1. IDSA GUIDELINES
Treatment of Aspergillosis: Clinical Practice
Guidelines of the Infectious Diseases Society
of America
Thomas J. Walsh,1,a Elias J. Anaissie,2 David W. Denning,13 Raoul Herbrecht,14 Dimitrios P. Kontoyiannis,3
Kieren A. Marr,5 Vicki A. Morrison,6,7 Brahm H Segal,8 William J. Steinbach,9 David A. Stevens,10,11
Jo-Anne van Burik,7 John R. Wingard,12 and Thomas F. Patterson4,a
1
Pediatric Oncology Branch, National Cancer Institute, Bethesda, Maryland; 2University of Arkansas for Medical Sciences, Little Rock;
3
The University of Texas M. D. Anderson Cancer Center, Houston, and 4The University of Texas Health Science Center at San Antonio, San
Antonio; 5Oregon Health and Sciences University, Portland; 6Veterans Affairs Medical Center and 7University of Minnesota, Minneapolis,
Minnesota; 8Roswell Park Cancer Institute, Buffalo, New York; 9Duke University Medical Center, Durham, North Carolina; 10Santa Clara Valley
Medical Center, San Jose, and 11Stanford University, Palo Alto, California; 12University of Florida, College of Medicine, Gainesville, Florida;
13
University of Manchester, Manchester, United Kingdom; and 14University Hospital of Strasbourg, Strasbourg, France
EXECUTIVE SUMMARY guidelines is to summarize the current evidence for
treatment of different forms of aspergillosis. The quality
Aspergillus species have emerged as an important cause
of evidence for treatment is scored according to a stan-
of life-threatening infections in immunocompromised
dard system used in other Infectious Diseases Society
patients. This expanding population is composed of
of America guidelines. This document reviews guide-
patients with prolonged neutropenia, advanced HIV in-
lines for management of the 3 major forms of asper-
fection, and inherited immunodeficiency and patients
gillosis: invasive aspergillosis, chronic (and saprophytic)
who have undergone allogeneic hematopoietic stem cell
forms of aspergillosis, and allergic forms of aspergillosis.
transplantation (HSCT) and/or lung transplantation.
Given the public health importance of invasive asper-
This document constitutes the guidelines of the Infec-
gillosis, emphasis is placed on the diagnosis, treatment,
tious Diseases Society of America for treatment of as-
and prevention of the different forms of invasive as-
pergillosis and replaces the practice guidelines for As- pergillosis, including invasive pulmonary aspergillosis,
pergillus published in 2000 [1]. The objective of these sinus aspergillosis, disseminated aspergillosis, and sev-
eral types of single-organ invasive aspergillosis.
There are few randomized trials on the treatment of
Received 23 October 2007; accepted 24 October 2007; electronically published
4 January 2008. invasive aspergillosis. The largest randomized con-
These guidelines were developed and issued on behalf of the Infectious trolled trial demonstrates that voriconazole is superior
Diseases Society of America.
It is important to realize that guidelines cannot always account for individual
to deoxycholate amphotericin B (D-AMB) as primary
variation among patients. They are not intended to supplant physician judgment treatment for invasive aspergillosis. Voriconazole is rec-
with respect to particular patients or special clinical situations and cannot be
considered inclusive of all proper methods of care or exclusive of other treatments
ommended for the primary treatment of invasive as-
reasonably directed at obtaining the same results. Accordingly, the Infectious pergillosis in most patients (A-I). Although invasive
Diseases Society of America considers adherence to these guidelines to be
voluntary, with the ultimate determination regarding their application to be made
pulmonary aspergillosis accounts for the preponder-
by the physician in light of each patient’s individual circumstances. ance of cases treated with voriconazole, voriconazole
a
T.J.W. and T.F.P. served as co-chairs for the Infectious Diseases Society of
has been used in enough cases of extrapulmonary and
America Aspergillus Guidelines Committee.
Reprints or correspondence: Dr. Thomas F. Patterson, The University of Texas disseminated infection to allow one to infer that vor-
Health Science Center at San Antonio, Dept. of Medicine/Infectious Diseases,
iconazole is effective in these cases. A randomized trial
7703 Floyd Curl Dr., MSC 7881, San Antonio, TX 78229-3900 (patterson
@uthscsa.edu). comparing 2 doses of liposomal amphotericin B (L-
Clinical Infectious Diseases 2008; 46:327–60 AMB) showed similar efficacy in both arms, suggesting
2008 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2008/4603-0001$15.00
that liposomal therapy could be considered as alter-
DOI: 10.1086/525258 native primary therapy in some patients (A-I). For sal-
IDSA Guidelines for Aspergillosis • CID 2008:46 (1 February) • 327

2. vage therapy, agents include lipid formulations of amphotericin strength of the randomized study, the panel recommends vor-
(LFAB; A-II), posaconazole (B-II), itraconazole (B-II), caspo- iconazole for primary treatment of these very uncommon man-
fungin (B-II), or micafungin (B-II). Salvage therapy for invasive ifestations of invasive aspergillosis (B-III).
aspergillosis poses important challenges with significant gaps Management of the chronic or saprophytic forms of asper-
in knowledge. In patients whose aspergillosis is refractory to gillosis varies depending on the condition. Single pulmonary
voriconazole, a paucity of data exist to guide management. aspergillomas may be best managed by surgical resection (B-
Therapeutic options include a change of class using an am- III), whereas chronic cavitary and chronic necrotizing pul-
photericin B (AMB) formulation or an echinocandin, such as monary aspergillosis require long-term medical therapy (B-III).
caspofungin (B-II); further use of azoles should take into ac- The management of allergic forms of aspergillosis involves
count host factors and pharmacokinetic considerations. Re- a combination of medical and anti-inflammatory therapy. For
fractory infection may respond to a change to another drug example, management of allergic bronchopulmonary aspergil-
class (B-II) or to a combination of agents (B-II). The role of losis (ABPA) involves the administration of itraconazole and
combination therapy in the treatment of invasive aspergillosis corticosteroids (A-I).
as primary or salvage therapy is uncertain and warrants a pro-
spective, controlled clinical trial. INTRODUCTION
Assessment of patients with refractory aspergillosis may be Heretofore considered to be an unusual cause of infection,
difficult. In evaluating such patients, the diagnosis of invasive Aspergillus species have emerged as important causes of mor-
aspergillosis should be established if it was previously uncertain bidity and mortality in immunocompromised patients [2–4].
and should be confirmed if it was previously known. The drug Invasive aspergillosis currently constitutes the most common
dosage should be considered. Management options include a cause of infectious pneumonic mortality in patients under-
change to intravenous (IV) therapy, therapeutic monitoring of going HSCT and is an important cause of opportunistic re-
drug levels, change of drug class, and/or combination therapy. spiratory and disseminated infection in other immunocom-
Antifungal prophylaxis with posaconazole can be recom- promised patients [5–11]. Furthermore, Aspergillus species
mended in the subgroup of HSCT recipients with graft-versus- also produce a wide range of chronic, saprophytic, and allergic
host disease (GVHD) who are at high risk for invasive asper- conditions. Although other forms of aspergillosis, such as
gillosis and in neutropenic patients with acute myelogenous ABPA, allergic sinusitis, and saprophytic infection, are also
leukemia or myelodysplastic syndrome who are at high risk for causes of morbidity, they are seldom life-threatening.
invasive aspergillosis (A-I). Management of breakthrough in- Throughout this document, treatment recommendations are
vasive aspergillosis in the context of mould-active azole pro- rated according to the standard scoring system of the Infec-
phylaxis is not defined by clinical trial data. The approach to tious Diseases Society of America and United Stated Public
such patients should be individualized on the basis of clinical Health Service for rating recommendations in clinical guide-
criteria, including host immunosuppression, underlying dis- lines, as summarized in table 1.
