Journal Club Discussion - Inhaled Amikacin in prevention of Ventilator associated pneumonia

1. JOURNAL CLUB
INSTITUTE OF CRITICAL CARE
MEDICINE

3. BACKGROUND
• VAP : most frequent presentation of hospital acquired infections of the lower
respiratory tract.
• Leading cause of nosocomial infections worldwide.
• Incidence estimates vary from 2-30 episodes per 1000 days of mechanical
ventilation.
• Clinically significant disease develops in 5-40% of intubated critically ill patients.
• Attributable mortality of up to 13% and contributes to increased systemic
antibiotic consumption, duration of mechanical ventilation, length of ICU stay, and
costs.

4. • Typically peaks after 7 days of mechanical ventilation.
• Previous research has identified a potential therapeutic window to prevent the
progression of VAP.
• Various preventative strategies such as reduced sedation, weaning protocols,
positioning, cuff management, oral and digestive care have been implemented,
but have not sufficiently reduced the burden of VAP.
• VAP arises mainly due to microaspirations around the tracheal tube cuff and the
formation of biofilms leading to bacterial spread in the tracheobronchial tree.
Nosocomial pneumonia in 27 ICUs in Europe: perspectives from the EU-VAP/CAP study.
Eur J Clin Microbiol Infect Dis 2017
Ventilator-associated pneumonia in adults: a narrative review. Intensive Care Med 2020

5. BENEFITS OF INHALED ANTIBIOTICS
• High tracheobronchial and pulmonary concentrations.
• Reduction of systemic exposure to antibiotics, and hence their toxicities.
• Antibiotic deposition in the tracheal tube biofilm, otherwise out of reach
through the systemic route.
Pharmacokinetics of high-dose nebulized amikacin in mechanically ventilated healthy subjects.
Intensive Care Med 2008

6. • There has been a resurgence of interest in the usage of nebulised
antibiotics in recent years owing to the appearance of MDR
pathogens.
• Associated with reduced emergence of resistant bacteria.
Palmer LB, Smaldone GC. Reduction of bacterial resistance with inhaled antibiotics
in the intensive care unit. Am J Respir Crit Care Med 2014

8. CONCLUSION: Findings did not support the use of inhaled Amikacin
adjunctive to standard-of-care intravenous antibiotic therapy in
mechanically ventilated patients with Gram-negative pneumonia

10. CURRENT RECOMMENDATIONS
• Pathogen-specific
• Suggested to use both inhaled and systemic antibiotics rather than
systemic alone (weak recommendation, very low quality evidence)
• Reasonable to consider adjunctive inhaled antibiotic as a therapy of last
resort for patients not responding to intravenous antibiotics alone.
Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 Clinical
Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society

11. HYPOTHESIS
A 3-day course of inhaled Amikacin initiated after the
third day of invasive mechanical ventilation might
reduce the incidence of ventilator-associated pneumonia

12. STUDY DESIGN
• Investigator-initiated, multicentre, double-blinded, randomised,
controlled superiority trial
• 19 ICUs in France
• Conducted by the Regional Hospital Centre of Tours
• Funded by a grant from the French Ministry of Health
• Trial period: July 2017 to March 2021
• Approved by the Regional Ethics Committee

13. INCLUSION CRITERIA
• Age >18 years
• Undergone invasive mechanical ventilation for at least 72 hours
• French social security coverage

14. EXCLUSION CRITERIA
• Patients on invasive mechanical ventilation for >96 hours
• Suspected or confirmed ventilator-associated pneumonia
• Severe acute kidney injury (KDIGO 2/3) without renal replacement therapy
• Chronic kidney disease (GFR <30 ml/min)
• Ventilation via a Tracheostomy tube
• Extubation scheduled within the next 24 hours
• Receiving systemic aminoglycoside therapy
• Pregnant patients
• Patients with Myasthenia gravis

15. INTERVENTION COMPARATOR
Nebulised Amikacin (sulphite-free powder)
(Merck, France) solubilised in sterile water at
a dose of 20mg/kg IBW OD* 3 days via a
vibrating mesh nebuliser (Aerogen, Ireland)
Placebo: 0.9% sodium chloride (saline),
identical administration regimen with
equivalent volume
• Nebulisation once a day for 3 consecutive days beginning after 72 hours of
invasive mechanical ventilation. (maximal dose of 2g)
• Nebuliser placed upstream in the inspiratory limb of the ventilator circuit, with or
without active humidification according to the preference of the attending
physician.
• Ventilator settings, sedation, muscle relaxation were at the discretion of the
attending physician.
• All centres adhered to international guidelines for VAP prevention.

16. • To ensure blinding, all nebulisers were taped prior to the study start.
• Nebulisers were supplied with an opaque tubing.
• Measurements of serum amikacin concentrations were prohibited until 48
hours after completion of the intervention.

