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

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



Sponsors


Source

Assistance Publique - Hôpitaux de Paris

Oversight Info

Has Dmc

Yes


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.

Detailed Description

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 impact on the emergence of
resistance. Half of enrolled women will have repeated measurement of serum concentration of
cefoxitin: 6 blood samples collected within 6 hours following the injection of one of the
doses received between the 3rd and the last day of treatment. A security assessment by an
independent committee will be conducted on the first five patients enrolled.

The precise incidence of ESBL-producing E.coli acute pyelonephritis without severity symptoms
in the 8 participating centers is unknown. At BICHAT hospital, the incidence of
ESBL-producing E.coli in 2008 was 0.66/100 admissions (57 778 admissions/year). It was
0.46/1000 hospitalisation days at BEAUJON in 2009 with 36.5% from urine samples. The same
year, Saint-Louis hospital recorded 18 bacteremias secondary to infection with ESBL-producing
E.coli with 6% originating from a UTI. Those last numbers underestimate the actual incidence
of ESBL-producing E coli pyelonephritis at that hospital, only taking into account the UTI
associated with bacteremias. We estimate that there are approximately 10 cases of
ESBL-producing E.coli pyelonephritis in these centers each year.

Outline and conduct of the study/investigations performed by the CIC As soon as the
antibiogram is available, confirming diagnosis of an ESBL-producing E. coli and after
verification of the inclusion criteria, information and obtention of the the written consent,
cefoxitin (2 grams intravenous perfusion of 30 minutes every 6 hours) will be given for 10
days. A control visit and urine culture will be performed at day 2, day 7 and at the end of
treatment, day 10. A rectal swab will be performed at enrolment before the first dose of
antibiotic, at the end of treatment (day 10) and at day 40. The inclusion period will be 2
years and each patient's participation will last 40 days.

The PK study will be performed on 20 patients enrolled at one of the 4 CIC at hospital
Saint-Louis, BICHAT, HENRI-MONDOR and HEGP. Measurement of serum concentration of cefoxitin
will be done on the 3rd day of treatment, or between the 9th and 12th dose of antibiotic.
Samples will be taken as follows: t0 (immediately before beginning infusing cefoxitin); t30
min (at the end of infusion); t45 min ; t1h ; t3h ; t6h (before the next dose) for a total of
6 samples.

Evaluation criteria for the primary objective Clinical and microbiological response defined
at the end of cefoxitin treatment by the presence of the 3 following criteria: (i) afebrile
(temperature > 36° 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.

Evaluation criteria for the secondary objective (i) Clinical and microbiological response at
48h after beginning treatment with cefoxitin; (ii) Early relapse at day 40; (iii) PK/PD
parameters; (iv) side effects of cefoxitin.

Statistics, PK/PD modelling, cefoxitin dosing regimen optimisation Qualitative variables will
be reported in percentage of the studied subjects and quantitative variables by a median.
Comparisons will use non-parametric tests. The tests will be bilateral and use a significance
threshold of 5%. The rate of clinical and microbiological response at the end of treatment
with cefoxitin will be reported as a percentage with an estimate of the confidence interval
(CI) of 95% (using a binomial distribution). PK analysis will be conducted using a population
approach and average PK parameters for cefoxitin will be estimated as well as interpatient
variability. The PK population analysis will examine different demographic and clinical
covariables in order to weigh their influence on PK/PD parameters; the studied covariables
will be: age, weight, BMI, blood pressure and creatinine clearance. In order to study the
relationship between pharmacokinetics and clinical response at H48 and at the end of
treatment as well as at J40±5, the patients' PK parameters will be compared using the
Wilcoxon and Mann-Whitney non-parametric tests.

ESBL-producing E.coli strains responsible for pyelonephritis in women: typing and
identification of subtype

ESBL-producing strains will be screened with the synergy method, using a disk containing a
3rd generation cephalosporin, like cefotaxime, and another disk containing a β-lactamase
inhibitor, clavulanic acid, according to the recommendations of the competent authorities of
antibiogram. The isolated strains will then be analysed further on three main aspects: (i)
the phylogenetic group will be determined by multiplex PCR (ii) the strains' sequence-typing
will be done using Multiple Sequence Typing (iii) the presence of 46 genes associated with
extra-intestinal virulence factors will be identified through multiplex PCR.

