Efficacy and Pharmacokinetic/Pharmacodynamic Parameters of Cefoxitin in Women With Acute Uncomplicated Pyelonephritis Due to Extended-spectrum β-lactamase Producing Escherichia Coli (FOXICOLI)

This study is currently recruiting participants. (see Contacts and Locations)
Verified August 2013 by Assistance Publique - Hôpitaux de Paris
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier:
NCT01820793
First received: February 19, 2013
Last updated: April 7, 2014
Last verified: August 2013
  Purpose

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.


Condition Intervention
Uncomplicated Pyelonephritis Due to ESBL-producing E.Coli
Drug: Cefoxitin

Study Type: Interventional
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.

Resource links provided by NLM:


Further study details as provided by Assistance Publique - Hôpitaux de Paris:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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;


Estimated Enrollment: 40
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)
Arms Assigned Interventions
Experimental: cefoxitin
this study is centered on women with uncomplicated pyelonephritis due to ESBL-producing E. coli.
Drug: Cefoxitin
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

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Inclusion Criteria: Acute uncomplicated pyelonephritis with a positive urine culture for ESBL-producing E. coli (cefoxitin-sensitive); antibiotic treatment should have been prescribed before inclusion for the empirical treatment of pyelonephritis, providing it is not active in vitro against ESBL-producing E. coli strain.
  • Presenting at least a functional sign of urinary infection (dysuria, cloudy urine, pain on urination, pelvic or lumbar pain)
  • Temperature >38 ° or < 36° during the infectious episode
  • Imaging of the urinary ways realized within (echography) 72 hours preceding the inclusion.

Exclusion Criteria:

  • Pregnant women
  • β-lactam allergy;
  • urological abnormality;
  • antimicrobial therapy active in vitro against ESBL-producing E.coli pyelonephritis instituted prior to enrolment;
  • life expectancy <30 days;
  • creatinine clearance <30 ml/min;
  • patient under guardianship or without healthcare coverage.
  • Sign of sepsis severe or septic shock
  • Major cognitive confusions
  • Patients having refused to give her consent form in writing
  • Not membership in a national insurance scheme or in the Universal Health Coverage (CMU).
  • Immunosuppression.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01820793

Contacts
Contact: Agnès LEFORT, Pr 331 40 87 52 27/ 45 68 agnès.lefort@bjn.aphp.fr
Contact: Raphaël LEPEULE, Dr 331 40 87 52 27/ 59 50 raphaël.lepeule@bjn.aphp.fr

Locations
France
Agnès LEFORT Recruiting
Clichy, France, 92110
Contact: Agnès LEFORT, Pr    01 40 87 52 27    agnes.lefort@bjn.aphp.fr   
Contact: Raphaël LEPEULE, Dr    01 40 87 52 27    raphael.lepeule@bjn.aphp.fr   
Principal Investigator: Agnès LEFORT, Pr         
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
Principal Investigator: Agnès LEFORT, Pr Assistance Publique - Hôpitaux de Paris
  More Information

No publications provided

Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT01820793     History of Changes
Other Study ID Numbers: P120202, 2012-002730-36
Study First Received: February 19, 2013
Last Updated: April 7, 2014
Health Authority: France: Ministry of Health

Keywords provided by Assistance Publique - Hôpitaux de Paris:
antibiotic resistance
E.coli
cefoxitin
pyelonephritis

Additional relevant MeSH terms:
Pyelonephritis
Nephritis, Interstitial
Nephritis
Kidney Diseases
Urologic Diseases
Pyelitis
Cefoxitin
Cefotaxime
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 22, 2014