A Review on the Clinical Use of Inhaled Amphotericin B

JOURNAL OF AEROSOL MEDICINE AND PULMONARY DRUG DELIVERY
Volume 22, Number 3, 2009
© Mary Ann Liebert, Inc.
Pp. 213–227
DOI: 10.1089/jamp.2008.0715
A <strong>Review</strong> on the Clinical Use of Inhaled Amphotericin B
Abstract
Laura Kuiper, Pharm.D. 1,2 and Elisabeth J. Ruijgrok, Pharm.D., Ph.D. 2
Background: Despite the systemic toxicity of amphotericin B (AMB), it still has a place in treatment or prophylactic
regimes of fungal infections.
Methods: A strategy for minimizing the potential of systemic side effects is to bring it in direct contact with the
body site most likely to be infected, such as the administration of AMB as an aerosol. Nebulized amphotericin
has been used in humans since 1959. However, due to a lack of sufficient data regarding efficacy, its use is still
not established. Little is known about the optimal dose, frequency, duration of administration, and the pharmacokinetics
of inhaled AMB in humans.
Results and Conclusions: In this review, published data regarding inhaled AMB are summarized, including
available descriptions regarding preparation, dose, efficacy, and toxicity, and its place in therapy is discussed.
The results from the studies that were reviewed in this article indicate that inhaled AMB may have a place in
the prophylactic regimens of patients with prolonged neutropenia and in lung transplant recipients. Furthermore,
nebulized (liposomal) AMB may have a place in the treatment of allergic bronchopulmonary aspergillosis
(ABPA) in patients with corticosteroid-dependent ABPA.
Key words: amphotericin B, aerosol, nebulization
Introduction
HE INCIDENCE OF FUNGAL INFECTIONS has dramatically in-
Tcreased
over the past decades. (1) For example, Candida
bloodstream infections are increasingly frequent and are often
associated with clinical evidence of sepsis syndrome and
high attributable mortality. (2,3) Other invasive infections seen
with increasing prevalence include infections with Aspergillus
species, of which Aspergillus fumigatus is the main
causative agent. (4–6) Aspergillus spp. are respiratory pathogens
and pulmonary infections are usually acquired through
inhalation of the fungus spores with subsequent colonization
of the airways. In patients with altered local or systemic
defense mechanisms, colonization may cause disease. (7) The
fungus causes a variety of disorders in the lung, ranging
from aspergilloma in patients with lung cavities, to chronicnecrotizing
aspergillosis in those who are mildly immunocompromised
or suffer from a chronic lung disease. In severely
immunocompromised patients, invasive pulmonary
aspergillosis (IPA) is a severe and commonly fatal disease.
Invasive aspergillosis occurs in 3–16% of lung transplant recipients
with a mortality of 60–80%. (8) In hematopoietic stem
cell transplant recipients the incidence of invasive aspergillosis
ranges from 5–12%. (5,6)
1 Department of Pharmacy, Ikazia Hospital Rotterdam, The Netherlands.
2 Department of Pharmacy, Maasstad Hospital, Rotterdam, The Netherlands.
213
Original Article
AMB deoxycholate (AMBd; from Bristol-Myers-Squibb,
New York) has been the most widely used and consistently
effective antifungal agent for Aspergillus infections over the
past 40 years. Because of the limitations of azole antifungal
agents regarding the spectrum of antifungal activity and tolerability,
AMB still has a place in treatment or prophylactic
regimes of fungal infections. (9–11) However, it can produce a
wide variety of acute and chronic side effects, the most important
of which is nephrotoxicity. In order to reduce the
toxicity of AMB, and thus permitting administration of
higher doses, lipid formulations of AMB have been developed.
(12) Three lipid formulations are commercially available:
AmBisome (L-AMB; from Astellas Pharma U.S, Inc.,
Japan), a true liposome structure; Abelcet (ABLC; from
Cephalon, Inc., Fraser, PA), an amphotericin B lipid complex
with a ribbon-like structure; and Amphocil/Amphotec
(ABCD from Sequus Pharmaceuticals, Menlo Park, CA), an
amphotericin B colloid dispersion, composed of disc-like
structures. Another approach to minimize the potential for
systemic side effects and to improve efficacy is to bring AMB
into direct contact with the body site most likely to be infected,
for instance by the administration of (lipid) AMB as
an aerosol. (9,10,13–17) Animal studies (in mice and rats) on the
aerosolization of AMB have been reported. (18–30) These stud-

214
ies showed that nebulized (lipid) AMB was efficacious with
regard to treatment as well as prevention of IPA. Nebulization
of AMB resulted in substantial lung tissue concentrations
and low systemic exposure. (20,21,23,28,29) Furthermore,
AMB was still detectable in lungs of rats 6 weeks after nebulization
of a single dose. (28) L-AMB was shown to nebulize
better than AMBd (20) with a longer lung retention (22) and no
negative effect on pulmonary surfactant in contrary to
AMBd. (25) In vitro research showed that deoxycholate caused
alterations in the activity of pulmonary surfactant, which
suggests that perhaps any detrimental effect on lung function
may be related to the deoxycholate component as the
causative agent rather than AMB itself. (25) In man,
aerosolized AMB has been used as early as 1959. (31) Currently
the use of aerosolized AMB has found its way into
several clinical practices such as the antifungal prophylaxis
in lung transplant recipients. However, due to a lack of sufficient
data regarding efficacy, the value of its use still has
to be determined. In order to gather the information that is
known about inhaled AMB, a literature search is performed.
In this review, the data are summarized, including available
data regarding preparation, dose, efficacy, and toxicity and
its place in therapy is discussed.
Data sources
A MEDLINE search was conducted until June 2008 using
the key terms “amphotericin and aerosol*,” “aerosol and amphotericin,”
“amphotericin and nebul*,” and “inhaled amphotericin.”
<strong>Review</strong> of the reference lists of the identified articles
was performed.
Medical devices for administration of aerosols
The wide variety of aerosol delivery systems requires a
careful choice. Although they allow direct delivery of drug
to target cells, aerosol delivery systems can be inefficient. Deposition
of inhaled aerosols depends on several factors that
may be broadly divided into subject-related characteristics
(fast or slow inhalation, disease-induced structural changes)
and device-related characteristics (fine-particle fraction, particle
size distribution, and mass of aerosol produced). (32–34)
In order to choose a system for nebulizing (lipid) AMB, criteria
such as target tissue (central airways in allergic bronchopulmonary
aspergillosis (ABPA) versus peripheral airways
in IPA) and inhalation mode (cystic fibrosis patients
with chronic inhalation technique vs. weakened hematological
patients) should therefore carefully be addressed.
