Ventilator-associated Pneumonia Clinical Trial
Official title:
Impact of Susceptibility Testing Directly on the Deep Respiratory Samples of Patients Suspected Pneumonia Ventilator ( VAP ) Late ( > 5 Days) in Intensive Care Unit on the Adequacy of Antibiotic Treatment to Carbapenems Sparing on Day 1
Inappropriate antibiotic therapy in ventilator-associated pneumonia (VAP) is associated with
increased mortality. The international guidelines recommend using broad spectrum
antimicrobials especially in patients who received previous antimicrobials, with risk factors
of muti-drug resistant (MDR) VAP or after 5 days of mechanical ventilation. Using
broad-spectrum antibiotics for 48h until the results of conventional cultures and
antimicrobial susceptibility testing (AST) are available, may promote the emergence of
drug-resistant bacteria. Exposure to imipenem, as short as 1 to 3 days, is associated with a
5-fold increase in the risk of imipenem resistance in the gut microbiota of ICU patients
(Armand-Lefevre AAC 2013). Performing AST directly on clinical respiratory samples would
hasten the process by at least 24h.
The diagnostic performance of a rapid method combining mass spectrometry and direct AST
[DAST] are previously analyzed, and compared it with the conventional method (mass
spectrometry with conventional AST [CAST]) and its potential impact was assessed on
antimicrobial use in 85 patients (Le DORZE M et al - Clin. Microbiol. Infect. 2015).
The results produced by the dast were useable in 85,9% of the cases and the sensitivity and
negative predictive values of DAST were 100% for all antibiotics tested, except gentamicin
(97.1% [95%CI = 93.3-101] and 97.4% [93.7-101], respectively) and amikacin (88.9% [81.7-96.1]
and 96.4% [92.1-100.7], respectively), compared with CAST. Specificity and positive
predictive values ranged from 82.9 (74.2-91.5) to 100%, and from 86.4 (78.5−94.2) to 100%,
respectively. If results had been reported to the clinicians, that DAST would have saved
carbapenem prescription in 17 cases (22%) and would have allowed immediate narrow spectrum
antimicrobials in 35/85 (41.2%) cases. But, the benefit of DAST was based on a simulation and
should be now tested in a randomized fashion. This project is a prospective multicenter
study. The hypothesis is that, DAST compared to CAST, would increase the number of adequate
antimicrobial therapy within 24 hours in case of late VAP (> 5 days under mechanical
ventilation) with Gram negative bacilli (GNB) in IC patients while sparing carbapenems
(imipenem and meropenem). The primary objective is to determine the impact of a strategy
using DAST on the rate of day1 adequate therapy without carbapenems in case of late VAP due
to GNB.
Inappropriate antibiotic therapy in ventilator-associated pneumonia (VAP) is associated with
increased mortality. The international guidelines recommend using broad spectrum
antimicrobials especially in patients who received previous antimicrobials, with risk factors
of muti-drug resistant (MDR) VAP or after 5 days of mechanical ventilation. Using
broad-spectrum antibiotics for 48h until the results of conventional cultures and
antimicrobial susceptibility testing (AST) are available, may promote the emergence of
drug-resistant bacteria. Exposure to imipenem, as short as 1 to 3 days, is associated with a
5-fold increase in the risk of imipenem resistance in the gut microbiota of ICU patients
(Armand-Lefevre AAC 2013). Performing AST directly on clinical respiratory samples would
hasten the process by at least 24h.
The diagnostic performance of a rapid method combining mass spectrometry and direct AST
[DAST], are previously analyzed and compared it with the conventional method (mass
spectrometry with conventional AST [CAST]) and its potential impact was assessed on
antimicrobial use in 85 patients (Le DORZE M et al - ICAAC 2013, and clinical microbiology
and infections submitted).
The results produced by the dast were useable in 85,9% of the cases and the sensitivity and
negative predictive values of DAST were 100% for all antibiotics tested, except gentamicin
(97.1% [95%CI = 93.3-101] and 97.4% [93.7-101], respectively) and amikacin (88.9% [81.7-96.1]
and 96.4% [92.1-100.7], respectively), compared with CAST. Specificity and positive
predictive values ranged from 82.9 (74.2-91.5) to 100%, and from 86.4 (78.5−94.2) to 100%,
respectively. If results had been reported to the clinicians, that DAST would have saved
carbapenem prescription in 17 cases (22%) and would have allowed immediate narrow spectrum
antimicrobials in 35/85 (41.2%) cases. But, the benefit of DAST was based on a simulation and
should be now tested in a randomized fashion.
