IDSA GUIDELINESTreatment of Aspergillosis: Clinical PracticeGuidelines of the Infectious Diseases Societyof AmericaThomas J. Walsh,1,a Elias J. Anaissie,2 David W. Denning,13 Raoul Herbrecht,14 Dimitrios P. Kontoyiannis,3Kieren A. Marr,5 Vicki A. Morrison,6,7 Brahm H Segal,8 William J. Steinbach,9 David A. Stevens,10,11Jo-Anne van Burik,7 John R. Wingard,12 and Thomas F. Patterson4,a1 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, SanAntonio; 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 ValleyMedical 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, FranceEXECUTIVE SUMMARY guidelines is to summarize the current evidence for treatment of different forms of aspergillosis. The qualityAspergillus 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 Societypatients. 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 . 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 published4 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 superiorDiseases Society of America. It is important to realize that guidelines cannot always account for individual to deoxycholate amphotericin B (D-AMB) as primaryvariation 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 beconsidered 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 invasiveDiseases Society of America considers adherence to these guidelines to bevoluntary, 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 andAmerica 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 trial7703 Floyd Curl Dr., MSC 7881, San Antonio, TX 78229-3900 (firstname.lastname@example.org). 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
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 pulmonaryvoriconazole, 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 involvescount host factors and pharmacokinetic considerations. Re- a combination of medical and anti-inﬂammatory therapy. Forfractory 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 andcombination 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 commondosage 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 speciesmended in the subgroup of HSCT recipients with graft-versus- also produce a wide range of chronic, saprophytic, and allergichost disease (GVHD) who are at high risk for invasive asper- conditions. Although other forms of aspergillosis, such asgillosis and in neutropenic patients with acute myelogenous ABPA, allergic sinusitis, and saprophytic infection, are alsoleukemia 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 arevasive 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 Publicsuch 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 antifungaldosing, therapeutic monitoring of drug levels, a switch to IV MICROBIOLOGY AND EPIDEMIOLOGY OFtherapy, 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 specieseration for surgical resection of the infected focus. These in- recovered from cases of invasive aspergillosis . The nextclude 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 . Some institutionsmyelitis, pericardial infection, and endocarditis (B-III). Res- may have a predominance of A. ﬂavus or A. terreus as the mosttoration of impaired host defenses is critical for improved out- frequently recovered species of Aspergillus . A. terreus iscome 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 resistancesteroids 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 . Invasive diseases caused by Aspergillus speciesosteomyelitis and endocarditis. There are very limited data on include infections of the lower respiratory tract, sinuses, andthese infections, and most involve D-AMB as primary therapy skin as portals of entry. The CNS, cardiovascular system, andsimply 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.
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 committeessemination 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-glucanand pulmonary aspergilloma. Allergic conditions encompass assay result and radiologically compatible CT ﬁndings) in anallergic Aspergillus sinusitis and allergic bronchopulmonary as- immunocompromised host with clinical ﬁndings of infectionpergillosis . 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 deﬁnitionsthroughout 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 anGroup and National Institute of Allergy and Infectious Diseases Aspergillus species. A study by Stevens and Lee  that ex-Mycoses Study Group formed a Consensus Committee to de- amined response of invasive aspergillosis to itraconazole usingvelop standard deﬁnitions for invasive fungal infections for Mycoses Study Group deﬁnitions found similar outcomes forclinical research . 