For the delivery of AMB aerosol, some practical aspects
should be taken into account: what is the best method to generate
these aerosols, can currently available preparations be
nebulized and do patients tolerate the aerosol. (35) Filling a
nebulizer must be done with care, with regard to the light
sensitivity (oxidation) of reconstituted AMBd preparations.
In addition, AMBd may foam in the nebulizer, especially
when the compound is suspended by shaking. (36)
To be effective, AMB aerosols must be delivered in sufficient
doses into the central and/or peripheral regions of the
lung. Aspergillus infections reported in lung transplant recipients
were located in central lung regions in approximately
57% of cases and in peripheral lung regions 32%. (37)
Aspergillus fumigatus spores have a spore size of 3–5 �m. (4)
To reach the same regions in the lung, theoretically AMB
KUIPER AND RUIJGROK
aerosols should have an equivalent mass median aerodynamic
diameter (MMAD). (34) Dry powder inhalations with
(liposomal) AMB are being developed. (38,39) Until these are
available, the only way to administer aerosolized AMB is by
using a nebulizer.
Hypothetically, the required delivered dose should be at
least several milligrams, in order to reach adequate drug concentration
levels in the epithelial lining fluid as well as in the
lung tissue. By using conventional nebulizers only 10–20%
of the delivered dose will reach the lung (lung dose). Thus,
the aerosolizing solution has to contain at least several milligrams
of AMB to achieve adequate lung doses. Ideally, a
nebulizer should produce sufficient respirable particles in
short period of time. Beyer et al. (14) demonstrated that various
jet and ultrasonic nebulizers generate a substantial number
of AMB particles with a diameter of less than 5 �m (fine
particle fraction) from which pulmonary deposition can be
expected. Diot et al. (35) also showed that an AMB suspension
can be effectively nebulized by a variety of nebulizers and
delivered to the lungs of patients colonized with Aspergillus.
At first, three different nebulizers were tested for inhaled
mass and particle size distribution. The pulmonary disposition
of 5 mg AMB nebulized by these three nebulizers was
measured in three patients using a direct isotopic method
based on stable labeling of AMB with 99m Tc. However, Corcoran
et al. (37) showed that the estimated pulmonary doses
varied by as much as a factor of 2 when comparing different
nebulizers. Treatment time varied from 13 to 38 min. Several
other studies have shown the dependency of the aerosol
droplet size and aerosol output on the type of nebulizer
as well. (36,40)
In one study AMB in a lipid formulation was found to
nebulize better than the AMBd suspension in terms of drug
levels in chamber air and lung tissue. (20) The lower levels for
AMBd appeared to be closely associated with foaming in the
nebulizer reservoir. Several animal studies showed an equal
or even increased pulmonary deposition and retention of
drug or efficacy with aerosolized (ligand anchored) lipid
formulations of AMB compared with AMBd. (18–21)
In short, nebulizing AMB is possible and lung deposition
of AMB can be obtained. Lipid formulations of AMB seem
to nebulize better than AMBd. However, selection of the nebulizer
is of great importance, because of its influence on important
aspects as droplet size, fine particle fraction, and output,
and therefore on the lung deposition and efficacy of the
treatment. From in vitro data recommendations for nebulizing
AMBd could be a Respigard II (Marquest Inc., Englewood,
CO) or a Cirrus (Intersurgical, Wokingham, UK) (36)
For aerosolizing ABLC the AeroEclipse C1 Breath Actuated
Nebulizer (Monoghan Medical, Plattsburgh, NY) seems a
good nebulizer. (37) L-AMB was effectively nebulized with an
adaptive aerosol delivery (AAD) system (Halolite AAD or
ProDose AAD; Romedic/Medic-Aid, Meerssen, The Netherlands).
(41)
Pharmacokinetics
In order to be effective, the inhaled drug must be delivered
in a sufficient dose to the site of disease. (37) To optimize
drug delivery, Corcoran et al. (37) performed a series of in vitro
studies with ABLC, comparing aerosol size and output rates
of 12 different nebulizer delivery systems. Estimated lung

REVIEW ON THE CLINICAL USE OF INHALED AMPHOTERICIN B 215
doses, based on measurements of aerosol size and nebulizer
output, varied by as much as a factor of 2 when comparing
different nebulizers. Based on these in vitro studies, a delivery
system (AeroEclipse, Amherst, NY) was selected for a
radioisotope aerosol deposition study with Technetium-labeled
ABLC (5 mg/mL, 35 mg) in six single- and six double-lung
recipients. In single lung recipients, the average deposited
doses were 3.9 � 1.6 mg (mean � SD) in the allograft
versus 2.1 � 1.1 mg in the native lung. In double-lung recipients,
the average deposited doses were 4.0 � 1.3 mg in
the right lung and 2.8 � 0.8 mg in the left lung. Clearly, there
was a great difference between the dose (amount put in the
nebulizer) and the lung dose (amount that reached the lung).
Only 10–20% of the dose reached the lungs. Drug delivery
to central and peripheral lung regions was well balanced
with central depositions of 56–59% and peripheral deposition
of 44–41%. This corresponds well with the above-mentioned
patterns of Aspergillus infections in lung transplant recipients.
This may be explained by the fact that both
pathogen and therapy enter the lung as aerosols of similar
size (ABLC measured mass median diameter � 3.7 �m vs.
Aspergillus fumigatus spores 3–5 �m). Delivery to the native
lung was in some cases suboptimal, due to inadequate ventilation
and subsequent low exposure to the aerosol.
Marra et al. (42) showed in eight lung transplant recipients
that detectable concentrations of AMB (0.68 � 0.36 and 0.5 �
0.31 mg/L, respectively) can be attained in both the upper
and lower bronchoalveolar lavage (BAL) samples following
aerosol administration of 30 mg AMBd (5 mg/mL in 15–20
min; lung dose circa 1.5–3 mg). (42) The lavage procedure consisted
of administration of 50 mL of NaCl 0.9% via a bronchoscope
and subsequent aspiration of 30 mL. In order to interpret
the found drug concentrations in diluted BAL
samples, the MIC for Aspergillus fumigatus (about 0.5 mg/L)
should be taken into account. Clearly, this study showed that
drug concentrations in epithelial lining fluid (which are reflected
by BAL concentrations) were well above the MIC of
the most commonly found Aspergillus mold. After all, the
concentration in the BAL samples is, due to the dilution with
NaCl, lower than the concentration in the epithelial lining
fluid.
