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.

Administration.

Clinical trials of ribavirin aerosol were carried out with a large volume nebulizing system, the SPAG. The drug was approved for general use with this aerosol generator. A diagram of the SPAG unit is shown in Figure 13-6. It is a large volume, pneumatically powered nebulizer operating on a jet shearing principle, with baffling of aerosol particles and a drying chamber to reduce particle size further to a level of approximately 1.3 μm, MMD. Solutions in the SPAG reservoir should be replaced after 24 hours. Residual solution in the reservoir should be discarded before adding newly reconstituted solution. The drug solution should always be visually inspected for particulate matter or discoloration before use.

The nebulizer is connected to a hood as the patient interface. The manufacturer specifically warns against administration of the drug to infants requiring mechanical ventilation because of the risk of drug precipitation occluding expiratory valves and sensors or the endotracheal tube. The sickest infants with RSV are likely to need ventilatory support, however, and there are reports of drug use with mechanical ventilation. Demers and colleagues³⁵ provided detailed information concerning precautions with ventilator use during administration of the drug. A clinical study of aerosol administration with mechanical ventilation of infants with severe RSV infection was reported by Smith and associates³³; these authors showed that treatment reduced duration of ventilation, oxygen support, and hospital stay. Although labor-intensive, mechanical ventilatory administration of ribavirin actually simplifies environmental control.

Mode of action

The mechanism of action by which ribavirin exerts its virostatic effect is not completely understood. Viral inhibition is probably based on its structural resemblance to the nucleosides used to construct the DNA chain.²⁸ Figure 13-7 shows the structures of the natural nucleoside guanosine with ribavirin, which is a synthetic nucleoside analogue. During the formation and assembly of new viral protein within the cell, ribavirin is most likely taken up instead of the natural nucleoside to form the DNA chain; this prevents construction of viable viral particles and subsequent shedding of virus into the bloodstream. Figure 13-8 is a conceptual illustration of the process. Ribavirin does not prevent the attachment or the penetration of RSV into the cell and does not induce interferon.²⁸

When given by inhaled aerosol, ribavirin levels are much greater in respiratory secretions than in the bloodstream. Waskin¹¹ provided a referenced summary of ribavirin kinetics. With 8 to 20 hours of aerosol treatment, peak plasma levels are 1 to 3 μg/mL, and respiratory secretion levels are greater than 1000 μg/mL. The minimal inhibitory concentration (MIC) for RSV is 4 to 16 μg/mL. The half-life of ribavirin is about 9 hours in plasma and about 1 to 2 hours in respiratory secretions, which is the rationale for almost continuous administration by aerosol.

Side effects

Side effects seen with aerosolized ribavirin are listed in the product literature and have been reviewed by Waskin.¹¹ The following list summarizes adverse effects reported, including those seen with adults receiving the drug:

Although all of the above-listed effects have been reported, common effects clinically are pulmonary function deterioration, equipment malfunction from drug precipitate, and skin irritation from excess drug precipitation.

Environmental contamination with aerosolized ribavirin

There is concern among health care workers over exposure to ribavirin. The drug has potential for mutagenic and carcinogenic effects based on in vitro and animal studies.¹¹ The effect on fertility is uncertain, but the drug has caused testicular lesions in rats. The effect on pregnancy is of particular concern because the drug is teratogenic or embryocidal in animal species. Acute effects from aerosolized ribavirin reported by health care workers have included precipitation on contact lens and conjunctivitis, headache (51%), rhinitis, nausea, rash, dizziness, pharyngitis, and lacrimation (10% to 20%). Several cases of bronchospasm or chest pain have been reported by individuals with reactive airways disease. The symptoms noted have resolved within hours after discontinuing exposure to the drug.³⁶

Minimal levels of ribavirin exposure are difficult to specify because of the lack of dose-response data for humans.³⁷ Corkery and others³⁸ stated that the California Department of Health Services recommended an acceptable occupational airborne concentration for 8 hours of limited exposure to be 1/1000 of the lowest no-observed-effect level, which would be 2.5 μg/m³.