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 Treatmentgillosis), as observed in immunocompromised patients with of Cancer–Mycoses Study Group document clearly articulatescancer, was developed. Three levels of certainty of invasive as- that the consensus deﬁnitions are not intended to be a directpergillosis were deﬁned: proven, probable, and possible. Al- guide to practice . Third, the deﬁnitions are principallythough the deﬁnitions are intended for use in the context of applicable to immunocompromised patients with cancer andclinical and/or epidemiological research, they provide a stan- HSCT recipients. These deﬁnitions are currently being reﬁneddard set of criteria by which guidelines can be developed for to reﬂect increasing understanding of the patterns of invasivethe 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 mediature 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 differentiatewithin 3 categories: host factors, clinical manifestations (symp- aspergillosis from other ﬁlamentous fungal infections, such astoms, 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 thoracoscopicproven or probable infection requires the recovery of an or- biopsy are standard procedures for establishing a diagnosis ofganism. The ﬁrst exception includes the fairly frequent occur- invasive pulmonary aspergillosis. Fluid and tissue specimensrence 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 microscopicThe 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
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 may26]. However, results of cytologic examination, pathologic ex- be lower, possibly because of a lower residual fungal burdenamination, direct smears, and culture may be falsely negative or anti-Aspergillus antibodies [53, 54]. The combined use offor clinical specimens from patients who are already receiving serum galactomannan antigen measurement and detection ofsystemic 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 . Several variables, includingnot be performed directly in the affected area or when the antifungal therapy or prophylaxis, signiﬁcantly reduce levels ofbronchoscope or biopsy needle could not reach the infected circulating galactomannan [35, 52]. False-positive results havetissues). Thus, lack of a positive culture or direct smear result been reported in several contexts, including in patients whodoes not rule out the diagnosis of invasive aspergillosis. More- have received certain antibiotics (pipercillin-tazobactam andover, recovery of Aspergillus species from clinical specimens by amoxicillin-clavulanate), in cases of neonatal colonization withinvasive procedures may be impractical in patients who are Biﬁdobacterium, the in cases in which plasmalyte is used inhemodynamically 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 ispatients 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 ofby 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 TachypleusAlthough these radiological features are characteristic, they are or Limulus assay [62–66]. The Tachypleus or Limulus assaynot diagnostic of invasive pulmonary aspergillosis. Infections used to detect the presence of (1r3)-b-D-glucans is a variationdue to other angioinvasive ﬁlamentous fungi, such as Zygo- of the limulus assay used to detect endotoxin. The presence ofmycetes, Fusarium species, and Scedosporium species, as well as (1r3)-b-D-glucans in serum signiﬁes the presence of fungalto Pseudomonas aeruginosa and Nocardia species, may cause a invasion but is not speciﬁc for Aspergillus species . False-halo sign and other radiological features described for asper- positive results can occur in a variety of contexts, such asgillosis. 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 vitroin 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) . The Fungitell assay The availability of the galactomannan EIA also may con- (Associates of Cape Cod) for detection of (1r3)-b-D-glucanstribute 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 aspergillosisin animal models and in patients as a surrogate marker for [66, 69]. One study reported that, among 283 patients withdetection of invasive aspergillosis [32–42]. Galactomannan an- acute myeloid leukemia and myelodysplastic syndrome whotigen has also been detected in CSF samples from patients with were receiving antifungal prophylaxis, the (1r3)-b-D-glucanCNS aspergillosis [43–45] and in bronchoalveolar lavage ﬂuid assay was sensitive and speciﬁc in early detection of 20 provenspecimens 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 infacilitate 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 DNAvestigational. 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- . Combining non–culture-based diagnostics (e.g., PCR andonstrated good sensitivity in the detection of invasive asper- GM and GM and [1r3]-b-D-glucan) is an important research330 • CID 2008:46 (1 February) • Walsh et al.