Hypothesis - DAST as compared to CAST, would increase the number of adequate antimicrobial
therapy within 24 hours in case of late VAP (> 5 days under mechanical ventilation) with Gram
negative bacilli (GNB) in ICUs while sparing carbapenems (imipenem and meropenem).
Primary objective - To determine the impact of a strategy using DAST on the rate of day1
adequate therapy while sparing carbapenems in case of late VAP due to GNB.
Secondary objectives are:
1. To evaluate the impact of the DAST strategy compared to CAST on the following outcomes:
- Adequate antimicrobial therapy at Day1 (with or without carbapenem)
- exposure to carbapenems at D14 and D28
- Broad spectrum antibiotic exposure at D14 and D28
- De-escalation at D1
- relapses or new VAP at D14 and D28.
- the emergence of ESBL producing GNB and / or resistant to broad-spectrum
antibiotics in clinical samples and in the intestinal microbiota at D3, D7, D14 and
D28, or until discharge of the ICU patient
- Changes in respiratory infection and organ failure
- Mechanical ventilation exposure between day 1 and 28
- Length of ICU stay.
- In-ICU mortality.
2. To evaluate the performance diagnostic of DAST compared to CAST
3. To achieve a minimization study of the costs of the DAST strategy compared to the CAST
strategy Experimental scheme and procedures This study is a multicentre, prospective,
parallel-group, open-label trial. After baseline screening, an independent, centralized,
computer-generated randomization sequence will be used to randomly assign patients in a
1:1 ratio to DAST or CAST groups. Random allocation will be stratified by centre;
investigators will be masked to assignment before, but not after, randomization, as per
our open-label design. This system will be password protected and access by the
principal investigator or study coordinator after the patient or surrogate give consent
and has met inclusion criteria. Although treatment assignments were not masked, all
investigators were unaware of aggregate outcomes during the study.
Number of patients According to our preliminary study, 76 patients could be enrolled within
one year in 3 ICUs and more than half will receive carbapenems initially. DAST would have
permit to spare carbapenems in 22% of the cases and to avoid inadequate penem use in 5 other
percent of the cases. The expected proportion of adequate antibiotic therapy without
carbapenem is 68%. In all, 68 patients per arm will be necessary to detect a 22% difference
between groups with a power of 90% (pooled variance Z test). The level of significance will
be 5%.
The hypothesis is that 15% of DAST will be non-contributive and if 5% patients are lost to
follow up, 90 patients per arm (140 patients overall) need to be enroll.
According to previous number in the preliminary study, 180 patients will be enrolled within
18 months of inclusion.
Inclusions - 180 patients will be enrolled during a 18 months period In all, 9 investigation
centers are associated to the study. Thus, around 1.1 patient need to be enrolled per month
during 18 month for each center Statistical analyses - Both group will be compared by
Cochrane Mantel HAENTZEL chi square for primary end point.
Other secondary objectives will require model for longitudinal data, model for censored data
that account for competing events (MDR acquisition, day 28 outcome).
The random unit is the patient. The first episode will be taken into account for the primary
end point.
In case of repeated VAP with GNB, samples will be proceeded according to their random
allocation arms (CAST of DAST) until day 28 or ICU discharge.
Data collected and definitions:
After obtaining an appropriate respiratory specimen for Gram stain and conventional culture,
initial antibiotic therapy (day 0) will be given according to the standards of care, in
agreement with international guidelines: Initial Empiric Antibiotic Therapy for patients with
late-Onset Disease or risk factors for MDR pathogens from ATS and IDSA 2005 (table 1-2-3)
avoiding carbapenem whenever possible.
The following data will be collected :
At admission to the ICU : age, sex, pre-existing comorbidities, previous location before
admission, admission category, reason for admission, SAPS II, the presence and type of organ
dysfunction using the sequential organ-failure assessment (SOFA) score, and use of mechanical
ventilation.
Between D1 and D3 : Microbiological results of the VAP episode (GNB identification, CAST and
DAST) Between D1 and D28 All infections occuring and the colonization by MDR SOFA score and
type of organ or system failure and CPIS score (D1,2,3,7,14,28) All antibiotics exposure.
Adequacy of the initial empirical antibiotics regimen for VAP suspected to be due to gram
negative organisms at inclusion will be recorded.
Inadequate antimicrobial treatment was defined as the use of antibiotics to which at least
one cultured isolate was resistant in vitro at day 1.
