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Efficacy and Pharmacokinetic/Pharmacodynamic Parameters of Cefoxitin in Women With Acute Pyelonephritis Without Severity Symptoms Due to Extended-spectrum β-lactamase Producing Escherichia Coli (FOXICOLI)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01820793
Recruitment Status : Terminated (Not enought inclusion)
First Posted : March 29, 2013
Last Update Posted : January 12, 2018
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Brief Summary:
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 or disease Intervention/treatment Phase
Acute Pyelonephritis Without Severity Symptoms Due to ESBL-producing E.Coli Drug: Cefoxitin Not Applicable

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 9 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Efficacy and Pharmacokinetic/Pharmacodynamic Parameters of Cefoxitin in Women With Acute Pyelonephritis Without Severity Symptoms Due to Extended-spectrum β-lactamase Producing Escherichia Coli.
Study Start Date : May 2013
Actual Primary Completion Date : July 2015
Actual Study Completion Date : November 2015

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: cefoxitin
this study is centered on women with pyelonephritis without severity symptoms 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 acute ESBL-producing E.coli pyelonephritis without severity symptoms and to perform on half of the participants repeated measurements of cefoxitin serum levels (6 blood samples within 6 hours following an injection).

Primary Outcome Measures :
  1. To assess Clinical and microbiological response [ Time Frame: 10 days ]
    Clinical and microbiological response defined at the end of cefoxitin treatment by the presence of the 3 following criteria: (i) afebrile (temperature > 36°C and < 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 :
  1. To detect of cefoxitin resistant strains [ Time Frame: 40±5 days ]
    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

  2. To assess the bacteriological Relapse [ Time Frame: 40 days ]
    Early relapse at day 40 defined by clinical and microbiological success at 10 days and absence of clinical signs at 40 days

  3. To evaluate Clinical and microbiological response [ Time Frame: 48 h ]
    Clinical and microbiological response at 48h after beginning treatment with cefoxitin

  4. to measure the Pharmacokinetic parameters [ Time Frame: 48 h ]
    measure of total clearance of elimination and Measure of the volume of distribution

  5. Measure of efficacy of cefoxitin [ Time Frame: 10 days ]
    side effects of cefoxitin all days

  6. To measure the Pharmacodynamic parameters [ Time Frame: 48 h ]
    PD parameters;

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Inclusion Criteria: Acute pyelonephritis without severity symptoms 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;
  • 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).

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01820793

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Clichy, France, 92110
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
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Principal Investigator: Agnès LEFORT, Pr Assistance Publique - Hôpitaux de Paris

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Responsible Party: Assistance Publique - Hôpitaux de Paris Identifier: NCT01820793    
Other Study ID Numbers: P120202
2012-002730-36 ( EudraCT Number )
First Posted: March 29, 2013    Key Record Dates
Last Update Posted: January 12, 2018
Last Verified: January 2018
Keywords provided by Assistance Publique - Hôpitaux de Paris:
antibiotic resistance
Additional relevant MeSH terms:
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Nephritis, Interstitial
Kidney Diseases
Urologic Diseases
Anti-Bacterial Agents
Anti-Infective Agents