Conflicts of Interest. Learning Objectives VAP. Common Organisms. Risk Factors for VAP. Gram Positive 10/13/2017

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1 Conflicts of Interest The author has no conflicts of interest to disclose Nebulized Antibiotics in VAP: Don t Hold Your Breath Luis M. Ramirez, Pharm.D. PGY1 Pharmacy Practice Resident University of Texas at Austin College of Pharmacy 2 Learning Objectives Following this presentation, the audience member will be able to: 1. Describe the definition, risk factors, and common organisms associated with ventilator-associated pneumonia (VAP) 2. Explain the current literature regarding nebulized antibiotics in VAP patients 3. Provide an evidenced-based recommendation on the appropriate use of nebulized antibiotics Definition: VAP Pneumonia occurring >48 hours after intubation Epidemiology Most common nosocomial infection in the intensive care unit (ICU) Occurs in 9-27% of all mechanically ventilated patients Estimated cost associated with VAP per patient: $40,000 Clinical cure rates rarely exceed 60% and recurrence rates remain high 3 Blackford MG, et al. Pharmacotherapy: A Pathophysiologic Approach, 10e Kalanuria AA, et al. Crit Care. 2014;18(2):208 Kollef MH, et al. Infect Control Hosp Epidemiol. 2012;33: Bassetti et al. Ann. Intensive Care (2016) 6:35 4 Risk Factors for VAP Common Organisms Age >60 years old COPD, ARDS, or coma Enteral nutrition, nasogastric tube MDR risk Reintubation, tracheostomy, or patient transport Patient Specific Witnessed aspiration H2RA s or PPI s Head trauma ICP Monitoring Preventable Supine Position Gram Positive Enteric Gram Negative Non-Enteric Gram Negative S. aureus (20-30% of isolates) 50% methicillinresistant 20-40% of isolates E. coli Klebsiella pnuemoniae P. aeruginosa (10-20% of isolates) 28-35% resistant to cefepime 19-29% resistant to piperacillin-tazobactam Acinetobacter baumanii 56-61% resistant to carbapenems Kalil AC, et al. Clin Infect Dis. 2016;63(5):e61-e Kalil AC, et al. Clin Infect Dis. 2016;63(5):e61-e

2 Risk Factors for MDR VAP Empiric Treatment Options for VAP Risk Factors for Multi-Drug Resistant (MDR) VAP Prior intravenous antibiotic use within 90 days Septic shock at the time of VAP ARDS preceding VAP 5 or more days of hospitalization prior to the occurrence of VAP Acute renal replacement therapy prior to the occurrence of VAP Kalil AC, et al. Clin Infect Dis. 2016;63(5):e61-e Gram Positive Antibiotics (MRSA Activity) Vancomycin Linezolid Gram Negative Antibiotics: β-lactam Based Agents Piperacillin-tazobactam Cefepime, ceftazadime Imipenem, meropenem Aztreonam Gram Negative Antibiotics: Non-β- Lactam Based Ciprofloxacin, levofloxacin Amikacin, gentamicin, tobramycin Colistin, polymyxin B Kalil AC, et al. Clin Infect Dis. 2016;63(5):e61-e Current Treatment Options for MDR Nebulization of Antibiotics VAP due to: Acinetobacter spp sensitive to polymixins/colistin or carbapenem resistant pathogens IV polymixin or colistin recommended Adjunctive inhaled colistin suggested Background Rationale Benefits Disadvantage of Up to 40% of cases caused by MDR Pseudomonas or Acinetobacter in ICU s Few antibiotic options PK changes in critically ill patients Avoids high systemic IV concentrations Reduced systemic ADE s/toxicities Poor lung penetration Ex: β-lactams, colistin, aminoglycosides, and glycopeptides Kalil AC, et al. Clin Infect Dis. 2016;63(5):e61-e Maragakis LL, et al. Expert Rev Anti Infect Ther. 2008;6: Zilberberg MD, et al. Critical Care. 2014;18(6):596. Smith BS, et al. Chest May;141(5): Bassetti M, et al. Ann Intensive Care. 2016; 6: 35. Zhang C, etl al. Respir Care Jun;61(6): Benefits of Nebulized Antibiotics Types of Nebulizers: Advantages & Disadvantages Higher drug concentrations (lungs) Decreased systemic toxicity Nebulizer Advantages Disadvantages Jet Easy to use Low cost Low drug delivery rate (15%) Difficult to clean Particle size >5 μm Localized effect VAP Reduced need for systemic antibiotics Bassetti M, et al. Ann Intensive Care. 2016; 6: 35. Zhang C, etl al. Respir Care Jun;61(6): Palmer LB. Infect Dis Clin North Am Sep;31(3): Zhang C, et al. Respir Care. 2016; 61(6): Dhanani J, et al. Critical Care. 2016; 20:

3 Types of Nebulizers: Advantages & Disadvantages Nebulizer Advantages Disadvantages Ultrasonic Good drug delivery (30-40%) Particle size μm Silent Increases drug temperature Inability to aerosolize viscous solutions Large device size Types of Nebulizers: Advantages & Disadvantages Nebulizer Advantages Disadvantages Vibrating Mesh Best drug delivery (40-60%) Adjustable drug particle size (<5 μm) Pores can clog High cost Difficult to clean Zhang C, et al. Respir Care. 2016; 61(6): Dhanani J, et al. Critical Care. 2016; 20: Zhang C, et al. Respir Care. 2016; 61(6): Dhanani J, et al. Critical Care. 2016; 20: Ideal Properties of an Aerosolized Antibiotic Solution Role of Inhaled Antibiotic Therapy in VAP Preservative Free, Sterile, Non- Pyrogenic Osmolality Adjusted IDSA 2016 Recommendation Weak recommendation, very low-quality evidence Suggests both inhaled and systemic antibiotics, rather than systemic antibiotics alone Particle Size Aerosolized Antibiotic Solution ph adjusted Reserved as treatment of last resort in patients who are not responding to IV antibiotics alone Used as an adjunct to IV antibiotic therapy May be used whether or not infecting organism is MDR Bassetti et al. Ann. Intensive Care (2016) 6: Kalil AC, et al. Clin Infect Dis. 2016;63(5):e61-e Rationale Nebulization of Antiinfective Agents in Invasively Mechanically Ventilated Adults: A Systematic Review and Meta-Analysis Solé-Lleonart C, Rouby JJ, Blot S, et al. Anesthesiology. 2017;126(5): Objective Background Determine efficacy and safety of antibiotic nebulization Increased use of nebulized antibiotics Safety and efficacy unknown Hypothesis: Nebulized antibiotics are safe and effective therapy in invasively mechanically ventilated adult patients

4 Methods Methods Data Systematic review and metaanalysis data from June 2014, March 2015, and July 2016 Databases Included Search Terms MEDLINE, PubMed, EMBASE, and Cochrane Library Database Aerosols, nebulizers and vaporizers, anti-bacterial agents, antimicrobial, pneumonia, ventilator associated Inclusion Criteria Randomized control trials (RCT), observational studies, and case series Use of jet, ultrasonic, or vibrating-mesh nebulizers Reported at least one of the following: Efficacy Outcome: Clinical resolution OR Safety Outcomes: Systemic Toxicity, cardiorespiratory complications Size 826 patients Methods Methods 1435 studies Exclusion Criteria Children, colonized-but-not-infected adults, and cystic fibrosis patients Burn, renal replacement therapies, and/or cardiopulmonary support patients 1358 studies (duplicates removed) 499 full-text articles 859 studies excluded 487 full-text excluded 11articles included in qualitative/quantitative synthesis Statistics Outcomes Pooled Evaluation Majority of studies had small sample sizes Performed for each outcome Heterogeneity Higgins I 2 Test Funnel Plot Assessment of publication bias Intervention Comparator Primary Efficacy Outcome Safety Outcomes Standard first-line IV antibiotics Nebulized antibiotics administered via adjunctive or substitution strategy Standard first-line IV antibiotics + IV colistin or aminoglycosides (AG) Clinical Resolution Systemic Toxicity Cardiorespiratory complications