Although there are no reports to date of serious effects from drug exposure by aerosol, precautions to limit or avoid exposure to the drug are well indicated, as advocated by Kacmarek.³⁹ Pregnant females, or those wishing to become pregnant should avoid exposure to the drug if possible. In addition, environmental containment is superior to personnel barrier protection alone. Standard surgical masks do not prevent inhalation of 1- to 2-μm particles. Dermal absorption of ribavirin seems to be negligible.⁴⁰ It may be helpful to use a containment system when the drug is aerosolized to an oxygen hood; several systems have been proposed in the literature.^41–43 All have common features of enclosure around the hood, with vacuum extraction and filtering of gas from the enclosure. Details needed for use can be found in the references given. It is recommended that the drug be administered in well-ventilated areas—that is, six or more air changes per hour.

Clinical use

Palivizumab is indicated for the prevention of serious lower respiratory tract disease caused by RSV in children and infants at high risk. Safety and efficacy were established for infants with BPD, infants born prematurely (less than 35 weeks), and children with congenital heart disease.⁴⁵

Dosage and administration

The powder for injection is lyophilized, and the drug is available at 50 mg/mL or 100 mg/mL. A premixed injection of 100 mg/mL is also available. The recommended dose is 15 mg/kg given intramuscularly once a month before the start of and throughout the RSV season.

Mode of action

Palivizumab is a humanized monoclonal antibody produced by recombinant DNA techniques, directed against the F protein of RSV. As an antibody against RSV, palivizumab provides neutralizing and fusion-inhibiting activity, preventing viral replication.

Adverse reactions

The most serious adverse reaction is anaphylaxis; however, this occurs in less than 1 per 100,000 cases. Other reactions that occurred in treatment and placebo groups included fever, upper respiratory infection, otitis media, rhinitis, rash, pain, hernia, and coughing and wheezing.³⁶

Clinical efficacy

In a large multicenter trial of infants at high risk of RSV infection, palivizumab given intravenously at 15 mg/kg reduced the rate of hospitalization resulting from RSV infection to 4.8% compared with 10.6% in placebo recipients.⁴⁶ Adverse events were similar in placebo and treatment groups.

Feltes and colleagues⁴⁷ found that palivizumab is safe and effective for RSV-positive children with congenital heart disease. In this study, 53% of the children had reduced hospital stays, and 73% had fewer days of supplemental oxygen use.

Clinical use

One disease state in which aerosolized antibiotics have been used more consistently for pulmonary infections is CF. Patients with CF are chronically infected with gram-negative organisms, such as P. aeruginosa, and the gram-positive bacterium Staphylococcus aureus as well as other microorgisms. In particular, chronic Pseudomonas infection leads to recurring acute respiratory infections. With the exception of the quinolone derivatives such as ciprofloxacin, antibiotics that are effective against Pseudomonas do not give sufficient lung levels to inhibit bacteria when taken orally. Antibiotics with poor oral bioavailability for lung tissue include aminoglycosides, penicillin derivatives, and cephalosporins. Consequently, either the intravenous or the inhaled aerosol route must be used.

Baran and colleagues⁴⁸ administered 40 mg of gentamicin by aerosol to eight children with CF and found high levels of drug (more than 20 μg/mL) in the bronchial secretions of seven of the children. Blood levels with the inhaled drug were low, supporting the case for minimal systemic toxicity by aerosol. Similar results with nebulized tobramycin (300 mg) were reported by Le Conte and associates.⁴⁹ By contrast, intramuscular injection of 1.5 mg/kg gave low levels of less than 2 μg/mL in bronchial secretions and, in some cases, undetectable levels.⁴⁸

Aerosol administration is attractive because of reduced cost potential and ease of use at home compared with intravenous therapy. Furthermore, fluoroquinolones such as ciprofloxacin and norfloxacin, which are active when taken orally, are not as suitable for prolonged maintenance or preventive therapy as the agents given by inhalation because of the risk of drug-resistant strains of bacteria.⁵⁰ A report of the clinical trial establishing the safety and efficacy of inhaled tobramycin (TOBI) in managing P. aeruginosa in patients with CF was published by Ramsey and colleagues.⁵¹ TOBI is used to manage chronic infection with P. aeruginosa in CF, as follows:

Efficacy with Burkholderia cepacia has not been shown using the inhaled route of administration.

