Save Your Breath: Use of Inhaled Antibiotics for Ventilator- Associated Infections

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1 Save Your Breath: Use of Inhaled Antibiotics for Ventilator- Associated Infections Jasmin Badwal, PharmD PGY- 2 Infectious Diseases Pharmacy Resident Department of Pharmacotherapy and Pharmacy Services, University Health System Pharmacotherapy Division, The University of Texas at Austin College of Pharmacy Pharmacotherapy Education and Research Center, UT Health San Antonio September 7, 2018 At the end of this session, the learner will be able to: 1. Summarize the pathophysiology of ventilator- associated infections and recognize treatment difficulties 2. Analyze mechanisms, benefits, and limitations for inhalational antibiotic delivery 3. Evaluate the utility, safety, and effectiveness of adjunctive inhalational antibiotics in patients with ventilator- associated infections

2 Assessment Questions: 1. Incidence of multi- drug resistant (MDR) infections is increasing in intensive care unit (ICU) patients a. True b. False 2. Which of the following are optimal characteristics for drugs used in inhaled formulations? a. Lipophilic b. Preservative free c. Positive charge d. Sterile e. All of the above 3. Current guidelines strongly suggest using inhaled antibiotics in treatment of ventilator- associated pneumonia (VAP) a. True b. False 4. Which of the following is NOT a potential benefit of using inhaled antibiotics in VAP? a. Higher concentrations achieved at infection site b. Reduced resistance development c. Reduced mortality risk d. Direct delivery to infection site *** To obtain CE credit for attending this program please sign in. Attendees will be ed a link to an electronic CE Evaluation Form. CE credit will be awarded upon completion of the electronic form. If you do not receive an within 72 hours, please contact the CE Administrator at ana.franco- martinez@uhs- sa.com *** Faculty (Speaker) Disclosure: Jasmin K. Badwal has indicated she has no relevant financial relationships to disclose relative to the content of her presentation Badwal 2

3 Ventilator associated infections I. Lower respiratory tract infections (LRTIs) 1-6 a. One of the leading causes of illness and death from infectious diseases worldwide b. Pneumonia: i. Infection characterized by inflammation in the lung ii. Defined as new lung infiltrate plus clinical evidence for infectious organism (new onset of fever, purulent sputum, leukocytosis, and decline in oxygenation) c. Ventilator associated infections (Table 1) i. Common complication in mechanically ventilated patients Table 1. Tracheobronchitis vs pneumonia Ventilator- associated tracheobronchitis (VAT) Ventilator- associated pneumonia (VAP) II. Pathophysiology 1-3,7,8 a. Sources i. Aspiration of oropharyngeal secretions or gastrointestinal (GI) contents ii. Endotracheal (ET) tube biofilm colonization iii. Contaminated respiratory equipment, medical aerosols, hospital air/water b. Mechanisms i. Pathogenic bacteria colonize the oropharynx after intubation ii. Placement of ET tube causes 1. Bypass of natural defenses against migration of upper respiratory tract organisms into the lower tract 2. Mucosal damage near cuff 3. Impaired mucociliary clearance iii. Use of acid- suppressing drugs increases the ph of gastric secretions which promotes growth of organisms in the GI tract iv. Presence and proliferation of microbial pathogens at the alveolar level leads to mechanical, humoral, and cellular host defense responses c. Common nosocomial pathogens Gram positive organisms Gram negative organisms S. aureus Streptococcus spp. d. Risk factors for multi- drug resistant (MDR) pathogens Definition Incidence Other clinical information LRTI involving tracheobronchial tree (conducting zone) in intubated patients LRTI involving lung parenchyma that occurs > 48 hours after intubation % 10-27% Signs/symptoms of infection with absence of radiographic evidence Associated with higher risk of developing VAP Mortality ranges from 20-50% Associated with prolonged hospitalization and time on mechanical ventilation Acinetobacter spp. E. coli Enterobacter spp. Klebsiella spp. P. aeruginosa Prior intravenous (IV) antibiotic use within 90 days Septic shock at time of VAP Acute respiratory distress syndrome (ARDS) preceding VAP 5 days of hospitaization Acute renal replacement therapy prior to onset Badwal 3

4 III. Diagnosis 8-11 a. No gold standard b. Centers for Disease Control and Prevention (CDC) Table 2. Clinically defined pneumonia per CDC Imaging test evidence Signs/symptoms/ laboratory Two or more serial chest imaging with at least one of the following: New/persistent OR progressive/persistent o Infiltrate, consolidation, cavitation, pneumatoceles (infants 1 year old) Note: In patients without underlying pulmonary/cardiac disease, one imaging test result is acceptable At least one of the following: Fever (> 38 C or > C) Leukopenia ( 4000 WBC/mm 3 ) or leukocytosis ( 12,000 WBC/mm 3 ) For adults 70 years old, altered mental status with no other recognized cause And at least two of the following: New onset of purulent sputum, change in sputum, increased secretions, or increased suctioning New onset or worsening cough, dyspnea, or tachypnea Rales or bronchial breath sounds Worsening gas exchange (O 2 desaturations, increased O 2 requirements, or increased ventilator demand) c. Clinical pulmonary infection score (CPIS) i. Score > 6 may indicate higher likelihood of VAP ii. Modified CPIS score is calculated from the first 5 variables Table 3. CPIS components Temperature ( C) 36.5 C and 38.4 C 38.5 C and 38.9 C 39 C and 36 C Leukocyte count (per mm 3 ) 4,000 and 11,000 < 4,000 or > 11,000 < 4,000 and > 11,000 plus band forms 500 Tracheal secretions Rare Abundant Abundant + purulent Oxygenation (PaO 2 /FiO 2 mmhg) > 240 or ARDS and no ARDS Pulmonary radiography No infiltrate Diffuse infiltrate Localized infiltrate Moderate/heavy growth of Culture of tracheal aspirate Mild growth of pathogenic Moderate/heavy growth of pathogenic bacteria and specimen bacteria or no growth pathogenic bacteria consistent with gram stain IV. Management 8,12,13 a. Systemic antibiotics i. Initial broad spectrum agents that cover S. aureus, P. aeruginosa, and other gram- negative bacilli (Appendix A) ii. iii. De- escalation as appropriate per culture results Duration: 7 days 1. Longer treatment may be indicated depending on clinical, radiologic, and laboratory parameters b. Inhaled antibiotics i. Infectious Diseases Society of America (IDSA) 1. Adjunctive inhaled antibiotics can be used in gram- negative VAP where isolates are only susceptible to aminoglycosides/polymyxins or if patients are not responding to systemic antibiotics 2. Weak recommendation, very low- quality evidence ii. European Society of Clinical Microbiology and Infectious Diseases (ESCMID) 1. Recommend against routine use of inhaled antimicrobial therapy due to lack of evidence of their efficacy and risk of respiratory complications Badwal 4