In another study concerning the pharmacokinetics of
aerosolized AMB, transplant recipients were administered
nebulized AMBd 6 mg once daily (1 mg/mL in 15–20
min). (43) Concentrations of AMB were measured in BAL fluid
after injection via the bronchoscope of 20 mL NaCl 0.9% and
in the bronchial aspirated secretions (BAS). Mean concentrations
of 1.46 mg/L in BAS and 15.75 mg/L in BAL were
reached at 4 h. At 24 h, concentrations were 0.37 mg/L and
11.02 mg/L, respectively. The BAL concentrations in this
study are considerably higher than those in the previous
study. This may be due to differences in the type of nebulizer
used to aerosolize AMBd, the BAL sample collection
method (use of a different amount of NaCl 0.9%) and the calculation
methods. The AMB concentrations in the epithelial
lining fluid mentioned above, were calculated assuming that
1% of the recovered BAL corresponded with the volume of
the epithelial lining fluid. (43)
The use of inhalation treatment of AMB is presumed to
result in low concentrations of AMB in serum. Diot et al. (35)
found AMB peak serum levels of less than 0.025 mg/L after
inhalation of 5 mg AMBd (1 mg/mL). (35) This concentration
is 20 times less than the 0.5–2 mg/L steady-state concentration
reported after intravenous treatment at usual dose (1
mg/kg). Montforte et al. (43) found undetectable serum levels
of AMB in five patients treated with 6 mg AMBd for inhalation
once a day (1 mg/mL in 15–20 min). In another
study concerning the pharmacokinetics of aerosol AMBd 10
mg twice daily (2 mg/mL in 15–20 min), serum AMB levels
were obtained in 15 patients before and 1 h after AMBd inhalation
three times a week. (14,44) In 150 of 168 (89%) samples,
levels were below the lower limit of detection (0.1
mg/L). In the remaining 18 samples levels between 0.1 mg/L
and 0.2 mg/L were found. In the dose ranging study of Myers
et al. (45) (5, 10, 15, or 20 mg twice a day in 10–15 min),
three patients receiving the 20-mg dose were observed to
have serum AMB trough concentrations of 2 mg/L (in the
therapeutic range). In most studies, however, serum levels
have not been determined.
The above-mentioned results of serum AMB measurements
vary from not detectable (dosage of 6 mg once daily)
to concentrations in the therapeutic range (dosage 20 mg
twice a day). These results suggest a dose–effect relation;
however, due to the variation in, among others, the patient
population, AMB concentrations in the nebulizer, and the
nebulizers used (most likely explanation), it is not possible
to draw any conclusions on this matter.
Inhalation of AMB seems to provide pulmonary doses that
can be expected to be effective for antifungal treatment (or
prophylaxis) in the lung. The mostly low serum concentrations
mentioned above indicate that the risk of systemic side
effects will be small. However, these data are limited, and
need to be confirmed in a larger study. Confirmation is of
high importance in view of the formidable toxicity of AMB
and the long treatment period that some indications require.
Efficacy
Lung transplant patients
Infectious complications in lung transplant patients are frequent.
It is difficult to protect the lung against infections, because
the lung has continuous contact with the environment,
and because of the use of immunosuppressive therapy. Although
bacterial infections occur more frequently; viral and
fungal infections have higher mortality rates. (46) Aspergillus
spp. are responsible for more than half of the fungal infections
in lung transplant recipients. Antifungal prophylaxis in
lung transplant recipients receiving immunosuppressive
treatment is recommended; however, controversy exists
about the drug to be used and the optimum prophylactic
dose. One frequently described prophylactic regimen is the
administration of nebulized AMB (often in combination with
systemic azole treatment). (16,42,43,46–54)
In 2001, Dummer et al. (51) did a survey on antifungal management
after lung transplantations in the United States. Of
the responding centers gave 76% antifungal prophylaxis after
transplantation in at least some subgroups of patients,
despite the absence of controlled trials. The agents used for
prophylaxis in order of preference were inhaled AMB (61%
of the centers), itraconazole (48%), parenteral AMB formulations
(25%), and fluconazole (21%); many centers used
more than one agent. In a worldwide survey, Husain et al. (8)
found 56% (24 of 43) of the hospitals using aerosolized AMB.
Several studies showed promising results of antifungal

216
prophylaxis in lung transplant recipients with inhaled AMBd
in different dosages (Table 1). (46–48) Dose, formulation and
nebulizer used in these studies are also shown in Table 1. Reichenspurner
et al. (48) observed a 2% incidence of Aspergillus
infections in a cohort study after the first 12 postoperative
months in 126 patients who received prophylaxis with inhaled
AMBd (5 mg three times a day to be increased to 20 mg three
times a day during posttransplant hospital stay) after surgery.
A historical control group of 101 patients showed a 12% incidence
(p � 0.005). The only side effect observed in the AMB
group was mild nausea. In a study concerning risk factors for
Aspergillus infection, Monforte et al. (47) found similar figures
of developed invasive aspergillosis (1.8%) after using AMBd
(6 mg three times a day, and after 3 months 6 mg/day for life;
1 mg/mL in 15–20 min) as antifungal prophylaxis. One patient
required withdrawal of the prophylaxis due to bronchospasms.
In the remaining patients AMB was well tolerated,
with only a few mild side effects. In an observational
study Calvo et al. (46) found no fungal infections in the early
postoperative period as a result of prophylaxis with fluconazole
(400 mg/day) and aerosolized AMBd (0.2 mg/kg three
times a day) in 52 patients. The use of fluconazole should not
influence the results regarding IPA, because fluconazole has
no activity against Aspergillus. (55)
Although these studies all describe the decrease in the incidence
of IPA with nebulized AMB, the retrospective design
as well as several other factors (e.g., the use of a historical
group as the control group) make it difficult to draw
firm conclusions.
Neutropenic patients
Aspergillus spp. are increasingly recognized as major fungal
pathogens in neutropenic patients. (5–7) As organ transplantations
and aggressive antineoplastic chemotherapy regimens
are becoming more frequent, growing numbers of
patients will be susceptible to Aspergillus infection. Invasive
disease probably develops after colonization of the large airways
and bronchi due to impaired neutrophil/macrophage
defense mechanisms and subsequent tissue invasion. (4,14)
Prophylaxis is a commonly used treatment strategy, because
the diagnosis of fungal infection is often delayed or difficult
to establish with certainty, and a delay in antifungal treatment
increases mortality. Several different approaches to
prophylaxis for invasive aspergillosis have been attempted.
(11,1,56) The new azoles have improved potency and
a broader spectrum than former azoles. However, no study
has yet convincingly shown that any means of prophylaxis
is completely protective.
Because of these unsatisfactory results, several research
groups investigated the use of inhaled AMB for the prophylaxis
of IPA (Table 2). In a retrospective cohort study concerning
the prophylactic efficacy of different antifungal strategies,
three regimens were compared: oral nystatin � oral
AMB (n � 228) versus oral AMB � oral azoles (n � 107) versus
oral AMB � intravenous AMBd � nebulized AMBd (10
mg/day; 1 mg/mL in 10 min) (n � 48). Invasive fungal infections
developed in 1.8, 12.1, and 0% of the patients, respectively.