direction that may improve the overall predictive value of these experience of administration of these agents is predominantlysystems. 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 differencesoratory 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 throughthe Clinical and Laboratory Standards Institute provide repro- AMBducible methods for antifungal susceptibility testing. Further AMB is a natural polyene macrolide antibiotic that consists ofstudies using these in vitro methods may lead to improved 7 conjugated double bonds, an internal ester, a free carboxylrationale 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 solubilizedpergillus 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 thecaused by isolates with elevated MICs [81, 82]. cell membrane of most medically important fungi), leading to Recognizing that other ﬁlamentous fungi, such as Fusariumspecies, Scedosporium species, various dematiaceous (pig- the formation of ion channels and fungal cell death. AMB alsomented) 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, resultingestablished 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 thenosis 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 inANTIFUNGAL COMPOUNDS USED FOR vivo activity against most Aspergillus species. Most isolates ofTREATMENT OF INVASIVE ASPERGILLOSIS A. terreus are resistant to AMB in vitro, in vivo, and in patients. Following IV administration, AMB becomes highly proteinOver 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 thepounds and strategies targeted against invasive aspergillosis kidney. Peak plasma concentrations of 2–4 mg/mL are achievedhave occurred . The following FDA-approved compounds following IV infusion of 1 mg/kg of D-AMB. Clearance fromhave in vitro, in vivo, and clinical activity against Aspergillus plasma is slow, with a b half-life of 24–48 h and a terminalspecies 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 intoconazole, 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 islicensed for prophylaxis of invasive aspergillosis in neutropenic aches, and bronchospasm. D-AMB–induced nephrotoxicity ispatients with leukemia and myelodysplasia and in allogeneic characterized by azotemia, urinary wasting of potassium andHSCT 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 invasiveMicafungin 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 hasStates for this indication. Antifungal management of invasive the potential to lead to renal failure and dialysis, particularlyaspergillosis 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 receivinglines 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
Table 2. Summary of recommendations for the treatment of aspergillosis. a Therapy bCondition Primary Alternative CommentsInvasive 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 3Invasive sinus aspergillosis Similar to invasive pulmonary aspergillosis Similar to invasive pulmonary aspergillosis Similar to invasive pulmo- nary aspergillosisTracheobronchial aspergillosis Similar to invasive pulmonary aspergillosis Similar to invasive pulmonary aspergillosis Similar to invasive pulmo- nary aspergillosisChronic 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 agentAspergillosis 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 fAspergillus 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 fAspergillus osteomyelitis and … Similar to invasive pulmonary aspergillosis Surgical resection of devi- septic arthritis talized bone and carti- lage is important for cu- rative intentAspergillus 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
Table 2. (Continued.) a Therapy bCondition Primary Alternative Comments fCutaneous aspergillosis … Similar to invasive pulmonary aspergillosis Surgical resection is indi- cated where feasible fAspergillus 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) gAspergilloma 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 itraconazoleChronic 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-gAllergic 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 effectAllergic 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 resolutionor stabilization of all clinical and radiographic manifestations. Other factors include site of infection (e.g., osteomyelitis), level of immunosuppression, andextent 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 beenestablished. d Posaconazole has been approved for the salvage treatment of invasive aspergillosis in the European Union but has not been evaluated as primary therapyfor 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, followedby 400 mg/day. Although used in some case reports, oral solution is not licensed for treatment of invasive aspergillosis. Parenteral formulation has beenstudied 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 hasnot been deﬁned). f Most of these cases have been treated primarily with deoxycholate AMB in individual case reports. Although the preponderance of cases treated withvoriconazole in the randomized trial consisted of pulmonary invasive aspergillosis, successful treatment of other cases of extrapulmonary and disseminatedinfection allows one to infer that voriconazole would also be effective in these cases, so that voriconazole is recommended as primary therapy for most ofthese patients. g A more recent classiﬁcation divides aspergilloma into 2 categories: chronic cavitary and single aspergilloma. The latter does not require antifungal therapybut does require surgical therapy under some circumstances, and the former requires long-term antifungal therapy. 333
