Aerosolized Antiinfective Agents

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					                    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
           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
         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
                      i. Not teratogenic
                            1. does not interfere with prenatal
                     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
       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
       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
                        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
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
                   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
                    3. viruses have the property of antigenic mutability
                           a. they change their appearance to the immune
       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
                   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
            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

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