5 Introduction to inhaled antibiotics I. Historical prevalence 1,7,14 a. Inhalational delivery of medicinal agents was used by Native Americans long before the creation of antimicrobials b. World Wars I and II led to major advancements in aerosolized administration technology c. Development of inhaled antibiotics started in the 1940s, however was halted in the 1970s due to a study associating aerosolized polymyxin with increased mortality II. Revival of interest 15,16 a. Secondary to emergence of multi- drug resistant organisms (MDRO) that are difficult to treat with current intravenous agents b. Established practice in cystic fibrosis (CF) patients as studies have demonstrated improvements in pulmonary function and quality of life, reduction in pulmonary exacerbations, and decreased hospitalizations with inhaled tobramycin c. Limited data for use in ventilator associated respiratory infections III. Rationale for potential use Direct delivery to infection site Pharmacokinetic (PK) and pharmacodynamic (PD) optimization Reduced resistance development Improvedtolerability and safety Pulmonary anatomy and physiology I. Structure and clearance 7,15,17 a. Inhaled air passes through the mouth, nose, larynx, trachea, and finally into the bronchial and alveolar airways (Figure 1) i. Larger particles collide and deposit in the upper airway through impaction ii. Very small particles are able to reach and deposit the alveolar region b. Particles unable to reach the respiratory bronchioles can be transported out by active mucociliary clearance c. Alveolar macrophages are able to phagocytize and digest deposited particles Figure 1. Respiratory airway 17 Badwal 5

6 II. Gas exchange (Figure 2) 18,19 a. Occurs at lung parenchyma i. Alveoli, alveolar ducts, and respiratory bronchioles b. Oxygen and carbon dioxide (CO 2 ) diffuse into the capillary and alveolus due to partial pressure differences c. Facilitated by thin membrane and increased surface area of alveolar surface (100 m 3 ) III. Changes with pneumonia 1,20 a. Hypoxemia causes vasoconstriction of pulmonary vasculature i. Blood shunts away from areas of low to high oxygenation to help facilitate gas exchange b. Chemokine- induced inflammatory response also reduces parenchymal blood flow Figure 2. Alveolar gas exchange 19 IV. Changes with intubation 21 a. ET tube should be positioned approximately 5 cm above the carina (cartilage ridge prior to bronchi split) b. Physiological effects i. Increased airway edema, secretions, and smooth muscle constriction ii. Potential perforation or other traumatic injuries Inhalational drug formulations I. Optimal characteristics 1-3,22 Systemic absorption - Lipophilic - Positive charge - Large molecular weight (MW) Safety and tolerability - Pyrogen and preservative free - Sterile - Isotonic and matched ph to airway epithelium (ph 6) II. Current inhalational antimicrobial agents 1 FDA approved Tobramycin (TOBI ) Aztreonam (Cayston ) Non- FDA approved Amikacin, gentamicin Colistin, polymyxin Colistin methanosulfate (CMS) Ceftazidime Vancomycin Investigational drug + delivery systems Amikacin (BAY ) Amikacin/fosfomycin (AFIS ) Vancomycin (AeroVanc ) Badwal 6

