Clinical trial NCT03147807: BetaLACTA® Test for Early De-escalation of Empirical Carbapenems in Pulmonary, Urinary and Bloodstream Infections in ICU
Official title: BetaLACTA® Test-guided Early De-escalation of Empirical Carbapenems in Pulmonary, Urinary and Bloodstream Infections Diagnosed in Intensive Care Unit - BLUE¬-CarbA Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Pneumonia
Urinary Tract Infections
Bloodstream Infection
Keywords: Carbapenems de-escalation, rapid diagnostic test,
Carbapenem-antimicrobial de-escalation-rapid diagnostic test
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2017-05-10
Enrollment: 75
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The emergence and rapid worldwide spread of Extended- Spectrum Beta-Lactamase-producing enterobacteriaceae (ESBLE) both in hospital and community, led physicians, and notably intensivists, to prescribe more carbapenems, particularly in the most fragile patients such as ICU patients. Unfortunately, the increased carbapenem consumption favored the emergence of carbapenem resistance mechanisms. Moreover, several preliminary results suggest that carbapenem could markedly impact the human intestinal microbiota, Thus, reduction of carbapenem exposure is widely desired both by national and international antibiotic plans. Therefore, the use of rapid diagnostic tests evaluating bacterial resistance to reduce inappropriate exposure to carbapenems could be a relevant solution. Due to its good diagnostic performance, the betaLACTA® test could meet these objectives.

Experimental plan :

Randomized, open-labeled non-inferiority clinical trial involving an in vitro diagnostic medical device (close to a phase III study), comparing two parallel groups:

* Experimental group: early carbapenems de-escalation since the second dose, guided by results of the betaLACTA® test performed directly on the bacterial pellet from the microbiological sample positive on direct examination.
* Control group: carbapenems de-escalation guided by definitive results of the antibiotic susceptibility test obtained 48 to 72h after microbiological sampling (reference strategy).

Detailed description: This study is conducted on ICU patients with a suspected pneumonia, primary blood-stream infection (BSI), and/or urinary tract infection (UTI).

The primary objective of the study is to demonstrate that in ICU infections treated empirically by carbapenems and documented with GNB on direct examination of a respiratory, urinary and/or blood sample(s), the early de-escalation guided by the results of the betaLACTA® test is not inferior to the reference strategy de-escalating on antibiotic susceptibility test (AST) results obtained 48-72h after sampling, in terms of mortality at D90 and infection recurrence in ICU.

The secondary objectives are to compare the early de-escalation guided by the betaLACTA® test results to the reference strategy de-escalating on the AST results on:

* The exposure to carbapenems.
* The total use of ICU and hospital resources and the cost-effectiveness.
* The occurrence of other infections.
* The colonization of the digestive tractus of patients with 3rd generation cephalosporins (3rdGC) resistant Gram-negative bacteria (GNB).

In addition, an ancillary study will be performed (only in participating centers from the Ile de France region) to compare :

* The composition of the intestinal microbiota among patients with an early de-escalation guided by the betaLACTA® test results and a standard de-escalation on AST results at 48-72h.
* The evolution of intestinal microbiota of patients after exposure to different beta-lactam antibiotics, from carbapenems or cefepim/ceftazidim during the empirical treatment, to the definitive beta-lactam antibiotic chosen to cure the infection after antibiotic susceptibility test results.
* The outcomes of ICU patients (mortality at D90, occurrence of infection, ICU length of stay, etc.) according to the composition of their intestinal microbiota and to its evolution during antibiotic treatment.

To meet these objectives, 646 patients will be enrolled.

Eligibility criteria: Inclusion Criteria:

* ICU patients ≥18 years.
* With a suspected pneumonia (according to CPIS definition), primary blood-stream infection (according to CDC definition), and/or urinary tract infection (according to IDSA Guidelines).
* And presence of ≥2 GNB/field on direct examination of a respiratory sample (quantitative bronchial aspirate with an available volume ≥ 1mL), urinary sample or blood culture.
* Leading to an empirical carbapenem prescription, not administered for more than 6 hours when considering the inclusion of the patient.
* Written informed consent signed by the patient / the trustworthy person / the next-of-kin / close relative, or inclusion in case of emergency and written informed consent will been signed by the patient as soon as possible.
* Patients affiliated to French social security.

Exclusion Criteria:

* Pregnancy.
* Allergy to beta-lactams.
* Patients already treated with ongoing carbapenems for another documented infection, blocking carbapenem de-escalation.
* Patients included in another interventional study.
* Patients in whom a procedure of withdrawing life-sustaining treatment was decided before inclusion.
* Moribund patients.
* Patients with aplasia.
* Patients under tutorship/curatorship or patient deprived of freedom

Primary outcomes:
measure: mortality at D90 and infection recurrence during the ICU stay
timeFrame: Day 90
Secondary outcomes:
measure: Exposure to carbapenems
timeFrame: from Day 0, through ICU discharge or until 28 days after inclusion in case of prolonged ICU stay
measure: Total use of ICU and hospital resources and cost-effectiveness of early de-escalation compared to standard de-escalation.
timeFrame: from Day 0,throught hospital discharge or until 28 days after inclusion in case of prolonged ICU stay
measure: Occurrence of other infections.
timeFrame: From Day 0 to ICU discharge (within the limit of 90 days).
measure: Colonization of the digestive tractus of patients with 3rd generation cephalosporins (3rdGC) resistant Gram-negative bacteria
timeFrame: From Day 0, through ICU discharge or until 28 days after inclusion in case of prolonged ICU stay
measure: Composition of intestinal microbiota at Day 0
timeFrame: from D0 to the end of the antimicrobial treatment of the infection leading to inclusion in the study, average 7-10 days
measure: Composition of intestinal microbiota at day 3
timeFrame: from D0 to the end of the antimicrobial treatment of the infection leading to inclusion in the study, average 7-10 days
measure: Composition of intestinal microbiota after antibiotic exposur
timeFrame: from D0 to the end of the antimicrobial treatment of the infection leading to inclusion in the study, average 7-10 days
Other outcomes:
Locations:
city: Paris
country: France
facility: Anesthesiology and Critical Care Medicine Department
Study officials:
affiliation: Assistance Publique - Hôpitaux de Paris
name: Marc GARNIER, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Garnier M, Gallah S, Vimont S, Benzerara Y, Labbe V, Constant AL, Siami S, Guerot E, Compain F, Mainardi JL, Montil M, Quesnel C; BLUE-CarbA study group.. Multicentre randomised controlled trial to investigate usefulness of the rapid diagnostic betaLACTA test performed directly on bacterial cell pellets from respiratory, urinary or blood samples for the early de-escalation of carbapenems in septic intensive care unit patients: the BLUE-CarbA protocol. BMJ Open. 2019 Feb 19;9(2):e024561. doi: 10.1136/bmjopen-2018-024561.