Aerosolized Antiinfective Agents
Generally speaking, the systemic routes (oral, IV) are preferred for administration of anti-infective agents. This includes treatment of most respiratory infections. There are special situations, however, where they are administered locally to the lung.
I.
Pentamidine isethionate a.
Brand Name: NebuPent b.
Indications i.
Indicated as a second-line therapy for the prevention of pneumocystis carinii pneumonia (PCP)
1.
opportunistic infection seen in AIDS and other individuals with suppressed immune systems ii.
Has also been used for treatment of acute episodes c.
Mode of Action i.
Antiprotozoal agent ii.
Exact mechanism of action is unknown
1.
blocks RNA and DNA synthesis
2.
inhibits oxidative phosphorylation
3.
interferes with folate transformation iii.
Routes of Administration
1.
parenteral a.
IV b.
IM
2.
local (inhalation) iv.
Preparation for Inhalation
1.
available as a vial containing 300 mg of powder
2.
the powder is dissolved in 6 mL of sterile water a.
normal saline can not be used as it forms a precipitate v.
Dosage
1.
prevention a.
300 mg by inhalation q4 weeks
2.
acute infection a.
300 mg by inhalation qd vi.
Administration
1.
Respirgard II nebulizer

a.
Two one-way valves b.
Expiratory filter
2.
powered at 5 to 7 L/min
3.
must deliver small particle size (1-2 microns) a.
to improve alveolar deposition b.
to prevent airway irritation vii.
Side Effects with Parenteral (IV, IM) Pentamidine
1.
Pain, swelling and abscess formation at IM injection site
2.
Thrombophlebitis and urticarial eruptions at IV injection site
3.
Hypoglycemia
4.
Impaired renal function
5.
Hypotension
6.
Leukopenia
7.
Hepatic dysfunction viii.
Side Effects with Aerosol Administration of Pentamidine
1.
Local airway effects a.
Cough and bronchial irritation b.
Shortness of breath c.
Bad taste (bitter or burning) d.
Bronchospasm and wheezing e.
Spontaneous pneumothoraces
2.
Systemic effects a.
Conjunctivitis b.
Rash c.
Neutropenia d.
Pancreatitis e.
Renal insufficiency f.
Abnormal glucose levels g.
Digital necrosis in feet h.
Appearance of extrapulmonary P. carinii infection
3.
Preventing airway effects a.
Use a ß2 adrenergic agent or Atrovent prior to treatment with pentamidine

ix.
Environmental Contamination by Nebulized Pentamidine
1.
The following concerns exist: a.
Exposure to the drug itself from the exhaust aerosol i.
Not teratogenic
1.
does not interfere with prenatal development ii.
Not mutagenic
1.
does not cause genetic mutation iii.
Minimal carcinogenic potential iv.
Has caused conjunctivitis and bronchospasm in healthcare workers b.
Risk of infection with tuberculosis (TB), a disease associated with AIDS i.
TB is spread via airborne transmission ii.
Pentamidine aerosol can cause coughing and expulsion of droplet nuclei containing tuberculosis bacilli x.
Environmental Precautions
1.
use a nebulizer system with one-way valves and expiratory filter
2.
stop nebulization if the patient takes the mouthpiece out of the mouth a.
use thumb control on the power gas tubing
3.
screen patients for cough history and pretreat with bronchodilator
4.
administer aerosol in a negative pressure room, with six air changes per hour, or use isolation booth, hood assembly with an exhaust fan and high efficiency filter
5.
use barrier protection (gloves, mask, eyewear) for healthcare workers
6.
screen AIDS patients for TB, and treat when infection exists
7.
healthcare workers should be routinely screened for TB
8.
pregnant women and nursing mothers should avoid exposure to the drug
9.
all practitioners should limit exposure to the drug xi.
Clinical Application
1.
aerosol therapy for prophylaxis of PCP a.
In the 1992 CDC recommendations, oral TMP-SMX was preferred over aerosol pentamidine for prophylaxis of PCP, as long as adverse effects from TMP-SMX were absent or acceptable