Because in the third cohort the AMB was administered
in three different ways, it is not possible to assess to
what extent the nebulization of AMBd contributed to the result.
(57) In another cohort study, Coneally et al. (58) found that
invasive aspergillosis did not develop in 34 patients at risk,
KUIPER AND RUIJGROK
who were treated with nebulized AMBd (5 mg twice a day;
1.25 mg/mL in 10 min). In the 2 years before routine use of
antifungal prophylaxis, 14 of the 123 patients (11.4%) with prolonged
granulocytopenia developed invasive aspergillosis.
In an observational study, aerosolized AMBd inhalation
(10 mg twice a day; 2 mg/mL in 10–20 min) was used in 303
bone marrow transplantation (BMT) patients. (59) The overall
incidence of invasive fungal infection was 11/303 (3.6%) of
which only 6 (2%) were caused by Aspergillus species. Although
this was a noncomparative study, the results are encouraging
when they are compared to incidences of 11–16%
of invasive fungal infections after BMT without antifungal
prophylaxis reported by other investigators. (58,60) Erjavec et
al. (61) concluded from an observational study that nebulizing
AMBd did not appear to be effective in preventing IPA,
because 12 (28,6%) patients in their study developed proven
or probable IPA. The starting dose was 1 mg three times a
day, which was increased every day by 1 mg until 5 mg three
times a day. Thereafter, the dose was to be increased to 10
mg three times a day, unless severe side effects occurred.
Only 20 of the 42 patients managed to complete the scheduled
regimen increasing over time to 10 mg three times daily.
Meyers et al. (45) conducted a dose ranging trial in 26 patients
with neutropenia. Aerosolized AMBd was administered
by face mask nebulizer at 5, 10, 15, and 20 mg twice a
day and inhaled over 10 to 15 min. No patient developed
clinically suspicious or pathologically documented invasive
aspergillosis, and all doses were well tolerated. The authors
were unable to establish the ideal dose and schedule.
Schwartz (62) conducted a prospective randomized controlled
trial comparing inhaled AMBd (10 mg twice a day; 2
mg/mL in 15–20 min) with placebo in 382 neutropenic patients.
The incidence of invasive aspergillosis in patients who
received prophylactic aerosolized AMB was 4%. This did not
differ significantly from the 7% incidence in patients who received
no inhalational prophylaxis (p � 0.37), but the overall
incidence of IPA was lower than expected and varied
widely among participating centers. Rijnders et al., (41) however,
demonstrated in a randomized placebo controlled trial
in 271 patients a dramatic reduction of invasive aspergillosis
from 14% in the placebo group to 4% in the L-AMB group
(12.5 mg 2 days/week; 2.5 mg/mL in 30 min) (p � 0.005).
Most studies described a decrease in the incidence of IPA
with nebulized AMB. The only two prospective randomized
controlled studies, however, showed conflicting results. The
explanation why Schwartz et al. (62) did not find the same
promising results as Rijnders et al. (41) could be the low event
rate in the study of Schwartz, the use of different formulations
of AMB, or the use of different nebulizers.
In conclusion, nebulized (L-)AMB may have a place in the
prophylactic antifungal protocol to prevent IPA in patients
with prolonged neutropenia.
The above-mentioned studies describe the use of inhaled
AMB as prophylactic therapy. The only information about
the efficacy of inhaled AMB as a salvage therapy consists of
one case report, in which the value of inhaled AMB could
not be determined. (63)
Allergic bronchopulmonary aspergillosis
Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity
reaction to Aspergillus antigens that usually affects
patients with asthma. (64) ABPA has also been described

TABLE 1. USE OF INHALED AMPHOTERICIN B IN LUNG TRANSPLANT RECIPIENTS
Year of AMB Number of
Author publication formulation Dosea Nebulizer patients Outcome
Reichenspurner (48) 1997 AMBd 5 mg t.i.d. to be increased to n.d. 126 AMBd Significant reduction in rate of fungal- and
20 mg t.i.d. during 101 controls Aspergillus infections in AMB-group:
posttransplant hospital stay Rate/pateint for Asp: 0.00 vs. 0.11 after
3 months and 0.02 vs. 0.12 after 12 months
Montforte (47) 2001 AMBd 6 mg t.i.d., after 3 months jet nebulizer 55 Multivariate analysis showed nAMB to be
6 mg/day for life a preventive factor for developing Asp.
1 mg/mL in 15–20 min
Calvo (46) 1999 AMBd 0.2 mg/kg t.i.d. �1 month n.d. 52 No fungal infections were observed.
(mean (SD): 42 (27.5) days)
aWhen mentioned in the article dosing time, nebulizer load volume, concentration and treatment duration are described.
ABLC, Abelcet; AMBd, amphotericin deoxycholate; Asp, Aspergillus infection; nAMB, nebulized AMB; n.d., not described.

TABLE 2. USE OF INHALED AMPHOTERICIN B IN NEUTROPENIC PATIENTS
Year of AMB Number of
Author publication formulation Dosea Nebulizer patients Patient population Outcome
Laurenzi (57) 1996 AMBd 10 mg/day Acorn II with 48 nAMB AML, NHL, or BMT No invasive fungal infections
(1 mg/mL adult mask 2 control groups were observed versus 12%
in 10 min) (228 � 107 patients) Asp in 2 years before this
prophylactic treatment.
Coneally (58) 1990 AMBd 5 mg b.i.d. Cirrus 34 nAMB Granulocytopenia of No cases of invasive
(1,25 mg/mL (Inter-Surgical) 123 controls �0.5 � 109 /L � 10 days aspergillose during first
in 10 min) until year since institution of
granulocyte prophylaxis versus 11.4%
count �1.0 � 109 /L in 2 years prior to
institution of prophylaxis.
Hertenstein (59) 1994 AMBd 10 mg b.i.d. Inhalette 303 BMT Overall incidence of
(2 mg/mL in (Dräger, invasive fungal infections
10–20 min) until Germany) within the first 120 days
granulocyte after BMT was 3.6%
�1.0 � 109 /L (Asp 2%).
Meyers (45) 1992 AMBd Dose ranging: Airlife Misty-neb 26 BMT or leukaemia No patient developed Asp.
