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Practice Guidelines For The Diagnosis and Management of Aspergilosis 2016 Update by America
Practice Guidelines For The Diagnosis and Management of Aspergilosis 2016 Update by America
IDSA GUIDELINE
It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to sup-
plant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines
to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient’s
individual circumstances.
Keywords. aspergillosis; invasive aspergillosis; allergic aspergillosis; chronic aspergillosis; fungal diagnostics; azoles; echniocan-
dins; amphotericin.
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Therapy
Invasive sinus aspergillosis Similar to IPA Similar to IPA Surgical debridement as an adjunct to medical therapy
Patterson et al
Tracheobronchial Similar to IPA Adjunctive inhaled AmB may be useful Similar to IPA
aspergillosis
Aspergillosis of the CNS Similar to IPA Similar to IPA This infection is associated with the highest mortality among all of
Surgical resection may be beneficial in selected cases the different patterns of IA; drug interactions with anticonvulsant
therapy
Aspergillus infections of the Similar to IPA Similar to IPA Endocardial lesions caused by Aspergillus species require surgical
heart (endocarditis, resection; Aspergillus pericarditis usually requires
pericarditis, and pericardiectomy
myocarditis)
Aspergillus osteomyelitis and Similar to IPA Similar to IPA Surgical resection of devitalized bone and cartilage is important for
septic arthritis curative intent
Aspergillus infections of the Systemic IV or oral voriconazole plus intravitreal AmB or Similar to invasive pulmonary aspergillosis; limited data with Systemic therapy may be beneficial in management of Aspergillus
eye (endophthalmitis and voriconazole indicated with partial vitrectomy echinocandins and poor ocular penetration by this class endophthalmitis; ophthalmologic intervention and management
keratitis) is recommended for all forms of ocular infection; topical therapy
for keratitis is indicated
Cutaneous aspergillosis Similar to IPA Similar to IPA Surgical resection is indicated where feasible
Aspergillus peritonitis Similar to IPA Similar to IPA Removal of peritoneal dialysis catheter is essential
Empiric and preemptive For empiric antifungal therapy, Liposomal AmB (3 mg/kg/day IV), Preemptive therapy is a logical extension of empiric antifungal
antifungal therapy caspofungin (70 mg day 1 IV and 50 mg/day IV thereafter), therapy in defining a high-risk population with evidence of
micafungin (100 mg day), voriconazole (6 mg/kg IV every 12 h invasive fungal infection (eg, pulmonary infiltrate or positive GM
for 1 day, followed by 4 mg/kg IV every 12 h; oral therapy can assay result)
be used at 200–300 mg every 12 h or 3–4 mg/kg q 12 h)
Prophylaxis against IA Posaconazole: Voriconazole (200 mg PO BID), itraconazole suspension (200 mg Efficacy of posaconazole prophylaxis demonstrated in high-risk
Oral suspension: 200 mg TID PO every 12 h); micafungin (50–100 mg/day), caspofungin (50 patients (patients with GVHD and neutropenic patients with AML
Tablet: 300 mg BID on day 1, then 300 mg daily mg/day) or MDS)
IV: 300 mg BID on day 1, then 300 mg daily
Saprophytic or colonizing syndromes of Aspergillus
Aspergilloma No therapy or surgical resection Itraconazole or voriconazole; similar to IPA The role of medical therapy in the treatment of aspergilloma is
uncertain; penetration into preexisting cavities may be minimal
for AmB
Chronic cavitary pulmonary Similar to IPA Similar to IPA Innate immune defects demonstrated in most of these patients;
aspergillosis long-term therapy may be needed; surgical resection may lead to
significant complications; anecdotal response to IFN-γ.
Tranexamic acid may be helpful in management of hemoptysis
Allergic syndromes of
Aspergillosis
ABPA Itraconazole Oral voriconazole (200 mg PO every 12 h) or posaconazole Corticosteroids are a cornerstone of therapy for exacerbations;
(dosage depends on formulation) itraconazole has a demonstrable corticosteroid-sparing effect
Allergic rhinosinusitis caused Polypectomy and sinus washout with intranasal corticosteroids Antifungal therapy reserved for refractory or relapsing cases
by Aspergillus
Abbreviations: ABLC, amphotericin B lipid complex; ABPA, allergic bronchopulmonary aspergillosis; AmB, amphotericin B; AML, acute myelogenous leukemia; BID twice daily; CNS, central nervous system; GM, galactomannan; GVHD, graft-vs-host disease;
IA, invasive aspergillosis; IFN-γ, interferon gamma; IPA, invasive pulmonary aspergillosis; IV, intravenous; MDS, myelodysplastic syndrome; PO, oral; TID, 3 times daily.