ease, and site of infection, as well as consideration of antifungal
dosing, therapeutic monitoring of drug levels, a switch to IV MICROBIOLOGY AND EPIDEMIOLOGY OF
therapy, and/or a switch to another drug class (B-III). ASPERGILLOSIS
Certain conditions of invasive aspergillosis warrant consid- Organisms. Aspergillus fumigatus is the most common species
eration for surgical resection of the infected focus. These in- recovered from cases of invasive aspergillosis [12]. The next
clude but are not limited to pulmonary lesions contiguous with most commonly recovered species are Aspergillus flavus, As-
the heart or great vessels, invasion of the chest wall, osteo- pergillus niger, and Aspergillus terreus [13]. Some institutions
myelitis, pericardial infection, and endocarditis (B-III). Res- may have a predominance of A. flavus or A. terreus as the most
toration of impaired host defenses is critical for improved out- frequently recovered species of Aspergillus [14]. A. terreus is
come of invasive aspergillosis (A-III). Recovery from clinically resistant to AMB, but species, including A. flavus,
neutropenia in a persistently neutropenic host or reduction of Aspergillus lentulus, Aspergillus nidulans, Aspergillus ustus, As-
corticosteroids in a patient receiving high-dose glucocortico- pergillus glaucus, and others, can also demonstrate resistance
steroids is paramount for improved outcome in invasive [15–20].
aspergillosis. Classification and definitions. Aspergillosis causes patient
A special consideration is made concerning recommenda- afflictions that are classically defined as invasive, saprophytic,
tions for therapy of aspergillosis in uncommon sites, such as or allergic [21]. Invasive diseases caused by Aspergillus species
osteomyelitis and endocarditis. There are very limited data on include infections of the lower respiratory tract, sinuses, and
these infections, and most involve D-AMB as primary therapy skin as portals of entry. The CNS, cardiovascular system, and
simply because of its long-standing availability. Based on the other tissues may be infected as a result of hematogenous dis-
328 • CID 2008:46 (1 February) • Walsh et al.

3. Table 1. Infectious Diseases Society of America–United States Public Health Service grading system for
ranking recommendations in clinical guidelines.
Category, grade Definition
Strength of recommendation
A Good evidence to support a recommendation for use
B Moderate evidence to support a recommendation for use
C Poor evidence to support a recommendation
Quality of evidence
I Evidence from 1 properly randomized, controlled trial
II Evidence from 1 well-designed clinical trial, without randomization; from co-
hort or case-controlled analytic studies (preferably from 11 center); from
multiple time-series; or from dramatic results from uncontrolled
experiments
III Evidence from opinions of respected authorities, based on clinical experience,
descriptive studies, or reports of expert committees
semination or direct extension from contiguous foci of infec- for probable invasive aspergillosis with a surrogate non–culture-
tion. Saprophytic involvement includes Aspergillus otomycosis based method (i.e., a positive galactomannan assay or b-glucan
and pulmonary aspergilloma. Allergic conditions encompass assay result and radiologically compatible CT findings) in an
allergic Aspergillus sinusitis and allergic bronchopulmonary as- immunocompromised host with clinical findings of infection
pergillosis [22]. Although other classifications have been pro- that constitute the definition of probable invasive aspergillosis.
posed, reference to the above clinical conditions will be made Several other points bear note concerning these definitions
throughout these guidelines. of aspergillosis. First, the term “probable” denotes a relatively
Members of the European Organization for Research in high degree of certainty that the signs and symptoms of infec-
Treatment of Cancer–Invasive Fungal Infection Cooperative tion in the immunocompromised host are truly due to an
Group and National Institute of Allergy and Infectious Diseases Aspergillus species. A study by Stevens and Lee [24] that ex-
Mycoses Study Group formed a Consensus Committee to de- amined response of invasive aspergillosis to itraconazole using
velop standard definitions for invasive fungal infections for Mycoses Study Group definitions found similar outcomes for
clinical research [23]. Based on a review of the literature and proven and probable invasive aspergillosis, suggesting that com-
an international consensus, a set of research-oriented defini- bining these 2 categories is appropriate for outcomes analyses.
tions for invasive fungal infections (including invasive asper- Second, the European Organization for Research in Treatment
gillosis), as observed in immunocompromised patients with of Cancer–Mycoses Study Group document clearly articulates
cancer, was developed. Three levels of certainty of invasive as- that the consensus definitions are not intended to be a direct
pergillosis were defined: proven, probable, and possible. Al- guide to practice [23]. Third, the definitions are principally
though the definitions are intended for use in the context of applicable to immunocompromised patients with cancer and
clinical and/or epidemiological research, they provide a stan- HSCT recipients. These definitions are currently being refined
dard set of criteria by which guidelines can be developed for to reflect increasing understanding of the patterns of invasive
the treatment of invasive aspergillosis. aspergillosis in an expanded population of immunocompro-
The definition for proven aspergillosis requires histopatho- mised patients.
logical documentation of infection and a positive result of cul- Diagnosis. Aspergillus species grow well on standard media
ture of a specimen from a normally sterile site. The definition and can be identified to species level in most laboratories. Cul-
of probable aspergillosis requires the fulfillment of criteria ture confirmation, where possible, is important to differentiate
within 3 categories: host factors, clinical manifestations (symp- aspergillosis from other filamentous fungal infections, such as
toms, signs, and radiological features), and microbiological evi- fusariosis and scedosporiosis. Blood cultures are of limited util-
dence. Throughout these guidelines, the term “invasive asper- ity, because the results are often not positive even in dissem-
gillosis” will assume a diagnostic certainty of proven or inated infection. Bronchoalveolar lavage, transthoracic percu-
probable invasive aspergillosis. With 2 important exceptions, taneous needle aspiration, or video assisted thoracoscopic
proven or probable infection requires the recovery of an or- biopsy are standard procedures for establishing a diagnosis of
ganism. The first exception includes the fairly frequent occur- invasive pulmonary aspergillosis. Fluid and tissue specimens
rence of histopathological demonstration of hyphae consistent from these procedures may reveal characteristic angular di-
with Aspergillus species in patients with negative culture results. chotomously branching septate hyphae on direct microscopic
The other exception consists of fulfilling the diagnostic criteria examination and/or Aspergillus species on culture. Where fea-
IDSA Guidelines for Aspergillosis • CID 2008:46 (1 February) • 329

4. sible, specimens obtained from these procedures are cultured gillosis in patients with hematological malignancy [33, 35, 50–
on fungal media for optimal growth of Aspergillus species [25, 52]. However, the sensitivity in nonneutropenic patients may
26]. However, results of cytologic examination, pathologic ex- be lower, possibly because of a lower residual fungal burden
amination, direct smears, and culture may be falsely negative or anti-Aspergillus antibodies [53, 54]. The combined use of
for clinical specimens from patients who are already receiving serum galactomannan antigen measurement and detection of
systemic antifungal therapy and in cases in which the diagnostic pulmonary infiltrates by early use of CT should improve de-
procedure could not be performed directly in the affected area tection of invasive pulmonary aspergillosis and permit earlier
(e.g., when the bronchoscopic examination or washing could initiation of antifungal therapy [55]. Several variables, including
not be performed directly in the affected area or when the antifungal therapy or prophylaxis, significantly reduce levels of
bronchoscope or biopsy needle could not reach the infected circulating galactomannan [35, 52]. False-positive results have
tissues). Thus, lack of a positive culture or direct smear result been reported in several contexts, including in patients who
does not rule out the diagnosis of invasive aspergillosis. More- have received certain antibiotics (pipercillin-tazobactam and
over, recovery of Aspergillus species from clinical specimens by amoxicillin-clavulanate), in cases of neonatal colonization with
invasive procedures may be impractical in patients who are Bifidobacterium, the in cases in which plasmalyte is used in
hemodynamically unstable, are severely hypoxic, have low bronchioalveolar lavage fluids, and in patients with other in-
platelet counts, or have advanced coagulation deficits. Thus, vasive mycoses (including Penicillium, histoplasmosis, and blas-
other markers of infection are often used in the assessment of tomycosis) [36, 56–61]. Despite these limitations, this assay is
patients at risk for invasive aspergillosis. a useful adjunctive test to establish an early diagnosis, partic-
Increasing recognition of the halo sign and air-crescent sign ularly when used in serial screening of patients at high risk of
by improved CT technology in immunocompromised patients infection.