7 Drug delivery I. Physiologic barriers 1-3 Inhibitory sputum Distribution into infected distal lungs Edema + Secretions Blood shunting to higher O 2 areas Vasoconstri- ction II. Instilled antibiotics 1 a. Administration of intravenous antibiotic formulations through ET tube b. Unknown lung distribution and higher reported absorbed systemic concentrations III. Inhaled antibiotics 1-3,22-24 a. Nebulizers are devices of choice for inhaled antimicrobial therapy b. Varying amount of drug is lost as nebulized drug passes through artificial airway i. After administration of 300 mg tobramycin via jet nebulizer, only 5% of the dose was deposited in the lungs while > 50% of the dose retained in the nebulizer cup ii. After administration of 120 mg liposomal amikacin via a Pari LC Plus nebulizer, only 30% of the dose was deposited in the lungs while > 50% was trapped in the filter c. Lung deposition i. Varies depending on device ii. No study has assessed difference in particle size created depending on drug molecule iii. Optimal particle size for distal lung penetration is 1 µm 5 µm 1. Large droplets (> 5 µm) are more likely to get trapped in the circuit 2. Smaller particles (< 1 µm) get diffused and are more likely to be exhaled 3. Reported site targets a. Alveoli (1-3 µm) and bronchus (2-5 µm) d. Device comparison Table 4. Nebulizer overview Jet nebulizers Ultrasonic nebulizers Vibrating mesh/plate nebulizers Aerosol creation mechanism Particle size Advantages Disadvantages Compressed gas is forced through small hole into reservoir containing medication solution Dependent on solution properties and gas pressure/flow Low cost, high efficiency, disposable Low delivery speed, interference with vent gas delivery, wide performance variability with manufacturers Electric crystal vibrates at high frequency to break medication into microscopic fog Inversely proportional to vibration frequency High delivery delivery, ease of use, consistency High cost, increased solution temp (potential med stability issue), slightly larger particles vs jet, routine cleaning IV. Other factors that affect drug delivery 1,16,22,25 a. Ventilator circuit i. Nebulizer position 1. Modifies lung aerosol deposition 2. Jet nebulizer: 15 cm from ventilator 3. Continuous (ultrasonic or mesh) nebulizer: cm from Y- piece Vibrating mesh or plate pumps liquid droplets through multiple tapered apertures Determined by diameter of mesh/plate holes Ease of use, low residual drug volume, less heat, consistent particle size, higher drug output High cost, not suitable for concentrated/viscous solutions Badwal 7

8 ii. Humidification 1. Circuit humidity increases aerosol losses and has shown to decrease drug delivery by 40% b. Optimal ventilator settings Mode Higher drug delivery with pressure vs volume control Tidal volume (TV) TV 500 ml with long inspiratory time TV in ARDS patients - - > 6 ml/kg of ideal body weight, but may not be as effective Inspiratory flow Slow inspiratory flow (40 L/min vs 80 L/min) shown to increase aersolization deposition and increase efficiency Breath synchronization Synchronize with inspiratory flow to minimize loss of antibiotic during expiration c. Bronchodilator use i. May facilitate airway opening and mucus clearing ii. The Cystic Fibrosis Foundation recommends administration of bronchodilators prior to administration of inhaled antibiotics to allow drug to penetrate deeper into the lugs iii. Bronchodilators have not been studied in VAP or VAT patients receiving inhaled antibiotics Pharmacokinetic and pharmacodynamic optimization I. Dilemma 1,26,27 a. Many systemic agents have limited lung distribution and penetration with current dosing regimens b. Bactericidal activity against bacteria within purulent secretions may require antimicrobial concentrations > times the minimum inhibitory concentration (MIC) c. May not be able to safely optimize dosing to achieve higher levels needed to treat MDRO d. Newer systemic agents in combination with beta- lactamase inhibitors may be able to overcome this issue, and limited clinical data available is showing promising results II. Role of inhaled antibiotics a. Able to provide higher concentrations of the drug directly to the site of action (Table 5) b. Can optimize pharmacokinetic (PK) and pharmacodynamic (PD) parameters through dosing regimens with limited systemic effects III. PK/PD 1,2,28,29 a. Dose dependent absorption observed in lungs i. Optimal for concentration- dependent drugs such as aminoglycosides b. Metabolism complications i. Colistin methanesulfonate (CMS) conversion into colistin sulfate occurs in plasma ii. Unclear how much drug gets converted in lungs c. Clearance methodology and rate unknown i. Issue with time- dependent drugs such as B- lactams due to effect on dosing frequency Badwal 8

9 d. MIC breakpoints i. Approved breakpoints are based on achievable plasma concentrations after systemic administration and do not consider high local concentrations after inhaled therapy ii. The Spanish Antibiogram Committee recommends higher breakpoints for inhaled iii. tobramycin against P. aeruginosa (resistance at 128 mg/l vs 16 mg/l) Inhalational antibiotics may achieve target pharmacodynamic pattern even if target pathogen is reported to be resistant IV. Additional barriers 1 a. Lack of reliable preclinical data to aid development of future agents/delivery systems b. Difficult to measure concentration at lung surface or in epithelial/alveolar lining fluid (ELF/ ALF) (Figure 4) i. Unable to extrapolate from serum concentrations ii. Varying formulas using urea as marker of dilution c. Complicated time- concentration curve i. Confounded by aerosol deposition, particle dissolution, and lung permeation d. Difficult to replicate in- vivo conditions 1 Representation of the alveolar capillary barrier. The barrier consi Figure 4. Alveolar capillary barrier i. Oropharyngeal structures, differing flow rates depending on disease states, varying delivery devices, ventilation settings, etc. e. No clear consensus on optimal site of action within the lungs i. Tracheobronchial secretion, ELF/ALF, or tissue concentrations Table 5. PD targets and lung concentrations Agent PD MIC breakpoints Lung concentration with parameter (mg/l) 30 systemic abx CMS AUC/MIC P. aeruginosa S: 2 Undetectable in both animal A. baumannii S: 2 and human models Lung concentrations with inhaled abx 80 mg every 8 hrs neb ELF 1 hr: 6.73 mg/l ELF AUC 0-8 hrs: 29.8 mg*h/l 400 mg every 12 hrs neb ELF peak: 5,252 mg/l 400 mg every 12 hrs - mesh neb Median ELF peak: mg/l ET admin of 2 mg/kg Bronchial secretion: 400 mg/l Nebulized 40 mg Induced sputum: 17.8 mg/l 200 mg neb BAL: 102 mg/l Amikacin Peak/MIC P. aeruginosa A. baumannii S: 16 S: mg/kg bronchial secretion Mean peak: 4.4 +/- 0.7 mg/l 6 hrs: 4.1 +/- 0.7 mg/l Gentamicin 37,38 Peak/MIC P. aeruginosa S: 4 IM injection 2 mg/kg Bronchial secretion: <1mg/L A. baumannii S: 4 IV 240 mg daily ALF 2 hr: / mg/l Tobramycin 39,40 Peak/MIC P. aeruginosa S: 4 Dose based on target peak 8 A. baumannii S: 4 mg/l and trough 2 mg/l ELF 8 hr: / mg/l Ceftazidime 41,42 Time > MIC P. aeruginosa S: 8 4 g continuous infusion, conc 25 mg/kg every 3 hrs neb A. baumannii S: 8 measured after 2 days Median trough lung tissue: Mean ELF: 8.2 +/- 4.8 mg/l 24.8 mcg/g Vancomycin 43,44 AUC/MIC S. aureus S: 2 Doses with mean plasma level Rat model, unclear dose of 24 mg/l inhaled solution Mean ELF: 4.5 mg/l BAL: / mg/l Abbreviations: CMS = colistimethate sodium, AUC = area under the curve, MIC = minimum inhibitory concentration, ELF/ALF = epithelial/ alveolar lining fluid, S = susceptible, conc = concentration, neb = nebulizer, BAL = bronchoalveolar lavage Badwal 9