b.
Aerosolized pentamidine is now recommended as a second-line therapy for prophylaxis of PCP
2.
aerosol therapy for acute PCP a.
Montgomery and Assoc. (1987) i.
15 patients received aerosol pentamidine qd for 21 days ii.
13 out of 15 patients responded to the therapy b.
Conte and colleagues (1990) i.
Compared aerosol to IV pentamidine in 45 patients with mild to moderate first episodes of PCP ii.
IV shown to be more effective in treating
PCP
II.
Ribavirin a.
Brand Name: Virazole b.
FDA approval for clinical use in 1986 c.
Indications (American Academy of Pediatrics) i.
Patients hospitalized with RSV lower respiratory tract infection at high risk for severe/complicated RSV infection secondary to other conditions, such as the following:
1.
complicated congenital heart disease
2.
bronchopulmonary dysplasia, cystic fibrosis, or other chronic lung condition
3.
premature infants
4.
immunodeficiency
5.
recent transplant recipients
6.
those on chemotherapy for malignancy
7.
infants who are severely ill (PaO2 < 65 torr, increasing
PaCO2)
8.
patients on mechanical ventilation for RSV injection ii.
Hospitalized infants at increased risk of progressing from mild to complicated course because of younger age (,6 weeks) or underlying condition (multiple congenital anomalies, certain neurological or metabolic diseases) d.
Mode of Action i.
Not completely understood ii.
Probably based on its structural resemblance to the nucleosides used to construct the DNA chain iii.
Prevents construction and shedding of viable viral particles e.
Preparation i.
Supplied as 6 g of powder in a 100 mL vial

ii.
The powder is reconstituted first in the vial with 100 mL of sterile water then diluted to a total volume of 300 mL with sterile water in the nebulizer f.
Dosage i.
Ribavirin is given in a 20 mg/mL (2%) solution g.
Administration i.
Administered by small particle aerosol generator (SPAG) ii.
SPAG may be used with:
1.
tent
2.
hood
3.
mechanical ventilator iii.
12 to 18 hours per day for 3 to 7 days h.
Side Effects i.
Most common
1.
deterioration of pulmonary function
2.
skin irritation
3.
equipment malfunction from drug precipitate i.
Environmental Contamination with Aerosolized Ribavirin i.
Potential for mutagenic and carcinogenic effects ii.
Teratogenic and embriocidal iii.
Exposure to Ribavirin in Healthcare workers
1.
Effects reported by healthcare workers a.
precipitation on contact lenses b.
conjunctivitis c.
headache d.
rhinitis e.
nausea f.
rash g.
dizziness h.
pharyngitis i.
lacrimation j.
bronchospasm or chest pain in individuals with reactive airways disease
2.
Effects resolve themselves within hours after discontinuing exposure to the drug

j.
Environmental Precautions i.
Pregnant females, or those wishing to become pregnant, should avoid exposure ii.
Environmental containment
1.
scavenger a.
double tent enclosure b.
vacuum extraction and filtering of excess aerosol iii.
administer aerosol in a well ventilated area, with 6 air changes per hour k.
Nature of Viral Infection i.
Virus
1.
definition a.
an obligate intracellular parasite, containing either
RNA or DNA, that reproduces by synthesis of subunits within the host cell and that causes disease as a consequence of this replication
2.
Structure a.
Submicronic in size b.
Consists of a strand of RNA or DNA, surrounded by a protein coat c.
May or may not be surrounded by and envelope ii.
Sequence of viral infection
1.
Virus enters the body through a variety of routes a.
oral b.
inhaled c.
mucous membranes
2.
Virus invades the host cell a.
Multi-step process consisting of phases i.
Virus adsorbs to the cell ii.
Penetrates the cell iii.
Uncoats itself iv.
Recodes cell DNA v.
Assembles itself
3.
Virus sheds from the cell a.
Host cell usually dies in the process iii.
Diagnosis
1.
based on clinical signs a.
symptoms b.
age of patient c.
time of year
2.
definitive diagnosis a.
culture of virus b.
antibody titer iv.
Antiviral drug treatment is difficult

1.
attacking the intracellular virus may harm the host cell
2.
viral replication is maximal before the appearance of symptoms
3.
viruses have the property of antigenic mutability a.
they change their appearance to the immune system l.
Respiratory Syncytial Virus Infection i.
Causes bronchiolitis and pneumonia ii.
Almost all children are exposed by 2 years of age
1.
most have mild infection (cold) iii.
Outbreaks of RSV are seasonal
1.
peak during winter months (November to March) iv.
virus spreads easily by personal contact or hand contamination from surfaces v.
Prevention of serious RSV infection in high-risk infants
1.
Respiratory Syncytial Virus Immune Globulin
Intravenous (RSV-IGIV) a.
Trade name: Respigam b.
Monthly IV infusion during RSV season c.
Provides passive immunity
2.
Palivizumab a.
Trade name: Synagis b.
Monoclonal antibody c.
Monthly IM injection during RSV season
III.
Aerosolized Tobramycin a.
Historical Background on Use of Aerosol Antibiotics i.
Rationale
1.
to deliver the drug directly to the target organ (lung) with less systemic toxicity ii.
Antibiotics tried as inhaled aerosols
1.
neomycin
2.
methicillin
3.
gentamicin
4.
tobramycin
5.
amikacin
6.
colistin
7.
ceftazidime
8.
amphotericin iii.
Reasons why antiinfective therapy has not been previously accepted for general clinical use
1.
acute bacterial infections in the respiratory tract usually have a systemic component, which necessitates systemic drug therapy

