INHALED

ANTIBIOTICS

BY
Dr S.SNEHALATHA
2nd YEAR POST GRADUATE
 Contents
• Introduction
• Indications
• Advantages
• Disadvantages
• Various antibiotics in detail
• Treatment outcomes
• Future perspective
• Summary
Introduction
• The delivery of medications to the lungs via inhalation or
aerosolization has been a well recognized technique
• This mode of therapy is used successfully to deliver bronchodilators
and steroids to patients with asthma and COPD
• It is potentially a compelling strategy to target antimicrobial therapy
in the treatment of lower respiratory tract infections
Indications
• Bacterial infections in patients with
. 1. cystic fibrosis (CF),
2. non-CF bronchiectasis (NCFB), and
3. ventilator-associated pneumonia (VAP).
Advantages
• Effective in treatment of bacterial infection with underlying structural
lung diseases
• Higher local concentration of drug
• Lesser systemic absorption
• Lesser systemic adverse effects
Disadvantages
• Higher chances of development of resistance
• Local adverse effects
• Measurement of sputum concentrations is not an ideal method for
monitoring therapeutic delivery of these medications, as it is not
predictive of delivery to the distal airway, which is often the major site
of infection.
Local drug reactions
• Cough
• Wheezing
• Bronchospasm
• Hypersensitivity pneumonitis
• Hemoptysis
Properties of antibiotics

