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 infectionsCF
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 efficacyCF
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