Marcos I. Restrepo, MD, MSc, FCCP

Transcription

1 Thank you for viewing this presentation. We would like to remind you that this material is the property of the author. It is provided to you by the ERS for your personal use only, as submitted by the author by the author

2 Marcos I. Restrepo, MD, MSc, FCCP Pulmonary / Critical Care Medicine Associate Professor of Medicine Associate Program Director Pulmonary / Critical Care Program Medical Director, MICU South Texas Veterans Health Care System University of Texas Health Science Center San Antonio, TX

3 Disclosures Conflict of Interest HCAP/HAP/VAP panel expert IDSA/ATS Guidelines CAP/HCAP panel expert IDSA/ATS Guidelines Cough panel expert ACCP Guidelines Support PI - NIH/NHLBI - Award Number K23HL Macrolides as immunomodulators in Sepsis and Pneumonia The content is solely the responsibility of the author and does not necessarily represent the official views of the NIH/NHLBI Site PI - VA CSP 574 Corticosteroids for Severe CAP The funding agencies had no role in the preparation, review, or approval of this presentation. The views expressed in this presentation are those of the author and do not necessarily represent the views of the Department of Veterans Affairs, nor the UTHSCSA

4 Objective Review the application of aerosolized antibiotics for Ventilator Associated Pneumonia (VAP) or Ventilator associated tracheobronchitis (VAT) Focus on: Prevention Treatment Adverse events

5 Problem Antibiotics Prevention Treatment Issues Future

6 Problem

7 42-year-old 3 days post mechanical ventilation

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10 Endotracheal Tube Subglottic Secretions Endotracheal Tube Cuff Pooled Secretions in Airway Aspiration (micro-aspiration) Biofilm on ETT VAP Risk Factors Aspiration Elderly COPD Coma Head Trauma ARDS Supine Position Enteral Feeds * Reintubation Transport * * ** Modifiable condition *

11 Economic Burden of VAP * p< 0.05 Retrospective Matched Cohort Analysis of NASCENT Outcomes Cases (VAP) n=30 Control (No-VAP) n=90 Charges per pt, $ $198,200 $96,540 * Hospital cost, $ $76,730 $41,250 * Median Loss to hospital, $ $32,140 $19,360 Duration MV, d (median) * ICU LOS, d (median) * Duration Hosp LOS, d (median) * Higher cost: Hospital care and respiratory therapy Restrepo MI, et al. Infect Control Hosp Epidemiol 2010

12 Proportion of resistant P. aeruginosa isolates US I CU P. aeruginosa I solates Resistant to I mipenem, Ceftazidime, and Fluor oquinolones (NNI S, ) Imipenem Ceftazidime Fluoroquinolone Year 1 Gaynes R, Edwards JR, and the NNIS System. Clin Infect Dis. 2005;41(6): Fridkin SK, Gaynes RP. Clin Chest Med. 1999;20(2): NNIS System. Fluoroquinolone-resistant P. aeruginosa among ICU patients, At: For imipenem and ceftazidime, results of Cochran-Armitage χ 2 tests for trend were significant (P < 0.001). Percent Resistance K. pneumoniae non-susceptible to 3rd-generation cephalosporins ICU Patients Non-ICU Patients Year Fridkin SK, Gaynes RP. Clin Chest Med. 1999;20: Proportion of resistant Acinetobacter isolates US I CU Acinetobacter I solates Resistant to Amikacin, I mipenem, and Ceftazidime (NNI S, ) Amikacin Imipenem Ceftazidime Year In all instances, results of Cochran-Armitage χ 2 tests for trend were significant (P < 0.001). Reproduced with permission of Gaynes R, Edwards JR, and the NNIS System. Clin Infect Dis. 2005;41(6): % MRSA M RSA Rates in USA Lowy FD, NEJM 1999; MMWR 1997; NNIS

13 Mortality associated with initial antibiotic therapy in VAP Crude Mortality rate % NS 32 Alvarez- Lerma '96 < Alvarez-Lerma F, et al. CCM. 1996;22: Luna CM, et al. Chest 1997;111: Rello, J, et al. AJRCCM 1997;156: Inadequate vs NS 25 Luna '97 Rello '97 Kollef '99* Sanchez- Nieto '98 Adequate 50 NS NS 47 Ruiz ' 00 Dupont '01 Kollef MH, et al. Chest. 1999:115; Sanchez-Nieto JM, et al. AJRCCM. 1998;157: Ruiz M, et al. AJRCCM. 2000;162: Dupont H, et al. ICM. 2001;27:

14 Adapted from Boucher HW, et al Clin Infect Dis 2009

15 Restrepo MI, et al. Respiratory Care 2015 Pseudomonas aeruginosa ESBLs MRSA Acinetobacter baumannii Stenotrophomonas maltophilia