has greatly facilitated the diagnosis of invasive pulmonary as- Other potential circulating markers for detection of asper-
pergillosis in patients with hematologic conditions [27–31]. gillosis include (1r3)-b-D-glucans detected by the Tachypleus
Although these radiological features are characteristic, they are or Limulus assay [62–66]. The Tachypleus or Limulus assay
not diagnostic of invasive pulmonary aspergillosis. Infections used to detect the presence of (1r3)-b-D-glucans is a variation
due to other angioinvasive filamentous fungi, such as Zygo- of the limulus assay used to detect endotoxin. The presence of
mycetes, Fusarium species, and Scedosporium species, as well as (1r3)-b-D-glucans in serum signifies the presence of fungal
to Pseudomonas aeruginosa and Nocardia species, may cause a invasion but is not specific for Aspergillus species [67]. False-
halo sign and other radiological features described for asper- positive results can occur in a variety of contexts, such as
gillosis. Although these more characteristic radiological patterns through glucan contaminated blood collection tubes, gauze,
of invasive pulmonary aspergillosis have been well described depth-type membrane filters for blood processing, and in vitro
in neutropenic hosts, less is known about the features of these tests using various antibiotics (e.g., some cephalosporins, car-
lesions in other immunocompromised patients [27, 29]. bapenems, and ampicillin-sulbactam) [68]. The Fungitell assay
The availability of the galactomannan EIA also may con- (Associates of Cape Cod) for detection of (1r3)-b-D-glucans
tribute substantially toward a non–culture-based diagnosis of is approved by the US Food and Drug Administration (FDA)
invasive aspergillosis. EIA for galactomannan has been validated for the diagnosis of invasive mycoses, including aspergillosis
in animal models and in patients as a surrogate marker for [66, 69]. One study reported that, among 283 patients with
detection of invasive aspergillosis [32–42]. Galactomannan an- acute myeloid leukemia and myelodysplastic syndrome who
tigen has also been detected in CSF samples from patients with were receiving antifungal prophylaxis, the (1r3)-b-D-glucan
CNS aspergillosis [43–45] and in bronchoalveolar lavage fluid assay was sensitive and specific in early detection of 20 proven
specimens from patients with invasive pulmonary aspergillosis, or probable invasive fungal infections, including candidiasis,
although the use of EIA for galactomannan in such contexts fusariosis, trichosporonosis, and aspergillosis [66, 69]. The da-
is investigational [46, 47]. In addition to facilitating early de- tabase for this assay in other populations at high risk for in-
tection, serial assessment of galactomannan antigenemia may vasive aspergillosis is limited, and more research is required in
facilitate therapeutic monitoring [48, 49]. However, the use of these populations [66, 69]. PCR-based diagnosis, which am-
serial galactomannan for therapeutic monitoring remains in- plifies Aspergillus-specific fungal genes (usually ribosomal DNA
vestigational. Thus, duration of therapy should be determined, genes), has shown considerable promise for invasive aspergil-
not solely by normalization of antigenemia, but also by reso- losis [70–79]. However, these systems have not been standard-
lution of clinical and radiological findings. ized, are not commercially available, and remain investigational
Several well-conducted studies of this EIA system have dem- [80]. Combining non–culture-based diagnostics (e.g., PCR and
onstrated good sensitivity in the detection of invasive asper- GM and GM and [1r3]-b-D-glucan) is an important research
330 • CID 2008:46 (1 February) • Walsh et al.

5. direction that may improve the overall predictive value of these experience of administration of these agents is predominantly
systems. in adults, specific notice is given to the need for adjustment of
The development of standardized methodology for antifun- dosages in pediatric patients, to obtain plasma exposures com-
gal susceptibility testing is another recent advance in the lab- parable to those of adults. These pharmacological differences
oratory evaluation of Aspergillus species. Interpretive break- in pediatric and adult dosing are discussed in more detail else-
points have not been established for any of the antifungal agents where [87, 88].
against filamentous fungi. However, new developments through
the Clinical and Laboratory Standards Institute provide repro- AMB
ducible methods for antifungal susceptibility testing. Further
AMB is a natural polyene macrolide antibiotic that consists of
studies using these in vitro methods may lead to improved
7 conjugated double bonds, an internal ester, a free carboxyl
rationale for selection of antifungal compounds in the treat-
group, and a glycoside side chain with a primary amino group.
ment of invasive aspergillosis. Although azole resistance by As-
It is not orally absorbed. For IV use, AMB has been solubilized
pergillus species is unusual, patients exposed chronically to an-
with deoxycholate as micellar suspension (D-AMB). AMB pri-
tifungal triazoles have been reported to have refractory infection
marily acts by binding to ergosterol (the principal sterol in the
caused by isolates with elevated MICs [81, 82].
cell membrane of most medically important fungi), leading to
Recognizing that other filamentous fungi, such as Fusarium
species, Scedosporium species, various dematiaceous (pig- the formation of ion channels and fungal cell death. AMB also
mented) moulds, and Zygomycetes, may cause similar patterns binds to cholesterol (the main sterol of mammalian cell mem-
of infection, a definitive microbiological diagnosis should be branes), although with less avidity than for ergosterol, resulting
established where possible. Non-Aspergillus filamentous fungi in cellular injury and end organ dysfunction. A second mech-
may require different antifungal agents and may carry a prog- anism of action of AMB may involve oxidative damage of the
nosis that is distinct from those of Aspergillus species. cell through a cascade of oxidative reactions linked to lipo-
peroxidation of the cell membrane. AMB has in vitro and in
ANTIFUNGAL COMPOUNDS USED FOR vivo activity against most Aspergillus species. Most isolates of
TREATMENT OF INVASIVE ASPERGILLOSIS A. terreus are resistant to AMB in vitro, in vivo, and in patients.
Following IV administration, AMB becomes highly protein
Over the past decade, a considerable expansion in antifungal bound before distributing predominantly into the reticuloen-
drug research and the clinical development of several new com-
dothelial tissues (liver, spleen, bone marrow, and lung) and the
pounds and strategies targeted against invasive aspergillosis
kidney. Peak plasma concentrations of 2–4 mg/mL are achieved
have occurred [83]. The following FDA-approved compounds
following IV infusion of 1 mg/kg of D-AMB. Clearance from
have in vitro, in vivo, and clinical activity against Aspergillus
plasma is slow, with a b half-life of 24–48 h and a terminal
species and are licensed for treatment of invasive aspergillosis:
half-life of 15 days. Despite mostly undetectable concentra-
D-AMB and its lipid formulations (AMB lipid complex
tions in the CSF, D-AMB is active in the treatment of some
[ABLC], L-AMB, and AMB colloidal dispersion [ABCD]), itra-
fungal infections of the CNS because of its penetration into
conazole, voriconazole, posaconazole, and caspofungin.
infected brain tissue via a disrupted blood-brain barrier.
Voriconazole and D-AMB are the only compounds licensed
D-AMB causes acute infusion-related reactions and dose-
in the United States for primary treatment of invasive asper-
limiting nephrotoxicity. Infusion-related reactions include fe-
gillosis. The LFABs, itraconazole, and caspofungin are approved
ver, rigors, chills, myalgias, arthralgias, nausea, vomiting, head-
for salvage therapy of invasive aspergillosis. Posaconazole is
licensed for prophylaxis of invasive aspergillosis in neutropenic aches, and bronchospasm. D-AMB–induced nephrotoxicity is
patients with leukemia and myelodysplasia and in allogeneic characterized by azotemia, urinary wasting of potassium and
HSCT recipients with GVHD. Posaconazole also was approved magnesium, renal tubular acidosis, and impaired urinary con-
in the European Union for treatment of invasive aspergillosis centration ability. Azotemia attributable to D-AMB is partic-
that is refractory to an AMB formulation or to itraconazole. ularly common in the doses required for treatment of invasive
Micafungin and anidulafungin, which are also members of the aspergillosis. D-AMB–related azotemia is exacerbated by con-
class of echinocandins, have in vitro, in vivo, and clinical ac- comitant nephrotoxic agents, particularly cyclosporine and tac-
tivity against aspergillosis but are not licensed in the United rolimus. Renal toxicity associated with the use of D-AMB has
States for this indication. Antifungal management of invasive the potential to lead to renal failure and dialysis, particularly
aspergillosis is summarized in table 2. A comprehensive review in HSCT recipients and in patients with diabetes mellitus, pa-
of antifungal compounds is beyond the scope of these guide- tients with underlying renal impairment, and patients receiving
lines and is covered in detail elsewhere [84–86]. Because the concomitant nephrotoxic agents. Hospitalized patients receiv-
IDSA Guidelines for Aspergillosis • CID 2008:46 (1 February) • 331