10 Resistance I. Prolonged use of systemic broad spectrum agents is associated with development of MDR organisms a. Higher risk of sub- inhibitory concentrations in the lungs and failure to achieve both MIC and mutant prevention concentration (MPC) with systemic therapy II. Inhalational antibiotics may be associated with lower development of MDR organisms vs systemic therapy alone Table 6. Inhaled antibiotics and resistance Study Design Results Palmer LB, et al. (2014) 45 Double- blind, randomized, placebo- controlled study Intubated patients with purulent secretions and CPIS 6 Systemic + aerosolized antibiotic (AA) or saline placebo All tracheal aspirate cultures New MDR organisms during treatment AA 2/16 (13%) vs Placebo 6/11 (55%), P = 0.03 New drug resistance not observed in AA group Tolerability and safety I. Tolerability a. Often a limitation of use in cystic fibrosis patients due to bronchospasm b. Not evaluated in VAP studies as most patients were sedated to facilitate mechanical ventilation II. Adverse effects 1-3,23,46 a. Inhaled antibiotics assumed to be less toxic than systemic treatment due to limited absorption into blood stream i. Open- label study of 12 patients administered inhalational tobramycin 300 mg via jet nebulizer 1. Serum maximum concentration = 0.28 mg/l 2. Undetectable in 85% of patients after 18 hours b. However, effects of achieving high concentrations of potentially toxic agents in lung tissue have not fully been evaluated c. Adverse effects (AEs) associated with inhalational antibiotics Table 7. Summary of local adverse effects Inhaled Antibiotic Local AEs Aminoglycosides Bronchospasm, wheezing, cough Colistin Bronchospasm, pulmonary toxicity Aztreonam Bronchospasm, wheezing, cough, hemoptysis Vancomycin Bronchospasm Ceftazidime Wheezing, cough Badwal 10

11 Summary I. Analysis of inhaled antibiotics Pros Higher concentration achieved in ELF/ALF and bronchial secretions to target resistant organisms Lower risk of resistant organism development Less systemic adverse effects Cons Limited FDA approved agents Safety issues of using IV formulations No standardized dosing regimens Majority of administered drug is lost in circuit Varying particle size and deposition with different nebulizer machines High cost with new technology Varying ventilator settings and techniques Different methods to calculate lung concentrations Bronchospasm and risk of additional respiratory distress Unknown toxicities at tissue level Clinical question What is the optimal role of inhaled antibiotics in ventilator associated infections? I. Select observational studies Table 8. Observational studies for inhaled antibiotics Author (year) Intervention Organism Outcomes Mohr AM, et al. (2007) 47 N = 22 patients Systemic tx + either inhaled amikacin or tobramycin P. aeruginosa 54% Mean MV duration: 31 +/- 12 days Mean ICU LOS: 41 +/- 13 days Mean MV duration after inhaled abx: 4.3 days Reported 59% cure rate Czosnowski, QA, et al. (2009) 48 Arnold HM, et al. (2012) 49 N = 49 patients 60 total episodes of VAP Inhaled tobramycin = 44, amikacin = 9, costimethate = 9 Systemic abx use = 98% N = 93 patients Adjunctive aerosolized abx (AAA) vs no AAA (NAAA, systemic tx alone) Inhaled colistin = 19, tobramycin = 10 Migiyama Y, N = 44 et al. (2017) 50 VAP during course of ARDS P. aeruginosa and/or A. baumannii P. aeruginosa and/or A. baumannii TIS = inhaled tobramycin + systemic abx Control = systemic abx (P=0.04) Abbreviations: MV = mechanical ventilation, ICU = intensive care unit, LOS = length of stay Clinical success of initial cases: 36/49 (73%) Clinical success in those failing IV: 17/20 (85%) Clinical success in MDR organisms: 30/38 (79%) Microbiologic success: 29/41 (71%) Mortality: 6/49 (12%) AAA vs NAAA MV duration: / vs / days (P < 0.001) ICU days: / vs / days (P=0.001) 30- day mortality: 0% vs 17.6% (P = 0.063) Kaplan- Meier: AAA had higher probability of survival (P = 0.030) P. aeruginosa TIS vs Control ICU mortality: 22.7% vs 63.6% (P < 0.01) 28- day mortality: 14.3% vs 63.2% (P < 0.01) P. aeruginosa VAP recurrence: 22.7% vs 52.4% Badwal 11