Dosage and administration

TOBI is recommended for children 6 years of age or older. The usual dosage is 300 mg twice daily approximately 12 hours apart and not less than 6 hours apart for 28 days consecutively, with the following 28 days off of the drug. This cycle is repeated on a maintenance basis. The drug is formulated as a nebulizer solution with 300 mg in a 5-mL ampoule. In clinical trials, it was administered with the PARI LC Plus, with a DeVilbiss Pulmo-Aide compressor (DeVilbiss Healthcare, Somerset, Pa.). Other nebulizer delivery systems must be tested to ensure adequate drug output and particle size.

Patients should be instructed not to mix dornase alfa or any other drug with tobramycin in the nebulizer. Tobramycin should be inhaled after other therapies usually administered in CF, such as chest physiotherapy measures and other inhaled medications including bronchodilators or dornase alfa.

The drug should be stored at refrigerated temperatures of 2° C to 8° C (36° F to 46° F). After removal from refrigeration or if refrigeration is unavailable, the pouches in which the drug is provided can be stored at room temperature less than 25° C for up to 28 days. Drug ampoules should not be exposed to intense light. The solution may darken with aging if not refrigerated, although this does not change the drug activity if the manufacturer’s guidelines are followed.

Mode of action

Tobramycin is a member of the aminoglycoside family of antibiotics, so named because of their structure, which consists of amino sugars with glycosidic linkages. These antibiotics are effective in treating gram-negative infections and have a bactericidal effect. Tobramycin binds irreversibly to the 30S subunit of bacterial ribosomes. This binding blocks protein synthesis in the bacteria and causes cellular death. Serum tobramycin levels are approximately 1 μg/mL 1 hour after inhalation in patients with normal renal function.

Side effects

Side effects for parenteral and inhaled administration of tobramycin are listed in Box 13-1. Adverse effects with nebulized delivery are based on the clinical trial of Ramsey and colleagues⁵¹ and on 2 years of experience after the approval of inhaled tobramycin.

Precautions in use of nebulized tobramycin

Clinical efficacy

Clinical efficacy of inhaled tobramycin by nebulization was shown in the randomized controlled study by Ramsey and colleagues.⁵¹ In that study, which compared inhaled tobramycin with placebo in 521 patients with CF, 6 months of alternating inhaled tobramycin together with standard therapy for CF resulted in the following:

• Improved pulmonary function (Figure 13-9)

• Decreased density of P. aeruginosa in expectorated sputum

• Reduced need for intravenous antipseudomonal antibiotics and hospitalizations

• No development of significant bacterial resistance

Other studies, such as that by Gibson and colleagues,⁵⁷ have produced similar results indicating that inhaled tobramycin is safe and effective in treating P. aeruginosa in patients with CF.

Because inhaled tobramycin is effective in patients with CF, is it effective in other patients with P. aeruginosa infection? LoBue⁵⁸ reported that studies to date have been small or that the drug has not been used long-term. Inhaled tobramycin cannot be recommended for treatment other than for CF patients with P. aeruginosa infection.

Clinical use

Aztreonam was approved in December 1986 by the FDA as a monobactam, a synthetic bactericidal antibiotic; it is given as an intravenous solution. Inhaled aztreonam (Cayston) was approved in February 2010 to improve pulmonary symptoms in CF patients colonized with P. aeruginosa. Cayston is not indicated for patients younger than 7-years-old, or those with B. cepacia. It has been studied only in patients with a forced expiratory volume in 1 second (FEV₁) greater than 25% or less than 75% of predicted.

Dosage and administration

Cayston is supplied in a form that must be reconstituted. In a 28-day kit, each 2-mL single-use glass vial contains 75 mg of lyophilized aztreonam and must be mixed with the provided 1 mL of sterile diluent (0.17% sodium chloride). The reconstituted agent is delivered by itself using the Altera Nebulizer System (PARI Respiratory Equipment, Midloathian, Va.).

Each patient should be pretreated with a bronchodilator before each dosing. Cayston is given three times a day for 28 days on and 28 days off. The kit should be refrigerated; however, when the kit is ready to use, it can be stored at room temperature for 28 days.