6. Table 2. Summary of recommendations for the treatment of aspergillosis.
a
Therapy
b
Condition Primary Alternative Comments
Invasive pulmonary aspergillosis Voriconazole (6 mg/kg IV every 12 h for 1 L-AMB (3–5 mg/kg/day IV), ABLC (5 mg/ Primary combination ther-
day, followed by 4 mg/kg IV every 12 kg/day IV), caspofungin (70 mg day 1 IV apy is not routinely rec-
h; oral dosage is 200 mg every 12 h) and 50 mg/day IV thereafter), micafun- ommended based on
gin (IV 100–150 mg/day; dose not esta- lack of clinical data; ad-
c
blished ), posaconazole (200 mg QID dition of another agent
initially, then 400 mg BID PO after sta- or switch to another
d
bilization of disease ), itraconazole (dos- drug class for salvage
e
age depends upon formulation) therapy may be consid-
ered in individual pa-
tients; dosage in pediat-
ric patients for
voriconazole is 5–7 mg/
kg IV every 12 h and for
caspofungin is 50 mg/
m2/day; limited clinical
experience is reported
with anidulafungin; dos-
age of posaconazole in
pediatric patients has
not been defined; indi-
cations for surgical in-
tervention are outlined
in table 3
Invasive sinus aspergillosis Similar to invasive pulmonary aspergillosis Similar to invasive pulmonary aspergillosis Similar to invasive pulmo-
nary aspergillosis
Tracheobronchial aspergillosis Similar to invasive pulmonary aspergillosis Similar to invasive pulmonary aspergillosis Similar to invasive pulmo-
nary aspergillosis
Chronic necrotizing pulmonary Similar to invasive pulmonary aspergillosis Similar to invasive pulmonary aspergillosis Because chronic necrotiz-
aspergillosis (subacute inva- ing pulmonary aspergil-
sive pulmonary aspergillosis) losis requires a pro-
tracted course of
therapy measured in
months, an orally ad-
ministered triazole, such
as voriconazole or itra-
conazole, would be pre-
ferred over a parenter-
ally administered agent
Aspergillosis of the CNS Similar to invasive pulmonary aspergillosis Similar to invasive pulmonary aspergillosis This infection is associ-
ated with the highest
mortality among all of
the different patterns of
invasive aspergillosis;
drug interactions with
anticonvulsant therapy
f
Aspergillus infections of the … Similar to invasive pulmonary aspergillosis Endocardial lesions
heart (endocarditis, pericardi- caused by Aspergillus
tis, and myocarditis) species require surgical
resection; aspergillus
pericarditis usually re-
quires pericardiectomy
f
Aspergillus osteomyelitis and … Similar to invasive pulmonary aspergillosis Surgical resection of devi-
septic arthritis talized bone and carti-
lage is important for cu-
rative intent
Aspergillus infections of the Intraocular AMB indicated with partial Similar to invasive pulmonary aspergillo- Systemic therapy may be
f
eye (endophthalmitis and vitrectomy sis; limited data with echinocandins beneficial in manage-
keratitis) ment of aspergillus en-
dophthalmitis; ophthal-
mologic intervention
and management is rec-
ommended for all forms
of ocular infection; topi-
cal therapy for keratitis
is indicated
(continued)
332

7. Table 2. (Continued.)
a
Therapy
b
Condition Primary Alternative Comments
f
Cutaneous aspergillosis … Similar to invasive pulmonary aspergillosis Surgical resection is indi-
cated where feasible
f
Aspergillus peritonitis … Similar to invasive pulmonary aspergillosis …
Empirical and preemptive anti- For empirical antifungal therapy, L-AMB (3 … Preemptive therapy is a
fungal therapy mg/kg/day IV), caspofungin (70 mg day logical extension of em-
1 IV and 50 mg/day IV thereafter), itra- pirical antifungal therapy
conazole (200 mg every day IV or 200 in defining a high-risk
mg BID), voriconazole (6 mg/kg IV ev- population with evi-
ery 12h for 1 day, followed by 3 mg/kg dence of invasive fungal
IV every 12 h; oral dosage is 200 mg infection (e.g., pulmo-
every 12 h) nary infiltrate or positive
galactomannan assay
result)
Prophylaxis against invasive Posaconazole (200 mg every 8h) Itraconazole (200 mg every 12 h IV for 2 Efficacy of posaconazole
aspergillosis days, then 200 mg every 24 h IV) or prophylaxis demon-
itraconazole (200 mg PO every 12 h); strated in high-risk pa-
micafungin (50 mg/day) tients (patients with
GVHD and neutropenic
patients with AML and
MDS)
g
Aspergilloma No therapy or surgical resection Itraconazole or voriconazole; similar to in- The role of medical ther-
vasive pulmonary aspergillosis apy in treatment of as-
pergilloma is uncertain;
penetration into preex-
isting cavities may be
minimal for AMB but is
excellent for
itraconazole
Chronic cavitary pulmonary Itraconazole or voriconazole Similar to invasive pulmonary aspergillosis Innate immune defects
g
aspergillosis demonstrated in most
of these patients; long-
term therapy may be
needed; surgical resec-
tion may lead to signifi-
cant complications; an-
ecdotal responses to
IFN-g
Allergic bronchopulmonary Itraconazole Oral voriconazole (200 mg PO every 12 h) Corticosteroids are a cor-
aspergillosis or posaconazole (400 mg PO BID) nerstone of therapy;
itraconazole has a de-
monstrable corticoste-
roid-sparing effect
Allergic aspergillus sinusitis None or itraconazole Few data on other agents …
NOTE. ABLC, AMB lipid complex; AMB, amphotericin B; AML, acute myelogenous leukemia; BID, twice daily; GVHD, graft-versus-host disease; IV,
intravenous; L-AMB, liposomal AMB; MDS, myelodysplastic syndrome; PO, orally; QID, 4 times daily.
a
Duration of therapy for most conditions for aspergillosis has not been optimally defined. Most experts attempt to treat pulmonary infection until resolution
or stabilization of all clinical and radiographic manifestations. Other factors include site of infection (e.g., osteomyelitis), level of immunosuppression, and
extent of disease. Reversal of immunosuppression, if feasible, is important for a favorable outcome for invasive aspergillosis.
b
Alternative (salvage) therapy for patients refractory to or intolerant of primary antifungal therapy.
c
Micafungin has been evaluated as salvage therapy for invasive aspergillosis but remains investigational for this indication, and the dosage has not been
established.
d
Posaconazole has been approved for the salvage treatment of invasive aspergillosis in the European Union but has not been evaluated as primary therapy
for invasive aspergillosis.
e
Dosage of itraconazole in treatment of invasive pulmonary aspergillosis depends on formulation. The dosage for tablets is 600 mg/day for 3 days, followed
by 400 mg/day. Although used in some case reports, oral solution is not licensed for treatment of invasive aspergillosis. Parenteral formulation has been
studied in a limited series using a dosage of 200 mg every 12h IV for 2 days, followed by 200 mg daily thereafter (whether this is an optimal dosage has
not been defined).
f
Most of these cases have been treated primarily with deoxycholate AMB in individual case reports. Although the preponderance of cases treated with
voriconazole in the randomized trial consisted of pulmonary invasive aspergillosis, successful treatment of other cases of extrapulmonary and disseminated
infection allows one to infer that voriconazole would also be effective in these cases, so that voriconazole is recommended as primary therapy for most of
these patients.
g
A more recent classification divides aspergilloma into 2 categories: chronic cavitary and single aspergilloma. The latter does not require antifungal therapy
but does require surgical therapy under some circumstances, and the former requires long-term antifungal therapy.