12 II. Palmer LB, et al. (2008) 51 Aerosolized antibiotics and ventilator- associated tracheobronchitis in the intensive care unit Objective To determine effectiveness of aerosolized antibiotics in treating respiratory infections and potentially reducing use of systemic antibiotics in ventilated patients Methods Design Double- blind, single- center, randomized, placebo- controlled trial ( ) Patient population Medical and surgical intensive care units in New York Inclusion criteria Exclusion criteria 18 years of age Pregnancy Intubated and MV for 3 days Immunosuppressive agents (except CS) VAT: 2 ml of purulent lower respiratory tract Neutropenia (< 1,000 WBC/mm 3 ) secretions during 4 hr aspiration period with History of allergy to study agents organisms visualized on gram stain MV > 60 out of last 90 days CAP diagnosis (pneumonia < 3 days of admit) Intervention Systemic treatment per primary provider Choice of aerosolized antibiotic (AA) dependent on gram stain results o Gram positive: vancomycin- hydrochloride 120 mg in 2 ml normal saline every 8 hours o Gram negative: gentamicin- sulfate 80 mg in 2 ml normal saline every 8 hours o Both types: serial administration of vancomycin and gentamicin Administered via AeroTech II jet nebulizer 14 day treatment or until day of extubation Outcomes Primary Reduction in indices of respiratory infection (CDC- NNIS VAP and CPIS) Secondary Clinical: systemic WBC, systemic antibiotic use, mortality, MV weaning Microbiological: semi- quantitative tracheal aspirate cultures and resistance development Statistics Power calculation o 180 patients required to detect 25% change in incidence of VAP o Alpha = 0.05 and Beta = 0.8 Wilcoxon s rank- sum test, Kendall s correlation test, and Fisher s exact test were used for appropriate variables Multivariable regression analysis controlling for age and baseline pneumonia status Significance: p- value 0.05 (two- tailed test) Study completed early due to interim analysis Results Demographic and clinical characteristics Characteristic AA (n = 19) Placebo (n = 24) P- value Male, n (%) 14 (73.7) 14 (58.3) 0.35 Age (years), mean +/- SD / / APACHE II score, mean +/- SD / / CPIS, mean WBC, mean +/- SD / / Vent days before study tx, mean +/- SD / / Days between target sputum production and study tx initiation, mean +/- SD 3.2 +/ / Days on study tx, mean +/- SD / / Pts on target abx at randomization, n (%) 17 (89.5) 19 (79.2) 0.44 Sputum with GN organisms, n (%) 5 (26.3) 5 (20.8) 0.73 Sputum with GP organisms, n (%) 7 (36.8) 11 (45.8) 0.76 Bacterial isolates MRSA, n MSSA, n Pseudomonas sp., n Klebsiella sp., n Enterobacter, n Acinetobacter sp., n Badwal 12

13 Primary outcome AA (n = 19) Placebo ( n = 24) P- value n (%) or mean +/- SD P- value (from baseline) n (%) or mean +/- SD P- value (from baseline) (AA vs placebo) CDC VAP day 1 14/19 (73.6) - 18/24 (75) - 1 CDC VAP End of tx 6/19 (31.6) /24 (58.3) CDC VAP day 14 5/14 (35.7) /14 (78.6) CPIS day In the 5 patients with only VAT, zero progressed to VAP Controlling for age à AA 71% less likely to demonstrated CDC defined VAP vs placebo (adjusted OR 0.29, CI , P- value = 0.006) Secondary Microbiological response outcomes Cultures with zero growth o AA: week 1 [7/12 (58%)] vs week 2 [6/8 (75%)] o Placebo: week 1 [3/14 (21%)] vs week 2 [4/18 (22%)] Resistant organisms at end of treatment: 0/19 AA vs 8/24 (33%) placebo (P = ) Clinical response WBC (AA vs placebo) o Tx day 14: 9.2 +/- 3.3 vs /- 8.1 (P = 0.016) Initiation of additional abx for new or persistent infection (AA vs placebo) o 8 vs 17 patients (P = 0.042) 28- day mortality (AA vs placebo) o 4/19 (21.1%) vs 4/24 (16.7%) (P = 0.99) à due to multi- organ system failure Mechanical ventilation outcomes (AA vs placebo) o Weaned: 12/19 vs 9/24 (P = 0.052) o Weaned survivors: 12/15 vs 9/20 (P = 0.046) o Median ventilator- free days: 10 (range 26) vs 0 (range 27) (P = 0.069) Author s conclusions Study ended earlier due to significance of findings on interim analysis, larger trials still recommended Aerosolized abx were effective in resolution of respiratory infection signs in patients with VAT and were associated with reduced bacterial resistance and decreased use of systemic agents Reviewer s critique Strengths Randomized, placebo- controlled trial Comparison of two different diagnostic scores Variety of clinically relevant endpoints Limitations Single- center with small population Both VAT and VAP patients included No analysis on appropriateness of systemic dosing or what specific agents were administered Broad definition of resistance development No breakdown of what criteria were met for CDC definition and CPIS scores Tracheal aspirate cultures for clearance No outcome breakdown for those just meeting VAP criteria Overall conclusion Although this focused on VAT, majority of patients still had VAP upon randomization and had similar baseline characteristics Potential confounders include differences in isolates (more S. aureus in placebo group) and varying systemic agents administered Questionable significance of microbiological clearance from sputum cultures AA therapy was found to significantly lower VAP diagnosis and CPIS scores, however there was no breakdown as to what criteria were met and how many days of of systemic tx were received prior Limited power to observe significant effect on mortality, ventilation weaning, or vent- free days Abbreviations: VAT = ventilator- associated tracheobronchitis, VAP = ventilator- associated pneumonia, MV = mechanical ventilation, CAP = community acquired pneumonia, AA = aerosolized antibiotics, CDC- NNIS= Centers for Disease Control and Prevention- National Nosocomial Infections Surveillance, tx = treatment, abx = antibiotic, MRSA = methicillin- resistant S. aureus, MSSA = methicillin- susceptible S. aureus, vent = ventilation or ventilator, n = number, SD = standard deviation Badwal 13