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CNI and mTOR inhibitor immunosuppressive agents Significant increase in CNI levels by azole CNI and mTOR agents should be reduced
(approximately 30%–50% for CNI and greater for
rapamycin) at the time of initiating azole therapy
and serum levels for both agents monitored until
steady state is reached. Stopping of CNI or mTOR
may provoke graft rejection.
Corticosteroids Levels are increased by azoles May exacerbate immunosuppression favorable for
fungal growth. Prolonged coadministration may
elicit signs of excessive steroid exposure.
Antiretroviral agents for HIV Variable effects Frequently used in combination with other classes of
agents; monitoring of azole levels recommended,
and bidirectional drug–drug interactions common.
Rifampin/rifabutin Decreased levels of azole agents while rifampin/ Combined use of voriconazole, posaconazole,
rifabutin levels are increased isavuconazole, or itraconazole with rifampin/
rifabutin should generally be avoided. Some
combinations are considered contraindicated;
others may be managed by TDM and dose
adjustment.
Agents that cause QTc interval prolongation QT interval prolongation, torsades de pointes, and Assess risk benefit and administer with caution to
(fluoroquinolone and macrolide antimicrobials, other cardiac arrhythmias have been observed patients with cardiac disorders that increase the
quinine, quinidine, digoxin, amiodarone and other with azoles in combination with other agents or risk of arrhythmias.
antiarrhythmic drugs, calcium channel blockers, preexisting conditions that have these effects
psychiatric drugs, antihistamines, and other
agents)
Vincristine and other vinca alkaloid agents Neurotoxicity including peripheral neuropathy and Given the potential for serious toxicity, vincristine and
seizures in combination with azoles; azole other vinca alkaloids should generally not be
levels also increased coadministered with mold-active azoles.
Alternative antifungal therapy (eg, amphotericin B
formulation or echinocandin) should be used.
Cyclophosphamide Increased levels with coadministration of some Increased renal, hepatic, or genitourinary dysfunction
azoles
Abbreviations: CNI, calcineurin inhibitor; HIV, human immunodeficiency virus; mTOR, mammalian target of rapamycin; TDM, therapeutic drug monitoring.
glucocorticoids, digoxin, vinca alkaloids (eg, vincristine) and (eg, specific organ function, comorbidities, and receipt of con-
cyclophosphamide, and antiretroviral agents [260, 265–280]. comitant medications), severity of infection, concerns regarding
All of the azoles have important interactions via the CYP en- nonadherence, cost, TDM assay availability, possibly the dura-
zymes, notably CYP3A4, which can interact with a large num- tion of therapy [286], and the overall treatment plan. Determi-
ber of concomitant medications including tyrosine kinase nation of a plasma drug level, in conjunction with other
inhibitors, macrolides, and antiarrhythmics, among others. Active measures of clinical assessment, can help define factors that
transporters including the p-gp and the breast cancer resistance may have led to therapeutic failure with oral triazoles and re-
protein regulate access of the azoles to the drug-metabolizing en- open prospects for use of the same oral drug in the future pro-
zymes of enterocytes and the liver; the clinical importance of the vided pharmacokinetic issues are corrected.
transporters remains to be further defined [260, 281, 282]. Overviews of clinical scenarios that frequently justify TDM
Currently, 3 triazoles (itraconazole, voriconazole, and posa- are presented in Table 3. The therapeutic range for voriconazole
conazole) are considered to meet these criteria and have estab- and posaconazole have been primarily defined from single-
lished indications for TDM in IA [283, 284]. There is general center, retrospective studies and can only be considered a gene-
agreement that documentation of adequate (and in the case of ral guide for dosing [284].