• The characteristics that make a medication suitable for aerosolization

have been extensively studied.
• To ensure effective delivery of the medication and to achieve the
desired clinical effect with a limited side effect profile
Properties of antibiotics
• These medications must have relatively physiologic pH.
• They must also penetrate infected airway secretions,
• Should not be inactivated by the presence of other medication
• Should not provoke intolerable adverse effects such as
1. cough
2. Bronchospasm
3. hemoptysis
Who are our targets
• Pseudomonas Aeruginosa
• Staphylococcus aerues
• Klebsciella
• Enterobacter species
What all can be used
• Aminoglycosides
• polymyxins
• glycopeptides
• Beta lactams
• Monobactams
• fluoroquinolones have been evaluated for delivery via aerosolization
with variable results
The list of available and tested antibiotics
Tobramycin
• Class • Aminoglycosides
• Mechanism • Binding to the 30 S ribosomal subunit and
causing disruption of peptide synthesis
• Result • Effective in the treatment of chronic
Pseudomonas infection in subjects with cystic
fibrosis
• Dose • 300mg bd for 28 days and off the dose for
28days
• remarks • Tobramycin does not penetrate the lungs and
is ideal for local treatment
TOBI PODHALER
TOBI® PODHALER® capsule is a prescription inhaled
medication for cystic fibrosis patients whose lungs contain
bacteria called Pseudomonas aeruginosa.
One treatment cycle consists of 28 days on and 28 days off
treatment
Each dose of 4 capsules should be taken as close to 12 hours
apart as possible; each dose should not be taken less than 6 hours
apart
The powder from all 4 capsules must be inhaled to receive the
full dose of 112 mg
• Inhale 2 times from each capsule in order to empty it
Levofloxacin and ciprofloxacin
• Class • Fluoroquinolones
• interference with deoxyribonucleic acid (DNA)
• Mechanism synthesis.
• These antibiotics have activity against Gram-negative
bacteria, including P. aeruginosa, as well as some
• Result Gram-positive bacteria, although they do not have
reliable activity against methicillin-resistant
Staphylococcus aureus (MRSA).
• remarks • fluoroquinolones are characterized by significant
tissue penetration. To date, levofloxacin and
ciprofloxacin have been evaluated for delivery via
aerosolization in patients with CF, NCFB, and/or
VAP
 AZTREONAM
• Class • synthetic bactericidal monobactams
• Mechanism • It acts through inhibition of cell wall synthesis
and displays typical-lactam
• a short half-life and slow penetration into
• Result bronchial secretions.
• activity against Gram-negative bacteria, including
• remarks Pseudomonas aeruginosa
• has an elimination half-life of 2 h. Approximately
10% of the delivered dose is ultimately excreted
in the urine, and the remainder is thought to be
expectorated from the airways
Delivery system
• To optimize delivery of aerosol medications to the airway, systems are
designed with consideration of a number of factors that affect the
repairable dose delivered to the patient.
• Among these factors are the aerodynamic size of droplets produced
(expressed as mass median aerodynamic diameter [MMAD]), the size
distribution of the aerosol particles (geometric standard deviation), and the
output of the nebulizer.
• Ideal droplet size ranges from 1- to 5-m MMAD for airway deposition and
2-m MMAD for parenchymal deposition. Larger droplets ( 5-m MMAD)
are less likely to reach distal airways and can become trapped in the
ventilator circuit or endotracheal tube in mechanically ventilated patients
Delivery system
1. Jet system
2. Ultrasonic
3. Vibrating mesh
• There are three main types of nebulizers:
• Jet. This uses compressed gas to make an aerosol (tiny particles of
medication in the air).
• Ultrasonic. This makes an aerosol through high-frequency vibrations.
The particles are larger than with a jet nebulizer.
• Mesh. Liquid passes through a very fine mesh to form the aerosol
What is a jet nebulizer?
Jet nebulisers use compressed air
or oxygen passing through a
narrow orifice at 6–8 L/minute to
suck drug solution from a
reservoir into a feed tube. There
are fine ligaments in this tube,
and the impact of the solution on
these ligaments generates
droplets (Venturi principle
Ultrasonic nebulizer
• They are divided into two
categories (1) large-volume
ultrasonic nebulizers and (2)
small-volume ultrasonic
nebulizers. Whereas large-volume
ultrasonic nebulizers are most
commonly used to deliver
hypertonic saline for sputum
induction, small-volume ultrasonic
nebulizers are used for delivery of
inhaled medications
Mesh nebulizer
• This allows for consistent particle
sizes of medication to be dispensed
and inhaled. This type of nebulizer
is compact and portable, making it
easy to use on the go. It is also
known for its quick and efficient
delivery of medication, which is
ideal for acute respiratory
conditions
• For spontaneously breathing patients with CF and NCFB, nebulizer
systems have been developed and marketed for use with specific
antibiotics.
• Examples of this include Cayston, which is administered using the
Altera vibrating mesh nebulizer system (PARI Respiratory Equipment,
Midlothian, Virginia), and tobramycin solution for inhalation
• In general, these nebulizer systems are portable and able to deliver the
medications with minimal waste.
• Cayston administration requires 2–3 min for treatment and is given 3
times daily. TOBI administration requires 10–15 min for nebulization
and is given twice daily. To lessen this burden of treatment, dry
powder tobramycin for inhalation has been developed, which
decreases treatment time to 2–3 min. Other antibiotics have been
administered via investigational nebulizers not currently available on
the market
• Ideal methods for delivery of nebulized medications to mechanically
ventilated patients have not been determined.
• An important factor that affects drug delivery in these patients is the humidity
within the ventilator circuits.
• Delivery failure can result from hydroscopic growth and rainout effect within
the tubing.
• There are several available delivery systems in use. The AeroTech II (Biodex
Medical Systems, Shirley, New York) is a classic jet nebulizer that requires
continuous air flow and connection to the ventilator in the inspiratory branch.
• The AeroTech II can nebulize antibiotics, bypassing the humidification
system, and produces particles with an MMAD of 1.5 m.20
Did they really worked
• The potential of aerosolized antibiotics delivering concentrations of
effective drug directly to the site of infection while minimizing
systemic effects are appealing.
• Patients with CF and chronic Aeruginosa infection aerosolized
antibiotics are delivered via portable nebulizer systems and have
shown significant impacts on clinical outcomes.
• For the majority of patients with CF, these medications are part of a
therapeutic regimen that has increased median survival to 40y.
• Further advances in delivery systems and investigation into the
efficacy of more antibiotics are ongoing
Studies on cystic fibrosis
• Adult patients with CF, receiving levofloxacin, were at lower risk of
pulmonary exacerbations.
• In particular, the alternate continuous use (on/on) of inhaled antibiotics
has become increasingly popular—especially among patients infected
with P. aeruginosa with impairment of lung function.
• In contrast, the management of infections caused by all the classic
pathogens other than P. aeruginosa has not been well supported by the
results of clinical trials.
EPIC STUDY
• The epic trial tested four randomized regimens cycled therapy versus
culture driven therapy and 28 days of inhaled tobramycin inhalation
solution in the presence or absence of 14 days of oral ciprofloxacin
approximately 80% of patients remained free of P. Aeruginosa
infection for the duration of the study (18 months) with no difference
concerning time to first pulmonary exacerbation attributed to regularly
cycled therapy or the addition of ciprofloxacin
ELITE STUDY
• Open label randomized study comparing 28 to 56 days of inhaled
tobramycin inhaled solution it revealed approximately 90%
eradication at the end of therapy with 66 to 69% days of patients
having pseudomonas free cultures at the end of the 27 month study
• another study trail comparing inhaled colistin in and oral
ciprofloxacin to inhale the TIS and oral ciprofloxacin showed no
difference between regimens in eradication with approximately 62
percentage to 65% patients having pseudomonas infection free culture
at the end of six months therefore all though the evidence from these
studies as supports antibiotic eradication of new pseudomonas
infection there is no consensus yet for a specific therapy regimen
Points for clinical practice

