Background / Purpose of trial
Ventilator-associated
pneumonia (VAP) is a serious and common complication for patients in intensive care unit with considerable morbidity and mortality. Carbapenem resistance in Acinetobacter baumannii
(CRAB) infection has become increasingly prevalent worldwide and has been
associated with high mortality rate. Patients with
ventilator-associated pneumonia (VAP) caused by carbapenem-resistant
Acinetobacter baumanii (CRAB) , incidence of which has been rising
substantially, may be predisposed to poor outcome because of limited
therapeutic options. Polymyxins are one of the few agents that
can be used for treatment of CRAB infections, and there is considerable
evidence regarding their efficacy for VAP caused by CRAB.
Nebulized antibiotics have been used to treat
respiratory tract infections over last
70 years. There has been a recent
resurgence in interest for this administration route because of emergence
of multidrug-resistant (MDR) strains as causative pathogens of severe
respiratory tract infections. Many theoretical advantages of nebulized
antibiotics have been proposed, such as higher concentrations at the site of
infection and less systemic exposure.Several
theoretical reasons for using nebulized antimicrobial therapy in mechanically ventilated
patients have been postulated. With proper drug delivery, drug
is delivered directly to site of
infection so that concentrations in the lung are high and systemic
toxicity is minimized.
Furthermore, microflora of the gut is not altered, thus
reducing emergence of MDRO and infection
with Clostridium difficile. The high antibiotic concentrations achieved with
targeted therapy far exceed MIC and
result in a large ratio of maximum concentration to MIC, an index shown to be
important for eradication of these organisms in milieu of thick purulent
secretions, biofilm, and diminished mucociliary clearance.
Increasing prevalence of VAP caused by highly resistant P aeruginosa
and Acinetobacter has led to reintroduction of colistin (polymyxin E) in an
aerosolized form and IV form.The
mechanism of colistin’s bactericidal activity is destabilization of lipopolysaccharide
(LPS) of the outer membrane, and, in addition, it neutralizes LPS, thereby
decreasing antiendotoxin activitites.
Depending upon type of antibiotics used,
antibiotics administered via systemic administration may not penetrate parenchymal lung tissue and bronchial
secretions, resulting in insufficient drug concentration at target site. Moreover,
altered antibiotic pharmacokinetics in critically ill patients has been
recognized as an important factor that compromises optimal drug penetration. Inadequate
concentration of antibiotics at infection site may result in poor treatment
outcomes, particularly when MDR pathogens are etiology. Therefore, there
is a requirement for drugs that can demonstrate the achievement of high
concentrations at the site of infection, while also reducing risk of systemic toxicity
caused by intravenously administered antibiotics. Accordingly, aerosolized
antibiotics have been used as a rescue or adjuvant therapy in patients who do
not exhibit responses to systemic treatment alone.
As per the recent HAP/VAP guidelines (2016) of the
Infectious Diseases Society of America (IDSA) and American Thoracic Society
(ATS), adjunctive therapy with aerosolized antibiotics is recommended along
with administration of systemic antibiotics rather than systemic antibiotics
alone for patients with gram-negative VAP (not HAP) ‘only’ susceptible to
aminoglycosides or polymyxins (Colistin/Polymyxin B).
Hence we will be conducting this study where we
will administer aerozolized colistin in carbapenem resistant acinetobacter patients
and see the outcome
AIMS AND OBJECTIVE
The
study aims to investigate outcomes of
two different treatment approaches for Intensive Care Unit patients with
Ventilator-Associated Pneumonia (VAP) caused by Carbapenem Resistant
Acinetobacter baumannii. The two treatment approaches being compared are:
Intravenously Administered
Polymyxins alone
Combination
Therapy - IV Polymyxin along with Aerosolized Colistin Nebulization
Methodology
Study design
Randomized. Double blind placebo controlled trial
Study setting
Various intensive care units of
Department of Anaesthesiology, Pain Medicine & Critical Care
Inclusion criteria:
1) Hospitalized
adults, aged ≥ 18 years
2) Microbiologically
documented VAP due to A. baumannii with carbapenem resistant
strains
but susceptible to Polymyxin.
Exclusion
criteria :
Patients’
refusal
Known
allergies or sensitivities to nebulized colistin.
Pregnancy
Patients
not expected to survive beyond 48h.
Study
Protocol:
All
patients satisfying the inclusion criteria will be included in the study after
obtaining written informed consent from the patients’ legally
acceptable representative
Definition
of Ventilator Associated Pneumonia :
A
pneumonia where the patient is on mechanical ventilation for > 2 consecutive
calendar days on the date of event, with day of ventilator placement being Day
1
Pneumonia
will be identified by using a combination of imaging, clinical, and
laboratory criteria.
Microbiological
diagnosis of VAP will be established by positive cultures of endotracheal
aspirate or bronchoalveolar lavage with isolation of A. baumannii
with carbapenem resistant strains but susceptible to Polymyxin . Baseline
demographic data and severity of illness (Acute Physiology and Chronic Health
Evaluation (APACHE II)) , and Sequential Organ Failure Assessment(SOFA)
scores , septic shock and acute renal failure (defined by KDIGO
-The Kidney Disease: Improving Global Outcomes definition)comorbidities,
colistin regimen (intravenous versus intravenous and inhalatory) and length of
treatment will be recorded. Bacteriologic sampling will be performed
for all patients on the day that VAP is suspected (day 0), before new
antimicrobials are started. The response to treatment will
be assessed at the time of discharge from the ICU or at the end of
antimicrobial therapy, especially if the patient remained hospitalized for a
non VAP-related disease.
Included patients will be randomized into two
parallel groups whether they will receive combination therapy of intravenous
Polymyxins and aerosolized colistin or IV Polymyxins alone.
• IV
Polymyxin plus sulbactam or IV Polymyxin plus minocycline
• Aerosolized
colistin will be given as 4 MU (diluted in 4ml sterile normal saline 0.9%) by
nebulization two times per 24 h.
• Nebulization
will be given via an ultrasonic nebulizer.
• The
treatment duration will be maintained at least 14 days or till extubation.
• All
patients will be followed till 28days or death or hospital discharge.
Primary Outcome
Primary outcome will be clinical outcome of VAP
assessed at day 14 of therapy and classified as
Clinical
Cure
Clinical
Improvement
Clinical
Failure
Clinical
Success
Secondary
Outcomes
Microbiological outcome at
day 7 & day 14
Liberation from MV at day
28
ICU mortality
Hospital mortality
28- day mortality
Incidence of new onset or
worsening AKI
Incidence of bronchospasm
during nebulization
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