The determination of ESBL type will also be done by PCR.

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

Screening for enterobacteriaceae with reduced-sensitivity to cefoxitin will be done by
plating a rectal swab (or a stool sample) on DRIGALSKI media containing 10 mg/l of cefoxitin.
Acquired resistance mechanisms in species normally sensitive to cefoxitin (E. coli,
Klebsiella spp.) will be characterised: hyperproduction of Amp C in E. coli, hyperexpression
of efflux pumps and changes in purines in E. coli et K. pneumoniae. If comparing strains is
necessary, it will be done using ERIC2 PCR as previously described in literature.

Ethical aspects

The research protocol will be presented to the ethics committee, once consent from the
promoter is obtained (with proof of the required insurance and payment of fees). The opinion
of the committee will be included in a form delivered by the promoter to the competent
authorities before beginning the study. All enrolled patients will be required to sign an
informed consent before any investigation or treatment is performed. The consent forms will
be kept for 30 years by the CIC. Patients will be informed of the results after completion of
the study.

Expected public health impact of study

The expected benefits of using cefoxitin in women with uncomplicated acute ESBL-producing
E.coli pyelonephritis are (i) an clinical and microbiological effectiveness similar to that
of carbapenems;(ii) a decrease in the selection pressure on bacteria colonising the
gastrointestinal tract, thus contributing to prevent the emergence of carbapenemase-producing
Enterobacteriaceae (iii) a decrease in drug-associated cost.

Overall Status

Terminated

Start Date

2013-05-01

Completion Date

2015-11-01

Primary Completion Date

2015-07-01

Phase

N/A

Study Type

Interventional

Primary Outcome

Measure

Time Frame

To assess Clinical and microbiological response
10 days

Secondary Outcome

Measure

Time Frame

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
To measure the Pharmacodynamic parameters
48 h

Enrollment

9

Condition


Intervention

Intervention Type

Drug

Intervention Name


Description

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).

Arm Group Label

cefoxitin


Eligibility

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).

Gender

Female

Minimum Age

18 Years

Maximum Age

N/A

Healthy Volunteers

No


Overall Official

Last Name

Role

Affiliation

Agnès LEFORT, Pr
Principal Investigator
Assistance Publique - Hôpitaux de Paris

Location

Facility

Agnès LEFORT
Clichy 92110 France

Location Countries

Country

France


Verification Date

2018-01-01

Lastchanged Date

N/A

Firstreceived Date

N/A

Responsible Party

Responsible Party Type

Sponsor


Keywords


Has Expanded Access

No

Condition Browse


Secondary Id

2012-002730-36

Number Of Arms

1

Intervention Browse

Mesh Term

Cefoxitin

Cefotaxime



Arm Group

Arm Group Label

cefoxitin

Arm Group Type

Experimental

Description

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


Firstreceived Results Date

N/A

Why Stopped

Not enought inclusion

Acronym

FOXICOLI

Firstreceived Results Disposition Date

N/A

Study Design Info

Intervention Model

Single Group Assignment

Primary Purpose

Treatment

Masking

None (Open Label)


Study First Submitted

February 19, 2013

Study First Submitted Qc

March 26, 2013

Study First Posted

March 29, 2013

Last Update Submitted

January 11, 2018

Last Update Submitted Qc

January 11, 2018

Last Update Posted

January 12, 2018


ClinicalTrials.gov processed this data on August 24, 2018

Conditions

Conditions usually refer to a disease, disorder, syndrome, illness, or injury. In ClinicalTrials.gov, conditions include any health issue worth studying, such as lifespan, quality of life, health risks, etc.
Interventions

Interventions refer to the drug, vaccine, procedure, device, or other potential treatment being studied. Interventions can also include less intrusive possibilities such as surveys, education, and interviews.
Study Phase

Most clinical trials are designated as phase 1, 2, 3, or 4, based on the type of questions that study is seeking to answer:

In Phase 1 (Phase I) clinical trials, researchers test a new drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.

In Phase 2 (Phase II) clinical trials, the study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety.

In Phase 3 (Phase III) clinical trials, the study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.

In Phase 4 (Phase IV) clinical trials, post marketing studies delineate additional information including the drug's risks, benefits, and optimal use.

These phases are defined by the Food and Drug Administration in the Code of Federal Regulations.



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