INHALED ANTIMICROBIAL THERAPY
Advantage:
Ability to provide a greater concentration of antibiotics directly into the
target organ, the lung, avoiding systemic complications with a
noninvasive method.
Disadvantage:
• The high cost.
• The inefficiency of the currently available delivery systems in
delivering drugs to the lower airways.
• The time spent by the patient.
Successful development of aerosolized anti-microbial therapy depend
on 3 major factors
1. Nature of disease process.
Diseases that involve infection of the airway without a substantial
systemic component (eg, cystic fibrosis, bronchiectasis) are much more
suitable for aerosolized therapy than diseases of the parenchyma that are
associated with substantial risk of systemic complications (eg,
pneumococcal pneumonia).
2. The delivery system.
Produce respirable particles & targeting lower airways
3. The antimicrobial agent.
Schematic outlining the factors that prevent extrapolation of lung
dose from the nominal dose placed in the delivery system
Nominal dose
Aerosolized
Remained in device (Dead volume & impaction)
Vented to external environment
Inhaled
Deposited
Extrapulmonary deposition
Exhaled
Pulmonary deposition
Bronchial deposition
Systemic
exposure
Alveolar deposition
Excretion
Indications for aerosolized anti-microbial:
- Bacterial infections.
- Fungal infections.
- Viral infections.
Bacterial infections:
1- Tobramycin sulfate:
- TOBI is a sterile preservative-free aqueous solution containing
300mg tobramycin/5mL
- Licensed for long-term management of chronic pulmonary infection
due to Pseudomonas aeruginosa in cystic fibrosis patients aged 6
years and older.
- TOBI should be administered over 15 minutes, using a hand-held
PARI LC PLUS reusable nebuliser in repeated cycles of 28 days on
drug followed by 28 days off drug. It is hoped that intermittent
administration will allow bacteria that become resistant to
tobramycin to regain sensitivity.
- Patients should inhale TOBI, 300mg twice daily (as close as possible
to 12 hours) during the 28 day on drug period regardless of age or
weight.
- TOBI for inhalation is a new formulation of tobramycin which is
preservative-free. This is an advantage over nebulised intravenous
formulations of tobramycin in terms of airway tolerability
2- Pentamidine isothionate:
NebuPent® is a preservative free powder for solution (for nebulization)
containing 300mg pantamidine isothionate
• Licensed for treatment and prevention (prophylactic) of pneumonia
caused by Pneumocystis carinii (PCP) in HIV patients.
• Dose: Inhalation 300 mg every 4 weeks via Respirgard® II.
Deliver until nebulizer is gone (30-45 minutes).
Requirements for commercial jet nebulizer
• First, they need to provide small particles (mass median
aerodynamic diameter of approximately 1 mm) to optimize
delivery to the lung periphery rather than to the central airways.
• Second, they must incorporate an exhalation filter to reduce
environmental contamination.
Respirgard® II
- Its design incorporates an external baffle to remove large particles
from the aerosol, and the treatment time is 40 minutes to nebulize 6
mL, with approximately 10% of the drug depositing in the lung.
- Because alveolar clearance of relatively insoluble particles is slow
compared to the clearance of particles depositing in ciliated airways
(weeks instead of hours), the drug needs to be administered at only 2week or 4-week intervals
3- Colomycin (colistimethate sodium):
• Colistimethate is FDA approved for intravenous or intramuscular
injection but not as a liquid to be inhaled via nebulizer.
• After mixing with sterile water and a buffer, colistimethate
undergoes spontaneous hydrolysis to the bioactive form colistin.
A component of colistin, polymyxin E1, is toxic to lung tissue.
• phase III trials is now being conducted on a new dry powder
antibiotic formulation which drastically reduces the daily treatment
time.
• The new inhalation system is called Colobreathe, for use by cystic
fibrosis patients whose lungs are infected by pseudomonas
aeruginosa bacteria.
Fungal infections:
• Amphotericin B is tested to be prophylactically administered via
inhalation for invasive pulmonary aspergillosis which is one of the
most devastating complications of bone marrow transplantation
and aggressive anticancer chemotherapy regimens.
• Its use has not been adequately evaluated.
Viral infections:
Ribavirin:
• Ribavirin aerosol is indicated in the treatment of carefully selected
hospitalized infants and young children (<3 yrs old) with severe
lower respiratory tract infections due to respiratory syncytial virus
(RSV).
• Suspected to be teratogenic so never to be given to lactating or
pregnant females also health care workers should be protected from
exposure.
• Dose: A concentration of 20 mg/mL (6 g reconstituted with 300
mL of sterile water without preservatives) administered for 12-18
hours/day for 3 days, up to 7 days in length using Viratek®.
• Aerosol inhalation is done only by Viratek® Which is a small
particle aerosol generator (SPAG-2).
• The nebulizer generates a fine aerosol of hydrated Virazole, and
the drying chamber further dehumidifies the aerosol.
• It may be also connected to mechanical ventilation circuit.
Zanamivir:
• Powder for oral inhalation: 5 mg/blister [4 blisters per Rotadisk®
foil pack packaged with Diskhaler® inhalation device.
• Used for the prophylaxis & treatment of uncomplicated acute
illness due to influenza virus A and B in patients who have been
symptomatic for no more than 2 days.
• Two inhalations (10 mg total) twice daily for a period depending
on indication.
• Reports of neuropsychiatric events have been submitted.
Notes from the lecture
Suppurative diseases:
Diseases which produce a large amount of purulent sputum.
1- Bronchectasis.
2- Lung abscess.
3- Empyema (pus in pleural cavity).
Bronchectasis
Permanent dilatation and destruction of bronchi and airways
associated with irreversible damage of wall.
It may be:
Congenital:
Deficiency of immunoglobulins or deficiency in mucocilliary
escalator (immotile syndrome)
Acquired:
Occurs as a cause of cystic fibrosis which is a genetic disease with a
defect in cilia and lung so favor infection.
Treatment:
1- Physiotherapy and chest percussion.
2- Antibiotics to decrease incidence of infection due to increased
mucus, pus and lung destruction.
3- Surgical treatment. In cases of:
- Localized disease.
- Severe hemoptysis.
- Offensive sputum.
Note: Accumulated experience with tobramycin and colistin indicates
that bronchospasm can be a significant adverse effect. It can be prevented
or resolved by inhaled bronchodilators but in some cases it precludes the
use of aerosol antibiotics.
Table 1—Indications for Aerosolized Antibiotics*
Bacterial Infections
Proven beneficial effects
Suppressive therapy for Pseudomonas in
CF patients
Probably beneficial
Mild exacerbations with Pseudomonas in
CF patients
Pseudomonas in patients with non-CF
bronchiectasis
Highly controversial with
serious risks
Ventilator-associated pneumonia
No information but of
potential benefit
Ventilator tracheostomy–associated
tracheobronchitis
Chronic purulent bronchitis with
Pseudomonas
Other Infections
Amphotericin B for Aspergillus spp after lung transplantation
Pentamidine for Pneumocystis prophylaxis
*CF = cystic fibrosis.