Besides the initial respiratory specimen at inclusion, all other microbiological assessments
from specimens taken between day 0 = inclusion and day 14 for will be recorded.
Multidrug-resistant bacteria were defined according to MAGIORAKOS Clin Microbiol infect,
2012. Broad spectrum antimicrobials were defined as antibiotics belonging to ranks 4 to 6
(Piperacillin+Tazobactam, Ticarcillin+Clavulanic Acid 4th generation cephalosporin,
Antipseudomonal 3rd generation cephalosporin, Carbapenems) (Weiss et al, Clin. MICROB.
Infect. 2015). For the purpose of this study, de-escalation was considered if the pivotal
antibiotic was switched for an antibiotic with a narrower spectrum than the empirical
treatment, according to a ranking of molecules from a recent study performed on behalf of the
""de-escalation"" study (Weiss et al, Clin. MICROB. Infect. 2015)"
;
Status | Clinical Trial | Phase | |
---|---|---|---|
Completed |
NCT01406951 -
Diagnostic Value of sTREM-1 and PCT Level as Well as CPIS Score for Ventilator-Associated Pneumonia Among ICU Sepsis Patients
|
N/A | |
Completed |
NCT00893763 -
Strategies To Prevent Pneumonia 2 (SToPP2)
|
Phase 2 | |
Recruiting |
NCT03581370 -
Short Infusion Versus Prolonged Infusion of Ceftolozane-tazobactam Among Patients With Ventilator Associated-pneumonia
|
Phase 3 | |
Completed |
NCT02070757 -
Safety and Efficacy Study of Ceftolozane/Tazobactam to Treat Ventilated Nosocomial Pneumonia (MK-7625A-008)
|
Phase 3 | |
Completed |
NCT03348579 -
Hospital-acquired Pneumonia in Intensive Care Unit
|
||
Completed |
NCT04242706 -
VITAL - VAP Prevention by BIP (Bactiguard Infection Protection) ETT Evac in Belgian ICUs
|
Phase 4 | |
Recruiting |
NCT05589727 -
Application of Ventilator-Associated Events (VAE) in Ventilator-Associated Pneumonia (VAP) Notified in Brazil
|
||
Not yet recruiting |
NCT06168734 -
Cefepime-taniborbactam vs Meropenem in Adults With VABP or Ventilated HABP
|
Phase 3 | |
Completed |
NCT02515448 -
A Pharmacokinetic-pharmacodynamic Dose Comparison Study of 8 mg/kg of Inhaled or Parenteral Gentamicin in 12 Mechanically Ventilated Critically Ill Patients Treated for Ventilator-associated Pneumonia
|
Phase 1 | |
Completed |
NCT01972425 -
Biomarker-based Exclusion of VAP for Improved Antibiotic Stewardship
|
N/A | |
Completed |
NCT02838160 -
Effectiveness of Different Educational Strategies on the KAP, Psychological and Clinical Outcomes
|
N/A | |
Completed |
NCT01467648 -
The Pharmacodynamics of Doripenem Between 4-hour and 1-hour Infusion in Patients With Ventilator-associated Pneumonia
|
Phase 4 | |
Completed |
NCT00364299 -
Prevention of Ventilator-Associated Pneumonia by Automatic Control of the Tracheal Tube Cuff Pressure
|
N/A | |
Not yet recruiting |
NCT03018431 -
CT Scan and Lung Ultrasonography to Improve Diagnostic of Ventilation Acquired Pneumonia in ICU
|
N/A | |
Completed |
NCT02515617 -
Medico-economic Study of the Subglottic Secretions Drainage in Prevention of Ventilator-associated Pneumonia (DEMETER)
|
N/A | |
Completed |
NCT02585180 -
Subglottic Secretions Surveillance to Predict Bacterial Pathogens Involved in Ventilator-associated Pneumonia
|
N/A | |
Completed |
NCT02583308 -
Impact of the Subglottic Secretions Drainage on the Tracheal Secretions Colonisation
|
N/A | |
Recruiting |
NCT01546974 -
Ventilator-associated Pneumonia (VAP) and Humidification System
|
Phase 4 | |
Completed |
NCT02060045 -
Prevention Ventilator Associated Pneumonia
|
N/A | |
Terminated |
NCT00543608 -
Clinical Efficacy of Intravenous Iclaprim Versus Vancomycin in the Treatment of Hospital-Acquired, Ventilator-Associated, or Health-Care-Associated Pneumonia
|
Phase 2 |