16 Clinical Infectious Diseases 2016

17 Antibiotics

18 Ventilator-Associated Indications for Nebulized Antibiotics in mechanically ventilated patients Tracheobronchitis 67% Pneumonia 64% Sole-Lleonart C, et al. Clin Microbiol Infect 2016 In patients with VAT, it is not recommended the use of antibiotic therapy Weak recommendation, low-quality evidence IDSA/ATS HAP/VAP Guidelines Clin Infect Dis 2016

19 Nebulized Antibiotics Lung Deposition Particle Size Aerosol Generator Ventilator Settings

20 Best Aerosolized Antibiotics Characteristics Highly active (type and specialized formulation) Concentration-dependent (dosing) Post-antibiotic effect High concentrations (concentration & time) Minimal toxicity Well tolerated at the epithelial surface Penetrate infected sputum (delivery system) Avoid inactivation in the airway or by other medications

21 Nebulized Antibiotics fold higher than MIC

22 Aerosolized Antibiotics Aminoglycosides Gentamicin Colomycin Amikacin Liposomal amikacin Neomycin Sisomycin Tobramycin Polymixins Colistin/Polymixin B Glycopeptides Vancomycin Monobactams Aztreonam lysine Beta-lactams Ceftazidime Ticarcillin Fluoroquinolones Ciprofloxacin Palmer LB. Curr Opin Pulm Med 2015 Tested for VAP or VAT

23 Aminoglycosides

24 Aminoglycosides Better inhaled than IV High tissue concentration Induce rapid and potent bacterial killing Renal toxicity

25 Ultrasonic nebulizer Jet nebulization Technology Pulmonary Drug Delivery System Breath-enhanced jet nebulizer Delivery Devices Vibrating mesh nebulizer

26 Nebulizers Jet 48% Ultrasonic 39% Tracheal Instillation 14% Vibrating Mesh 9% Sole-Lleonart C, et al. Respir Care 2016 online

27 Nebulized Antibiotics TV 500 ml Long inspiratory time (increased I:E ratio) Decrease inspiratory flow Remove heat/moisture exchange

28 Mesh Nebulizer

29 Prevention

30 Hours IDSA/ATS. Am J Respir Crit Care Med IDSA/ATS Clin Infect Dis 2016 Admission to the hospital Ventilator associated pneumonia Prevention x > 48 hrs on mechanical ventilation

31 Prevention of ICU Acquired Pneumonia with Aerosolized Antibiotics Randomized Studies Non- Randomized Studies AA prevented ICU acquired pneumonia Increase emergence of bacterial resistance Falagas ME, et al. Crit Care 2006; 10:R123.

32 Systemic & Aerosolized Antibiotics RCT in chronically intubated critically ill patients Multiple courses of systemic Antibiotics Palmer LB and Smaldone GC. Am J Respir Crit Care Med 2014

33 Systemic & Aerosolized Antibiotics RCT in chronically intubated critically ill patients Multiple courses of systemic Antibiotics AA Eradicated existing MDRO Reduce pressure from systemic antibiotics for new antimicrobial resistance Palmer LB and Smaldone GC. Am J Respir Crit Care Med 2014

34 ICU acquired pneumonia was reduced by AA AA reduced the rate of P. aeruginosa colonization AA did not have a higher rate of serious drug-related toxicity

35 Treatment

36 Hours IDSA/ATS. Am J Respir Crit Care Med IDSA/ATS Clin Infect Dis 2016 Admission to the hospital Ventilator associated pneumonia x > 48 hrs on mechanical ventilation Treatment

37 Inhaled or Endotracheally instilled Antimicrobials Meta-analysis - RCT n=5 (non-cystic Fibrosis) Results OR 95%CI Clinical success (ITT) Clinical success (CE) All-cause mortality Microbiological success Toxicity CE clinically evaluable & ITT intent to treat Fixed effect model only presented no differences compared to random effects model Ioannidou E, et al. J Antimicrob Chemother. 2007

38 Emergency of Resistance Meta-analysis - RCT n=5 (non-cystic Fibrosis) Susceptible pathogen became resistant after the completion of the treatment Acquired Resistance Sisomycin-resistant Klebsiella spp. Tobramycin-resistant strain Gentamycin-resistant strain 3/46 (6.5%) Ioannidou E, et al. J Antimicrob Chemother. 2007

39 Aerosolized Antibiotics for the treatment of Pneumonia Intent to Treat Favors aerosolized alone Favors aerosolized + systemic Clinical Evaluable Ioannidou E, et al. J Antimicrob Chemother. 2007