333

8. ing D-AMB have been reported to sustain a high frequency of relationships for ABLC and ABCD have not been well studied.
renal insufficiency and an excess mortality [89, 90]. Whether higher dosages of LFABs are beneficial in the treatment
of CNS aspergillosis, in other sites of infection, or in certain
LFAB conditions is also not well defined. Dosages of LFABs in pe-
Three LFABs have been approved in the United States and the diatric and adult patients achieve similar plasma exposures of
European Union: ABCD (Amphocil or Amphotec), ABLC AMB.
(Abelcet), and a small unilamellar vesicle L-AMB (AmBisome).
Because of their reduced nephrotoxicity in comparison with Antifungal Triazoles
D-AMB, these compounds allow for the infusion of higher The antifungal triazoles are synthetic compounds that have 1
dosages of AMB. Higher dosages are required for equivalent triazole ring attached to an isobutyl core (e.g., voriconazole,
antifungal efficacy, because amphotericin has to be released ravuconazole, and isavuconazole) or to an asymmetric carbon
from the synthetic phospholipids when in close proximity to atom with a lipophilic complex mixed functional aromatic
ergosterol, allowing for delivery of enough AMB to the site of chain (e.g., itraconazole and posaconazole). These 2 classes of
infection. anti-Aspergillus triazoles vary in their pharmacology and mech-
Each of the lipid formulations has plasma pharmacokinetic anisms of resistance. Fluconazole, which also is an antifungal
properties that are distinct from those of AMB. All 3 LFABs triazole, is not active against invasive aspergillosis. Voriconazole
preferentially distribute to reticulo endothelial system tissues is FDA approved for the primary treatment of invasive asper-
and functionally spare the kidney. In the kidney, less AMB is gillosis. Itraconazole is licensed for treatment of invasive as-
released from the lipid carrier, because the synthetic phospho- pergillosis in patients who are refractory to or intolerant of
lipids have a greater affinity for AMB than does cholesterol in standard antifungal therapy. Posaconazole is FDA approved for
renal epithelial cell membranes. prevention of invasive aspergillosis in neutropenic patients re-
Infusion-related adverse effects of fever, chills, and rigor are ceiving remission induction chemotherapy for acute myelo-
less frequent with L-AMB, compared with D-AMB. However, genous leukemia or myelodysplastic syndrome and for HSCT
individual cases of substernal chest discomfort, respiratory dis- recipients with GVHD. The antifungal triazoles target ergosterol
tress, and sharp flank pain have been noted during infusion of biosynthesis by inhibiting the fungal cytochrome P450–depen-
L-AMB, and in a comparative study, hypoxic episodes asso- dent enzyme lanosterol 14-a-demethylase, resulting in altered
ciated with fever and chills were more frequent in ABCD re- cell membrane function and cell death or inhibition of cell
cipients than in D-AMB recipients. Mild increases in serum growth and replication. The triazoles also inhibit cytochrome
bilirubin and alkaline phosphatase levels have been observed P450–dependent enzymes of the fungal respiration chain. The
with all 3 formulations. Idiosyncratic reactions to one LFAB anti-Aspergillus triazoles are active in vitro and in vivo against
do not preclude the use of another LFAB. all common species of Aspergillus. Although some isolates of
ABLC and ABCD are approved at dosages of 5 mg/kg/day A. fumigatus have been found to be resistant to itraconazole,
and 3–4 mg/kg/day, respectively, and L-AMB is approved at a resistance to the anti-Aspergillus triazoles has been unusual thus
dosage of 3–5 mg/kg/day for salvage therapy of invasive as- far; however, recent studies suggest that the rate may be in-
pergillosis. A dosage of 3 mg/kg/day of L-AMB is used initially creasing [82, 93].
for empirical antifungal therapy in persistently febrile neutro- Voriconazole. Voriconazole is formulated as tablets or as a
penic patients. The optimal dosage for treatment of invasive sulfobutyl-ether cyclodextrin solution for IV administration.
aspergillosis has not been defined for any of the LFABs. Al- Sulfobutyl-ether cyclodextrin and voriconazole dissociate in
though many experts would use the higher dosage range for plasma and follow their own disposition. As the cyclodextrin
treatment of documented infection, there are no data from molecule is renally cleared, accumulation of the vehicle occurs
controlled trials supporting higher dosages. Although L-AMB in individuals with renal insufficiency. The consequences of
has been safely administered at dosages as high as 15 mg/kg/ plasma accumulation of sulfobutyl-ether cyclodextrin are un-
day, one study did not demonstrate a trend to a dose-response certain at this time, and caution is advised when using the IV
relationship [91]. That higher dosages of L-AMB are not nec- formulation in patients with renal impairment (C-III). The
essarily equivalent to greater response rate was recently dem- relative benefits and uncertain risks of the sulfobutyl-ether cy-
onstrated by Cornely et al. [92]. This recent prospective, ran- clodextrin parenteral solution of voriconazole in the context
domized trial of L-AMB, which compared a dosage of 3 mg/ of invasive aspergillosis and renal failure should be determined
kg/day with a dosage of 10 mg/kg/day for primary treatment on an individual patient basis. This concern does not apply to
of proven and probable invasive aspergillosis in 201 patients, orally administered voriconazole. The oral formulation has
found similar survival rates and overall response rates; greater good bioavailability in the fed or fasted state. Voriconazole is
toxicity was seen in the higher-dosage group. The dose-response widely distributed in mammalian tissues, with CSF levels of
334 • CID 2008:46 (1 February) • Walsh et al.

9. ∼50% in plasma levels. The elimination half-life of ∼6 h war- Absorption is improved when the capsules are taken with food
rants twice-daily dosing. Voriconazole is hepatically metabo- or an acidic cola beverage. HPCD solution of itraconazole pro-
lized, with only 5% of the drug appearing unchanged in the vides more-uniform oral bioavailability that is further enhanced
urine. This agent exhibits nonlinear pharmacokinetics, with in the fasting state. Systemic absorption of the cyclodextrin
maximum concentration in plasma and area under the curve carrier is negligible.
increasing disproportionally with increasing dose. Voriconazole Itraconazole is extensively metabolized in the liver and is
is both a substrate and an inhibitor of CYP2C19, CYP2C9, and excreted in metabolized form into bile and urine. The major
CYP3A4. The patient’s current medications should be reviewed metabolite, hydroxy-itraconazole, possesses antifungal activity
for potentially deleterious drug interactions. Allelic polymor- that is similar to that of itraconazole [96–98]. Most observed
phisms in CYP2C19 may result phenotypically in rapid or slow reactions to itraconazole are transient and include nausea and
metabolism of voriconazole, possible resulting in significant vomiting, hypertriglyceridemia, hypokalemia, and elevated he-
variation in plasma concentrations. Single-nucleotide poly- patic aminotransferase enzyme levels. Gastrointestinal intol-
morphisms contributing to slow metabolism are represented erance appears to be more frequent with oral HPCD itracon-
in higher frequencies among non-Indian Asian populations azole solution. Because itraconazole use may infrequently cause
than among other populations. negative inotropic effects, it should be administered with cau-
Treatment of invasive aspergillosis with voriconazole is ini- tion to patients with ventricular dysfunction. Itraconazole is a
tiated with a loading dose of 6 mg/kg IV every 12 h for 2 doses, substrate of CYP3A4 but also interacts with the heme moiety
followed by 4 mg/kg every 12 h. These dosages are greater than of CYP3A4, resulting in noncompetitive inhibition of oxidative
those routinely administered for oral therapy (200 mg every metabolism of many CYP3A4 substrates. Serious interactions
12 h). Oral therapy can be approximated to the standard IV
with some chemotherapeutic agents (e.g., cyclophosphamide)
dosage by using 4 mg/kg/dose rounded up to convenient pill
further limit its use [99].