2.
respiratory infections, especially with consolidation or cavitation, are thought to have poor regional ventilation, which would prevent aerosol delivery to the affected lung areas
3.
lack of scientific dose-response data b.
Brand Name: TOBI c.
Only aerosolized agent approved by the FDA for clinical use (1997) d.
Indications i.
Treat or prevent early colonization with Pseudomonas aeruginosa in individuals with cystic fibrosis ii.
Maintain present lung function or reduce the rate of deterioration in cystic fibrosis e.
Mode of Action i.
Bactericidal against gram negative organisms
1.
blocks protein synthesis in the bacteria and causes cellular death f.
Preparation i.
Available as a solution with 300 mg active ingredient in a 5 mL ampule g.
Dosage i.
Adults and children ≥ 6 years of age, 300 mg bid, 28 days on,
28 days off the drug h.
Administration i.
Small volume nebulizer
1.
PARI LC Plus ii.
Can not be mixed with other solutions in nebulizer iii.
Should be inhaled after other treatment usual in cystic fibrosis are completed
1.
inhaled medications a.
ß-adrenergic agents b.
dornase alpha (Pulmozyme)
2.
chest physiotherapy i.
Storage i.
Refrigerate
1.
may store at room temperature for up to 28 days a.
solution may darken if not refrigerated i.
does not alter drug activity ii.
protect from intense light
1.
packaged in foil pouch j.
Side Effects i.
Parenteral administration
1.
ototoxicity a.
loss of hearing

b.
vertigo c.
nausea
2.
nephrotoxicity
3.
neuromuscular blockade a.
worsening of neuromuscular disorders
4.
hypomagnesemia
5.
allergic reactions
6.
fetal harm a.
deafness ii.
Aerosol administration
1.
voice alteration
2.
tinnitus
3.
non-significant decrease in susceptibility of P. aeruginosa to tobramycin k.
Advantages of Inhaled vs. Systemic Tobramycin i.
Reduced cost potential ii.
Ease of use at home iii.
More suitable for prolonged administration
1.
minimal risk of drug resistance l.
Clinical Efficacy i.
Demonstrated by Ramsey and colleagues (521 patients)
1.
improved pulmonary function
2.
decreased density of P. aeruginosa in expectorated sputum
3.
reduced need for IV antibiotics and hospitalization for P. aeruginosa infection
4.
no significant development of bacterial resistance m.
General Considerations in Aerosolizing Antibiotics i.
Some antibiotic solutions are more viscous
1.
compressors must be suitably powerful
2.
flow rates may need to be higher (10-12 L/min) ii.
Healthcare worker exposure should be minimized
1.
one-way valves
2.
expiratory filters
3.
thumb control for gas flow iii.
Agents may cause bronchial irritation
1.
pretreat with bronchodilator iv.
Drug incompatibility
1.
antibiotic agents should not be mixed with other solutions v.
specific orders must be written for those agents not approved for aerosolization
IV.
Inhaled Zanamivir a.
Brand Name: Relenza

b.
FDA approved for general clinical use in 1999 c.
Indication i.
Treatment of uncomplicated influenza illness in adults, during the early onset (within the first 2 days) of infection d.
Administration i.
DPI (Diskhaler)
1.
Four 5 mg blisters in a Rotadisk
2.
The drug package contains five Rotadisks with one
Diskhaler device e.
Dosage i.
Adults and children ≥ 12 years of age, 10 mg (2 inhalations) bid for 5 days f.
Mode of Action i.
Neuraminidase inhibitor
1.
binds with and blocks the enzyme’s action a.
inhibits virus particle separation b.
prevents virus release from infected cells g.
Adverse Effects i.
Bronchospasm ii.
Deterioration of lung function iii.
Under treatment of bacterial infection
1.
not effective against bacterial infection that may exhibit flu-like symptoms iv.
allergic reactions h.
Clinical Efficacy and Safety i.
Among patients who were febrile and began treatment ≤ 30 hours after onset of symptoms, treatment with zanamivir resulted in a shortening of 3 days in the median time to alleviation of symptoms ii.
Patients with less severe symptoms and lower temperatures had less benefit from treatment iii.
Treatment with zanamivir may carry increased risk with patients with COPD or asthma
1.
label has warning that it is not generally recommended for patients with underlying airways disease because of the risk of serious adverse effects

iv.
Zanamivir is not approved for prophylaxis to prevent influenza, nor does it reduce the risk of transmission of the virus to others i.
Cost versus Efficacy i.
Zanamivir is of no benefit in persons with infections other than influenza
1.
There is no readily available test to confirm presence of influenza resulting in possibly inappropriate use ii.
There is modest reduction in symptoms for the cost of the drug