voriconazole, nontoxic) serum levels in the first 4–7 days after
starting therapy (when a patient is at a pharmacokinetic steady Itraconazole
state) is preferable for any patient with suspected or document- Itraconazole capsules require low gastric pH for dissolution, and
ed aspergillosis. Less agreement exists whether TDM is neces- are therefore poorly absorbed in many patient populations with
sary during primary triazole prophylaxis, but low plasma relative achlorhydria associated with their underlying disease or
levels of itraconazole and posaconazole suspension have been pharmacotherapy. Itraconazole suspension is better absorbed,
associated with higher probability of breakthrough infection, but is associated with higher gastrointestinal adverse effects,
and limited data suggest that high levels of posaconazole may which are especially problematic in populations who already
be associated with toxicity [285]. have nausea, vomiting, or diarrhea. Although a variable rate
The need for continued or repeat monitoring is a patient- of breakthrough IA has been reported in patients on itracona-
specific decision influenced by the clinical status of the host zole prophylaxis, relatively few studies have examined the
Populations with increased pharmacokinetic Impaired gastrointestinal function; hepatic (voriconazole, posaconazole, itraconazole); pediatric patients,
variability elderly patients, obese patients, critically ill patients
Changing pharmacokinetics Intravenous-to-oral switch, changing GI function, changing hepatic or renal function, physiological instability
Interacting medications Patient receiving medication that induces CYP3A4, antacids, proton pump inhibitors (itraconazole capsules,
posaconazole suspension), antiretroviral medications
Possibly corticosteroids (voriconazole)
Severe disease Extensive infection, lesions contiguous with critical structures, CNS infection, multifocal or disseminated
infection
Compliance Important issue with longer-term consolidation therapy or secondary prophylaxis
Suspected breakthrough infection TDM can help to establish whether fungal disease progression occurred in the setting of inadequate
antifungal exposure
Suspected drug toxicity, especially neurotoxicity Although exposure-response relationships are described for other toxicities (eg, hepatotoxicity, bone
(voriconazole) disease), the utility of TDM to prevent their occurrence is less well established
Table developed from Andes et al [283]; Ashbee et al [284]. Additional studies are needed to assess role of TDM for isavuconazole and for posaconazole extended-release tablet and intravenous
formulations.
Abbreviations: CNS, central nervous system; CYP, cytochrome P450; GI, gastrointestinal; TDM, therapeutic drug monitoring.
relationship of itraconazole plasma concentrations and treatment disproportionately to administered doses due to saturable me-
efficacy for aspergillosis. Based primarily on prophylaxis data, most tabolism in adults. For patients with very low voriconazole lev-
experts recommend dosing itraconazole to achieve trough concen- els, coadministering omeprazole (a CYP2C19 inhibitor) has
trations >0.5–1 µg/mL (combined itraconazole/hydroxyitracona- been reported to “boost” voriconazole area under the curve by
zole troughs >1.5 µg/mL). There are limited data suggesting that 41% [289]. Fundamental pharmacokinetics of voriconazole are
higher trough concentrations of itraconazole (>3 µg/mL) may be different in children (linear) than in adults (nonlinear) [290].
associated with increased toxicity [287]. In pediatric patients weighing <50 kg, higher voriconazole
doses are needed [291] and drug monitoring is paramount
Voriconazole
(see specific evidence discussion following Recommendation
Various target concentrations associated with voriconazole effi-
45 below).
cacy have been reported, mostly from single-institution retro-
spective studies [214, 283]. Most experts would aim for dosing Posaconazole
to achieve a voriconazole trough of >1–1.5 µg/mL for efficacy Increasing evidence supports an exposure–response relation-
but <5–6 µg/mL to minimize toxicity, primarily CNS toxicity. Vi- ship for plasma posaconazole concentrations for prophylaxis
sual changes can be related to elevated voriconazole concentra- and treatment of IFIs [250]. This, in conjunction with the fact
tion but generally resolve spontaneously and without long-term that posaconazole levels (using the suspension formulation) are
sequelae. Although voriconazole trough concentrations can be el- commonly low (<0.7 µg/mL) in patients with documented IA
evated in patients with hepatic dysfunction, available data do not receiving salvage treatment [1], makes prudent a strategy of
support the concept of a threshold level that could adequately monitoring posaconazole serum concentrations in patients
discriminate who will be at higher risk for hepatotoxicity [229]. with IA who are on chronic posaconazole suspension. On the
In a prospective, randomized blinded single-center trial of other hand, a clear relationship has not been identified between
TDM during voriconazole therapy in 100 patients, the propor- posaconazole concentrations and the risk of breakthrough IA in
tion of voriconazole discontinuation due to adverse events was the pivotal posaconazole registration trials [254, 292] in which
significantly lower in the TDM group than in the non-TDM the event rate (breakthrough IA) was low. Therefore, TDM dur-
group (4% vs 17%; P = 0.02) [288]. More importantly, higher ing posaconazole prophylaxis may be best used in evaluating
rates of complete or partial response were observed in patients potential breakthrough infections. There is limited evidence
managed with TDM (81% vs those without TDM 57%; to suggest that peak or trough posaconazole concentrations
P = 0.04). This study and several others suggest that antifungal are predictive of subsequent hepatic or other toxicities, although
TDM may reduce drug discontinuation due to adverse events higher rates of toxicity have been anecdotally observed in some
and improve the likelihood of a therapeutic response. There patients with high serum levels (>1.5 µg/mL) achieved with the
are no widely validated algorithms on how to dose voriconazole. delayed-release tablet formulation.