5, 10, 15, or 20 mg Medication patients undergoing
b.i.d. (1.7–5 mg/mL system with intense chemotherapy
in 10–15 min) ultra fit
anesthesia
face mask
(Travenol
Health Care
Corporation,
Valencia, CA)
Schwartz (62) 1999 AMBd 10 mg b.i.d. RespirGard II 227 nAMB Expected granulocytopenia No significant difference is
(2 mg/mL in (MarQuest, 155 controls of �0.5 � 109 /L � 10 days found in the incidence of
15–20 min) Englewood, CO), proven, probable or
until study PariBoy or possible invasive Asp.
endpoint Pari IS II (4% vs. 7%, p � 0.37).
(both Pari
Werke, Starnberg,
Germany)
Erjavec (61) 1997 AMBd Increasing from Pari-InhalerBoy 42 Granulocytopenia of Twelve (28%) patients
1 mg t.i.d. to (Pari-Werk GmbH, �0.5 � 109 /L � 7 days developed proven or
10 mg t.i.d. Germany) possible invasive fungal
until infections. nAMB does
granulocytopenia not appear useful in
ended preventing IPA
Rijnders (41) 2008 L-AMB 12.5 mg 2 days/ Halolite/Prodose 139 L-AMB Prolonged granulocytopenia Significant difference in
week (5 mg/mL Adaptive Aerosol 132 controls incidence of IPA
in 30 min) until Delivery System (4% vs. 14%, p � 0.005).
end of (Romedic/
granulocytopenia Medic-Aid,
Meerssen, The
Netherlands)
a When mentioned in the article dosing time, nebulizer load volume, concentration, and treatment duration are described.
AMBd, amphotericin deoxycholate; AML, acute myeloid leukemia; Asp, Aspergillus infection; BMT, bone marrow transplantation; IPA, invasive pulmonary aspergillosis; L-AMB, AmBisome; nAMB,
nebulized amphotericin B; NHL, non Hodgkin’s lymphoma.

REVIEW ON THE CLINICAL USE OF INHALED AMPHOTERICIN B 219
after lung transplantation and in cystic fibrosis patients, and
is associated with an accelerated decline in lung function.
(65–67) Standard therapy exists in high doses of corticosteroids,
although the long-term benefits are not clear and
chronic use is associated with serious side effects. (67) An alternative
treatment strategy is to reduce the Aspergillus colonization
in the lung by using antifungal agents, such as inhaled
AMB. Data regarding the effectivity of nebulized AMB
are based on case reports. (65,66,68,69) In these cases, nebulized
AMB seemed to contribute to the control of ABPA and to the
reduction of the dose of oral prednisolon. Used formulations
and doses are described in Table 3.
Nebulized (L-)AMB may have a place in the treatment of
ABPA in patients with corticosteroid-dependent ABPA.
However, the effectiveness and the safety should be further
investigated in a placebo-controlled study.
Aspergillus empyema
Aspergillus empyema is a rare condition, which predominantly
affects patients with chronic lung damage. (70) In a case
report of an Aspergillus empyema complicating a bronchopleural
fistula, conventional therapy with intravenous
and intrapleural AMBd failed to control the Aspergillus infection.
Nebulized AMBd induced bronchospasm. However,
nebulized L-AMB was well tolerated in a dose of 50 mg twice
daily during 6 weeks. However, the hypothesis that nebulized
L-AMB contributed to the successful outcome in this
patient, cannot be confirmed, because of the concomitant administration
of oral itraconazol.
Aspergillus-related ulcerative tracheobronchitis
Aspergillus-related tracheobronchitis was seen in three
transplant recipients with fibrinous material covering their
bronchial anastomoses. (71) All three patients received prophylactic
antifungal therapy with aerosolized AMBd (10 mg
three times a day for 6–8 weeks) after transplantation, without
systemic antifungal therapy. When tracheobronchitis
was diagnosed during bronchoscopy 3–8 months later, therapy
with aerosolized AMBd 10 mg three times daily was
started again in combination with oral itraconazol.
Short-term prophylaxis (6–8 weeks) with nebulized AMBd
did not seem to prevent Aspergillus-related tracheobronchitis,
and should be continued until bronchoscopy shows complete
healing of the anastomoses. However, aerosolized
AMBd in combination with oral itraconazol did seem to be
effective in treating such local forms of Aspergillus infections.
Two other case reports described patients with an Aspergillus
tracheobronchitis: an Aspergillus tracheobronchitis
following influenza A infection and a tracheobronchial aspergillosis
in a patient with AIDS. Both patients were successfully
treated with a combination of antifungal drugs, including
nebulized AMBd (respectively, 10 mg two times a
day or 10–20 mg/day). (72,73) Because of the concomitant administration
of other antifungal therapy, it remains unclear
to what extent aerosolized AMBd contributed to the successful
outcome.
Candidal anastomotic infection
Anastomotic infection is an uncommon but potentially
life-threatening complication after lung transplantation. (74)
Mostly Aspergillus organisms are involved in these infections,
but there are also a few reports of anastomotic infections
with Candida organisms. Because of the limited number
of cases, the optimal therapy is unknown. In three cases
the patients were treated with intravenous AMBd (6–10
days), followed by inhaled AMBd (50 mg/day for 1 week,
50 mg/week for 6–12 weeks) and oral fluconazol. Intravenous
AMBd was used only as initial therapy, because prolonged
use in combination with cyclosporine in transplant
recipients may lead to significant nephrotoxicity. Oral fluconazole
and inhaled AMBd were used as maintenance therapy.
This combination led to successful treatment in all three
anastomotic infections. The role of the nebulized AMBd in
the clinical improvement of these patients cannot be fully
evaluated, because of the concomitant administration of oral
fluconazol.
Bronchopulmonary candidiasis
A frequent complication of the massive use of antibiotics
is superinfection by Candida albicans. It has been observed
that these complications are particularly frequent
in patients with chronic bronchitis. (75) Administration
(oral or parenteral) of nystatin or AMBd was effective in
the treatment of candidiasis of the digestive tract, but not
of the lungs. Currently therapy with azoles is used for
these kind of infections. Before these drugs were available,
Oehling et al. (75) investigated the use of inhaled AMBd and
inhaled nystatin for the treatment of pulmonary candidiasis.
Of the 33 patients 9 were treated for 10 days with nebulized
AMBd (5 mg two to four times a day by a Heyernebulizer)
and 24 with nebulized nystatin (50,000 units
two to four times a day). After treatment, C. albicans was
no longer present in the sputum of, respectively, 88 and
84% of the patients. The authors concluded that at that
time aerosol therapy with one of these substances was the
only effective way to eliminate bronchopulmonary candidiasis.
Endobronchial histoplasmosis
Kilburn described a case of endobronchial histoplasmosis
treated with inhaled AMBd (1 mg/kg in two periods of inhalation/day).
(31) Although the treatment was well tolerated,
the therapeutic result after 60 days of treatment was equivocal.
