coli.|
- To assess Clinical and microbiological response [ Time Frame: 10 days ] [ Designated as safety issue: No ]Clinical and microbiological response defined at the end of cefoxitin treatment by the presence of the 3 following criteria: (i) afebrile (temperature < 38°C), (ii) resolution of urinary symptoms present at the time of diagnosis: dysuria, urgency, frequency, cloudy urine, pain on urination, pelvic or lumbar pain (iii) sterile urine culture.
- To detect of cefoxitin resistant strains [ Time Frame: 40±5 days ] [ Designated as safety issue: No ]detection of cefoxitin resistant strains colonising the gastrointestinal tract of women with pyelonephritis before treatment with cefoxitin, emergence of resistance under treatment and determination of associated mechanisms of resistance to cefoxitin
- To assess the bacteriological Relapse [ Time Frame: 40 days ] [ Designated as safety issue: No ]Early relapse at day 40 defined by clinical and microbiological success at 10 days and absence of clinical signs at 40 days
- To evaluate Clinical and microbiological response [ Time Frame: 48 h ] [ Designated as safety issue: No ]Clinical and microbiological response at 48h after beginning treatment with cefoxitin
- to measure the Pharmacokinetic parameters [ Time Frame: 48 h ] [ Designated as safety issue: No ]measure of total clearance of elimination and Measure of the volume of distribution
- Measure of efficacy of cefoxitin [ Time Frame: 10 days ] [ Designated as safety issue: No ]side effects of cefoxitin all days
- To measure the Pharmacodynamic parameters [ Time Frame: 48 h ] [ Designated as safety issue: No ]PD parameters;
|Study Start Date:||July 2013|
|Estimated Study Completion Date:||September 2015|
|Estimated Primary Completion Date:||September 2015 (Final data collection date for primary outcome measure)|
this study is centered on women with uncomplicated pyelonephritis due to ESBL-producing E. coli.
proof of concept study to evaluate the efficacy of cefoxitin (2 grams every 6 hours for 10 days) in 40 women presenting with acute uncomplicated ESBL-producing E.coli pyelonephritis and to perform on half of the participants repeated measurements of cefoxitin serum levels (6 blood samples within 6 hours following an injection).
Other Name: Cefoxitin
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01820793
|Contact: Agnès LEFORT, Pr||331 40 87 52 27/ 45 68||agnès.firstname.lastname@example.org|
|Contact: Raphaël LEPEULE, Dr||331 40 87 52 27/ 59 50||raphaël.email@example.com|
|Clichy, France, 92110|
|Contact: Agnès LEFORT, Pr 01 40 87 52 27 firstname.lastname@example.org|
|Contact: Raphaël LEPEULE, Dr 01 40 87 52 27 email@example.com|
|Principal Investigator: Agnès LEFORT, Pr|
|Principal Investigator:||Agnès LEFORT, Pr||Assistance Publique - Hôpitaux de Paris|