Clinical Trial: 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 Status: Terminated
Recruit Status: Terminated
Study Type: Interventional

Official Title: Efficacy and Pharmacokinetic/Pharmacodynamic Parameters of Cefoxitin in Women With Acute Pyelonephritis Without Severity Symptoms Due to Extended-spectrum β-lactamase

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 t

Detailed Summary:

Clinical Study:

This is a prospective, multicentric, non-comparative, proof of concept study evaluating the efficacy of cefoxitin in women with acute ESBL-producing E. coli pyelonephritis without severity symptoms. This antibiotic is already commercially available and its tolerability profile is well known, but it has never been previously evaluated to treat this particular type of infection.

The primary objective of this study is to assess the clinical and microbiological response to treatment with cefoxitin in women with acute pyelonephritis without severity symptoms due to ESBL-producing E. coli.

The secondary objectives are:

In women with pyelonephritis caused by ESBL-producing E.coli:

  • Gain a better understanding of the current epidemiology of ESBL-producing E. coli associated with febrile UTI
  • Assess the impact of cefoxitin use on the emergence of resistance in the colonising bacteria of the gastrointestinal tract in women with pyelonephritis treated with cefoxitin and identify the associated mechanisms
  • Characterise the PK/PD parameters for cefoxitin in order to optimise the dosage strategy for that antibiotic
  • Assess the tolerance profile of cefoxitin

Determination of sample size, feasibility of enrolment No determination of the minimal sample size could be calculated in this proof of concept study but a total enrolment of 40 patients in the 8 participating centers seems adequate to evaluate the efficacy of cefoxitin for treating uncomplicated acute pyelonephritis and to study its
Sponsor: Assistance Publique - Hôpitaux de Paris

Current Primary Outcome: 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.


Original Primary Outcome: 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 < 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.


Current Secondary Outcome:

  • 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
  • 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
  • To evaluate Clinical and microbiological response [ Time Frame: 48 h ]
    Clinical and microbiological response at 48h after beginning treatment with cefoxitin
  • to measure the Pharmacokinetic parameters [ Time Frame: 48 h ]
    measure of total clearance of elimination and Measure of the volume of distribution
  • Measure of efficacy of cefoxitin [ Time Frame: 10 days ]
    side effects of cefoxitin all days
  • To measure the Pharmacodynamic parameters [ Time Frame: 48 h ]
    PD parameters;


Original Secondary Outcome: Same as current

Information By: Assistance Publique - Hôpitaux de Paris

Dates:
Date Received: February 19, 2013
Date Started: May 2013
Date Completion:
Last Updated: December 12, 2016
Last Verified: December 2016