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Uso degli antibiotici per aerosol

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1 Uso degli antibiotici per aerosol
Andrea Novelli Dipartimento di Scienze della Salute Sezione di Farmacologia Clinica & Oncologia

2 Transparency Declaration
Honoraria or grant support received from: Gilead Menarini MSD Valeas Zambon Group

3 AEROSOL THERAPY Introduction
Dioskurides, (ca 40 – 90 AD) an ancient Greek physician, pharmacologist and botanist is considered the father of aerosolized medicine, being the first to have prescribed inhaled fumigation as a medical treatment. In modern medicine, the first reports of nebulized antibiotics in clinical practice were made in 1950s. TOBI was the first approved by FDA on December 1997 for P. aeruginosa RTI treatment in CF patients. Inhaled gentamicin or colistin have also been administered in CF children. In 2010 FDA approved aztreonam lysine in CF children aged >7yrs.

4 Amikacin Comparison of mean serum and bronchial secretion concentrations in pneumoniae patients
Weers J, Advanced Drug Delivery Reviews, 2015

5 Aerosol delivery ADVANTAGES DISADVANTAGES Less systemic toxicity
Delivery to site of action Higher concentrations available in the lung DISADVANTAGES Time and effort Delivery device constraints

6 Aerosolized antibiotics for treatment of specific infections
CF NCFB VAP Aminoglycosides Gentamicin Amikacin Liposomal amikacin Neomycin Sisomycin Tobramycin Yes Polymyxins Colistin/polymixin B Glycopeptides Vancomycin Monobactams Aztreonam lysine b-lactams Ceftazidime Ticarcillin Fluoroquinolones Ciprofloxacin CF = cystic fibrosis NCFB = non-CF bronchiectasis VAP = ventilator-associated pneumonia Restrepo MI et al., Respiratory Care, 2015

7 Aerosolized antibiotics Treatment outcomes to assess the efficacy
CF NCFB VAP Survival Yes Prophylactic Bacterial eradication Clinical improvement* Reduce exacerbations Improve quality of life Decrease sputum bacterial load Decrease local inflammation * Some studies used Clinical Pulmonary Infection Scores CF = cystic fibrosis NCFB = non-CF bronchiectasis VAP = ventilator-associated pneumonia Restrepo MI et al., Respiratory Care, 2015

8 Antibiotic nebulization therapy
DRUG FORMULATION DELIVERY Choice of antibiotic Dose and regimen High concentration Preservative-free Ready to use Clinically validated nebulizer Particle size optimal for delivery to endo-bronchial space Nebulization time Cole PJ, J Chemother, 2001

9 Aerosolized antibiotics Ideal properties
Bassetti M et al., Ann Intensive Care, 2016

10 Aerosolized antibiotics Incidence of cough as a function of osmolarity of nebulized solution
Weers J, Advanced Drug Delivery Reviews, 2015

11 Approved inhaled antibiotics currently used in clinical practice
Generic name Brand name Disease indications Formulation Recommended/dose/frequency Aztreonam Cayston CF Inhalation solution 75 mg TID Colistin Colomycin CF; VAP Powder dissolved in saline 1-2 MIU ( mg) BID Colobreathe Dry powder 125 mg (1,7 MIU) BID Tobramycin TOBI Inhalation solution (pH=6.0) 300 mg BID Bethkis Inhalation solution (pH=5.0) TOBI Podhaler 112 mg BID Quon BS et al., Ann Am Thorac Soc, 2014, MOD

12 Off-label inhaled antibiotics currently used in clinical practice
Generic name Brand name Disease indications Formulation Recommended/dose/frequency Amikacin N/A Non TB mycobacteria Injectable solution + saline mg BID Amphotericin B Fungizone Post-transplant fungal prophylaxis or treatment Injectable solution + sterile water Prophylaxis: mg OD Abelcet Lipid complex Prophylaxis: mg OD Ambisome Liposomal Ceftazidime Fortaz VAP CF VAP: 1gx8 CF: 1g BID Gentamicin Non-CF bronchiectasis 80 mg BID Tobramycin Quon BS et al., Ann Am Thorac Soc, 2014

13 Aerosolized antibiotics Annual prevalence among CFFPR patients stratified by age
Dasenbrook EC et al., Journal of Cystic Fibrosis, 2015

14 Aerosolized antibiotics in CF patients Change in FEV1% from baseline following treatment
Weers J, Advanced Drug Delivery Reviews, 2015

15 L. Mooney, K.G. Kerr, M. Denton
Survival of Stenotrophomonas maltophilia following exposure to concentrations of tobramycin used in aerosolized therapy for cystic fibrosis patients L. Mooney, K.G. Kerr, M. Denton International Journal of Antimicrobial Agents, 17 (2001): 63-66

