Introduction of aerosolized pentamidine

Both systemic administration and aerosol administration of pentamidine have been used for the treatment of Pneumocystis pneumonia (PCP), which occurs as a common opportunistic respiratory infection in patients with AIDS. In addition to the prophylactic use of aerosolized pentamidine, the aerosol form has been used for the treatment of acute episodes. The first report by Montgomery and associates¹ was for therapy of acute episodes of PCP.

Rationale for aerosol administration

The rationale for aerosol administration of pentamidine to treat or prevent PCP is based on the same rationale for other inhaled aerosol drugs used to treat the pulmonary system: local targeted lung delivery, with fewer or less severe side effects compared with systemic administration. Aerosolized pentamidine produces significantly higher lung concentrations than intravenous administration.² The San Francisco prophylaxis trial showed that 300 mg of aerosolized pentamidine every 4 weeks was effective in preventing PCP in patients with HIV infection.³ Subsequent clinical experience with aerosolized pentamidine did not show improved clinical efficacy compared with oral drugs such as trimethoprim-sulfamethoxazole (TMP-SMX; Septra and Bactrim), and toxic side effects still occurred.

Description of pneumocystis pneumonia

The organism P. carinii was first noted in the lungs of guinea pigs by Chagas in 1909 and Carini in 1910. It was named as a new organism by Delanöe and Delanöe in 1912 as Pneumocystis carinii, to describe the cystic form in the lungs and its earlier discoverer. Mammals are commonly infected with the organism at an early age, probably through an airborne vector. Disease occurs when there is suppression of the immune system. When not contained by a competent immune system, P. carinii causes PCP. Before the AIDS pandemic, PCP was reported in malnourished infants in the 1940s and 1950s and in the 1970s in premature infants able to survive.⁴ PCP produces a foamy intraalveolar exudate that contains cysts of P. carinii. The life cycle of P. carinii and the resulting pneumonia are illustrated in Figure 13-2. Both pentamidine and TMP-SMX are effective against PCP and are usually given parenterally to treat an acute episode.

Conflicting names for P. carinii may be found in scientific reading. Stringer and associates⁵ described the name change to Pneumocystis jiroveci in honor of Otto Jírovec, a Czech parasitologist. However, in a letter to the editor, Hughes⁶ pointed out that the name change is not valid or final because it has not been registered in the International Code of Botanical Nomenclature. Hughes⁶ also pointed out that the name change would cause confusion with discussion of P. carinii because many clinicians still use this terminology. In a letter, Gigliotti⁷ continued the stance taken by Hughes that no clear evidence exists that an official name change has occurred.

What is known is that P. carinii or P. jiroveci is a fungus. The acronym PCP for Pneumocystis pneumonia remains the same.⁵

Dosage and administration

Details of dose and administration of NebuPent, the aerosolized brand name of pentamidine, can be found in the manufacturer’s literature. The following summary is not intended to replace the more detailed instructions that accompany the drug.

Administration.

Approval of aerosolized pentamidine by the U.S. Food and Drug Administration (FDA) was for administration with the Respirgard II nebulizer (Vital Signs, Inc, Totowa, N.J.). This is a small volume nebulizer (SVN) system, powered by compressed gas, fitted with a series of one-way valves and an expiratory filter (Figure 13-3). This nebulizer system has been described by Montgomery and associates.² The Respirgard II nebulizer should be powered with a flow rate of 5 to 7 L/min from a 50-psi source or, alternatively, by controlling the flow with a 22- to 25-psi pressure source connected to the small-bore tubing of the nebulizer. Pressures below 20 psi are insufficient to produce the desired particle size necessary for peripheral delivery of the drug. These requirements with Respirgard II are found in the manufacturer’s literature and discussed further by Corkery and colleagues.⁸ It may also be noted that Pentamidine may also be administered in a room or tent that acts as a “vacuum” to draw any particles that have escaped to a filter. Capturing of these particles results in less exposure to the respiratory therapist.

Nebulizer performance.

Although nebulized pentamidine was approved for general clinical use with the Respirgard II nebulizer system, other nebulizers have been used to administer the drug. At present, the manufacturer recommends use with a Respirgard II nebulizer system.

The general requirement for effective nebulization of pentamidine is a particle size or distribution of sizes with a mass median diameter (MMD) of 1 to 2 μm. This particle size is needed for the following two reasons:⁵

1. To achieve peripheral intraalveolar deposition targeted at the location of the microorganism

2. To reduce or prevent airway irritation seen with larger particle sizes, which deposit more in larger airways

Studies by Vinciguerra and Smaldone⁹ and by Smaldone and associates¹⁰ have examined nebulizer performance and compared treatment time and patient tolerance of aerosolized pentamidine with Respirgard II versus other nebulizers. Treatment times and efficiency in drug availability were greater with the AeroTech II (CIS-US, Bedford, Mass.) than the approved Respirgard II.