Mode of action

Aztreonam displays in vitro activity against gram-negative aerobic bacteria. It binds to penicillin-binding proteins of pathogens such as P. aeruginosa, inhibiting bacterial cell wall synthesis and ultimately death of the cell.

Precautions in use of nebulized aztreonam

As mentioned earlier, Cayston can cause bronchospasm and decrease a patient’s FEV₁. All patients should be screened for baseline pulmonary function results and be treated with a bronchodilator before administering Cayston.

It has been reported that Patients have experienced severe allergic reactions with injectable aztreonam. Careful observation is warranted when first using Cayston because it could cause an allergic reaction. If any signs occur during the delivery of Cayston, the treatment should be stopped immediately and the health care team should be informed.

The use of antibiotics in the absence of infection may lead to the development of drug-resistant bacteria. Cayston should not be used in CF patients not infected with P. aeruginosa.

General considerations in aerosolizing antibiotics

Several points should be noted when nebulizing antibiotic drugs, especially if an injectable formulation is used, although this is not recommended for routine clinical use.

Clinical use

Zanamivir (Relenza) is an antiviral agent approved for use in the treatment of uncomplicated influenza illness in adults and children older than 5 years of age during the early onset (within the first 2 days) of infection. The agent has an off-label use for treatment and prophylaxis of H1N1 influenza A (“swine flu”). An oral antiinfluenza agent, oseltamivir phosphate (Tamiflu) is also available as 30-mg, 45-mg, and 75-mg capsules and oral liquid, 12 mg/mL. It is indicated in the treatment and prophylaxis of influenza in patients 1 year of age and older. Tamiflu has an off-label use in H1N1 influenza A. In addition, two older drugs, amantadine and rimantadine, have been used for prophylaxis and treatment of acute symptoms of influenza. Both of these agents are resistant to H1N1 influenza A. Table 13-2 summarizes information about these four agents, only one of which (zanamivir) is available by inhalation. Prophylactic vaccination against influenza, especially in high-risk patients with cardiovascular or respiratory disease, remains the unqualified recommendation, despite the availability of drugs to treat acute infection.

Dosage and administration

Zanamivir is available in a dry powder inhaler (DPI), the Diskhaler device, for oral inhalation. Each blister contains 5 mg of drug, providing a dose of 5 mg per inhalation. There are four blisters in a Rotadisk, and the drug package contains five Rotadisks with one Diskhaler device. The dose for adults and children 5 years of age or older is two inhalations (two blisters, for a total of 10 mg) taken twice a day approximately 12 hours apart for 5 days. The complete drug package has the equivalent of 5 days of treatment because each Rotadisk contains 1 day’s dosage. Patients should finish the entire 5-day course of drug.

Mode of action

The general mechanism of viral infection was described previously with ribavirin (see discussion of the nature of viral infection). Zanamivir represents a new class of antiviral agents, termed neuraminidase inhibitors, which act by binding to the viral enzyme neuraminidase and blocking the action of the enzyme. The influenza virus has an envelope and a protein coat surrounding the viral RNA and targets the respiratory tract. Briefly, as illustrated in Figure 13-10, the virus envelope for both influenza A and influenza B has two surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA).

HA binds to a sugary molecule, sialic acid (SA), on the surface of a cell to be infected. This binding leads to fusion of virus and cell membranes and allows adsorption and penetration of the virus into the cell. However, when the newly minted viral particles bud from the cell and are ready to be released, the viral envelope acquires sialic acid from the cell, along with its own HA and NA receptors. Without NA, the viral HA would combine with the sialic acid again, “sticking” the viral particles to each other and to the cell surface, preventing further infection. NA cleaves part of the sialic acid to prevent HA and SA combination and prevents viral aggregation (clumping). NA is essential for virus release from infected cells, prevents virus aggregation, and may decrease virus inactivation by respiratory mucus. Zanamivir is able to bind to NA and block the enzyme action. By inhibiting NA, zanamivir inhibits viral particle separation and cellular release needed for systemic infection to proceed.⁶²

Zanamivir is given by inhalation because the binding ability of the drug also prevents good absorption when given orally. Inhalation also delivers the drug to the affected organ directly. Approximately 4% to 17% of an inhaled dose is absorbed systemically. Zanamivir has limited plasma protein binding (less than 10%) and is excreted unchanged in the renal system. It is apparently not metabolized to other products in vivo. Its serum half-life is 2.5 to 5.1 hours. Any unabsorbed drug is excreted in the feces.