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 certainLFAB 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 ofEuropean 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 TriazolesD-AMB, these compounds allow for the infusion of higher The antifungal triazoles are synthetic compounds that have 1dosages 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 carbonfrom the synthetic phospholipids when in close proximity to atom with a lipophilic complex mixed functional aromaticergosterol, allowing for delivery of enough AMB to the site of chain (e.g., itraconazole and posaconazole). These 2 classes ofinfection. 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 antifungalproperties that are distinct from those of AMB. All 3 LFABs triazole, is not active against invasive aspergillosis. Voriconazolepreferentially 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 oflipids have a greater afﬁnity for AMB than does cholesterol in standard antifungal therapy. Posaconazole is FDA approved forrenal 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 HSCTindividual cases of substernal chest discomfort, respiratory dis- recipients with GVHD. The antifungal triazoles target ergosteroltress, 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 alteredciated with fever and chills were more frequent in ABCD re- cell membrane function and cell death or inhibition of cellcipients than in D-AMB recipients. Mild increases in serum growth and replication. The triazoles also inhibit cytochromebilirubin and alkaline phosphatase levels have been observed P450–dependent enzymes of the fungal respiration chain. Thewith all 3 formulations. Idiosyncratic reactions to one LFAB anti-Aspergillus triazoles are active in vitro and in vivo againstdo 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 thusdosage 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 apenic 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 inthough many experts would use the higher dosage range for plasma and follow their own disposition. As the cyclodextrintreatment of documented infection, there are no data from molecule is renally cleared, accumulation of the vehicle occurscontrolled trials supporting higher dosages. Although L-AMB in individuals with renal insufﬁciency. The consequences ofhas 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 IVrelationship . That higher dosages of L-AMB are not nec- formulation in patients with renal impairment (C-III). Theessarily equivalent to greater response rate was recently dem- relative beneﬁts and uncertain risks of the sulfobutyl-ether cy-onstrated by Cornely et al. . This recent prospective, ran- clodextrin parenteral solution of voriconazole in the contextdomized trial of L-AMB, which compared a dosage of 3 mg/ of invasive aspergillosis and renal failure should be determinedkg/day with a dosage of 10 mg/kg/day for primary treatment on an individual patient basis. This concern does not apply toof proven and probable invasive aspergillosis in 201 patients, orally administered voriconazole. The oral formulation hasfound similar survival rates and overall response rates; greater good bioavailability in the fed or fasted state. Voriconazole istoxicity was seen in the higher-dosage group. The dose-response widely distributed in mammalian tissues, with CSF levels of334 • CID 2008:46 (1 February) • Walsh et al.
∼50% in plasma levels. The elimination half-life of ∼6 h war- Absorption is improved when the capsules are taken with foodrants 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 enhancedurine. This agent exhibits nonlinear pharmacokinetics, with in the fasting state. Systemic absorption of the cyclodextrinmaximum 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 isis both a substrate and an inhibitor of CYP2C19, CYP2C9, and excreted in metabolized form into bile and urine. The majorCYP3A4. The patient’s current medications should be reviewed metabolite, hydroxy-itraconazole, possesses antifungal activityfor potentially deleterious drug interactions. Allelic polymor- that is similar to that of itraconazole [96–98]. Most observedphisms in CYP2C19 may result phenotypically in rapid or slow reactions to itraconazole are transient and include nausea andmetabolism 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 causethan 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 atiated with a loading dose of 6 mg/kg IV every 12 h for 2 doses, substrate of CYP3A4 but also interacts with the heme moietyfollowed by 4 mg/kg every 12 h. These dosages are greater than of CYP3A4, resulting in noncompetitive inhibition of oxidativethose routinely administered for oral therapy (200 mg every metabolism of many CYP3A4 substrates. Serious interactions12 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 .sizes (B-III), although use of oral voriconazole in these doses The recommended dosage range of oral itraconazole in adultsis investigational and has not been carefully studied. Because is 400 mg/day (capsules) and 2.5 mg/kg twice daily (HPCDpatients initially received IV therapy in the original randomized solution). In pediatric patients aged 15 years, a dosage of oralclinical trial of voriconazole, parenteral therapy, where feasible, itraconazole HPCD solution of 2.5 mg/kg twice daily has beenis recommended to approximate the results of that study. Be- recommended . The approved adult dosages of IV HPCDcause of the more accelerated metabolic clearance in pediatric itraconazole are 200 mg twice daily for 2 days, followed by 200patients, the doses of voriconazole may be higher . A main- mg once daily for a maximum of 12 days. Because of the erratictenance 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 invasivereceiving oral therapy, may be useful in some patients, either aspergillosis only in the oral formulation. Posaconazole exhibitsto evaluate for potential toxicity or to document adequate drugexposure, especially in progressive infection (B-III) . 