40 Amikacin and Ceftazidime Acquisition of per-treatment antibiotic resistance Lu Q, et al. Am J Respir Crit Care 2011

41 Nebulized Antibiotics Zampieri FG, et al. Crit Care 2015; 19:150 Zampieri FG, et al. Crit Care 2015; 19:295

42 Nebulized Antibiotics Increase clinical cure rate No effect Microbiology cure rate Length of stay Mortality Zampieri FG, et al. Crit Care 2015; 19:150 Zampieri FG, et al. Crit Care 2015; 19:295

43 Aerosolized Colistin Improved clinical and microbiological response No effect on mortality or nephrotoxicity Quality of the Evidence: Poor Valachis A, et al. Crit Care Med 2015

44 HAP/VAP Guideline Recommendations For patients with VAP due to Gram-negative bacilli that are susceptible to only aminoglycosides or polymyxins (colistin or polymyxin B), we suggest both inhaled and systemic antibiotics, rather than systemic antibiotics alone Weak recommendation, very low-quality evidence In patients with HAP/VAP caused by Acinetobacter species that is sensitive only to polymyxins, we recommend intravenous polymyxin (colistin or polymyxin B), Strong recommendation, low-quality evidence and we suggest adjunctive inhaled colistin Weak recommendation, low-quality evidence IDSA/ATS HAP/VAP Guidelines Clin Infect Dis 2016

45 HAP/VAP Guideline Recommendations In patients with HAP/VAP caused by carbapenem-resistant pathogen that is sensitive only to polymyxins, we recommend intravenous polymyxins (colistin or polymyxin B), and we suggest adjunctive inhaled colistin Strong recommendation, low-quality evidence Weak recommendation, low-quality evidence In patients with VAT, it is not recommended the use of antibiotic therapy Weak recommendation, low-quality evidence IDSA/ATS HAP/VAP Guidelines Clin Infect Dis 2016

46 Issues

47 Gentamicin Amikacin Tobramycin Colistin Restrepo MI, et al. Respiratory Care 2015 Side Effects Nephrotoxicity Neurotoxicity Wheezing * - Cough * - Bronchospasm Hypersensitivity pneumonitis Hemoptysis * _ Average Incidence: - Not reported + <10%; %, %, ++++ >40% Reported greater incidence (>30%) in NCFB

48 Vancomycin Aztreonam Ceftazidime Restrepo MI, et al. Respiratory Care 2015 Side Effects Nephrotoxicity Neurotoxicity Wheezing Cough _ Bronchospasm Hypersensitivity pneumonitis Hemoptysis Average Incidence: - Not reported + <10%; %, %, ++++ >40% Reported greater incidence (>30%) in NCFB

49 Use of Aerosolized Antibiotics 79% Lack of evidence-based guidelines Health Care Workers n=84 Sole-Lleonart C, et al. Respir Care 2016 online

50 Issues with aerosolized antibiotics Penetration to sick lung Inactivation by inhibitors in sputum Changes during aerosolization Expenses ($$$) Emergence of resistance Local toxicity Bronchoconstriction or airway hyperresponsiveness Systemic effects Ventilator adjustment Appropriate cleaning and storage Environmental problems Off label use

51 Future

52 Inhaled Amikacin Solution BAY as Adjunctive Therapy in the Treatment of Gram-Negative Pneumonia (INHALE 1) NCT Inhaled Amikacin Solution (BAY ) as Adjunctive Therapy in the Treatment of Gram-Negative Pneumonia (INHALE 2) NCT Aerosolized Vancomycin in Methicillin-Resistant Staphylococcus Aureus Pneumonia Under Mechanical Ventilation NCT Efficacy Study of Colistimethate Sodium Inhalation in Patients With Ventilator-associated Pneumonia NCT

53 Addition of Tobramycin Inhalation in the Treatment of Ventilator Associated Pneumonia (VAPORISE) NCT Aerosolized Antibiotics in the Treatment of Ventilator Associated Pneumonia (AAINTVAP) NCT Aerosolized Tobramycin or Vancomycin Persistent Methicillin Resistant Staphylococcus Aureus Eradication Protocol (PMEP) (PMEP) - in CF patients NCT Aerosolized Vancomycin

54 Unmet needs for the future Delivery Systems Appropriate dosing Effect of antibiotics in viscous purulent secretions Adjunctive therapies to systemic antibiotics Enhanced and modified antibiotics Combination of antibiotics with immunomodulators, mucolytics, etc.

55 Conclusions Inhalation antibiotic therapies are an alternative for specific patients infected with multidrug resistant pathogens causing ventilator associated pneumonias Complexity of aerosolized antibiotic therapies need to take into account several factors to show promising result Future research is needed to assess new inhalational antibiotic therapies and the impact on clinical outcomes

56 Thank you!!! Questions? San Antonio, TX River Walk during Christmas