5 Adjunctive vs Substitution Strategy RCT s Studies Included Strategy Intervention Comparison Adjunctive First-line + IV colisitin/aminoglycosides + First-line Nebulized colistin/aminoglycosides + Substitution First-line + Nebulized colisitin/aminoglycosides IV colistin/aminoglycosides Study Palmer et al Palmer & Smaldone et al Niederman et al Lu et al Hallal et al Nebulized Antibiotic Vancomcyin or gentamicin Vancomcyin or gentamicin Placebo Group Aerosolized saline Aerosolized saline Nebulizer Device Ceftazadime & amikacin Tobramcyin + placebo IV Ceftazadime & amikacin or cipro IV tobramcyin + placebo Admin. Strategy Primary Efficacy Outcome Jet - Clinical resolution (reduction in CDC- NNS & CPIS Scores) Jet - Eradication of MDRO Amikacin None Vibrating- Mesh Vibrating- Mesh Adjunctive Substitution PK/PD analysis in tracheal aspirates Clinical & bacterial cure of VAP after 8d Safety Outcomes None Nephrotoxicity Nephrotoxicity, respiratory complications Respiratory complications Jet Substitution Resolution of VAP Systemic toxicity 25 Rattanaumpawan IV antibiotic + IV antibiotic + Jet & Adjunctive Clinical resolution Systemic et al colistin saline Ultrasonic toxicity, respiratory complications 26 Observational Studies Included Study Ghannam et al Kofteridis et al Doshi et al Tumbarello et al Arnold et al Nebulized Antibiotic Amikacin Colistin Tobramcyin Placebo Device Admin. Strategy IV amikacin, gentamicin, or colistin Jet Nebulizer Colistin IV colistin Vibratingmesh nebulizer IV Colistin + aersolized colistin IV Colistin + aerosolized colistin Colistin or tobramcyin IV colistin IV colistin IV antibiotics Jet Nebulizer; Vibrating mesh nebulizer Jet & ultrasonic nebulizers Not defined Primary Efficacy Outcomes Safety Outcomes Substitution Clinical resolution Nephrotoxicity, respiratory complications Adjunctive Clinical resolution Systemic toxicity, respiratory complications Adjunctive Clinical resolution None Adjunctive Clinical resolution Nephrotoxicity Adjunctive Mortality (30d and in-hospital) Nephrotoxicity, respiratory ADE s 27 Clinical Result (Adjunctive Strategy) Studies Clinical Resolution 1 RCT: Niederman et al Observational: Kofteridis et al Doshi et al Tumbarello et al Patients Nebulized Antibiotics Results RCT: No significant difference in clinical resolution in both groups OR 1.30 (95% CI: 0.22 to 7.55) Observational: Clinical resolution was significantly higher in the NA group OR 0.51 (95% CI: 0.34 to 0.77) 28 Clinical Result (Adjunctive Strategy) Clinical Result (Adjunctive Strategy) Results (continued) Clinical Resolution Pooled meta-analysis of all studies (n = 437 patients): Better clinical resolution rates in patients receiving nebulized antibiotics OR 0.53 (95% CI: 0.36 to 0.80)

6 Clinical Result (Substitution Strategy) Safety Result (Adjunctive Strategy) Systemic Toxicity: Nephrotoxicity Studies Clinical Resolution 1 Observational: Ghanntam et al Patients Nebulized Antibiotics Results Higher rates of clinical resolution in the NA group OR 9.53 (95% CI: 1.85 to 49.2) Studies 2 RCT s: Niederman et al Rattanaumpawan et al Observational: Kofteridis et al Tumbarello et al Arnold et al Patients Nebulized Antibiotics Results No significant difference seen between both groups Safety Result (Adjunctive Strategy) Safety Result (Substitution Strategy) Systemic Toxicity: Nephrotoxicity Studies 1 RCT: Hallal et al Observational: Ghannam et al Patients Nebulized Antibiotics Results RCT: No difference (95% CI: to 0.05) Observational: Less occurrence of nephrotoxicity w/ NA (95% CI: to -0.08) Safety Result (Substitution Strategy) Safety Result Systemic Toxicity: Cardiorespiratory Complications 35 Studies Patients 4 RCT s: Niederman et al Rattanaumpawan et al Lu et al Hallal et al Observational: Kofteridis et al Arnold et al Nebulized Antibiotics Results RCT: 9% increase in respiratory complications Risk difference, 0.09 (95% CI: 0.01 to 0.18) Observational: No difference in ADEs Risk difference 0.00 (95% CI: 0.04 to 0.04) Combined meta-analysis Risk difference, 0.04 (95% CI: 0.02 to 0.11) 36 6

