AEROZOLIZED

ANTIINFECTIVE AGENTS
RESPIRATORY CARE PHARMACOLOGY
Objectives
• 1. Define terms that pertain to aerosolized antiinfective agents (C1)
• 2. List the available inhaled antiinfective agents used in respiratory
therapy and their indications (C1)
• 3. Compare between specific antiinfective agent formulations (C2)
• 4. Explain the route of administration available for the various inhaled
antiinfective agents (C2)
• 5. Explain the mode of action and list the side effects for the various
antiinfective agents (C2)
• 6. Explain the use of each antiinfective agent in the treatment of lung
disease (C2)
• Cystic fibrosis (CF): Inherited disease of the exocrine glands, affecting the
pancreas, respiratory system, and apocrine glands. Symptoms usually begin in
infancy and are characterized by increased electrolytes in the sweat, chronic
respiratory infection, pancreatic insufficiency, and reduced fertility (females) and
sterility (males).
• Pneumocystis pneumonia (PCP): Interstitial plasma cell pneumonia caused by the
organism Pneumocystis carinii (now known as Pneumocystis jiroveci). This
pneumonia is common among patients with lowered immune system response.
• Respiratory syncytial virus (RSV): Virus that causes formation of
syncytial masses in infected cell structures.
• Virostatic: Stopping a virus from replicating.
• Virucidal: Killing a virus.
• Virus: Obligate intracellular parasite, containing either DNA or RNA,
that reproduces by synthesis of subunits within the host cell and
causes disease as a consequence of this replication.
 INTRODUCTION
• Antiinfective agents currently approved for administration as inhaled aerosols:
pentamidine isethionate (NebuPent), ribavirin (Virazole), tobramycin (TOBI),
aztreonam (Cayston), and zanamivir (Relenza).
 Pentamidine - to prevent and treat Pneumocystis pneumonia (PCP) in patients with AIDS,

 Ribavirin - to treat respiratory syncytial virus (RSV).

 A monoclonal antibody preparation, palivizumab (Synagis), offers prophylaxis and treatment for
RSV infection.
 Inhaled tobramycin and aztreonam are available for the management of Pseudomonas aeruginosa
infections in patients with cystic fibrosis (CF).
 Zanamivir is an inhaled antiviral agent used to treat influenza.
 CLINICAL INDICATIONS
Indication for Aerosolized Pentamidine:

• Pentamidine by inhalation is indicated for the prevention of Pneumocystis

pneumonia (PCP) in high-risk HIV–infected patients who have a history of one or
more episodes of PCP or a peripheral CD4+ (T4 helper cell) lymphocyte count of
200/mm3 or less.

Indication for Aerosolized Ribavirin:

• Aerosolized ribavirin is indicated for the treatment of hospitalized infants with

severe lower respiratory tract infection caused by RSV.
Indication for Aerosolized Tobramycin:

• Aerosolized tobramycin is indicated for the management (control) of chronic P. aeruginosa

infection in CF.

Indication for Aerosolized Aztreonam:

• Aerosolized aztreonam is indicated to improve pulmonary symptoms in CF patients with P.

aeruginosa infection.

Indication for Inhaled Zanamivir:

• Inhaled zanamivir is indicated for the treatment of uncomplicated acute illness caused by
influenza virus in adults and children age 7 years and older who have been symptomatic
for no more than 2 days. It may also be used prophylactically in children 5 years and older
against the influenza virus.
IDENTIFICATION OF AEROSOLIZED
ANTIINFECTIVE AGENTS
 Aerosolized Pentamidine (NebuPent)

• Pentamidine isethionate (NebuPent) is an antiprotozoal agent that is active

against Pneumocystis carinii (now known as Pneumocystis jiroveci), the
causative organism for PCP.

• Pentamidine can be given either parenterally or as an inhaled aerosol, but it

is not absorbed with oral administration.

• Both systemic administration and aerosol administration of pentamidine

have been used for the treatment of Pneumocystis pneumonia (PCP)

• PCP occurs as a common opportunistic infection in patients with AIDS.

Aerosolized Pentamidine (NebuPent)

Rationale for Aerosol Administration

• The rationale for aerosol administration of pentamidine to treat or prevent

PCP is based on: local targeted lung delivery, with fewer or less severe side
effects compared with systemic administration.