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 bevisual disturbances (characterized principally by photopsia); achieved for up to a week with posaconazole therapy, whichhepatotoxicity, which may be dose limiting (manifested by el- may impact its use in primary therapy. Posaconazole undergoesevated 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 CYP450exposed areas), visual hallucinations; and others . 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 .enteral solution that also uses HPCD as solubilizer. Absorption Laboratory animal studies demonstrate activity of the oralfrom the capsular formulation, which is enhanced by low gastric formulation in the prevention and treatment of experimentalpH and dietary lipids, may be erratic or negligible in the fasting pulmonary and disseminated aspergillosis [101, 102]. Recentlystate, particularly in granulocytopenic patients with cancer and completed clinical trials are consistent with these laboratoryin patients with hypochlorhydria, and its use in seriously ill ﬁndings, demonstrating activity in the prevention of invasivepatients with life-threatening infection is not recommended. aspergillosis in neutropenic patients with acute myelogenous IDSA Guidelines for Aspergillosis • CID 2008:46 (1 February) • 335
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 bound3 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 slowlythe 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. excreted. Therapeutic drug monitoring. A growing body of evidence At the currently investigated dosages, all echinocandins aresuggests patient-to-patient variability in the pharmacokinetics generally well tolerated, and only a small fraction of patientsof triazoles used for treatment or prophylaxis in invasive as- enrolled in the various clinical trials have discontinued therapypergillosis [95, 103, 106, 107]. Absorption issues (for itracon- because of drug-related adverse events. The most frequentlyazole 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 withcontribute in various degrees to this variability . Although other basic polypeptides, the echinocandins have the potentialthe available data do not allow consensus and speciﬁc rec- to cause histamine release; however, histamine-like symptomsommendations for therapeutic drug monitoring, accumulating have been observed only in isolated cases, which may be relatedreports suggest that plasma drug level monitoring may play an to infusion rates that are more rapid than recommended. Theimportant role in optimizing the safety (for voriconazole and current echinocandins appear to have no signiﬁcant potentialﬂucytosine) 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 tacrolimustient 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 caspofunginaspergillosis. 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, thedocumented) should be individualized as determined by the concomitant use of both drugs should be done with cautionclinical 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 provenplasma drug level, in conjunction with other measures of clin- invasive aspergillosis that is refractory to or intolerant of otherical 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 loadingsures 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.  reportedEchinocandins: Caspofungin, Micafungin, and Anidulafungin the use of higher doses of caspofungin (70 mg/day) for use inThe echinocandins are a novel class of semisynthetic amphi- salvage combination therapy of invasive aspergillosis. In casesphilic lipopeptides composed of a cyclic hexapeptide core of markedly reduced hepatic function, adult patients shouldlinked to a variably conﬁgured N-acyl side chain . The receive a daily dose of 35 mg. Caspofungin administration atechinocandins act by noncompetitive inhibition of the synthesis 50 mg/m2/day in children provides exposure that is comparableof 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 .ogenic fungi. Together with chitin, the rope-like glucan ﬁbrils Micafungin and anidulafungin have activity against Aspergillusare responsible for the cell wall’s strength and shape. They are species but are not approved for that indication, and optimalimportant in maintaining the osmotic integrity of the fungal doses for aspergillosis have not been established. Micafungincell 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-labelof their distinct mechanism of action, the echinocandins have trial. However, on a mg/kg basis, higher doses may be neededthe potential for use in combination regimens with currently in young children and infants to achieve a plasma exposureavailable 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.
