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

NCT01820793 | Terminated DMC

• 2 other identifiers: P1202022012-002730-36
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

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.

Conditions

Acute Pyelonephritis Without Severity Symptoms Due to ESBL-producing E.Coli

Keywords

antibiotic resistance; E.coli; cefoxitin; pyelonephritis

Outcome Measures

Primary Outcomes (1)

• To assess Clinical and microbiological response

  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.

  10 days

Secondary Outcomes (6)

• To detect of cefoxitin resistant strains

  40±5 days

• To assess the bacteriological Relapse

  40 days

• To evaluate Clinical and microbiological response

  48 h

• to measure the Pharmacokinetic parameters

  48 h

• Measure of efficacy of cefoxitin

  10 days

Study Arms (1)

cefoxitin

EXPERIMENTAL

this study is centered on women with pyelonephritis without severity symptoms due to ESBL-producing E. coli.

Drug: Cefoxitin

Interventions

Cefoxitin DRUG

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).

cefoxitin

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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).

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (1)

Agnès LEFORT

Clichy, 92110, France

Location

MeSH Terms

Conditions

Escherichia coli Infections; Pyelonephritis

Interventions

Cefoxitin

Condition Hierarchy (Ancestors)

Enterobacteriaceae Infections; Gram-Negative Bacterial Infections; Bacterial Infections; Bacterial Infections and Mycoses; Infections; Nephritis, Interstitial; Nephritis; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Pyelitis; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Cephamycins; Cephalosporins; beta-Lactams; Lactams; Amides; Organic Chemicals; Thiazines; Sulfur Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Agnès LEFORT, Pr

  Assistance Publique - Hôpitaux de Paris

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 19, 2013
• First Posted: March 29, 2013
• Study Start: May 1, 2013
• Primary Completion: July 1, 2015
• Study Completion: November 1, 2015
• Last Updated: January 12, 2018

Record last verified: 2018-01

Locations

FR (1)