Dosage and Administration

• The approved dose of aerosolized pentamidine (NebuPent) for prophylaxis

of PCP in AIDS patients is 300 mg given by inhalation once every 4 weeks.
Aerosolized Pentamidine (NebuPent)

• Particles should be of the size 1 to 2 micrometer to:

 achieve peripheral intraalveolar deposition targeted at the location of the microorganism
 reduce or prevent airway irritation seen with larger particle sizes, which deposit more in
larger airways

Mode of action

• The exact mode of action is unknown. The toxic effect of the drug on P. carinii
may be due to multiple actions.

• Pentamidine blocks RNA and DNA synthesis, inhibits oxidative phosphorylation,

and interferes with folate transformation.
Aerosolized Pentamidine (NebuPent)

• When given by inhaled aerosol, pentamidine reaches significantly higher

concentrations in the lung than when given intravenously.

• The inhaled drug first binds to lung tissue.

• The drug is slowly absorbed into the circulation and distributed to body
tissues, as with parenteral administration and prolonged aerosol
administration can result in systemic accumulation.
Aerosolized Pentamidine (NebuPent)

Side Effects

• Parenteral use of pentamidine has resulted in the following:

• Pain, swelling, and abscess formation at the site of injection with intramuscular
administration
• Thrombophlebitis and urticarial eruptions with intravenous administration

• Hypoglycemia

• Impaired renal function and azotemia

• Hypotension

• Leukopenia

• Hepatic dysfunction
Aerosolized Pentamidine (NebuPent)

• Side effects with aerosol administration can be differentiated into local

airway effects and systemic effects.

• Local airway effects:

• Cough and bronchial irritation in 36% of patients in one study

• Shortness of breath

• Bad taste (bitter or burning) of the aerosol impacting in the oropharynx

• Bronchospasm and wheezing in 11% of patients

• Spontaneous pneumothoraces
Aerosolized Pentamidine (NebuPent)

• Systemic reactions
• Conjunctivitis

• Rash

• Neutropenia

• Pancreatitis

• Renal insufficiency

• Dysglycemia (hypoglycemia and diabetes)

• Digital necrosis in both feet

• Appearance of extrapulmonary P. carinii infection

Aerosolized Pentamidine (NebuPent)

Environmental Contamination by Nebulized Pentamidine

• Exposure to the drug itself from the exhaust aerosol

• Risk of infection with tuberculosis (TB), a disease associated with AIDS,

from patients being treated with aerosolized pentamidine.

• Studies have shown that low levels of pentamidine can be detected in

health care workers exposed to the drug during treatments.

• Health care workers have also complained of conjunctivitis and

bronchospasm when aerosolizing the drug.
 Ribavirin (Virazole)

• Ribavirin (Virazole) is classified as an antiviral drug; it is active against RSV,

influenza viruses, and herpes simplex virus.

• Ribavirin is virostatic, not virucidal, and inhibits DNA and RNA (retrovirus)
viruses.

Clinical Use

• Generally, the drug is not recommended for routine RSV infection, but it
may be considered for life-threatening infections.
Ribavirin (Virazole)

Respiratory syncytial virus infection

• Respiratory syncytial virus (RSV) can cause bronchiolitis and pneumonia.

• Almost all children are exposed to RSV by their second year of life, and in
most the infection is mild and self-limiting.

• Outbreaks of RSV pneumonia are seasonal and peak during winter months.

• The virus spreads easily by personal contact or hand contamination from

surfaces.
Ribavirin (Virazole)

Dosage and Administration

• Ribavirin is given as a 20-mg/mL solution, which is administered by

nebulizer for 12 to 18 hours per day, for a minimum of 3 days and not more
than 7 days.

• The drug is available in powder form, which needs to be reconstituted and

diluted and administered using a specialized large volume nebulizer.

Mode of Action

• Mechanism of action – not completely understood.

Ribavirin (Virazole)

• Viral inhibition

• The half life of ribavirin - 9 hours in plasma and about 1 to 2 hours in

respiratory secretions, the rationale for almost continuous administration
by aerosol.
Ribavirin (Virazole)

Side Effects

• Pulmonary: Deterioration of pulmonary function and worsening of asthma

or chronic obstructive pulmonary disease (COPD) occur; pneumothorax,
apnea, and bacterial pneumonia have been described.

• Cardiovascular: Cardiovascular instability, including hypotension, cardiac

arrest, and digitalis toxicity, has been noted.

• Dermatologic/topical: Rash, eyelid erythema, and conjunctivitis have been

noted.
Ribavirin (Virazole)

• Hematologic: Effects on blood cells have been reported with oral or

parenteral administration but not with aerosol use. Reticulocytosis (excess
of young erythrocytes in the circulation) has been reported with aerosol
use.