Weight-based dosing is recommended to rapidly achieve thera- The introduction of posaconazole extended-release tablets
peutic range, with incremental increases and monitoring and the intravenous formulation of posaconazole more easily
(ie, 50% increase in daily dose) for the patient who has trough achieve increased posaconazole serum drug levels, even in pa-
levels <1 µg/mL. Voriconazole concentrations often increase tients with risk factors for posaconazole malabsorption [244,
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Preclinical and Laboratory Assessment of Combination Antifungal When Should Antifungal Susceptibility Testing Be Performed, and
Therapy How Should Results Be Interpreted and Affect Management?
Recommendation.
23. Combinations of polyenes or azoles with echinocandins
suggest additive or synergistic effects in some preclinical 24. Routine AFST of isolates recovered during initial infection
studies. However, variable test designs and conflicting results is not recommended. AFST of Aspergillus isolates using a ref-
of preclinical and in vitro testing have led to uncertainty as to erence method is reserved for patients suspected to have an
how to interpret the findings (weak recommendation; low- azole-resistant isolate or who are unresponsive to antifungal
quality evidence). agents, or for epidemiological purposes (strong recommenda-
tion; moderate-quality evidence).
Evidence Summary. The rationale for combination therapy is
to maximize treatment by targeting multiple targets or metabol- Evidence Summary. The goal of AFST is to detect resistant
ic pathways or different points in the same pathway to improve isolates that are more likely to fail therapy [312, 313]. Consider-
efficacy through achieving an additive or synergistic effect. able progress since the previous guideline has occurred toward
Other potential benefits include lowering the risk for emergence achieving this goal. The European Committee on Antibiotic
of drug resistance and the potential for shorter courses of ther- Susceptibility Testing (EUCAST) and the Clinical and Labora-
apy or lower doses of therapy in an attempt to reduce toxicity. tory Standards Institute (CLSI) have published standardized but
Antifungal drug combinations have been evaluated in multi- different AFST methodologies in recent years [314, 315]. Asper-
ple in vitro studies and studied in animal models. Combinations gillus minimum inhibitory concentrations (MICs) utilizing EU-
of polyenes or azoles with echinocandins have been most stud- CAST and CLSI methodologies from more recent clinical
ied, and additive or synergistic effects have been noted in the studies and large surveys have been determined. Although clin-
majority of (but not all) studies when compared to monother- ical breakpoints are not yet defined by CLSI, epidemiological
apy (especially echinocandins alone) [295–299]. Unfortunately, cutoff values—the upper limit of wild-type MIC distributions
there are no standardized or validated protocols for in vitro syn- which aid in the determining the likelihood of resistance in As-
ergy testing, and there are substantive differences in study de- pergillus spp—have been proposed by CLSI [316–319]. Estab-
sign, laboratory assay conditions, definitions of endpoints, lishing epidemiological cutoff values for azoles and Aspergillus
species and strains tested, animal models, drug choice and con- fumigatus, utilizing in vitro pharmacokinetic/pharmacodynam-
centrations/doses, drug monotherapy comparator, inoculation ic studies, in vivo correlation of mutations and failure, and clin-
size, and portal of pathogen administration. Furthermore, cor- ical experience aided derivation of proposed azole clinical
relations between in vitro findings and in vivo observations have breakpoints by EUCAST [312, 320–324]. Taken together,
not always been consistent, and differences in drug metabolism these advances resulted in the recommendation by some experts
between animals and humans make comparisons difficult. Also in Europe to perform routine voriconazole AFST [323].
of importance is the order of administration. Some studies have The advances of molecular techniques have led to important
suggested that prior azole administration subsequently reduces changes to Aspergillus taxonomy contributed to by the phyloge-
polyene activity [300–307]. netic species recognition concept [325]. This method, based on
Antagonism during the use of combination therapy has also sequencing of several targets for species recognition analysis,
been suggested by some studies, especially between polyenes has identified new cryptic species, some of which are more resis-
and certain azoles [308]. By comparison, the combination of tri- tant to current antifungal drugs [326]. Azole resistance in fila-
azole and echinocandin agents exhibit synergistic to additive in- mentous fungi primarily involves mutations in the CYP51A
teractions in the same systems [309]. However, a murine model target enzyme or promoter that lead to specific or pan-azole re-
demonstrated possible antagonism between itraconazole and sistance, and is described more frequently in A. fumigatus com-
micafungin [310]. In vitro studies demonstrate that the combi- plex than other species [327–333]. Other azole resistance
nation of triazole and polyene may be antagonistic [310] or that mechanisms are also described [334–339]. Resistance to the echi-
there may be synergy or antagonism depending on the dose nocandins is uncommon, as is resistance to AmB apart from As-
used [309, 311]. In addition to reduced antifungal activity, pergillus terreus, Aspergillus nidulans, and Aspergillus lentulus
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