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 someTREATMENT 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 shouldtreatment of the different forms of aspergillosis. For each form be conﬁrmed. Therapeutic options include a change of classof 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 clinicalobservational 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 salvagelosis is the most common life-threatening form of invasiveaspergillosis, more emphasis is placed on its management than therapy, an additional antifungal agent might be added toon 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 bealso 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 fromalmost always progress to relentless fatal pneumonia. In neu- neutropenia. Surgical resection of Aspergillus-infected tissuetropenic patients, this pneumonia may be characterized by dev- may be useful in patients with lesions that are contiguousastating 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 erosionpergillosis 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 thatprogression of this infection, the early administration of an- treatment of invasive pulmonary aspergillosis be continued fortifungal 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-termKey Recommendations therapy of invasive aspergillosis is facilitated by the availabilityEarly 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 aspergillosistrolled 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 berecommended (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. Themized 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 granulocyteformulation is recommended (A-III). A randomized trial com- recovery . The use of serial serum galactomannan assayspared 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
gational [48, 49]. Progressive increase in Aspergillus antigen treatment groups, the patient population included those withlevels 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 trendﬁcient 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 .ical trials on the treatment of invasive aspergillosis. Invasive This study found that patients randomized to either arm hadpulmonary aspergillosis is a life-threatening infection associated similar outcomes but poor overall responses (patients withwith 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 lessother 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-  compared an initial dosage of L-AMB of 10 mg/kg/dayspective, randomized trial for the treatment of invasive pul- for 2 weeks with a dosage of 3 mg/kg/day. In that study, amongmonary 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. 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 invasivepatient had intolerance to the ﬁrst drug. This study demon- aspergillosis. However, the available data indicate that thestrated 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 pulmonarysponse at end of therapy. Successful outcome was achieved in aspergillosis and other forms of invasive aspergillosis is also53% 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 thoseSurvival 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-AMBof voriconazole had fewer severe drug-related adverse events. and is likely to be at least as effective as D-AMB as an alternativeHowever, 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 oron 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% . 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 andantifungal 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 ortreatment of invasive aspergillosis [119, 120] and another recent intolerant of D-AMB [24, 128]. In a study of 76 evaluabledose comparison study of L-AMB  have been reported. An patients, all of whom were able to take oral therapy, 30 patientsearlier 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 . More recent studies of the parenteral for-Research in Treatment of Cancer . Although this study mulation of b-hydroxy-propyl-cyclodextrin itraconazole in thefound 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.
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 laboratoryserum 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 trial1250 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, andvasive pulmonary aspergillosis that is refractory to primary cost-beneﬁt ratios of primary combination antifungal therapytherapy 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 bebecause 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 toof 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 vitrotrolled, open-label trial using Data Review Committee–assessed and in vivo to AMB. The aggregate body of data thus farglobal response at end of treatment was 42% for the posacon- warrants that an antifungal triazole should be used insteadazole group and 26% for the control group . 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) . 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. fumigatusﬁrmatory 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 . Multiazole-resistant Aspergillus species havestudy were a selected population who had received prior ther- also been recently reported . Antifungal susceptibility test-apy, and for posaconazole salvage studies, patients were also ing, especially in the context of prior azole therapy, may beselected on the basis of their ability to receive the oral for- warranted as a guide to therapy, although very limited clinicalmulation of posaconazole. The salvage study also demonstrated data support this approach. Pending susceptibility data, thea direct relationship between serum concentration and response administration of a different class of agent (AMB formulationrate. 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 ofmaximum absorption of compound is known to occur. Thus, invasive pulmonary aspergillosis. Persistent neutropenia andfurther increases in the oral adult dosage are unlikely to yield chronic GVHD are 2 of the most important variables for poorhigher 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 ofbeen conducted by replacing the compound to which the pa- invasive pulmonary aspergillosis. Although colony-stimulatingtient is intolerant or against which the infection is progressing. factors are widely used to attempt to reduce the duration ofWhether both drugs should be administered simultaneously neutropenia, there are limited data from randomized, con-has seldom been prospectively studied , 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 pulmonaryapy of invasive aspergillosis . The addition of a second aspergillosis in patients with prolonged neutropenia (durationantifungal agent to a ﬁrst agent that is failing or toxic is usually of neutropenia, 110 days) . 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 ofagainst invasive aspergillosis [109, 131–137]. However, not all their cancer chemotherapy, those neutropenic patients whoantifungal combinations are beneﬁcial, and some may be del- are not receiving a colony-stimulating factor may beneﬁteterious [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