7 Results: Risk of Critique Study Selection Risk of Performance Detection Attrition Reporting Other Hallal 2007 LOW LOW LOW LOW LOW LOW Lu 2011 LOW HIGH HIGH LOW LOW LOW Niederman 2012 LOW LOW LOW LOW LOW LOW Palmer 2008 LOW LOW LOW LOW LOW LOW Palmer 2014 LOW LOW LOW MEDIUM LOW LOW Rattanaumpawan 2010 LOW HIGH HIGH LOW LOW LOW Strengths Strict inclusion criteria Utilized PRISMA guidelines for metaanalysis Limitations Use of jet nebulizers Only ½ of studies randomized Sub-therapeutic dosing in studies prior to 2014 Heterogeneous populations Doses of Nebulized Antibiotics Used in Studies Doses of Nebulized Antibiotics Used in Studies Study Palmer et al Palmer & Smaldone et al Niederman et al Lu et al Hallal et al Randomized Controlled Trials Nebulized Antibiotic Vancomycin 120 mg Q8H/NS 2 ml Gentamicin 80 mg Q8H/NS 2 ml Vancomycin 120 mg Q8H Gentamicin 80 mg Q8H Amikacin 400 mg Q8H Amikacin 400 mg Q12 or Q24H Ceftazadime 15 mg/kg Q3H; max: 120 mg/day Amikacin 25 mg/kg Q24H Tobramycin 300 mg/5 ml Q12H or Q24H Rattanaumpawan et al Colistin 75 mg Q12H/NS 4 ml Study Ghannam et al Kofteridis et al Doshi et al Tumbarello et al Arnold et al Observational Controlled Trials Nebulized Antibiotic Colistin 100 mg Q8H Tobramycin 300 mg BID Gentamicin 100 mg TID Amikacin 100 mg TID or 300 mg BID Colistin 80 mg BID Colistin 75 mg Q12H or Colisitin 150 mg Q12H Colisitin 80 mg TID Colistin 150 mg BID/NS 5 ml or Tobramycin 300 mg/ns 5 ml BID Recommended Nebulized Colistin Dosing Authors Conclusion Antibiotic Indication Dose Colistin Pneumonia, HAP, or VAP 150 mg Q8H over 60 minutes Tobramcyin Cystic Fibrosis 300 mg Q12H Efficacy Nebulized antibiotics might increase likelihood of clinical resolution (especially for VAP caused by MDR pathogens) Protective effect on development of MDR pathogens Safety Reduced risk of nephrotoxicity with nebulized antibiotics ~10% increased risk for respiratory complications Colistin. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL

8 Efficacy Summary Studies showed that nebulized antibiotics may be associated with potentially higher cure rates Safety Studies showed that overall, nebulized antibiotics showed reduced systemic toxicity The most serious adverse effect associated with nebulized antibiotics was respiratory failure Recommendation: Target Population No clinical improvement after hrs on standard IV antibiotics for VAP Patient has risk factors for MDR gram negative pathogens Cultures positive for MDR pathogens (if available) Past medical history negative for pulmonary conditions such as asthma, COPD, or ARDS Utilization of ultrasonic nebulizers or vibrating mesh nebulizers Potential Future Therapies Vancomycin Inhalation Powder (AeroVanc ) Amikacin Inhale (Proprietary Preparation) Aerosolized Amikacin/Fosfomycin Ciprofloxacin Dry Powder Inhalation Inhaled Levofloxacin (Quinsair ) Inhaled Liposomal Amikacin (Arikayce ) Acknowledgements Evaluator: Dr. Merry Daniel, Pharm. D, BCCCP Preceptors: Dr. Lane Farrell, Pharm. D, BCCCP Dr. Cheryl Wakeford, Pharm. D, BCPS Palmer LB. Infect Dis Clin North Am Sep;31(3): Nebulized Antibiotics in VAP: Don t Hold Your Breath Luis M. Ramirez, Pharm.D. PGY1 Pharmacy Practice Resident University of Texas at Austin College of Pharmacy 8

9 Appendix A: ADE AG ARDS CDC-NNS COPD CPIS H2RA ICP IDSA IV MDR MDRO MRSA NA NS PK/PD PPI PRISMA RCT VAP Adverse Drug Events Aminoglycosides Acute Respiratory Distress Syndrome Centers for Disease Control-National Nosocomial Infections Surveillance Chronic Obstructive Pulmonary Disease Clinical Pulmonary Infections Score H2-antagonists Intracranial Pressure Infectious Diseases Society of America Intravenous Multi-Drug Resistant Multi-Drug Resistant Pathogens Methicillin-Resistant Staphylococcus aureus Nebulized Antibiotics Normal Saline Pharmacokinetics/Pharmacodynamics Proton Pump Inhibitors Preferred Reporting Items for Systematic Reviews and Meta-analyses Randomized Control Trial Ventilator Associated Pneumonia Appendix B: Arnold HM, Sawyer AM, Kollef MH: Use of adjunctive aerosolized antimicrobial therapy in the treatment of Pseudomonas aeruginosa and Acinetobacter baumannii ventilator-associated pneumonia. Respir Care. 2012; 57: Bassetti M, Luyt CE, Nicolau DP, Pugin J. Characteristics of an ideal nebulized antibiotic for the treatment of pneumonia in the intubated patient. Ann Intensive Care. 2016;6(1):35. doi: /s x. Blackford MG, Glover ML, Reed MD. Lower Respiratory Tract Infections. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 10e. New York, NY: McGraw-Hill; = Accessed October 03, Colistin. Lexi-Drugs. Lexicomp. Wolters Kluwer Health, Inc. Riverwoods, IL. Available at: Accessed October 13, Dhanani J, Fraser JF, Chan HK, Rello J, Cohen J, Roberts JA. Fundamentals of aerosol therapy in critical care. Crit Care. 2016;20(1):269.

