Pentamidine can cause bronchospasm and airway irritation in humans . This appears to be caused by the pentamidine moiety itself, because similar irritation is seen in nonisethionate salts of pentamidine. Because P. carinii habitats the alveolus and because of the potential adverse effects of pentamidine on the airways, pentamidine ideally should be aerosolized in a small particle, between 1 and 2 mm. Studies that make in vitro comparisons of nebulizers cannot be valid unless the particle sizes are identical. The present state of knowledge cannot allow determination of the most effective device because not all the devices have been comparatively tested in humans [10,11]. The optimal particle size for alveolar deposition is between 1 and 3 mm, with 1 mm achieving more peripheral distribution and less airway distribution [12-14]. However, 19% of particles as small as 2 mm still impact in the tracheobronchial regions. The ideal device should have a particle size of 1 -2 mm with a high output. Particles between 0.5 and 1 mm have relatively less alveolar deposition than particles between 1 and 2 mm. Other features, such as reservoirs, flows, and external filters, may also be important . However, any nebulizer with particle sizes, on average, greater than 8 mm would not deliver adequate drug to the alveoli.
Commercially available nebulizers that might be used in the United States to aerosolize pentamidine are of two types: ultrasonic and jet. Included in the ultrasonic class are the Microinhaler (Siemens), FisoNeb (Fisons, New Bedford, MA), Pulmosonic (DeVilbiss, Somerset, PA), Portosonic (DeVilbiss). Included among the jet nebulizers are Respirgard II (Marquest Medical Products, Englewood CO), Aerotech II (Cadema, Middletown, NY), and Centimist (Marquest).
The Microinhaler has been largely abandoned because of the large particle size of nearly 20 mm and is now unavailable to the United States .
The FisoNeb and Pulmosonic nebulizers both operate at a frequency of 1.3 MHz that generates a mass median aerodynamic diameter (MMDA) of 4-6 mm [9,10]. The Pulmosonic nebulizer has been reported not to deliver many particles smaller than 2 mm and, therefore, is unsuitable for pentamidine administration . The Portosonic (DeVilbiss) device is a 2.3-MHz ultrasonic nebulizer and may offer the combination of less than 2-mm MMAD and a high output. In any study using ultrasonic nebulizers, the output and particle size of each device need to be periodically sampled, because the frequency of the piezoelectric crystal may alter with age . Any MMADs between 0.5 and 2 mm are available. The Respirgard nebulizer II has one-way valves that control a drug reservoir, allow entrainment of room air in patients whose minute ventilation is high, act as a baffle to decrease particle size, and direct expired air to a filter that scavenges remaining drug and prevents environmental contamination. The Centimi nebulizer is a similar device, with a larger reservoir and no expiration filter. The Aerotech II nebulizer has internal baffles in the jet nebulizer and, therefore, may allow recycling of the drug; however, it has a higher flowrate and lacks a reservoir, so much of the drug may not be available for inhalation in patients with normal minute ventilation. Nevertheless, in a direct comparison between the Respirgard II and the Aerotech II nebulizers, the latter delivered 2.5-5 times more drug [15,16]. The increased concentration of pentamidine may actually exceed the tolerance of patients; anecdotal reports of severe coughing with pentamidine doses greater than 100 mg led a 40-mg dose to be used in now-abandoned prophylaxis studies. This dose would probably not be as effective as a 300-mg dose delivered with the Respirgard II device, but it would be less expensive.
Despite their availability, neither dry powder nor metered-dose inhalers have been used to deliver aerosolized pentamidine. The use of metered-dose inhalers may be problematic because these devices are better suited for frequent delivery of small doses rather than intermittent delivery of the large doses that have been therapeutically successful in prophylaxis of PCP. Dry powder devices may produce an increased incidence of cough due to airway deposition.
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