sizes (B-III), although use of oral voriconazole in these doses
The recommended dosage range of oral itraconazole in adults
is investigational and has not been carefully studied. Because
is 400 mg/day (capsules) and 2.5 mg/kg twice daily (HPCD
patients initially received IV therapy in the original randomized
solution). In pediatric patients aged 15 years, a dosage of oral
clinical trial of voriconazole, parenteral therapy, where feasible,
itraconazole HPCD solution of 2.5 mg/kg twice daily has been
is recommended to approximate the results of that study. Be-
recommended [100]. The approved adult dosages of IV HPCD
cause of the more accelerated metabolic clearance in pediatric
itraconazole are 200 mg twice daily for 2 days, followed by 200
patients, the doses of voriconazole may be higher [94]. A main-
mg once daily for a maximum of 12 days. Because of the erratic
tenance dosage of 7 mg/kg twice daily in pediatric patients is
bioavailability of itraconazole, measurements of plasma con-
recommended by the European Medicines Agency for the at-
centrations of itraconazole by bioassay or by HPLC are rec-
tainment of plasma levels comparable to those of adults. Load-
ommended during oral therapy of invasive aspergillosis (A-III).
ing regimens in pediatric populations have not been adequately
Posaconazole. Posaconazole is structurally similar to itra-
studied. Measurement of serum levels, especially in patients
conazole but has been studied in the treatment of invasive
receiving oral therapy, may be useful in some patients, either
aspergillosis only in the oral formulation. Posaconazole exhibits
to evaluate for potential toxicity or to document adequate drug
exposure, especially in progressive infection (B-III) [95]. not only linear kinetics but also saturable absorption; thus, oral
Voriconazole’s profile of adverse reactions includes transient loading doses are not possible. Steady-state levels may not be
visual disturbances (characterized principally by photopsia); achieved for up to a week with posaconazole therapy, which
hepatotoxicity, which may be dose limiting (manifested by el- may impact its use in primary therapy. Posaconazole undergoes
evated serum bilirubin, alkaline phosphatase, and hepatic ami- hepatic metabolism via glucuronidation and also has the ca-
notransferase enzyme levels); skin rash (usually in sunlight- pacity for drug-drug interactions through inhibition of CYP450
exposed areas), visual hallucinations; and others [85]. 3A4 isoenzymes. Significantly more toxicity was observed in
Itraconazole. Itraconazole is a high molecular weight, patients with acute leukemia or myelodysplasia who were re-
highly lipophilic compound that is formulated as capsules, oral ceiving posaconazole for prophylaxis than in such patients re-
solution in hydroxypropyl-b-cyclodextrin (HPCD), and par- ceiving prophylactic fluconazole or itraconazole [92].
enteral solution that also uses HPCD as solubilizer. Absorption Laboratory animal studies demonstrate activity of the oral
from the capsular formulation, which is enhanced by low gastric formulation in the prevention and treatment of experimental
pH and dietary lipids, may be erratic or negligible in the fasting pulmonary and disseminated aspergillosis [101, 102]. Recently
state, particularly in granulocytopenic patients with cancer and completed clinical trials are consistent with these laboratory
in patients with hypochlorhydria, and its use in seriously ill findings, demonstrating activity in the prevention of invasive
patients with life-threatening infection is not recommended. aspergillosis in neutropenic patients with acute myelogenous
IDSA Guidelines for Aspergillosis • CID 2008:46 (1 February) • 335

10. leukemia and in HSCT recipients with GVHD, as well as in istration. They exhibit dose-proportional plasma pharmaco-
salvage therapy for refractory invasive aspergillosis [103–105]. kinetics with a b half-life of 10–15 h that allows for once-daily
The dosage of the oral suspension of prophylaxis is 200 mg dosing. All echinocandins are highly (195%) protein bound
3 times per day, and the dosage for salvage treatment is 800 and distribute into all major organ sites, including the brain;
mg administered in 2 or 4 divided doses. The dosage in pe- however, concentrations in uninfected CSF are low. Caspofun-
diatric patients is not established. Limited data are available on gin and micafungin are metabolized by the liver and slowly
the use of therapeutic drug monitoring, but in one study, im- excreted into the urine and feces. Anidulafungin is slowly de-
proved efficacy occurred with higher posaconazole drug levels graded nonenzymatically in plasma and then hepatically
[103]. excreted.
Therapeutic drug monitoring. A growing body of evidence At the currently investigated dosages, all echinocandins are
suggests patient-to-patient variability in the pharmacokinetics generally well tolerated, and only a small fraction of patients
of triazoles used for treatment or prophylaxis in invasive as- enrolled in the various clinical trials have discontinued therapy
pergillosis [95, 103, 106, 107]. Absorption issues (for itracon- because of drug-related adverse events. The most frequently
azole and posaconazole), drug-drug interactions (for all tria- reported adverse effects include increased liver aminotransfer-
zoles), and pharmacogenetic differences (for voriconazole) all ase enzyme levels, gastrointestinal upset, and headaches. As with
contribute in various degrees to this variability [84]. Although other basic polypeptides, the echinocandins have the potential
the available data do not allow consensus and specific rec- to cause histamine release; however, histamine-like symptoms
ommendations for therapeutic drug monitoring, accumulating have been observed only in isolated cases, which may be related
reports suggest that plasma drug level monitoring may play an to infusion rates that are more rapid than recommended. The
important role in optimizing the safety (for voriconazole and current echinocandins appear to have no significant potential
flucytosine) and efficacy (for itraconazole, posaconazole, and for drug interactions mediated by the CYP450 enzyme system.
possibly, voriconazole) of antifungals with significant interpa- Caspofungin can reduce the area under the curve of tacrolimus
tient pharmacokinetic variability among a complex patient by ∼20% but has no effect on cyclosporine levels. However,
population, such as patients at risk for or who have invasive cyclosporine increases the area under the curve of caspofungin
aspergillosis. The necessity of documenting or continuing ther- by ∼35%; because of transient elevations of hepatic amino-
apeutic drug monitoring (once therapeutic concentrations are transferase enzyme levels in single-dose interaction studies, the
documented) should be individualized as determined by the concomitant use of both drugs should be done with caution
clinical status of the host (e.g., specific organ function, co- (B-III). Finally, inducers of drug clearance and/or mixed in-
morbidities, and receipt of concomitant medications) and the ducer/inhibitors, namely efavirenz, nelfinavir, nevirapine, phen-
overall treatment plans. Although further work is needed to ytoin, rifampin, dexamethasone, and carbamazepine, may re-
validate therapeutic drug monitoring approaches for antifun- duce caspofungin concentrations.
gals, the committee recommends that determination of a Caspofungin is indicated in patients with probable or proven
plasma drug level, in conjunction with other measures of clin- invasive aspergillosis that is refractory to or intolerant of other
ical assessment, may be another factor in evaluating reasons approved therapies. The currently recommended dosage regi-
for therapeutic failure attributable to suboptimal drug expo- men of caspofungin in adults consists of a single 70-mg loading
sures or for toxicity attributable to the drug (B-III). dose on day 1, followed by 50 mg/day thereafter, administered
by slow IV infusion of ∼1 h. Maertens et al. [109] reported
Echinocandins: Caspofungin, Micafungin, and Anidulafungin the use of higher doses of caspofungin (70 mg/day) for use in
The echinocandins are a novel class of semisynthetic amphi- salvage combination therapy of invasive aspergillosis. In cases
philic lipopeptides composed of a cyclic hexapeptide core of markedly reduced hepatic function, adult patients should
linked to a variably configured N-acyl side chain [108]. The receive a daily dose of 35 mg. Caspofungin administration at
echinocandins act by noncompetitive inhibition of the synthesis 50 mg/m2/day in children provides exposure that is comparable
of 1,3-b-glucan, a polysaccharide in the cell wall of many path- to that obtained at a dosage of 50 mg/day in adults [110].
ogenic fungi. Together with chitin, the rope-like glucan fibrils Micafungin and anidulafungin have activity against Aspergillus
are responsible for the cell wall’s strength and shape. They are species but are not approved for that indication, and optimal
important in maintaining the osmotic integrity of the fungal doses for aspergillosis have not been established. Micafungin
cell and play a key role in cell division and cell growth. Because at a mean daily dose of 111 mg was used in one open-label
of their distinct mechanism of action, the echinocandins have trial. However, on a mg/kg basis, higher doses may be needed
the potential for use in combination regimens with currently in young children and infants to achieve a plasma exposure
available standard antifungal agents. that is comparable to that in adults [111, 112]. Although an-
All current echinocandins are only available for IV admin- idulafungin is active in experimental pulmonary aspergillosis,
336 • CID 2008:46 (1 February) • Walsh et al.