14 III. Rattanaumpawan P, et al. (2010) 52 Randomized controlled trial of nebulized colistimethate sodium as adjunctive therapy of ventilator- associated pneumonia caused by gram- negative bacteria Objective To determine if nebulized colistimethate sodium (CMS) is safe and beneficial as an adjunctive therapy for gram negative VAP Methods Design Open- label, single- center, randomized controlled trial (July 2006 September 2009) Patient population ICU patients in Bangkok, Thailand Inclusion criteria 18 years of age Gram negative VAP diagnosis: MV for 48 hours, symptoms (fever, leukocytosis, purulent tracheal secretions), new/progressive pulmonary infiltrates, GN bacilli isolated from ET tube aspirate Intervention Systemic plus nebulized sterile normal saline (NSS) or nebulized CMS (75 mg of colistin base in 4 ml) Administered via jet or ultrasonic nebulizer for 10 minutes or until solution container was empty Systemic agents (regimen and duration) were determined by patient s physician Nebulized agents were given until discontinuation of systemic tx Outcomes Clinical o Favorable (resolution of all s/sx, and improvement or progression on imaging) o Death related to VAP o Death related to other causes or indeterminate Microbiologic o Favorable (actual or presumed eradication) o Presumed persistence o Indeterminate Complications o Bronchospasm o Renal impairment (rise of SCr by 2 mg/dl if no baseline or x 2 if pre- existing insufficiency) Statistics Sample size calculation o With nebulized CMS, favorable clinical outcome should be increased to 80% from 55% o Sample size required = 51/group o Alpha = 5% and Beta = 20% Descriptive statistics, unpaired Student s T- test, chi squared, or Fisher s exact test as appropriate Statistical significance with P- value 0.05 Demographics and clinical characteristics (n = 100) Results Characteristic CMS (n = 51) NSS (n = 49) P- value Male, % Age (years), mean +/- SD / / Chronic renal failure, % Malignancy, % Late- onset VAP (>4 days), % APACHE II, mean +/- SD / / Prior abx use within 72 hrs, % Duration of nebulized tx (days) 1) 9.5 +/ ) / ) mean +/- SD, 2) median 2) 12 2) 13 1) Initial systemic abx Imipenem or meropenem, % CMS, % Piperacillin/tazobactam, % Cefoperazone/sulbactam, % rd /4 th gen cephalosporin, % Isolated GNB A. baumannii, % P. aeruginosa, % ESBL K. pneumoniae, % ESBL E. coli, % S. maltophilia, % MDR A. baumannii or P. aeruginosa, % Badwal 14

15 Outcomes (CMS vs NSS) Author s conclusions Clinical Microbiologic Favorable Favorable o 51% vs 53.1% (RR 0.96, P = 0.84) o 60.9% vs 38.2% (P = 0.03) o All alive at day 28 Complications Death due to VAP Bronchospasm o 39.2% vs 36.7% (RR 1.07, P = 0.8) o 7.8% vs 2% (P = 0.36) Overall mortality Renal impairment o 43.1% vs 40.8% (RR 1.06, P = 0.81) o 25.5% vs 22.4% (P = 0.82) No beneficial effect observed on clinical outcomes with use of nebulized CMS however well tolerated Reviewer s critique Strengths Randomized and placebo controlled trial Variety of clinically relevant endpoints Similar comorbidities, severity of illness, and isolated organisms Limitations Not double- blinded Unknown extent of conversion of CMS into active colistin and lung deposition Cultures from ET aspirate No objective clinical improvement scoring Varying nebulizer machines Small patient population Majority received > 72 hrs of systemic tx prior No discussion of ventilator settings Did not meet sample size requirement Overall conclusion Patients had similar comorbidities, severity of illness, and isolated organisms No additional clinical benefit was noted with use of nebulized CMS, however patient s conditions may have already improved by the time treatment was initiated as they already on broad- spectrum systemic therapy Microbiologic clearance through tracheal aspirate cultures does not always correlate to treatment success This does not support use of adjunctive nebulized CMS for VAP treatment Abbreviations: ICU = intensive care unit, VAP = ventilator associated pneumonia, MV = mechanical ventilation, GN = gram negative, ET = endotracheal tube, CMS = colistimethate sodium, NSS = nebulized sterile saline, tx = treatment, s/sx = signs and symptoms, SCr = serum creatinine, abx = antibiotics, ESBL = extended spectrum beta- lactamase, MDR = multi- drug resistant, RR = relative risk, SD = standard deviation IV. Liu C, et al. (2017) 53 Aerosolized amikacin as adjunctive therapy of ventilator- associated pneumonia caused by multidrug- resistant gram- negative bacteria: a single- center randomized controlled trial Objective To evaluate the safety and efficacy of aerosolized amikacin as an adjunctive therapy for VAP caused by MDR gram negative bacteria Methods Design Single- center, double- blind, randomized, placebo controlled trial Timeline: June 2014 June 2016 Patient population ICU patients in Chinese hospital at high risk of MDR bacteria Inclusion criteria Exclusion criteria > 18 years of age Pregnancy (including feeding period) Mechanical ventilation > 48 hours Allergy or adverse effect to amikacin or New onset and/or progressive pulmonary aerosolized therapy infiltrates on imaging Acute on chronic renal insufficiency MDR gram negative bacteria from tracheal Airway obstructive factors or limitation aspirate ( 10 5 CFU/mL) resistant to 3 Immunosuppression antibiotics Requiring small tidal volume (< 6 ml/kg) Clinical features: Temp 38 C and WBC 10,000/mm 3 /WBC < 4,000/mm 3 Intervention Receipt of adjunctive aerosolized amikacin (AA) (400 mg every 8 hours for 20 minutes) vs normal saline (4 ml at same frequency) in addition to systemic antibiotics for 7 days Aerosolized agents administered through a jet nebulizer All patients had the same ventilator settings during nebulization Use of systemic antibiotics during treatment was determined by attending physician based on clinical criteria and culture results Badwal 15