• Equipment-related: Equipment-related adverse effects with ribavirin

treatment include occlusion and impairment of expiratory valves and
sensors with ventilator use and endotracheal tube blockage from drug
precipitate.
 Palivizumab (Synagis)

• It is a type of monoclonal antibodies.

Clinical Use

• Palivizumab is indicated for the prevention of serious lower respiratory tract

disease caused by RSV in children and infants at high risk.

Dosage and Administration

• The powder for injection is lyophilized, available at 50 or 100 mg/mL.

• Recommended dose - 15 mg/kg, i.m. once a month before the start of and
throughout the RSV season.
Palivizumab (Synagis)

Mode of Action

• Palivizumab is a humanized monoclonal antibody produced by recombinant

DNA techniques, directed against the F protein of RSV.

• Palivizumab provides neutralizing and fusion-inhibiting activity, preventing

viral replication.

Adverse Reactions

• The most serious adverse reaction is anaphylaxis; however, this occurs in

less than 1 per 100,000 cases.
Palivizumab (Synagis)

• Other reactions that occurred in treatment and placebo groups included

fever, upper respiratory infection, otitis media, rhinitis, rash, pain, hernia,
and coughing and wheezing.
 Aerosolized Tobramycin (TOBI)

Clinical Use

• Cystic fibrosis (CF): Patients with CF are chronically infected with gram-
negative organisms, such as P. aeruginosa, and the gram-positive
bacterium Staphylococcus aureus as well as other microorganisms.
Aerosolized Tobramycin (TOBI)

Dosage and Administration

• TOBI is recommended for children 6 years of age or older.

• Dosage is 300 mg twice daily approximately 12 hours apart and not less than 6
hours apart for 28 days consecutively, with the following 28 days off of the drug
– cycle repeated on a maintenance basis.

• The drug is formulated as a nebulizer solution with 300 mg in a 5-mL ampoule.

• Patients should be instructed not to mix dornase alfa or any other drug with
tobramycin in the nebulizer.
Aerosolized Tobramycin (TOBI)

• Tobramycin should be inhaled after other therapies usually administered in

CF, such as chest physiotherapy measures and other inhaled medications
including bronchodilators or dornase alfa.

Mode of Action

• These antibiotics are effective in treating gram-negative infections and have

a bactericidal effect.

• Tobramycin binds irreversibly to the 30S subunit of bacterial ribosomes and

binding blocks protein synthesis in the bacteria and causes cellular death.
Aerosolized Tobramycin (TOBI)

Side Effects
 Aerosolized Aztreonam (Cayston)

• Aerosolized aztreonam is used to improve Pseudomonas aeruginosa

infection in patients with CF.

• Patients should be pretreated with a bronchodilator before administering

aerosolized aztreonam.

• Cayston is not indicated for patients younger than 7-years-old.

• Each 2-mL single-use glass vial contains 75 mg of lyophilized aztreonam

and must be mixed with the provided 1 mL of sterile diluent.

• Cayston is given three times a day for 28 days on and 28 days off.
 Inhaled Zanamivir (Relenza)

• Zanamivir is available for administration with a dry powder inhaler (DPI) to

treat acute symptoms of influenza.

• The agent has an off-label use for treatment and prophylaxis of H1N1
influenza A (“swine flu”).

• An oral antiinfluenza agent, oseltamivir phosphate (Tamiflu) is also available

as 30-mg, 45-mg, and 75-mg capsules and oral liquid, 12 mg/mL.
Inhaled Zanamivir (Relenza)

Dosage and Administration

• Zanamivir is available in a dry powder inhaler

(DPI), the Diskhaler device, for oral
inhalation.

• Each blister contains 5 mg of drug, providing

a dose of 5 mg per inhalation.

• The dose for adults and children 5 years of

age or older: two inhalations (two blisters) bd
approximately 12 hours apart for 5 days.
Inhaled Zanamivir (Relenza)

Mode of Action

• Zanamivir represents a new class of antiviral agents, termed neuraminidase

inhibitors, which act by binding to the viral enzyme neuraminidase and
blocking the action of the enzyme.

Adverse Effects

• Bronchospasm and deterioration of lung function

• Undertreatment of bacterial infection

• Allergic reactions
Inhaled Zanamivir (Relenza)

• Other adverse effects occurring in a small percentage of patients included

gastrointestinal (diarrhea, nausea, vomiting) and respiratory (bronchitis;
cough; sinusitis; ear, nose, and throat infections) effects and dizziness and
headaches.
THANK YOU