Pulmonary zygomycosis
Pulmonary zygomycosis is a rare but serious complication
in neutropenic patients. A patient with chronic lympho-cytic
leukemia who underwent allogenic nonmyeloablative
stem cell transplantation developed pneumonia. (76)
Pseudallescheria boydii and Rhizomucor were isolated from
BAL culture samples. The P. boydii responded favorably to
high-dose caspofungin; however, the patient remained ill
because of the coexisting zygomycosis. A trial of low-dose
liposomal AMB was unsuccessful due to rapid increase in
serum creatinine levels. Treatment with aerosolized ABLC
(50 mg/day) was started and after 3 weeks the CT scan
showed radiographic recovery. Inhaled ABLC was continued
for 5 months, and no recurrence of fungal pneumonia
occurred.

TABLE 3. USE OF INHALED AMPHOTERICIN B IN THE TREATMENT OF SEVERAL FUNGAL INFECTIONS
Year of AMB Number Patient
Author publication formulation Dosea Nebulizer of patients population Outcome
Casey (65) 2002 AMBd 16–40 mg/day in n.d. 1 ABPA Improved FEV1 and dose reduction of
divided doses prednisone.
during 4 months
Tiddens (66) 2003 L-AMB 50 mg once a week Halolite 5 ABPA Prednisone could be stopped in four patients
(�8 mL in 150 min) and reduced in one patient.
Suzuki (68) 2002 AMBd 2,5 mg/mL t.i.d. n.d. 1 ABPA Therapy (including nAMB) improved
asthmatic symptoms and count of
eosinophils and serum IgE level decreased.
Laoudi (69) 2008 AMBd 5 mg b.i.d. n.d. 3 ABPA Improved FEV1 and decreased count of
eosinophils and serum IgE level.
Purcell (70) 1995 AMBd � 50 mg b.i.d. during Turboturrett 2 1 Aspergillus Within 3 days the patient became apyrexial
L-AMB 6 weeks empyema and after 4 weeks all sputum and pleural
fluid cultures were negative for Aspergillus.
Birsan (71) 1998 AMBd 10 mg t.i.d. for n.d. 1 Aspergillus- NAMB in combination with oral itraconazol
6–8 weeks related seems to be effective in treating Aspergillustracheobronchitis
related tracheobronchitis.
Boots (72) 1999 AMBd 10 mg b.i.d. n.d. 1 Aspergillus- The patient survived due to combination
related therapy with among others nAMB.
tracheobronchitis
Dal Conte (73) 1996 AMBd 10–20mg/day in Respirgard II 1 Aspergillus- The general conditions of the patient
10 mL related gradually improved during combination
tracheobronchitis therapy with among others nAMB.
Palmer (74) 1998 AMBd 50 mg/day for n.d. 3 Candidal NAMB �oral fluconazol led to successful
1 week, 50 mg/ anastomotic treatment in all 3 anastomotic infections.
week for infection
6–12 weeks
Oehling (75) 1975 AMBd 5 mg 2–4 times a Heyernebulizer 9 nAMB Bronchopulmonary After treatment C. albicans was no longer
day for 10 days (Bad Ems, 25 Candidiasis present in the sputum of 88% (nAMB) and
FRG) nystatine 84% (nebulized nystatin)of the patients
Kilburn (31) 1959 AMBd 1 mg/kg in 2 periods n.d. 1 Endobronchial The therapeutic result was equivocal.
of inhalation/day histoplasmosis
Safdar (76) 2004 ABLC 50 mg/day for RespiGuard-II 1 Pulmonary Resolution of cough and radiographic
5 months zygomycosis recovery
aWhen mentioned in the article dosing time, nebulizer load volume, concentration and treatment duration are described.
AMB, amphotericin B; n.d., not described; ABPA, Allergic bronchopulmonary aspergillosis; L-AMB, AmBisome; AMBd, amphotericin deoxycholate; ABLC, Abelcet.

REVIEW ON THE CLINICAL USE OF INHALED AMPHOTERICIN B 221
Safety
Due to its high hydrophobicity, the risk of detrimental local
effects on pulmonary function is of concern when administering
AMB directly into the lung. (77) AMB is prepared
in conjunction with the deterging agent deoxycholic acid in
order to solubilize the AMB. (78) Data from in vitro studies
suggest that perhaps any detrimental effect on lung function
may be related to alterations in the activity of pulmonary
surfactant, and would thus implicate the deoxycholate component
as the causative agent rather than AMB itself. (25,78)
The toxicity of inhaled AMBd (30 mg/day; 10 mg/mL in
7–10 min) was evaluated in two observational studies in
granulocytopenic patients. Dose, formulation and nebulizer
used in these studies are shown in Table 4. The results
showed that cough, bronchospasms, dyspnoea, nausea, and
an unpleasant aftertaste are common. Although these side
effects led to discontinuation of treatment in 22% of patients
in one study, it was concluded that the safety profile was acceptable.
(79,80) On the contrary, Ruiz et al. (81) found no adverse
reactions in an observational study in 18 patients
treated prophylactically with nebulized L-AMB.
Erjavec et al. (61) observed the tolerance of aerosolized
AMBd (increasing from 1 mg three times a day to 10 mg
three times a day) in 61 neutropenic episodes in 42 hematooncologic
patients. Twenty-two patients experienced side effects
(coughing, dyspnea) and only 48% of them managed to
complete the schedule regimen increasing to 10 mg three
times daily. The authors concluded that inhaled AMBd was
so poorly tolerated that it has little to offer in preventing IPA
in granulocytopenic patients.
In some prospective, noncomparative studies the shortterm
safety and tolerability of aerosolized ABLC was demonstrated.
(50,82) In one study, ventilated patients received 100
mg and extubated patients received 50 mg ABLC administered
by face mask jet nebulizer (Table 4) once daily for 4
days, then once a week for 2 months. In another study, 40
patients received 50 mg ABLC administered by the same jet
nebulizer once every day for 4 days, then once a week for
13 weeks. Nausea or vomiting occurred in less than 2% of
the patients and no clinically significant bronchospasm was
apparent. Five percent of all patients developed a 20% or
more decline in the FEV1/FVC ratio. (50,52)
Rijnders et al. (41) observed no drug-related serious adverse
events after inhalation of L-AMB (12.5 mg 2 days/week; 5
mg/mL in 30 min). Due to the higher incidence of cough
during inhalation of L-AMB, more patients treated with
L-AMB discontinued inhalation than patients treated with
placebo.
In a retrospective cohort study the safety and tolerability
of nebulized AMBd (10 mg twice a day) and L-AMB (20 mg
twice a day) in 38 lung transplant recipients were compared.