16 Outcomes Primary Secondary Bacteriological eradication Emergence of new organism resistant to CPIS, serum creatinine (day 7), VAP cure, weaning rate, mortality (day 28) amikacin Statistics Power calculation o Minimum 42 patients to detect 20% difference in bacterial eradication o Alpha = 0.05 and Beta = 0.8 Parametric continuous variables compared using unpaired t- test Wilcoxon s rank sum test used to assess nonparametric continuous variables Pearson Chi- square test used for categorical variables Significance: two- sided alpha of P < 0.05 Results Demographics and clinical characteristics (n = 51) Bacterial isolates and susceptibility Characteristics AA (n = 27) Placebo (n = 25) P- value Male, n (%) 16 (59) 16 (64) Age in yrs, mean +/- SD / / APACHE II, mean +/- SD / / CPIS, mean +/- SD 8.1 +/ / Vent days prior, mean +/- SD / / ICU LOS prior, mean +/- SD 16 +/ / Cause of mechanical ventilation Respiratory, n (%) 13 (48) 12 (48) - Cardiac, n (%) 4 (15) 2 (8) - Multi- organ failure, n(%) 2 (7) 3 (12) - Sepsis, n (%) 3 (11) 3 (12) - Systemic antibiotic use Carbapenem, n (%) 17 (37) 14 (35) BL/BLI, n (%) 9 (20) 5 (13) FQ, n (%) 14 (30) 12 (30) Cephalosporin, n (%) 6 (13) 9 (23) AA Placebo Organism Total isolates Susceptible to Total isolates Susceptible to (n = 32) amikacin (n = 13) (n = 28) amikacin (n = 15) A. baumannii P. aeruginosa K. pneumoniae S. maltophilia E. coli Primary outcome Eradication at day 7 o Patients: AA 11/27 vs placebo 4/25 (41% vs 16%, P = 0.049) o Isolates: AA 13/32 vs placebo 4/28 (41% vs 14%, P = 0.024) New resistance to amikacin not detected on day 28 Secondary outcomes Outcome Amikacin (n = 27) Placebo (n = 25) P- value Final CPIS, mean +/- SD 4.2 +/ / Temp( C), mean +/- SD) 37 +/ / Oxygenation index (mmhg), mean +/- SD 261 +/ / WBC (10 3 /mm 3 ), mean +/- SD 8.4 +/ / Day 7 SCr (umol/l), median (IQR) 72.9 ( ) 61.4 ( ) Bronchospasm, n (%) 3 (11) 1 (4) - VAP cure rate, % Vent weaning, n (%) 13 (48) 8 (32) day mortality, % Badwal 16

17 Author s conclusions Strengths Limitations Adjunctive therapy of inhaled amikacin for VAP was effective at eradicating existing MDR organisms, improvement in CPIS, and no new development of drug resistance or kidney dysfunction Mortality benefit was not found Reviewer s critique Double blind, randomized controlled trial Broke down systemic agents received in addition to aerosolized Similar severity of illness between patient groups Standardized process prior to nebulized agent administration Tracheal aspirate culture dependence Limited patient number No described definition of VAP cure Off- label amikacin dose and formulation Combined serum creatinine endpoint No evaluation on appropriate dosing of systemic agents nor how many days of tx received prior to initiation of inhaled abx Overall conclusion Microbiologic clearance through tracheal aspirate cultures does not always correlate to clinical success No difference observed in mortality, adverse effects, cure rate, nor weaning rate Only benefit was shown in reduction in CPIS score, however questionable clinical significance Potential confounder if standardized ventilator settings were not appropriate for patient s condition This does not support use of adjunctive aerosolized amikacin in VAP treatment Abbreviations: VAP = ventilator- associated pneumonia, GN = gram negative, ICU = intensive care unit, MDR = multi- drug resistant, temp = temperature, AA = aerosolized amikacin, SCr = serum creatinine, vent = ventilation or ventilator, n = number, SD = standard deviation, IQR = interquartile range V. New nebulizer technology Randomized, Table 9. Clinical trials with drug- delivery devices Design Intervention Results Lu Q, et al. Nebulized ceftazidime and amikacin N = 40 (20 aerosol vs 20 IV) (2011) 54 prospective, in VAP caused by P. aeruginosa - - > comparative vibrating plate technology phase II trial Ceftazidime (15 mg/kg/3 hrs) and amikacin (25 mg/kg/day) vs intravenous ceftazidime/amikacin for 8 days No significant difference in Treatment success: 70% vs 55% (P = 0.33) Mortality on day 28: 10% vs 5% (P = 0.55) Median vent- free days: 14 vs 8 (P = 0.18) Median ICU days: 24 vs 16 (P = 0.08) On day 7 of IV tx, 4/5 isolated P. aeruginosa strains from BAL were I or R Niederman MS, et al. (2012) 55 Multicenter, randomized, double- blind, placebo- controlled, phase II trial BAY à investigational amikacin + pulmonary drug delivery system (PDDS) for treatment of gram- negative VAP BAY mg q 12 hrs vs 400 mg q 24 hrs + aerosol placebo vs placebo q 12 hrs N = 69 (21 with BAY q 12 vs 26 with BAY q 24 vs placebo) Clinical cure rates if received 7 days of tx 93.8% vs 75% vs 87.5% (P = 0.467) Mean number of abx/pt/day 0.9 vs 1.3 vs 1.9 (P = 0.02) No difference in microbiologic eradication Kollef MF, et al. Randomized, (2017) 56 double- blind, placebo- controlled, parallel group, phase II trial Amikacin fosfomycin inhalation system (AFIS) in gram- negative VAP à vibrating plate technology Amikacin 300 mg/ fosfomycin 120 mg vs placebo (saline) twice daily for 10 days or extubation All patients received IV meropenem or impenem for 7 days N = 143 (71 AFIS vs 72 placebo) Change in mean CPIS score Baseline: 5 +/- 3.1 vs 4.8 +/- 3.4 (P = 0.81) Day 10: No significant change (- 1 from baseline for both) 28- day mortality: 24% vs 17% (P = 0.32) Mean vent- free days: 9.8 vs 12.5 (P = 0.02) Positive tracheal cultures Day 7: 17% vs 41% (P = 0.002) - Abbreviations: VAP = ventilator associated pneumonia, IV = intravenous, vent = ventilator or ventilation, tx = treatment, I = intermediate, R = resistant, abx = antibiotics, pt = patient Badwal 17