11. there is relatively little reported experience describing its use day) and showed similar efficacy in both arms but greater tox-
in the treatment of invasive aspergillosis. icity in the higher-dose arm. These results suggest that L-AMB
may be considered as alternative primary therapy in some
TREATMENT GUIDELINE OVERVIEW patients (A-I). For salvage therapy, agents include LFABs (A-
II), posaconazole (B-II), itraconazole (B-II), caspofungin (B-
The following practice guidelines provide recommendations for
II), or micafungin (B-II). In that context, the diagnosis should
treatment of the different forms of aspergillosis. For each form
be confirmed. Therapeutic options include a change of class
of aspergillosis, the objective, treatment options, outcome of
using an AMB formulation or an echinocandin (B-II); ad-
treatment, evidence, values, benefits and harms, and key rec-
ditional use of an azole should take into account prior therapy,
ommendations are specified, where appropriate. The panel per-
host factors, and pharmacokinetic considerations.
formed extensive review of all the randomized, controlled, and
In the absence of a well-controlled, prospective clinical
observational trials published in the English-language literature.
trial, routine administration of combination therapy for pri-
Final recommendations were discussed by the panel and de-
mary therapy is not routinely recommended (B-II). The com-
termined by consensus. Because invasive pulmonary aspergil-
mittee recognizes, however, that in the context of salvage
losis is the most common life-threatening form of invasive
aspergillosis, more emphasis is placed on its management than therapy, an additional antifungal agent might be added to
on other aspects of clinical infection. Many of the statements current therapy, or combination antifungal drugs from dif-
concerning treatment of invasive pulmonary aspergillosis are ferent classes other than those in the initial regimen may be
also applicable to other forms of invasive aspergillosis. used (B-II). In addition, management of breakthrough in-
vasive aspergillosis in the context of mould-active azole pro-
INVASIVE ASPERGILLOSIS phylaxis or suppressive therapy is not defined by clinical trial
data but would suggest a switch to another drug class (B-
III). Paramount to the successful treatment of invasive pul-
INVASIVE PULMONARY ASPERGILLOSIS monary aspergillosis is the reversal of immunosuppression (e.g.,
Without adequate therapy, invasive pulmonary aspergillosis will reduction in the dosage of corticosteroids) or recovery from
almost always progress to relentless fatal pneumonia. In neu- neutropenia. Surgical resection of Aspergillus-infected tissue
tropenic patients, this pneumonia may be characterized by dev- may be useful in patients with lesions that are contiguous
astating hemorrhagic infarction or progressive necrotizing with the great vessels or pericardium, lesions causing he-
pneumonia. Without adequate therapy, invasive pulmonary as- moptysis from a single focus, and lesions causing erosion
pergillosis is further complicated by dissemination to the CNS into the pleural space or ribs (B-III).
or by extension to contiguous intrathoracic structures, includ- Duration of antifungal therapy for invasive pulmonary as-
ing the great vessels and the heart. Because of the potential pergillosis is not well defined. We generally recommend that
progression of this infection, the early administration of an- treatment of invasive pulmonary aspergillosis be continued for
tifungal therapy while diagnostic evaluation is undertaken is a minimum of 6–12 weeks; in immunosuppressed patients,
critical. therapy should be continued throughout the period of im-
munosuppression and until lesions have resolved. Long-term
Key Recommendations therapy of invasive aspergillosis is facilitated by the availability
Early initiation of antifungal therapy in patients with of oral voriconazole in stable patients. For patients with suc-
strongly suspected invasive aspergillosis is warranted while cessfully treated invasive aspergillosis who will require sub-
a diagnostic evaluation is conducted (A-I) [29, 92]. The de- sequent immunosuppression, resumption of antifungal ther-
cision of medical therapy for treatment of invasive pulmonary apy can prevent recurrent infection (A-III) [113, 114].
aspergillosis has been greatly facilitated by a randomized, con- Therapeutic monitoring of invasive pulmonary aspergillosis
trolled trial of voriconazole versus D-AMB. includes serial clinical evaluation of all symptoms and signs, as
Because of better survival and improved responses of initial well as performance of radiographic imaging, usually with CT,
therapy with voriconazole, primary therapy with D-AMB is not at regular intervals. The frequency with which CT should be
recommended (A-I). For primary treatment of invasive pul- performed cannot be universally defined and should be indi-
monary aspergillosis, IV or oral voriconazole is recom- vidualized on the basis of the rapidity of evolution of pul-
mended for most patients (A-I). Oral therapy can be maxi- monary infiltrates and the acuity of the individual patient. The
mized by using a dose of 4 mg/kg rounded up to convenient volume of pulmonary infiltrates may increase for the first 7–
pill sizes (B-111). For seriously ill patients, the parenteral 10 days of therapy—especially in the context of granulocyte
formulation is recommended (A-III). A randomized trial com- recovery [27]. The use of serial serum galactomannan assays
pared 2 initial dosages of L-AMB (3 mg/kg/day and 10 mg/kg/ for therapeutic monitoring is promising but remains investi-
IDSA Guidelines for Aspergillosis • CID 2008:46 (1 February) • 337

12. gational [48, 49]. Progressive increase in Aspergillus antigen treatment groups, the patient population included those with
levels over time signifies a poor prognosis. However, resolution possible aspergillosis. When those patients with possible as-
of galactomannan antigenemia to a normal level is not suf- pergillosis are excluded from the analysis, the data reveal a trend
ficient as a sole criterion for discontinuation of antifungal toward improved response in patients with proven and prob-
therapy (B-III). Further data elucidating the prognostic and able aspergillosis who were treated with the higher dosage,
therapeutic value of serial galactomannan levels in patients with which is consistent with the data from animal models dem-
invasive pulmonary aspergillosis are needed. onstrating a dose-response relationship [32, 121]. Another
study randomized patients with documented invasive asper-
Evidence gillosis to receive ABCD (6 mg/kg/day) versus D-AMB (1 mg/
Data on antifungal therapy. There are few randomized clin- kg/day) for primary treatment of invasive aspergillosis [119].
ical trials on the treatment of invasive aspergillosis. Invasive This study found that patients randomized to either arm had
pulmonary aspergillosis is a life-threatening infection associated similar outcomes but poor overall responses (patients with
with severe morbidity and mortality. Invasive pulmonary as- complete and partial responses, 17% in the ABCD group vs.
pergillosis may be the source for dissemination to the CNS and 23% in the D-AMB group), and those receiving ABCD had less
other critical organs. This infection has been extremely difficult nephrotoxicity (25% vs. 49%). More recently, Cornely et al.
to study in prospective, randomized trials. The largest pro- [92] compared an initial dosage of L-AMB of 10 mg/kg/day
spective, randomized trial for the treatment of invasive pul- for 2 weeks with a dosage of 3 mg/kg/day. In that study, among
monary aspergillosis demonstrated that voriconazole was su- 201 patients, overall outcomes in the 2 arms were similar (46%
perior to D-AMB, followed by other licensed antifungal therapy in the high-dose arm vs. 50% in the low-dose arm), but there
[115]. All patients had proven or probable invasive aspergillosis, was more toxicity (32% vs. 20%) in the high-dose arm, sug-
and most of them had pneumonia. Voriconazole was admin- gesting that higher doses were not beneficial in these patients,
istered at a dosage of 6 mg/kg every 12 h for 2 doses as a the majority of whom had early invasive pulmonary aspergil-
loading dose, followed by 4 mg/kg every 12 h IV for the first losis diagnosed by CT.
