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

• Status: Terminated
• Trial end date: 2015-11-01
• Target enrollment: 0
• Participant gender: Female

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.

• Phase: N/A
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Assistance Publique - Hôpitaux de Paris
• Treatments: Cefotaxime; Cefoxitin

Criteria

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).