Urinary Tract Infections Clinical Trial
Official title:
Evaluation of the Non-inferiority of Cefoxitin Versus Imipenem/Cilastatin in the Treatment of Urinary Tract Infections Caused by ESBL-producing Escherichia Coli
Background Information: Infections caused by extended-spectrum β-lactamase (ESBL)-producing
Escherichia coli are becoming increasingly common owing to incorrect use of antibiotics and
cross-transmission in healthcare establishments. These give rise to major problems in
standard clinical practice: penicillins and cephalosporins cannot be used, and resistance to
the other classes of antibiotics normally used, such as fluoroquinolones or cotrimoxazole, is
very frequently observed. The current therapeutic strategy involves the use of a carbapenem,
which represents the last effective solution on an individual level. However, the growing use
thereof is contributing, collectively, to the development of resistance due to the production
of carbapenemases, which will become a major public health problem, with a potential
therapeutic dead-end. This observation is particularly worrying due to the very small number
of antibiotic agents currently in development.
Infectious disease specialists and microbiologists are thus examining alternative agents to
carbapenems in the management of infections caused by ESBL-producing E. coli. One of the
avenues which could be developed is the use of known agents, already on the market, which are
active in vitro on ESBL-producing E. coli, but which are not currently recommended for this
indication in standard practice due to the lack of conclusive studies. Cefoxitin, an
antibiotic belonging to the cephamycin group, could thus represent an alternative of
particular interest in the treatment of infections caused by ESBL-producing E. coli, and help
limit the use of carbapenems.
The implementation of a prospective, randomized, non-inferiority study on ertapenem and
cefoxitin is of the most interest from a methodological perspective. It will enable
recommendations to be drawn up, with a high level of evidence, very long-awaited in the
field.
Primary objective: To evaluate the bacteriological non-inferiority of cefoxitin versus
imipenem in the treatment of non-severe urinary tract infections (other than cystitis) caused
by ESBL-producing E. coli susceptible in vitro to cefoxitin.
Secondary objectives:
- To evaluate the clinical non-inferiority of cefoxitin versus imipenem in the treatment
of non-severe urinary tract infections (other than cystitis) caused by ESBL-producing E.
coli susceptible in vitro to cefoxitin.
- To evaluate the impact of cefoxitin and imipenem on the emergence of multiresistant
bacteria in the gut flora.
Rationale:
Commensal enterobacteriaceae of the digestive tract, mostly represented by E.coli, can cause
a wide range of infections such as urinary tract infections or severe bacteraemia. For
several years now, the misuse of antibiotics and cross-transmission in hospitals have led to
the emergence of Enterobacteriaceae producing extended-spectrum β-lactamases (ESBL). The
rising prevalence of ESBL is estimated at 8.2% in healthcare settings and at 6.2% in the
community.
Carbapenems are considered the reference treatment for ESBL-producing E.coli (EESBL)
infections. They often remain the last effective treatment on an individual level. But on a
larger scale, their increasing use contributes to the emergence of resistance that might soon
become a major public health issue.
Although the prevalence of ESBL remains low, the rate of ESBL epidemics in French hospitals
has increased hugely since 2004. This could become a cause of concern especially because very
few antibacterial agents are currently in development.
So infectiologists and microbiologists have to consider alternatives to carbapenems to treat
infections caused by EESBL, which is stipulated in the new recommendations from the French
High Council for Public Health and the Infectious Disease Society of America.
Older and well-known molecules that have proved to be effective in-vitro against EESBL may be
an option. However due to a lack of conclusive studies, they're still not recommended in
these cases. Cefoxitin, a cephamycin antibiotic, may be a good alternative treatment for
EESBL infections and contribute to spare the use of carbapenems.
Originality and innovation:
Previous studies of cephamycins have shown encouraging results, but they were mostly cohort
trials with retrospective data or subsets of non-randomized studies. So a randomized
prospective non-inferiority study comparing ertapenem and cefoxitine is necessary. If the
results show non-inferiority of cefoxitine versus ertapenem, immediate clinical application
should ensue and lead to new recommendations, highly anticipated by the infectiologists who
support this project via their clinical research network.
Project feasibility:
The pace of inclusions has been calculated based on recent data on cefoxitine,
trimethoprim/sulfamethoxazole and ciprofloxacin sensitivity EESBL, 68% of EESBL are
susceptible to céfoxitine and resistant to trimethoprim/sulfamethoxazole and ciprofloxacin.
In 2011, 16 French laboratories, involved in the EARSS network, isolated 582 EESBL strains
from blood culture. In the university hospital of Nancy, 205 EESBL strains were isolated from
urine cultures in 2012. The challenge of including 250 patients with ESBL E.coli positive
urine culture, in 18 months and in about 20 participating French centers, seems highly
feasible.
Recent data showed that 68% of EESBL are susceptible to céfoxitine and resistant to
trimethoprim/sulfamethoxazole and ciprofloxacin. In the university hospital of Nancy, 205
EESBL strains were isolated from urine cultures in 2012. The challenge of including 250
patients with ESBL E.coli positive urine culture, in 18 months and in about 20 participating
French centers, seems highly feasible.
Expected benefits for patients and/or public health Immediate benefits are expected, on an
individual level and on a wider scale. Indeed for the patient, the use of narrow-specturm
antibiotics, but with an equivalent efficacy, decreases the risk of selecting even more
highly resistant bacteria than EESBL in the digestive tract, such as carbapenemase-producing
enterobacteriaceae (CPE). A patient colonized with CPE is at high risk of developing a CPE
infection and the rates of recovery are low because of the small number of antibiotics that
remain effective.
At the community level, the main challenge is the preservation of carbapenems (one of the
last families of antibiotics still effective in the treatment of ESBL infections), and the
restriction of its usage to the treatment of severe infections only. The increasing use of
carbapenems generates a high selection pressure on enterobacteriaceae which results in a
worrying increase of the prevalence of CPE. Moreover, the few remaining effective
antimicrobials induce high rates of side effects. The assessment of the non-inferiority of
older, well-known and active molecules such as cefoxitin is a highly anticipated and
encouraging research area, especially because the molecules currently under development are
far from being on the market.
Title: Non-inferiority study of cefoxitin versus imipenem as treatment for non-severe urinal
tract infections (excluding cystitis) caused by extended spectrum beta-lactamases producing
E.Coli susceptible to cefoxitin in-vitro
Primary objective: to show the bacteriological non-inferiority of cefoxitin versus imipenem
as a treatment for non-severe urinary tract infections (excluding cystitis) caused by
extended spectrum beta-lactamases producing E.Coli susceptible to cefoxitin in-vitro
Secondary objectives:
- to show the clinical non-inferiority of cefoxitin versus imipenem as a treatment for
non-severe urinary tract infections (excluding cystitis) caused by extended spectrum
beta-lactamases producing E.Coli susceptible to cefoxitin in-vitro
- to evaluate the impact of cefoxitin and imipenem on the emergence on multiresistant
bacteria in the digestive flora
;
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