Download CRITERI DI SCELTA DI UN FARMACO ANTIFUNGINO Il punto di

Uso degli antibiotici per aerosol
Andrea Novelli
Dipartimento di Scienze della Salute
Sezione di Farmacologia Clinica & Oncologia
Transparency Declaration
Honoraria or grant support received from:
• Gilead
• Menarini
• MSD
• Valeas
• Zambon Group
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.
Amikacin
Comparison of mean serum and bronchial secretion
concentrations in pneumoniae patients
Weers J, Advanced Drug Delivery Reviews, 2015
Aerosol delivery
• ADVANTAGES
• Less systemic toxicity
• Delivery to site of action
• Higher concentrations available in the lung
• DISADVANTAGES
• Time and effort
• Delivery device constraints
Aerosolized antibiotics for treatment of specific infections
Antibiotic
CF
NCFB
VAP
Aminoglycosides
Gentamicin
Amikacin
Liposomal amikacin
Neomycin
Sisomycin
Tobramycin
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Polymyxins
Colistin/polymixin B
Yes
Yes
Yes
Glycopeptides
Vancomycin
Yes
Monobactams
Aztreonam lysine
Yes
b-lactams
Ceftazidime
Ticarcillin
Yes
Yes
Fluoroquinolones
Ciprofloxacin
Yes
Yes
CF = cystic fibrosis
NCFB = non-CF bronchiectasis
VAP = ventilator-associated pneumonia
Restrepo MI et al., Respiratory Care, 2015
Aerosolized antibiotics
Treatment outcomes to assess the efficacy
Antibiotic
CF
NCFB
VAP
Survival
Yes
Prophylactic
Yes
Bacterial eradication
Yes
Clinical improvement*
Yes
Reduce exacerbations
Yes
Yes
Improve quality of life
Yes
Yes
Decrease sputum bacterial load
Yes
Yes
Decrease local inflammation
Yes
Yes
* 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
Antibiotic nebulization therapy
DRUG
• Choice of antibiotic
• Dose and regimen
DELIVERY
FORMULATION
• Clinically validated
nebulizer
• Particle size optimal
for delivery to endobronchial space
• Nebulization time
• High concentration
• Preservative-free
• Ready to use
Cole PJ, J Chemother, 2001
Aerosolized antibiotics
Ideal properties
Bassetti M et al., Ann Intensive Care, 2016
Aerosolized antibiotics
Incidence of cough as a function of osmolarity of nebulized solution
Weers J, Advanced Drug Delivery Reviews, 2015
Approved inhaled antibiotics currently used in
clinical practice
Generic name
Brand name
Disease
indications
Formulation
Recommended/dose/freq
uency
Aztreonam
Cayston
CF
Inhalation solution
75 mg TID
Colistin
Colomycin
CF; VAP
Powder dissolved in
saline
1-2 MIU (75-150 mg) BID
Colobreathe
CF
Dry powder
125 mg (1,7 MIU) BID
TOBI
CF
Inhalation solution
(pH=6.0)
300 mg BID
Bethkis
CF
Inhalation solution
(pH=5.0)
300 mg BID
TOBI Podhaler
CF
Dry powder
112 mg BID
Tobramycin
Quon BS et al., Ann Am Thorac Soc, 2014, MOD
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
250-500 mg BID
Amphotericin B
Fungizone
Post-transplant
fungal prophylaxis
or treatment
Injectable solution +
sterile water
Prophylaxis: 25-50
mg OD
Abelcet
Post-transplant
fungal prophylaxis
or treatment
Lipid complex
Prophylaxis: 50-100
mg OD
Ambisome
Post-transplant
fungal prophylaxis
or treatment
Liposomal
Prophylaxis: 50-100
mg OD
Ceftazidime
Fortaz
VAP
CF
Injectable solution +
saline
VAP: 1gx8
CF: 1g BID
Gentamicin
N/A
Non-CF
bronchiectasis
Injectable solution +
saline
80 mg BID
Tobramycin
N/A
CF
Injectable solution +
saline
80 mg BID
Quon BS et al., Ann Am Thorac Soc, 2014
Aerosolized antibiotics
Annual prevalence among CFFPR patients stratified by age
Dasenbrook EC et al., Journal of Cystic Fibrosis, 2015
Aerosolized antibiotics in CF patients