7 days, followed by 200 mg twice daily thereafter. D-AMB was For patients who are intolerant of or refractory to voricon-
administered at 1.0–1.5 mg/kg/day IV; other licensed antifungal azole, a formulation of AMB is an appropriate alternative. D-
therapy was permitted if the initial therapy failed or if the AMB historically has been used in the treatment of invasive
patient had intolerance to the first drug. This study demon- aspergillosis. However, the available data indicate that the
strated significantly improved survival, improved overall re- LFABs are as effective as D-AMB but less nephrotoxic [119,
sponse rate at 12 weeks of therapy, and improved overall re- 122–125]. That LFABs are effective against invasive pulmonary
sponse at end of therapy. Successful outcome was achieved in aspergillosis and other forms of invasive aspergillosis is also
53% of patients in the voriconazole arm and 32% of patients demonstrated in several large, open-label, compassionate-re-
in the D-AMB arm, resulting in an absolute difference of 21%. lease studies with a response rate of ∼40% [124–126]. For those
Survival rate at 12 weeks was 71% among voriconazole-treated patients with underlying hepatotoxicity or other contraindi-
patients and 58% among D-AMB–treated patients. Recipients cations to voriconazole, an LFAB is less toxic than is D-AMB
of voriconazole had fewer severe drug-related adverse events. and is likely to be at least as effective as D-AMB as an alternative
However, transient visual disturbances occurred more fre- for primary therapy.
quently with voriconazole, as discussed in the earlier section A study of caspofungin for patients who are intolerant of or
on antifungal compounds in this article. The efficacy of vori- refractory to conventional therapy also demonstrated a favor-
conazole was further demonstrated in pediatric and adult pa- able response rate of ∼40% [127]. Higher responses (50%)
tients receiving voriconazole for treatment of invasive asper- occurred with invasive pulmonary aspergillosis than with dis-
gillosis who were refractory to or intolerant of conventional seminated aspergillosis (23%). Drug-related nephrotoxicity and
antifungal therapy [116–118]; the overall response rate was 43% hepatotoxicity occurred in !5% of patients.
and 48% for pediatric and adult patients, respectively. Orally administered itraconazole has also been used to treat
Two earlier and smaller randomized trials of the primary patients with invasive aspergillosis who are refractory to or
treatment of invasive aspergillosis [119, 120] and another recent intolerant of D-AMB [24, 128]. In a study of 76 evaluable
dose comparison study of L-AMB [92] have been reported. An patients, all of whom were able to take oral therapy, 30 patients
earlier prospective, randomized trial of 2 dosages of L-AMB (39%) had a complete or partial response, with success rates
(1.0 mg/kg/day vs. 4.0 mg/kg/day) for treatment of invasive varying widely according to site of disease and underlying dis-
aspergillosis was conducted by the European Organization for ease group [128]. More recent studies of the parenteral for-
Research in Treatment of Cancer [120]. Although this study mulation of b-hydroxy-propyl-cyclodextrin itraconazole in the
found no difference in response rate or survival between the 2 treatment of invasive pulmonary aspergillosis that was refrac-
338 • CID 2008:46 (1 February) • Walsh et al.

13. tory to various forms of AMB have been reported, with overall port combination therapy as routine primary treatment of in-
response rates of 52% [129, 130]. Measurement of itraconazole vasive pulmonary aspergillosis. Although initial laboratory
serum levels are generally recommended to document ab- studies, case reports, and retrospective case series indicate en-
sorption of drug (B-II). Although evidence to support a cor- couraging findings, the efficacy of primary combination anti-
relation between higher drug levels and efficacy is limited, levels fungal therapy requires a prospective, randomized clinical trial
1250 ng/mL have been associated with more-favorable out- to justify this approach. Additional questions of optimal dosing,
comes. Salvage therapy of itraconazole for treatment of in- pharmacokinetic interactions, potential toxic interactions, and
vasive pulmonary aspergillosis that is refractory to primary cost-benefit ratios of primary combination antifungal therapy
therapy with voriconazole is not recommended because of also require further investigation.
the same mechanism of action or possible resistance and Impact of Aspergillus species. Consideration should be
because of the erratic bioavailability and toxicity (B-II). given to the infecting species of Aspergillus. Most isolates of A.
Posaconazole was approved in Europe for salvage treatment fumigatus are susceptible in vitro and responsive in vivo to
of patients with invasive aspergillosis who are refractory to AMB AMB, voriconazole, posaconazole, itraconazole, and caspofun-
or itraconazole. The overall success rate in an externally con- gin. However, most isolates of A. terreus are resistant in vitro
trolled, open-label trial using Data Review Committee–assessed and in vivo to AMB. The aggregate body of data thus far
global response at end of treatment was 42% for the posacon- warrants that an antifungal triazole should be used instead
azole group and 26% for the control group [103]. The differ- of AMB in the primary treatment of infection due to A.
ences in response between the treatment groups were preserved terreus (A-II) [18]. Although uncommon, some isolates of A.
across additional, prespecified subsets, including infection site fumigatus that are resistant to itraconazole have been reported.
(pulmonary or disseminated), hematological malignancy, Other species of Aspergillus may also be resistant to AMB, in-
HSCT, baseline neutropenia, and enrollment reason (refractory cluding A. lentulus, A. nidulans, A. ustus, and Aspergillus ver-
or intolerant). A difference in response was also seen in a con- sicolor. Known itraconazole-resistant isolates of A. fumigatus
firmatory analysis subpopulation (patients who received prior were recovered from patients who were not profoundly im-
antifungal therapy for 7–30 days before the start of salvage munosuppressed and otherwise should have responded to itra-
therapy). As with other salvage trials, patients enrolled in this conazole [140]. Multiazole-resistant Aspergillus species have
study were a selected population who had received prior ther- also been recently reported [82]. Antifungal susceptibility test-
apy, and for posaconazole salvage studies, patients were also ing, especially in the context of prior azole therapy, may be
selected on the basis of their ability to receive the oral for- warranted as a guide to therapy, although very limited clinical
mulation of posaconazole. The salvage study also demonstrated data support this approach. Pending susceptibility data, the
a direct relationship between serum concentration and response administration of a different class of agent (AMB formulation
rate. One should note, however, that these serum concentra- or echinocandin) may be warranted.
tions were achieved in patients receiving the highest adult dos- Use of colony-stimulating factors. Reversal of immuno-
age (800 mg administered in divided doses over 24 h) at which suppression is an important factor in successful treatment of
maximum absorption of compound is known to occur. Thus, invasive pulmonary aspergillosis. Persistent neutropenia and
further increases in the oral adult dosage are unlikely to yield chronic GVHD are 2 of the most important variables for poor
higher plasma concentrations. outcome in invasive aspergillosis [6, 141]. Failure to recover
Most of the prospective studies of second-line therapy have from neutropenia is often associated with a fatal outcome of
been conducted by replacing the compound to which the pa- invasive pulmonary aspergillosis. Although colony-stimulating
tient is intolerant or against which the infection is progressing. factors are widely used to attempt to reduce the duration of
Whether both drugs should be administered simultaneously neutropenia, there are limited data from randomized, con-
has seldom been prospectively studied [111], nor are there trolled trials to demonstrate that granulocyte colony-stimulat-
compelling prospective clinical data to support combination ing factor or granulocyte-macrophage colony-stimulating fac-
antifungal therapy over single-agent therapy for primary ther- tor prevents the development of invasive pulmonary
apy of invasive aspergillosis [131]. The addition of a second aspergillosis in patients with prolonged neutropenia (duration
antifungal agent to a first agent that is failing or toxic is usually of neutropenia, 110 days) [142]. Although high-risk neutro-
practiced out of understandable desperation. Nevertheless, lim- penic patients with invasive aspergillosis may already be re-
ited in vitro, in vivo, and nonrandomized clinical trial data ceiving granulocyte colony-stimulating factor or granulocyte-
suggest the benefit of some forms of combination therapy macrophage colony-stimulating factor as a component of
against invasive aspergillosis [109, 131–137]. However, not all their cancer chemotherapy, those neutropenic patients who
antifungal combinations are beneficial, and some may be del- are not receiving a colony-stimulating factor may benefit
eterious [138, 139]. There are insufficient clinical data to sup- from the addition of granulocyte colony-stimulating factor
IDSA Guidelines for Aspergillosis • CID 2008:46 (1 February) • 339