(83) Two patients receiving AMBd and one patient receiving
L-AMB experienced serious adverse drug reactions,
such as shortness of breath and difficult breathing, possibly
related to aerosolized drug administration. Eleven patients
experienced minor adverse drug reactions during treatment
with either AMBd (n � 6) or L-AMB (n � 5). There were no
significant differences in pulmonary toxicity, average serum
creatinine or organ rejection (p � 0.1). The authors concluded
that both formulations were safe and well tolerated over a
large number of medication exposures (1,206 doses of AMBd
and 1,149 doses of L-AMB).
Comparison of the safety of ABLC (100 mg (ventilated) or
50 mg (extubated)/day) with AMBd (50 mg (ventilated) or
25 mg (extubated)/day for 4 days, then once per week for 7
weeks; 5 mg/mL in 10–15 min) was conducted in a randomized,
blinded study in 100 lung transplant recipients. (49)
This study demonstrated that inhalation of ABLC aerosol
was generally better tolerated than inhalation of AMBd. Participants
who received AMBd were more likely to experience
adverse events (odds ratio 2.16; 95% CI 1.10–4.24; p �
0.02). Although the study was not designed to measure efficacy,
both treatment strategies were associated with a low
rate of invasive pulmonary infection in the early posttransplant
period.
Administration of lipid-based formulations may result in
the increased observation of a pathological finding of
mononuclear cells with clear vacuoles in cytoplasm obtained
from bronchoalveolar fluid, also known as “foamy macrophages.”
(17) A study comparing AMBd inhalation with
ABLC inhalation observed foamy macrophages in 31.3% of
ABLC patients compared with only 12.8% of AMBd patients.
Clinical outcomes were not significantly different; therefore,
the relevance of these histopathological findings is not clear.
Lipid formulations can extend the half-life of the drug and
decrease wide variation of drug concentrations in the respiratory
tract, while increasing its residence time in the lung. (84)
In an animal study lung AMB retention was more than eight
times higher in animals treated with L-AMB compared to
AMBd. (22)
A further important point of concern is the possibility of
systemic absorption of AMB, particularly in transplant recipients
who receive other nephrotoxic drugs such as cyclosporine
or tacrolimus. As described above, the use of inhalation
treatment of AMB is presumed to result in low
concentrations of AMB in serum. Data of animal studies of
inhaled AMB showed a low systemic exposure. (20,21,23,28,29)
However, data on the systemic absorption of inhaled AMB
are still limited. Rijnders et al. (41) observed no systemic toxicity
and creatinine values the day after the last inhalation
were comparable to baseline.
In conclusion, several reports were promising about the
tolerance of aerosolized AMB; however, some other studies
reported conflicting data. The apparent differences in the incidence
of side effects in these studies might be explained by
the various concentrations of AMB and the different devices
used. Aerosolized lipid-based formulations of AMB might
be better tolerated than aerosolized AMBd. Little is known
about the systemic toxicity of inhaled AMB.
Discussion
The use of aerosols for targeting medication to the receptor
sites in the lung has multiple advantages compared to
systemic administration, including the use of less drug to
provide the same therapeutic effect and the reduction in the
likelihood of systemic side effects. (32)
The topic of nebulization of (L)-AMB has been discussed
in many published reports. However, this has not resulted
in any official labeling of nebulized AMB, possibly because
evidence for this practice has not been thoroughly investigated.
Despite the disappointing outcomes noted in some trials,
several studies have demonstrated a significant reduction in
the incidence of IPA following prophylaxis with aerosolized

TABLE 4. USE OF INHALED AMPHOTERICIN B IN SAFETY STUDIES
Year of AMB Number Patient
Author publication formulation Dosea Nebulizer of patients population Outcome
Dubois (79) 1995 AMBd 30 mg/day (10 mg/mL Respirgard II 18 Granulocytopenic after Four stopped treatment because
in 7–10 min) until (MarQuest BMT or after of nausea en vomiting, nine
granulocytopenia Medical, chemotherapy for instances (in seven patients)
ended Englewood, leukemia of bronchospasm, nine
Colo), increases of cough (in four
patients), three increases in
dyspnea
Gryn (80) 1993 AMBd 30 mg/day (10 mg/mL Misty Neb 29 Prolonged The major side effects were
in 10 min) until (Baxter granulocytopenia cough, aftertaste and
granulocytopenia Healthcare) (�2 weeks) nausea/vomiting
ended
Ruiz (81) 2005 L-AMB 24 mg three times a 22 ACORN 18 allogeneic No adverse reactions
week for 1 week, hematopoietic stem
then once weekly cell transplant
recipients
Erjavec (61) 1997 AMBd Increasing from 1 mg Pari-InhalerBoy 42 Granulocytopenia 22 patients experienced side
t.i.d. to 10 mg t.i.d. (Pari-Werk �7 days effects (coughing, dyspnea)
until granulocytopenia GmbH,
ended Germany)
Palmer (50) 2001 ABLC 100 mg (ventilated) or Hudson RCI 51 Lung-, or heart-lung Nausea or vomiting occurred
50 mg (extubated)/day Up-Draft, transplant recipients in less than 2% of the
for 4 days, then once model 1724 patients and no clinically
per week for 2 months significant bronchospasm
(5 mg/mL in 15-30 min) was apparent. Five percent of
all patients developed a 20%
or more decline in the
FEV1/FVC ratio

Rijnders (41) 2008 L-AMB 12.5 mg 2 days/week Halolite/Prodose 139 Prolonged Significant difference in
(5 mg/mL in 30 min) Adaptive L-AMB granulocytopenia incidence of IPA
until end of Aerosol 132 (4% vs. 14%, p � 0.005).
granulocytopenia Delivery System controls
(Romedic/
Medic-Aid,
Meerssen,
The Netherlands)
Lowry (83) 2007 AMBd 10 mg b.i.d. n.d. 18 AMBd, Lung transplant Two AMBd and one L-AMB
L-AMB 20 mg b.i.d 11 L-AMB, recipients patient experienced shortness
9 both of breath and difficult
breathing. six AMBd and five
L-AMB patients experienced
minor adverse drug reactions
Drew (49) 2004 ABLC 100 mg (ventilated) Hudson RCI 100 Lung transplant Patients who received AMBd
or 50 mg (extubated)/ Up-Draft, recipients were more likely to
AMBd 50 mg (ventilated) or model 1724 experience adverse events
25 mg (extubated)/day (Hudson (odds ratio 2.16; 95% CI
for 4 days, then once Respiratory 1.10–4.24; p � 0.02).
per week for 7 weeks Care,
(5 mg/mL in 10–15 min) Temecula, CA)
Alexander (82) 2006 ABLC 50 mg/day for 4 days, Hudson RCI +40 allogeneic Cough, nausea, vomiting or taste
then once per week for Up-Draft, hematopoietic disturbance followed 2.2%
13 weeks model 1724 stem cell transplant of 458 total inhaled ABLC
(Hudson recipients administrations. Five percent
Respiratory of the inhaled ABLC
Care, Temecula, administrations was associated
California, USA) with a 20% or more decline in
FEV1 or FVC o
aWhen mentioned in the article dosing time, nebulizer load volume, concentration, and treatment duration are described.