18 Conclusions I. Significant risks are associated with use of inhaled antibiotics a. Safety and tolerability have not been well studied b. No standardized dosing regimen or administration c. Limited feasibility in clinical practice II. Initial observational studies were hypothesis generating as they showed positive outcomes with use of inhaled antibiotics, however significant bias may exist III. Randomized controlled trials have shown benefit through CPIS or microbiologic clearance, however no improvement in ventilation days, length of stay, or mortality were observed a. No focused outcome evaluation in MDR or pan- resistant (XDR) organisms b. Many confounders exist such as type of nebulizer used, appropriateness of systemic antibiotics received, and days of systemic treatment received prior to initiation c. Questionable clinical significance of findings Final recommendations I. Routine use in ventilator- associated infections is not recommended a. No standardized dose/frequency, questionable significance of clinical improvement, and no observed benefit in objective outcomes II. If susceptible, would recommend use of novel beta- lactamase and beta- lactamase inhibitor combination drugs instead III. May consider use in VAP caused by extremely MDR/XDR gram- negative organisms where systemic treatment options are limited a. Would recommend FDA- approved inhalational tobramycin as adjunctive therapy b. Duration dependent on clinical improvement and/or extubation status IV. Additional randomized- controlled trials are recommended comparing novel systemic agents with or without use of adjunctive inhaled antibiotics in VAP caused by MDR/XDR organisms Badwal 18

19 Appendix A I. IDSA recommendations for empiric VAP treatment a. All patients with suspected VAP should be covered against P. aeruginosa, S. aureus, and other gram- negative bacilli in all empiric regimens b. Risk factors for multidrug- resistant VAP i. Prior intravenous antibiotic use within 90 days ii. Septic shock at time of VAP iii. ARDS preceding VAP iv. 5 days of hospitalization prior to the occurrence of VAP v. Acute renal replacement prior to VAP onset c. Additional risk factors for MRSA or Pseudomonas VAP/HAP i. Prior intravenous antibiotic use within 90 days d. Empiric management P. aeruginosa Single agent Double coverage No risk factors for resistance ICUs with 10% gram- negative isolates resistant to agent Risk factor for resistance ICUs with > 10% gram- negative isolates resistant to agent ICUs where local susceptibility rates are not available Specific agent dependent on local antimicrobial susceptibility testing S. aureus MSSA No risk factors for resistance ICUs with < 10% - 20% of S. aureus isolates are methicillin resistant Piperacillin- tazobactam, cefepime, levofloxacin, meropenem MRSA Risk factor for resistance ICUs with > 10% - 20% of S. aureus isolates are methicillin resistant Vancomycin Linezolid References 1. Wenzler E, Fraidenburg DR, Scardina T, et al. Inhaled antibiotics for gram- negative respiratory infections. Clin Microbiol Rev. 2016;29(3): Palmer LB. Inhaled antibiotics for ventilator- associated infections. Infect Dis Clin North Am. 2017;31(3): Palmer LB. Ventilator- associated infection: the role for inhaled antibiotics. Curr Opin Pulm Med. 2015;21(3): Metersky ML, Wang Y, Klompas M, et al. Trend in ventilator- associated pneumonia rates between 2005 and JAMA 2016;316(22): Kampf G, Wischnewski N, Schulgen G, et al. Prevalence and risk factors for nosocomial lower respiratory tract infections in German hospitals. J Clin Epidemiol. 1998;51(6): Rello J, Ausina V, Castella J, et al. Nosocomial respiratory tract infections in multiple trauma patients. Influence of level of consciousness with implications for therapy. Chest. 1992;102(2): Blackford MG, Glover ML, Reed MD. Chapter 85. Lower respiratory tract infections. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach, 9e New York, NY: McGraw- Hill; Accessed July 20, Badwal 19

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