17. RANDOMISATION
• Assigned to either the experimental or the control group in a 1:1 ratio as
per a computer-generated randomisation scheduled stratified by centre.
• Allocation concealment and block sizes (blocks of 4) generated by a
statistician otherwise not involved in the trial.
• Ensured by a centralised secure online server and not disclosed to
patients or hospital staff involved in patient care

19. OUTCOMES
PRIMARY
• First episode of ventilator-associated pneumonia from randomisation to day 28
• Adjudicated by a blinded centralised committee on the basis of definitions from
international guidelines (IDSA/ATS 2016 Clinical Practice Guidelines) requiring a
positive quantitative bacterial culture in a pulmonary sample and new infiltrates on
chest radiograph with at least 2 of the following findings:
1. Fever
2. Hyperleukocytosis
3. Leukopenia
4. Purulent secretions

21. KEY SECONDARY OUTCOMES
• Incidence density (per 1000 patient-days of mechanical ventilation) of
adjudicated VAP
• Incidence of VAP due to Gram-negative bacteria with in-vitro susceptibility
to Amikacin
• Ventilator-associated events comprising of:
1. Ventilator-associated conditions - VAC (i.e., worsening oxygenation
over 2 days after a stable or improvement period)
2. Infection-related ventilator-associated complications - IVAC (i.e.,
worsening oxygenation associated with signs of infection and initiation of
antibiotic therapy)
3. Possible VAP - PVAP (IVAC accompanied by a documented bacterial
component)

22. • Number of days with administration of at least one systemic antibiotic
• Number of antibiotic-days (sum of the number of systemic antibiotic
treatment received each day)
• Number of day of mechanical ventilation from randomisation to day 28
• Number of days in the ICU
• Number of days in the hospital from randomisation to day 90
• Mortality at days 28 and 90
• Evaluation of nebulisation safety and side effects
• Subgroup analysis involving patients with tracheobronchial bacterial
colonization and tracheobronchitis at randomization

23. STATISTICAL ANALYSIS
• Analysis performed according to the Intention-to-treat principle.
• Threshold for statistical significance was set at 5% with 95% confidence intervals
for all estimates.
• Time from randomisation to the first VAP episode was represented by cumulative
incidence curves.
• Proportional-hazards assumption not met, hence an analysis of the restricted
mean survival time (RMST) to ventilator-associated pneumonia was adopted,
with death and extubation as the competing events.
• Hazard ratios were calculated with the use of a Fine and Gray regression model

24. SAMPLE SIZE
• Based on a previous trial conducted by the same CRICS-TriggerSEP
Network (France 2013), taking into account the competing risk of death
and extubation, an expected incidence of first VAP episode of 6% in the
experimental group and 12% in the placebo group was assumed.
• A sample size of 850 patients was calculated to obtain a power of 80% to
show an efficacy with a two-sided alpha level of 0.05
Surveillance des infections nosocomiales en réanimation adulte. Réseau REA-Raisin,
France, résultats 2013

27. Demographically
well-matched

32. DISCUSSION
• In this large multicentre trial, a 3-day course of inhaled Amikacin
reduced the burden of ventilator-associated pneumonia by D28 as
compared with placebo.
• Safety profile: Less than 2% patients experienced serious adverse
effects.
• Incidence of VAP was higher than the conservative 12% estimate
used for sample size calculations based on previous studies.

33. STRENGTHS OF THE TRIAL
• Robust methodology including a double-blinded placebo-
controlled design.
• Multicentric.
• Robust assessment of the primary outcome with adequate
sample size achieved.

34. LIMITATIONS
• Trial not powered enough to investigate other patient-centric outcomes
such as death or length of stay in the ICU/hospital.
• Trial not powered to assess the potential benefit in reducing the usage of
systemic antibiotics to limit antibiotic-resistance selection pressure.
• About 78% of patients in both groups were already on systemic antibiotics
before the trial began, details of which are not provided. They may impact
VAP rates by themselves.

35. • Usage of inhaled 0.9% saline as the placebo, in itself may increase the
risk of ventilator-associated pneumonia.
• It is possible that nebulised Amikacin could sterilise the upper airway
secretions, thereby directly reducing the microbiological diagnosis of VAP
rather than truly reducing the rate of clinical pneumonias.
• Length of mechanical ventilation was exactly the same in both the groups
(median of 9 days). No hint of an improvement in possibly the most
proximate patient-centric endpoint.

36. CONCLUSION
• In this trial, a 3-day course of inhaled Amikacin reduced the burden
of ventilator-associated pneumonia as compared with placebo.
• However, more trials assessing meaningful patient-centric
clinical outcomes are needed before it is compelling enough to
change practice.
• Long term effect in reducing systemic antibiotic usage and
resistance remains to be seen.

37. THANK YOU