Adverse effects

The side effects discussed in the following sections have been noted during clinical trials and after release of zanamivir.

Clinical efficacy and safety

Clinical efficacy of zanamivir has been established in trials showing that inhaled zanamivir can shorten significantly the duration of influenza symptoms.^66,69,70 With uncomplicated influenza-like illness, treatment with 10 mg of zanamivir twice daily resulted in approximately 1 day of shortening of the median time to improvement in symptoms compared with placebo.⁶⁶ The time to improvement in major symptoms was defined as no fever and no or mild headache, myalgia, cough, and sore throat. Among patients who were febrile and began treatment 30 hours or less after onset of symptoms, treatment with zanamivir resulted in a shortening of 3 days in the median time to alleviation of symptoms.⁶⁶ There are no data on efficacy when zanamivir is started after more than 2 days of symptoms of influenza.

There was no consistent difference in treatment effect between patients with influenza A versus influenza B. However, the clinical trials of zanamivir enrolled predominantly patients with influenza A (89% influenza A versus 11% influenza B in one clinical trial). Patients with lower temperature and less severe symptoms in general derived less benefit from treatment with zanamivir.

Clinical trials of zanamivir were performed mainly with previously healthy subjects.^66,69,70 The manufacturer’s literature states that safety and efficacy of zanamivir for treating influenza have not been shown in patients with COPD. Zanamivir may carry risk for patients with COPD or asthma, as indicated in the discussion of side effects. Revised labeling for zanamivir adds a warning that zanamivir is not generally recommended for patients with underlying airways disease because of the risk of serious adverse effects.⁶⁶

Zanamivir is not approved for prophylaxis to prevent influenza, and it does not reduce the risk of transmission of the virus to others. However, some data suggest a prophylactic benefit with zanamivir in influenza A and influenza B in university and nursing home communities.⁷¹ Results of a controlled study of inhaled zanamivir for treatment and prevention of influenza in families in which one member developed influenza-like illness showed that zanamivir did reduce the rate of developing influenza in other family members. The proportion of families in which an initially healthy member developed influenza was 4% with zanamivir compared with 19% with placebo.⁷² In the trial, treatment of the index cases with zanamivir in families reduced the median duration of symptoms from 7.5 to 5.0 days, a significant reduction. Oseltamivir (Tamiflu) was approved for prevention of influenza A and influenza B in children 1 year of age or older who are in close contact with influenza. Adverse reactions were similar in both groups.³⁶

The safety and efficacy of zanamivir have been tested in children. In a study by Hedrick and others,⁷³ zanamivir was tested on children 5 to 12 years old. In the study of 471 children, 224 were given zanamivir, and the remaining children, the control group, were given placebo. The children taking zanamivir had reduced influenza symptoms 1.25 days before children in the placebo group. The zanamivir group returned to normal activities in less time and took fewer relief medications than placebo.

A final issue with the use of zanamivir or other antiinfluenza agents as acute treatment is the lack of a clinically easy and inexpensive diagnostic tool to confirm the presence of influenza infection. Zanamivir is not beneficial in patients with infections other than influenza. In the clinical trial by Hayden and colleagues,⁶⁶ 262 of 417 patients (63%) with influenza-like illness had confirmed influenza virus infection. As a result, symptoms alone can result in inappropriate use of antiinfluenza drugs, with attendant risks as outlined in the discussion of adverse effects. Inappropriate use contributes to increased cost.

The cost versus efficacy of zanamivir has been debated. There is modest reduction in symptoms for the cost of the drug; there is no readily available test to confirm the presence of influenza viral infection for use of the drug, resulting in possibly inappropriate use; and the drug carries increased risk for the patients who might benefit most—patients with reactive airways disease.