The promise of nebulized antibiotic therapy

Transcription

1 1 st ATHENA International Conference Athens, November 2015 Let s Talk About Inhaled Antibiotics Inhaled Antibiotics: The Story Stijn BLOT Dept. of Internal Medicine Faculty of Medicine & Health Science Ghent University, Ghent, Flanders (Belgium) Burns, Trauma and Critical Care Research Centre The University of Queensland, Brisbane, Queensland (Australia) Essentials to optimize antibiotic therapy Antimicrobial agent: PK/PD properties Adequate dosing Tissue penetration Infection site Pathogen + MIC Appropriate microbial coverage Pneumonia outcome Altered antimicriobial PK Critical illness Limitations of IV antibiotic administration PROBLEM Limited lung penetration Bad bacterial kill Clinical failure Inadequate [AB] at the infection site SOLUTION Higher AB dosages Toxicity risk Triggers MDR MICs

2 The promise of nebulized antibiotic therapy Reaching the deep lung through the tracheobronchial tree control of bronchial colonization (i.e. main source of parenchymal infection) Bypassing the alveolar-capillary barrier [AB] at the infection site more efficient bacterial kill AB diffusion from bronchial/alveolar compartments to systemic circulation due to physiological barriers systemic toxicity Rouby J-J, et al. Anesthesiol 2012 Extra-pulmonary deposition of the drug o Loss of AB deposition of AB particles in nontarget zones residual volume in nebulizer ventilatory circuit trachea, bronchial tree Nebulizing ABs is not new o 50 yrs ago: <2% of of dose reached alveoli o Insights in how to decrease extra-pulmonary deposition (and improve drug delivery) Optimize aerosol particle size o >50% (preferably 90%) of particles: <5 micron o >5 micron tracheobronchial tree Type of nebulizer: Depends on agent to be nebulized - bronchodilator bronchi - lung infection alveolar space o Jet nebulizers o Ultrasonic nebulizers o Vibrating mesh plate

3 Factors boosting extra-pulmonary deposition of the antibiotic o Turbulences in ventilatory circuit o Patient-ventilator asynchrony Measures to reduce extra-pulmonary deposition o Short infusion with propofol to avoid patientventilator asynchrony o Ventilatory settings: reduce flow turbulences VC with constant inspiratory flow (not constant more turbulence) Low respiratory frequency (12/min.) to duration inspiratory flow End-inspiratory pauze 20% of the duty cycle to keep particles in the alveolar space Dhand R, et al. Clin Chest Med 2008 Lu Q, et al. Am J Respir Crit Care Med 2011 Tip: checklist for nurse o Remove H&M exchanger and conventional humidifier o Place nebulizer on the inspiratory limb, cm from Y-piece o Controlled mode of mechanical ventilation o Avoid assisted modes of mechanical ventilation Constant inspiratory flow Tidal volume 7-9 ml/kg Respiratory frequency 12/min. I:E-ratio 1:1 End-inspiratory pauze 20% of the total duty cycle o Avoid patient-ventilator asynchrony o Consider continuous infusion of propofol during nebulization Dhand R, et al. Clin Chest Med 2008 Lu Q, et al. Am J Respir Crit Care Med 2011

4 Does nebulizing ABs reach higher tissue concentrations in the infected lung? Ferrari F, et al. Intensive Care Med 2009 Trough lung tissue concentrations of ceftazidime measured 3 h after the eight nebulization in the aerosol group (black bars) and steady state lung tissue concentrations of ceftazidime measured 24 h after the start of continuous intravenous infusion in the intravenous group (white bars). Dashed line: MIC Goldstein I, et al. AJRCCM 2002 Lung tissue concentrations of AMK measured 1 hour after the second administration performed 48 hours after the bacterial inoculation. MIC

5 Important note: AB concentrations lower in severe pneumonia Goldstein I, et al. AJRCCM 2002 Due to consolidation less aeration impact drug delivery but still significantly higher compared with IV administration! Does nebulizing ABs lead to a potent and more rapid bacterial kill? Ferrari F, et al. Intensive Care Med 2009 Lung bacterial burden after 24 h of ceftazidime administration. Grey area = lower limit of quantitation for bacterial counts

6 Goldstein I, et al. AJRCCM 2002 Lung bacterial burden of E. coli in lung segments collected 1 hour after the second aerosol or IV dose of AMK, or 48 hours after the bacterial inoculation in the untreated control group. Can nebulizing ABs reduce the risk of systemic toxicity? No reduction of systemic toxicity in inhaled antibiotics Normal lung: alveolar-capillary membrane offers a difficult to cross barrier for systemic diffusion Infected lung: permeability for AMK & CAZ Exception: Colistin low systemic diffusion even in severe pneumonia (large molecule?) potential of reduced nefrotoxicity of colistin

7 Conclusion based on experimental data Achieving adequate antibiotic concentrations at the infected site is a challenge in critically ill ventilated patients with pneumonia Higher tissue concentrations and a more rapid kill might be achieved through nebulizing antibiotics Be aware of conditions required to achieve optimal drug delivery (minimize extra-pulmonary deposition) Suggested readings Rouby J-J, et al. Aerosolized antibiotics for VAP. Anesthesiology 2012 Goldstein I, et al. Lung deposition and efficiency of nebulized amikacin during E. Coli pneumonia in ventilated piglets. Am J Respir Crit Care Med 2002 Ferrari F, et al. Nebulized ceftazidime in experimental pneumonia caused by partially resistant P. Aeruginosa. Intensive Care Med 2009 Michalopoulos AS, et al. Inhaled antibiotics in mechanically ventilated patients. Minerva Anesthesiol 2014 Lu Q, et al. Efficacy of high-dose nebulized colistin in VAP caused by multidrugresistant P. Aeruginosa and A. Baumannii. Anesthesiology 2012 Dhand R, et al. The role of aerosolized antimicrobials in the treatment of VAP. Respir Care 2007 Niederman M, et al. BAY achieves bactericidal tracheal aspirate amikacin concentrations in mechanically ventilated patients with gram-negative pneumonia. Intensive Care Med 2012