INHALED ANTIMICROBIAL THERAPY By Nortan Hashad Under Supervision of Prof. Seham Hafez

Ability to provide a greater concentration of antibiotics directly into the target organ, the lung, avoiding systemic complications with a noninvasive method. 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 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). Produce respirable particles & targeting lower airways Nature of disease process The delivery system The antimicrobial agent

Schematic outlining the factors that prevent extrapolation of lung dose from the nominal dose placed in the delivery system.

Nominal dose Remained in device (Dead volume & impaction)Aerosolized Inhaled Vented to external environment ExhaledDeposited Pulmonary depositionExtrapulmonary deposition Bronchial deposition Excretion Systemic exposure Alveolar deposition

Indications for aerosolized anti-microbial Viral infections Fungal infections Bacterial infections

I. Bacterial infection

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. Tobramycin sulfate

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

PARI LC PLUS

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). Pentamidine isothionate

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 2-week or 4-week intervals.

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. Colomycin (colistimethate sodium)

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. Colomycin (colistimethate sodium)

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. II. Fungal infections

III. Viral infection 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). Ribavirin

Dose: A concentration of 20 mg/mL (6 g reconstituted with 300 mL of sterile water without preservatives) administered for hours/day for 3 days, up to 7 days in length using Viratek®. Suspected to be teratogenic so never to be given to lactating or pregnant females also health care workers should be protected from exposure. Ribavirin

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. Viratek®

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.