ABLC, Abelcet; AMBd, amphotericin deoxycholate; BMT, bone marrow transplantation; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; L-AMB, Ambisome n.d., not described.

224
AMB. Only few of the trials on inhaled AMB were randomized
controlled clinical trials and methodologically sound.
Some studies demonstrated a decrease in the incidence of invasive
Aspergillus infections that was not statistically significant
or significance was not discussed. Besides the lack of
statistical analyses, other limitations of studies presented
herein include the lack of power to detect a difference between
the prophylaxis and control group, the lack of control
groups and the use of other antifungal prophylactic agents
in addition to inhaled AMB.
Regarding safety, administration of aerosol AMB was well
tolerated and safe, except for some mild effects related to
pulmonary irritation. The low serum concentrations suggest
that the risk of systemic side effects will be small. Relative
to AMBd, studies suggested that ABLC is better tolerated.
(25,78) In addition, lipid formulations of AMB are easier
to administer, because they are already in solution and do
not tend to foam as much as AMBd. (36)
Although aerosolized AMB may be advantageous, the
choice of the nebulizer and dose is of great influence on the
results of the treatment with aerosolized AMB. Described
treatment doses of aerosolized (lipid formulations of) AMB,
range from 6 mg once daily to 50 mg once daily or 50 mg
once a week. Different nebulizers were used, which makes
it very difficult to compare their results and to draw firm
conclusions on the optimal dose and nebulizer.
A disadvantage of aerosolizing AMB is the usually long
nebulization time, which is a great burden for patients and
a cause of incompliance with the inhalation therapy. To improve
compliance, nebulization time or frequency should be
reduced. Regarding dosing frequency, Rijnders et al. (41)
showed a significant reduction of IPA with nebulizing
L-AMB 12,5 mg twice a week. Ruijgrok et al. (28) showed in
a rat model of IPA an improved survival up to 6 weeks after
a single inhalation of L-AMB. This suggests that inhalations
with a frequency of twice a week or once a week could
still be protective.
The development of an AMB inhalation powder was described
in literature. (38,39) If tolerated well, this may make inhalation
therapy easier and may therefore improve the compliance.
Place in therapy
The use of intravenous (lipid formulation of) AMB is limited
by a wide variety of acute and chronic side effects, the
most important of which is nephrotoxicity. Early-generation
oral azole agents have limitations regarding the spectrum of
antifungal activity and tolerability. Fluconazole lacks efficacy
against filamentous fungi. Itraconazole and voriconazole
have a wider spectrum of activity. For itraconazole, the
poor tolerability of the cyclodextrin containing oral solution
and the unpredictable bioavailability of the capsule limits its
clinical usefulness. Voriconazole may have more potential
for hepatotoxicity than the other azole agents. (85,86) Prophylaxis
with posaconazole, a new-generation azole, was superior
to prophylaxis with fluconazole or itraconazole in the
prevention of proven or probable invasive fungal infection.
More serious adverse events, however, were possibly or
probably related to treatment in the posaconazole group. (56)
Primary prophylaxis with echinocandins seems to be an effective
and well-tolerated option, but they can only be ad-
KUIPER AND RUIJGROK
ministered intravenously. (87–90) Inhaled AMB may have a
place in the prophylactic regimen of invasive fungal infections.
A prospective randomized study is needed to compare
the efficacy of inhaled AMB versus posaconazole. However,
it remains to be seen if such a comparative trial ever will be
realized. Due to the rarity of Aspergillus infections a very
large number of patients will be needed. For example, in hematopoietic
stem cell transplant recipients the incidence of
invasive aspergillosis ranges from 5–12%. (5,6) Inhalation of
L-AMB reduced the incidence of invasive aspergilosis from
14% in the placebo group to 4% in the L-AMB group. (41)
Treatment with posaconazol reduced the incidence from 8
to 2%. (56) The sample size needed to show a reduction of invasive
aspergillosis from an assumed 4% with posaconazol
to 1% with L-AMB inhalation with 80% power (� � 0.05)
would be 430 patients per arm.
Although an exact cost-effective analysis is beyond the
scope of this review, the medication costs of inhaled lipid
formulations of AMB (administered once a week), could well
be much lower in comparison with recently approved azoles
and echinocandins.
Conclusion
Inhalation of different formulations of AMB is used among
others for the prevention and/or treatment of invasive aspergillosis
in patients with impaired immunity, such as lung
transplant recipients and patients with a prolonged neutropenia,
and in patients with ABPA. Also, it serves as an alternative
method of treatment for patients with pulmonary
problems or infections, which otherwise cannot be treated or
would be at risk of systemic adverse effects of the drugs.
The reports on the unlabeled use of aerosolized AMB are
encouraging. The observed differences in efficacy following
aerosolized AMB are likely the result of differences in study
design, dosing, administration time, and technique and variability
of studied patient populations.
In conclusion, the studies reviewed here indicate that inhaled
AMB may have a place in the prophylactic regimen of
IPA in patients with prolonged neutropenia and in lung
transplant recipients. Nebulized (L-)AMB may have a place
in the treatment of ABPA in patients with corticosteroid dependent
ABPA. However, the effectiveness and safety in
ABPA patients should be further investigated in a placebocontrolled
study. For the treatment of fungal infections, inhaled
AMB should be used only in combination with systemic
treatment.
The best and most comfortable way of using aerosolized
AMB seems to be the administration of a lipid formulation
of AMB (e.g., 25–50 mg) once a week with a carefully selected
nebulizer (i.e., an adaptive aerosol delivery system),
with a high peripheral lung dose (MMAD between 0.5 and
5 �m) and a high pulmonary delivery rate.
Acknowledgments
The authors acknowledge the assistance of Henk Spijker
for revising this manuscript.
Author Disclosure Statement
The authors received financial support from Cephalon.
Cephalon had no influence on this article.

REVIEW ON THE CLINICAL USE OF INHALED AMPHOTERICIN B 225
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Received on August 6, 2008
in final form, December 14, 2008
<strong>Review</strong>ed by:
Patrice Diot
John Patton
Mark Utell
Address correspondence to:
Laura Kuiper, Pharm.D.
Ikazia Ziekenhuis Rotterdam
Department of Pharmacy
Montessoriweg 1
3083 AN Rotterdam, The Netherlands
E-mail: laurakuiper@planet.nl