Aerosolized Colistin in Ventilator Associated Pneumonia caused by Carbapenem Resistant Acinetobacter

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 infectionso 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

Variousintensive 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