• Inhaled antibiotics continue to be

prescribed for cystic fibrosis patients
who receive cystic fibrosis
transmembrane conductance regulator
(CFTR) modulators to treat chronic
respiratory infections.
• Patients are recommended to continue
their existing treatment regimen while
receiving CFTR modulators.
• Clinicians are encouraged to balance
the simplification of treatment with the
risk of clinical deterioration due to
microbial infections when making
treatment decisions.
Bronchiectasis
• The role of inhalational antibiotics is not supported by large-scale
pivotal studies.
• However, in few the studies, subsets of patients had improvements in
bacterial density.
• Therefore, expert opinion advocates the use of these therapies in
individualized therapeutic regimens for patients with chronic
Pseudomonas or other gram-negative infections.
• In conclusion, this systematic review suggests that in adult
patients with clinically stable non-CF bronchiectasis
inhaled antibiotics may have microbiological and clinical
benefits in
1. reducing sputum bacterial load,
2. eradicating bacteria from sputum and
3. preventing acute exacerbations.
Inhaled antibiotics may provide an effective suppressive
antibiotic therapy
Conclusions
Regarding our view, the role of antibiotic aerosolized
therapy to manage ventilator associated infections,
especially those due to MDR Gram-negative
bacteria is promising,
• but clinical data are limited, and there are still
questions that require further research in order to
be answered. This is most important when
considering the marked heterogeneity in clinical
practice, with significant differences in the use of
aerosolized antibiotics between patients. First,
large randomized controlled trials should be
conducted to confirm the benefits of AA and to
explore the impact on antibiotic selection pressure
with the use of aerosolized antibiotics.
Monitoring
• How to monitor the effectiveness of aerosolized antibiotic treatment is
not clear, but in general,
• The clinical response rate
• Complete or partial resolution of the signs and symptoms of infection
by the end of therapy is frequently used to determine its effectiveness.
• Additionally, some researchers haves how the microbiological
eradication (i.e. no growth of the causative /colonization pathogen at
the end of therapy)might be useful, especially in subjects with CF
Monitoring….
• Measurement of sputum concentrations is not an ideal method for
monitoring therapeutic delivery of these medications,
• as it is not predictive of delivery to the distal airway, which is often
the major site of infection.4l
• Therefore, these correlations should be interpreted with caution and
studies showing efficacy with regard to clinically relevant end points
should be used to guide clinical decision making
Research
• In addition, despite considerable progress in understanding the effects
of pulmonary exacerbation on outcomes in CF, there are multiple
important knowledge gaps as regards the management of pulmonary
exacerbations, and evidence from more interventional studies is
needed to guide practice decisions.
• multicenter randomized trials are still needed to better define the
optimal regime and duration of treatment (long-term maintenance
therapy or repeated short-term therapy), and to compare the
effectiveness and safety of different inhaled antibiotics and between
inhaled and systemic antibiotics.
Research…
• Research may also need to focus on early (pre-emptive) treatment of
VAT to prevent evolution to VAP, using appropriate nebulized
antibiotics, especially in those at high risk for VAP development.
• Moreover, future research should focus how to refine aerosolized
treatment in terms of
1. delivery device technology,
2. adequate antibiotic dosing,
3. specific protocol design.
Summary
• Have clear anti microbial effect
• Still controversial as the
• Clinical efficacy is not yet proven
• BTS recommend long term usage
• Many Unanswered questions required research
References
• Fishman
• Murray and Nadal
• Elborn, J. S., Blasi, F., Burgel, P. R., & Peckham, D. (2023). Role of inhaled antibiotics in
the era of highly effective CFTR modulators. European Respiratory Review, 32(167).
• Elborn, J. Stuart, et al.(2023)
• Myrianthefs, P., Zakynthinos, G. E., Tsolaki, V., & Makris, D. (2023). Aerosolized
Antibiotics to Manage Ventilator-Associated Infections: A Comprehensive
Review. Antibiotics, 12(5), 801.
• Myrianthefs, Pavlos, et al
• Brodt, A. M., Stovold, E., & Zhang, L. (2014). Inhaled antibiotics for stable non-cystic
fibrosis bronchiectasis: a systematic review. European Respiratory Journal, 44(2), 382-393.
• Brodt, A. M., Stovold, E., & Zhang, L. (2014)
 Next seminar
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By Dr. R. Divya