16 Inhaled antibiotics for long-term therapy in cystic fibrosis Ryan G, Singh M, Dwan K
Authors’ conclusions Inhaled antibiotic treatment probably improves lung function and reduces exacerbation rate, but a pooled estimate of the level of benefit is not possible. The best evidence is for inhaled tobramycin. More evidence, from trials of longer duration, is needed to determine whether this benefit is maintained and to determine the significance of development of antibiotic-resistant organisms Cochrane Database of Systematic Reviews 2011, Issue 3. Art. No.: CD001021

17 Aerosolized drugs Relationship between aerodynamic diameter and site of lung deposition
Bassetti M et al., Ann Intensive Care, 2016

18 Advantages and disadvantages of different types of nebulizers
Jet nebulizers with corrugated tubing Cheap Easy to use Effective in delivering drugs that can not be delivered with pMDIs and DPIS Inefficient Difficult to clean Need compressed gas and additional tubing Breath-actuated & Breath-enhanced jet nebulizer Drug delivery only during inhalation Less mediaction wasted More efficient than JNs with tubing Need suffificent flow to trigger drug delivery Takes longer to deliver drug Not ventilator-enabled More expensive Ultrasonic nebulizers More efficient than jet nebulizers Large residual volume Inability to aerosolize viscous solutions Degradation of heat-sensitive materials Mesh nebulizers Fast, quiet, portable Self-contained power source Optimize particle size for specific drugs More efficient than other nebulizers Cleaning can be difficult Medication dosage must be adjusted in transition from JNs Not compatible with viscous liquids or those that crystallize on drying Ari A, Eurasian J Pulmonol, 2014

19 Aerosolized colistin Delivery values of CMS
Loaded dose/filling volume Aereoneb Go Colifin 2MIU/4 ml (160 mg) eFlow rapid LC Sprint Drug delivery rate (mg/min) 1.3 ± 0.3 9.6 ± 0.7 6.7 ± 0.5 Neb. time (min) 25.1 ± 0.7 5.6 ± 0.4 10.8 ± 0.7 Delivered dose (mg) 58.9 ± 1.3 63.0 ± 3.7 65.7 ± 3.6 Buttini F et al., International Journal of Pharmaceutics, 2016

20 Aerosolized antibiotics Daily treatment burden for various devices
Weers J, Advanced Drug Delivery Reviews, 2015

21 Nebuliser systems for drug delivery in cystic fibrosis Daniels T, Mills N, Whitaker P
Authors’ conclusions Clinicians should be aware of the variability in the performance of different nebuliser systems. Technologies such as adaptive aerosol delivery and vibrating mesh technology have advantages over conventional systems in terms of treatment time, deposition as a percentage of priming dose, patient preference and adherence. There is a need for long-term randomised controlled trials of these technologies to determine patient-focused outcomes (such as quality of life and burden of care), safe and effective dosing levels of medications and clinical outcomes (such as hospitalisations and need for antibiotics) and an economic evaluation of their use Cochrane Database of Systematic Reviews 2013, Issue 4. Art. No.: CD007639

22 Mortality rates in VAP patients treated with antibiotics
IT = inappropriate therapy IT-DIAT = inadequate therapy DIAT = delayed appropriate therapy Bassetti M et al., Ann Intensive Care, 2016

23 Nebulized Ceftazidime and Amikacin in a VAP patient Computed tomographic assessment of lung reaeration Lu Q et al., Am J Respirat Critical Care Med, 2011

24 A Randomized double-blind placebo-controlled dose-escalation phase 1 study of aerosolized amikacin and fosfomycin delivered via the PARI investigational eFlow® inline nebulizer system in mechanically ventilated patients A. Bruce Montgomery, MD,1 Shirley Vallance, RN,2 Tammy Abuan, RN, MSHA,1 Markus Tservistas, PhD,3 and Andrew Davies, MBBS, FCICM Background: This trial evaluated PK and safety of AMK/FOS solution using a vibrating plate nebulizer, in mechanically ventilated patients with VAT or VAP Results: 15 min after dosing with the 300/120mg AMK/FOS mean ± SD tracheal aspirate concentrations of AMK were 12,390 ± 3,986 mg/g, and FOS were 6,174 ± 2,548 mg/g (n¼6). Plasma concentrations were subtherapeutic Conclusions: High tracheal aspirate concentrations of amikacin and fosfomycin were achieved in mechanically ventilated patients with VAT or VAP after aerosolized administration. Airway clearance was rapid. No adverse respiratory effects were noted during or following drug administration JOURNAL OF AEROSOL MEDICINE AND PULMONARY DRUG DELIVERY Volume 27, Number 6, 2014