Change in FEV1% from baseline following treatment
Weers J, Advanced Drug Delivery Reviews, 2015
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
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
Aerosolized drugs
Relationship between aerodynamic diameter and site
of lung deposition
Bassetti M et al., Ann Intensive Care, 2016
Advantages and disadvantages of different types of nebulizers
Nebulizers
Advantages
Disadvantages
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 & Breathenhanced jet nebulizer
•
•
•
•
Drug delivery only during inhalation
Easy to use
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
•
•
Easy to use
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
Easy to use
•
•
•
More expensive
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
•
Aerosolized colistin
Delivery values of CMS
Loaded dose/filling
volume
Aereoneb Go
Colifin 2MIU/4 ml
(160 mg)
eFlow rapid
Colifin 2MIU/4 ml
(160 mg)
LC Sprint
Colifin 2MIU/4 ml
(160 mg)
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
Aerosolized antibiotics
Daily treatment burden for various devices
Weers J, Advanced Drug Delivery Reviews, 2015
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
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
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
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
Colistin against P. aeruginosa ATCC 27853 log10 CFU
and fAUC/MIC relationships
Thigh
Neutropenic mouse experimental model
Cheah SE et al., J Antimicrob Chemother, 2015
Lung
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
Colistin
Microbiological eradication with aerosolised and intravenous
(IV-AS) compared with intravenous (IV) alone
Liu D et al., Int J Antimicrob Agents, 2015
Outcome of ventilator-associated pneumonia due to multidrugresistant 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
Adjuncting aerosolized antibiotics in VAP patients
with APACHE II > 16
Probability of survival
Arnold HM et al., Respiratory Care, 2012
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
Aerosolized antibiotics
Adverse effects associated to use*
Frequency per antibiotic (%)
Adverse Effect
Aminoglycosides
Gentamicin
Amikacin
Tobramycin
Nephrotoxicity
NR
< 10
< 10
Neurotoxicity
NR
NR
< 10
Wheezing
< 10
< 10
11 – 20**
Cough
< 10
< 10
11 – 20**
21 – 40
< 10
11 – 20**
Hypersensitivity pneumonitis
NR
< 10
11 – 20
Hemoptysis
NR
NR
11 – 20
Others
< 10
< 10
< 10
Bronchospasm
* 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
Aerosolized antibiotics
Adverse effects associated to use*
Frequency per antibiotic (%)
Adverse Effect
Miscellaneous
Colistin
Vancomycin
Aztreonam
Ceftazidime
Nephrotoxicity
< 10
< 10
NR
NR
Neurotoxicity
NR
NR
NR
NR
Wheezing
NR
NR
11 – 20
< 10
Cough
NR
NR
21 – 40
< 10
Bronchospasm
NR
< 10
< 10
NR
Hypersensitivity
pneumonitis
< 10
NR
< 10
NR
Hemoptysis
NR
NR
21 – 40
NR
Others
< 10
< 10
< 10
< 10
* In patients with CF, NCFB and VAP
Restrepo MI et al., Respiratory Care, 2015
Aerosolized antibiotics
Reported cough in CF and NCFBE patients
Weers J, Advanced Drug Delivery Reviews, 2015
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
AmB-Lip 1 mg/kg aerosol
ELF concentrations in 35 patients*
* lung transplan recipient
Fauvel M et al., Int J Pharm, 2012
Aerosol therapy during mechanical ventilation:
an international survey with ICU physicians
Droplet size and pulmonary deposition
Ehrmann S et al., Intensive Care Med, 2013
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