SynopsisPentamidine is an aromatic diamidine derivative which has become one of the standard therapies forPneumocystis cariniipneumonia (PCP), particularly in patients with acquired immunodeficiency syndrome (AIDS). However, with parenteral administration of the drug there is a high risk of toxicity. Inhaled pentamidine produces much higher concentrations of drug on the bronchoalveolar surface with minimal systemic absorption. It has been used successfully for the treatment of PCP in AIDS patients, but its most valuable contribution has been as prophylaxis in AIDS patients at high risk of developing PCP. In prospective controlled studies there has been > 80% reduction in relapse rate with pentamidine. The reduction in relapse rate among patients who have experienced one previous episode of PCP has been 50 to 100% compared with historical control groups, over a follow-up period averaging about 6 months. Significant systemic adverse effects to inhaled pentamidine are rare. Respiratory effects associated with inhalation are common but usually controllable without treatment discontinuation. The ideal particle size for even distribution of pentamidine throughout the lung is considered to be 1 to 2&mgr;m. Jet nebulisers such as the ‘Respirgard II’ system produce a mass median aerodynamic diameter (MMAD) of particles in this range. Ultrasonic nebulisers produce larger particles. The implication from this difference is that while ultrasonic nebulisers may have poorer alveolar distribution and the incidence of local side effects (common with all formulations) may be higher, total drug delivery may be more efficient allowing effective PCP prophylaxis with lower dosages (120mgvs300mg monthly). However, there are no data available comparing the efficacies and tolerabilities of the different formulations of inhaled pentamidine. Nevertheless, inhaled pentamidine would seem poised to become routine prophylaxis in patients with AIDS or AIDS-related complex at risk of developing PCP.Antiprotozoal and Pharmacokinetic PropertiesPentamidine has been reported to have a destructive action againstP. carinii in vitro, reducing its viability to a similar extent as trimethoprim-sulfamethoxazole.After parenteral administration pentamidine becomes widely distributed and is strongly tissue bound, with highest concentrations achieved in the liver and kidney and lower levels in the lung and other tissues but not in the brain. Pentamidine is detectable in some tissues up to a year after the last dose of a course of parenteral therapy. After aerosol administration pentamidine is rarely detectable in the plasma, but bronchoalveolar concentrations are 5 to > 10 times higher than after intravenous administration.A variety of jet and ultrasonic nebulisers have been used to administer aerosolised pentamidine. Important differences between them would seem to be the mass median aerodynamic diameter of particles produced and the efficiency of total drug delivery. Smaller particles (<2&mgr;m) have a more uniform distribution throughout the lung, while greater deposition of larger particles in the large airways may be associated with bronchospasm.Therapeutic TrialsFor the treatment of mild PCP (usually first episodes) in AIDS patients the results of clinical trials with inhaled pentamidine have been encouraging, particularly with the ‘Respirgard II’ nebuliser, 300 or 600mg daily for up to 21 days; the success rate has ranged from 81% to 100%.There is considerably more evidence available to support the use of inhaled pentamidine as prophylaxis in patients at high risk of developing PCP. Many of the reported studies have included over 100 patients, with the mean follow-up time ranging from 4 to 10 months, and follow-up continuing for 18 months in some patients. Maintenance dosages of pentamidine ranged from 60 to 300mg per month delivered through a variety of aerosol formulations. The incidence of PCP recurrence during pentamidine prophylaxis was consistently low (6 to 16%). In two prospective studies which included control groups there was over 80% suppression of PCP episodes with pentamidine. A dose comparison study using the ‘Respirgard II’ nebuliser revealed significantly better prophylaxis with a dose of 300mg once monthly (6.2% recurrence) than with 30mg bimonthly (18.8%). However, using the ‘Fisoneb’ formulation or other ultrasonic nebulisers, dosages of ≤ 120mg monthly (usually 60mg every 2 weeks) provided effective prophylaxis with PCP recurrence rates in the range 5.9 to 16%.Adverse EffectsNo significant systemic effects definitely attributable to inhaled pentamidine have been reported in clinical trials, in marked contrast to the poor toxicity profile of parenterally administered pentamidine. However, there have been isolated reports of pancreatitis, maculopapular rash, hypoglycaemia and pneumothoraces. Also, there have been reports of atypical pulmonaryP. cariniiinfection and extrapulmonary pneumocystosis in patients receiving inhaled pentamidine. Cough and bronchospasm have been common during inhalation, but can usually be controlled by reducing the delivery rate or intensity of the aerosol stream and/or by pretreatment with a bronchodilator.Dosage and AdministrationVarious ultrasonic and jet (flow rate about 6 L/min) nebulisers have been used successfully for prevention of PCP in high-risk human immunodeficiency virus (HIV)-positive patients. The recommended dosage of inhaled pentamidine, employing a jet nebuliser delivering particles of small size (e.g. ‘Respirgard II’), is a single 300mg dose every 4 weeks. However, with ultrasonic nebulisers delivering larger particles successful prophylaxis has been demonstrated with a dosage of 60mg twice monthly.