10 Doshi NM, Cook CH, Mount KL, et al. Adjunctive aerosolized colistin for multi-drug resistant gramnegative pneumonia in the critically ill: A retrospective study. BMC Anesthesiol. 2013; 13:45. Ghannam DE, Rodriguez GH, Raad II, Safdar A: Inhaled aminoglycosides in cancer patients with ventilator-associated Gram-negative bacterial pneumonia: Safety and feasibility in the era of escalating drug resistance. Eur J Clin Microbiol Infect Dis. 2009; 28: Hallal A, Cohn SM, Namias N et al. Aerosolized tobramycin in the treatment of ventilatorassociated pneumonia: A pilot study. Surg Infect (Larchmt). 2007; 8: Kalanuria AA, Ziai W, Mirski M. Ventilator-associated pneumonia in the ICU. Crit Care. 2014;18(2):208. doi: /cc Kalil AC, Metersky ML, Klompas et al. 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. Clin Infect Dis. 2016;63(5):e61-e111. doi: /cid/ciw353. Kofteridis DP, Alexopoulou C, Valachis A et al. Aerosolized plus intravenous colistin versus intravenous colistin alone for the treatment of ventilator-associated pneumonia: A matched casecontrol study. Clin Infect Dis. 2010; 51: Kollef MH, Hamilton CW, Ernst FR. Economic impact of ventilator-associated pneumonia in a large matched cohort. Infect Control Hosp Epidemiol. 2012;33(3): doi: / Lu Q, Yang J, Liu Z, Gutierrez C, Aymard G, Rouby JJ. Nebulized Antibiotics Study Group: Nebulized ceftazidime and amikacin in ventilator-associated pneumonia caused by Pseudomonas aeruginosa. Am J Respir Crit Care Med. 2011; 184: Maragakis LL, Perencevich EN, Cosgrove SE. Clinical and economic burden of antimicrobial resistance. Expert Rev Anti Infect Ther. 2008;6(5): doi: / Niederman MS, Chastre J, Corkery K, Fink JB, Luyt CE, García MS: BAY achieves bactericidal tracheal aspirate amikacin concentrations in mechanically ventilated patients with Gramnegative pneumonia. Intensive Care Med. 2012; 38: Palmer LB. Inhaled Antibiotics for Ventilator-Associated Infections. Infect Dis Clin North Am. 2017;31(3): doi: /j.idc Palmer LB, Smaldone GC, Chen JJ, et al. Aerosolized antibiotics and ventilator- associated tracheobronchitis in the intensive care unit. Crit Care Med. 2008; 36: Palmer LB, Smaldone GC: Reduction of bacterial resistance with inhaled antibiotics in the intensive care unit. Am J Respir Crit Care Med. 2014; 189:

11 Rattanaumpawan P, Lorsutthitham J, Ungprasert P et al. Randomized controlled trial of nebulized colistimethate sodium as adjunctive therapy of ventilator-associated pneumonia caused by Gramnegative bacteria. J Antimicrob Chemother. 2010; 65: Smith BS, Yogaratnam D, Levasseur-Franklin KE, Forni A, Fong J. Introduction to drug pharmacokinetics in the critically ill patient. Chest. 2012;141(5): doi: /chest Solé-Lleonart C, Rouby JJ, Blot S et al. Nebulization of Antiinfective Agents in Invasively Mechanically Ventilated Adults: A Systematic Review and Meta-analysis. Anesthesiology. 2017;126(5): doi: /ALN Tumbarello M, De Pascale G, Trecarichi EM et al. Effect of aerosolized colistin as adjunctive treatment on the outcomes of microbiologically documented ventilator-associated pneumonia caused by colistinonly susceptible gram-negative bacteria. Chest. 2013; 144: Zhang C, Berra L, Klompas M. Should Aerosolized Antibiotics Be Used to Treat Ventilator- Associated Pneumonia? Respir Care. 2016;61(6): doi: /respcare Zilberberg MD, Shorr AF, Micek ST, Vazquez-Guillamet C, Kollef MH. Multi-drug resistance, inappropriate initial antibiotic therapy and mortality in Gram-negative severe sepsis and septic shock: a retrospective cohort study. Crit Care. 2014;18(6):596. doi: /s