Mode of action

The exact mode of action of pentamidine is unknown. The toxic effect of the drug on P. carinii may be due to multiple actions. Pentamidine blocks RNA and DNA synthesis, inhibits oxidative phosphorylation, and interferes with folate transformation.^4,11,12 Resistance to pentamidine by P. carinii has not been shown, and this may be due to the multiple effects of the drug on the metabolism of the organism.¹¹

When given by inhaled aerosol, pentamidine reaches significantly higher concentrations in the lung than when given intravenously.² The inhaled drug first binds to lung tissue. Although plasma levels are much less than with parenteral administration, the drug is slowly absorbed into the circulation and distributed to body tissues, as with parenteral administration. As a result, prolonged aerosol administration can result in systemic accumulation. Approximately 75% of the drug is excreted in urine and 25% in feces over the months after administration.

Side effects

The side effects seen with systemic therapy of PCP using either pentamidine or TMP-SMX provided part of the rationale for aerosol administration of pentamidine. Although both of these drugs are effective in most patients with PCP when given systemically, more than 50% of patients experience adverse side effects.

Environmental contamination by nebulized pentamidine

The following concerns exist regarding environmental contamination from nebulized pentamidine:

Pentamidine is not known to be teratogenic, based on its use in pregnant women with African sleeping sickness (trypanosomiasis), although detailed clinical data were not kept. The drug is not mutagenic, and its carcinogenic potential is considered minimal.¹¹ Studies have shown that low levels of pentamidine can be detected in health care workers exposed to the drug during treatments.^19,20 The investigators concluded that exposure probably occurred during treatment interruptions, usually caused by coughing episodes. Health care workers have also complained of conjunctivitis and bronchospasm when aerosolizing the drug.¹¹ On the basis of these reports and the long tissue half-life of pentamidine, contact with the drug should be kept to a minimum or prevented if possible.

The risk of contracting TB when treating AIDS patients with nebulized pentamidine is based on the association of TB and AIDS, the airborne mode of transmission of TB, and the fact that pentamidine aerosol can cause coughing and expulsion of droplet nuclei containing TB bacilli during aerosol treatments.

Aerosol therapy for prophylaxis of pneumocystis pneumonia: clinical application

Comparisons of the efficacy of aerosolized pentamidine with oral TMP-SMX, together with reports of serious adverse effects with aerosolized pentamidine, lead to a reevaluation of aerosol therapy with pentamidine for prophylaxis of PCP. General recommendations for prophylaxis of PCP have been published by the U.S. Centers for Disease Control and Prevention (CDC) in MMWR Recommendations and Reports for HIV-positive children²⁶ and for adults.²⁷ In the 2009 CDC recommendations, oral TMP-SMX was preferred for prophylaxis of PCP as long as adverse side effects from TMP-SMX were absent or acceptable.²⁷ Aerosolized pentamidine is recommended as an alternative therapy for prophylaxis of PCP if TMP-SMX cannot be tolerated.

Clinical use

Infection with RSV in children results in either bronchiolitis or pneumonia. Guidelines concerning the use of ribavirin were published by the Committee on Infectious Diseases of the American Academy of Pediatrics in 2009. Generally, the drug is not recommended for routine RSV infection, but it may be considered for life-threatening infections.³¹ The Agency for Healthcare Research and Quality (AHRQ) has designated ribavirin as “possibly ineffective.”³²

Ribavirin treatment by aerosol is expensive and risks environmental exposure to the drug by personnel. Studies have given conflicting results on whether the use of ribavirin significantly reduces outcomes such as ventilator days, oxygen needs, intensive care unit days, hospital days, or mortality.^33,34

Nature of viral infection

A summary of viruses and viral infection is presented to establish key principles and concepts needed for understanding the difficulties in treating viral diseases and the mode of action of ribavirin. A virus can be defined as an obligate intracellular parasite, containing either DNA or RNA, that reproduces by synthesis of subunits within the host cell and causes disease as a consequence of this replication.

Figure 13-4 illustrates the simple structure of a virus. These are primitive members of the animal kingdom, submicronic in size, that consist of a strand of DNA or RNA that is surrounded by a protein coat. A virus may or may not be surrounded by an envelope, whose glycoprotein spikes are partially obtained from the host cell.

The concept and sequence of a viral infection are shown in Figure 13-5. A virus enters the body through various routes (oral, inhaled, mucous membranes) and invades a host cell. This is a multistep process consisting of phases in which the virus adsorbs to the cell; penetrates the cell; uncoats itself; goes through a process of recoding cell DNA (transcription, translation, synthesis); assembles itself; and sheds from the cell. The host cell usually dies in the process. Clinically, signs of a viral infection do not occur until after the initial latent period, when the virus leaves the cell (see Figure 13-5). At this point, infection is well established. The diagnosis of viral illness is usually based on clinical signs, including the symptoms, age of the patient, and time of year. Definitive diagnosis requires isolating the virus or showing an antibody titer increase. Diseases produced by viruses include chickenpox, smallpox, fever blisters (herpes simplex virus), genital herpes, poliomyelitis, the common cold, AIDS, influenza, mumps, and measles.

Because of the nature of viral infection, as just outlined, antiviral drug treatment, whether for the common cold or for HIV infection, is difficult. In particular, there are three complications in treating viral disease with drugs, as follows:

Dosage and administration

Following is a summary of ribavirin dosage and administration. It is not intended to replace detailed instructions contained in the manufacturer’s literature, which should be reviewed before administering this drug. This includes the operating manual for the small particle aerosol generator (SPAG) nebulizing system.