25 Colistin against P. aeruginosa ATCC 27853 log10 CFU and fAUC/MIC relationships
Thigh Lung Neutropenic mouse experimental model Cheah SE et al., J Antimicrob Chemother, 2015

26 Colistin against MDR Gram-negatives
Colistin against MDR Gram-negatives* Time to bacterial eradication (TBE) in 147 VAP patients IV (n = 76) Aerosol (n = 73) *Mainly Acinetobacter sp. and P. aeruginosa Abdellatif S et al., Ann. Intensive Care, 2016

27 Colistin Microbiological eradication with aerosolised and intravenous (IV-AS) compared with intravenous (IV) alone Liu D et al., Int J Antimicrob Agents, 2015

28 No adverse effect such as nephrotoxicity or neurotoxicity was observed
Outcome of ventilator-associated pneumonia due to multidrug-resistant A. baumannii and P. aeruginosa treated with aerosolized colistin in neonates: a retrospective chart review Celik IH, Oguz SS, Demirel G, Erdeve O, Dilmen U We report our experience with aerosolized colistin in two preterm and one term neonate with A. baumannii and P. aeruginosa-related VAP We used 5 mg/kg (base activity)* aerosolized CMS every 12 h as an adjunctive therapy for VAP for 14, 14, and 16-day courses No adverse effect such as nephrotoxicity or neurotoxicity was observed Corresponding to ~150,000 IU of CMS Eur J Pediatr (2012) 171:311–316

29 Adjuncting aerosolized antibiotics in VAP patients with APACHE II > 16 Probability of survival
Arnold HM et al., Respiratory Care, 2012

30 Nebulized antibiotics for ventilator-associated pneumonia: a systematic review and meta-analysis Zampieri FG, Nassar APJr, Gusmao-Flores D, Taniguchi LU, Torres A and Ranzani OT Nebulized antibiotics may be beneficial for the treatment of VAP However, high heterogeneity and the small number of enrolled patients in the available studies preclude any optimistic conclusions regarding the benefits of nebulized antibiotics High-quality trials analyzing the value of nebulized antibiotics for VAP treatment are warranted Critical Care (2015) 19:150

31 Aerosolized antibiotics Adverse effects associated to use*
Frequency per antibiotic (%) Aminoglycosides Gentamicin Amikacin Tobramycin Nephrotoxicity NR < 10 Neurotoxicity Wheezing 11 – 20** Cough Bronchospasm 21 – 40 Hypersensitivity pneumonitis 11 – 20 Hemoptysis Others * In patients with CF, NCFB and VAP ** Reported greater incidence (> 30%) in patients with severe non-cystic fibrosis bronchiectasis Restrepo MI et al., Respiratory Care, 2015

32 Aerosolized antibiotics Adverse effects associated to use*
Frequency per antibiotic (%) Miscellaneous Colistin Vancomycin Aztreonam Ceftazidime Nephrotoxicity < 10 NR Neurotoxicity Wheezing 11 – 20 Cough 21 – 40 Bronchospasm Hypersensitivity pneumonitis Hemoptysis Others * In patients with CF, NCFB and VAP Restrepo MI et al., Respiratory Care, 2015

33 Aerosolized antibiotics Reported cough in CF and NCFBE patients
Weers J, Advanced Drug Delivery Reviews, 2015

34 Aerosolized amphotericin B as prophylaxis for invasive pulmonary aspergillosis: a meta-analysis Xia D, Sun WK, Tan MM, Zhang M, Ding Y, Liu ZC, Su X, Shi Y Conclusions: This analysis provides evidence supporting the notion that the prophylactic use of aerosolized AMB effectively reduces the incidence of IPA among high-risk patients. International Journal of Infectious Diseases 30 (2015) 78–84

35 AmB-Lip 1 mg/kg aerosol ELF concentrations in 35 patients*
* lung transplan recipient Fauvel M et al., Int J Pharm, 2012

36 Aerosol therapy during mechanical ventilation: an international survey with ICU physicians Droplet size and pulmonary deposition Ehrmann S et al., Intensive Care Med, 2013

37 Conclusion Aerosolized antibiotic therapy is recommended in CF patient management and has contributed to improved predicted survival Given the success of aerosolized antibiotics in patients with CF, this approach to therapy has been used in other patients with chronic airways infection, such as non-CF bronchiectasis, NTM, and VAT/VAP, with varying results There are sufficiently remarkable results in some patients suggesting that better designed studies and refined inclusion criteria may be necessary


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