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Consultants:
Thomas F. Patterson, MD, FACP, FIDSA
Chief, Division of Infectious Diseases
Professor of Medicine
Director, San Antonio Center for Medical Mycology
The University of Texas Health Science Center at San Antonio
John E. Bennett, MD
Laboratory of Clinical Infectious Diseases National Institute
of Allergy and Infectious Disease
National Institutes of Health
Bethesda, MD
Key Points
Prophylaxis
Diagnosis
Treatment
GuidelineCentral.com
Key Points
New agents and formulations along with recent studies of the use
of older agents are now available for treating patients with these
infections, and new diagnostic tools have increased the ability to
diagnose these infections in a timely manner.
1
Prophylaxis
Lung Transplant
The IDSA recommends antifungal prophylaxis with either a
systemic triazole such as voriconazole or itraconazole or an inhaled
amphotericin B (AmB) product for 34 months after lung transplant
(S-M).
2
Prophylaxis
Diagnosis
3
Diagnosis
Radiographic Diagnosis
The IDSA recommends performing a chest computed tomographic
(CT) scan whenever there is a clinical suspicion of invasive pulmonary
aspergillosis (IPA) regardless of chest radiograph results (S-H).
Bronchoscopy
The IDSA recommends performing a bronchoscopy with BAL in
patients with a suspicion of IPA (S-M).
Significant comorbidities such as severe hypoxemia, bleeding, and platelet
transfusion-refractory thrombocytopenia may preclude BAL.
The yield of BAL is low for peripheral nodular lesions, so that percutaneous or
endobronchial lung biopsy should be considered.
The IDSA recommends the use of a standardized BAL procedure and sending the
BAL sample for routine culture and cytology as well as non-culture-based methods
(e.g., GM) (S-M).
4
Treatment
Echinocandins
Echinocandins are effective in salvage therapy (either alone or in
combination) against IA, but the IDSA does not recommend their
routine use as monotherapy for the primary treatment of IA (S-M).
Triazoles
Triazoles are preferred agents for treatment and prevention of IA in
most patients (S-H).
5
Combination Therapy
Combinations of polyenes or azoles with echinocandins suggest
additive or synergistic effects in some pre-clinical studies (W-L).
However, variable test designs and conflicting results of preclinical and in vitro
testing have led to uncertainty as to how to interpret the findings.
Susceptibility Testing
Routine antifungal susceptibility testing of isolates recovered during
initial infection is NOT recommended (S-M).
Antifungal susceptibility testing of Aspergillus isolates using a reference method
is reserved for patients suspected to have an azole resistant isolate, who are
unresponsive to antifungal agents, or for epidemiological purposes.
6
Treatment
7
Biomarkers to Assess Response
Serial monitoring of serum GM can be used in the appropriate patient
subpopulations (hematologic malignancy, HSCT) who have an elevated
GM at baseline to monitor disease progression, therapeutic response,
and predict outcome (S-M).
Pediatric Aspergillosis
Treatment of aspergillosis in children uses the same recommended
therapies as in adult patients. However, the dosing is different and for
some antifungals is unknown (S-H).
8
Treatment
Extrapulmonary Aspergillosis
CNS
The IDSA recommends voriconazole as primary therapy for CNS
aspergillosis (S-M).
Lipid formulations of AmB are reserved for those intolerant or refractory to
voriconazole (S-M).
Endophthalmitis
The IDSA recommends that Aspergillus endophthalmitis be treated
with systemic oral or intravenous voriconazole plus intravitreal
voriconazole or intravitreal AmB deoxycholate (S-W).
Keratitis
The IDSA recommends that clinicians treat Aspergillus keratitis
with topical natamycin 5% ophthalmic suspension or topical
voriconazole (S-M).
Paranasal Sinuses
The IDSA recommends that both surgery and either systemic
voriconazole or a lipid formulation of AmB be used in invasive
Aspergillus fungal sinusitis but that surgical removal alone can be
used to treat Aspergillus fungal ball of the paranasal sinus (S-M).
Enlargement of the sinus ostomy may be needed to improve drainage and prevent
recurrence.
9
Cutaneous
As cutaneous lesions may reflect disseminated infection, the IDSA
recommends treatment with voriconazole in addition to evaluation for
a primary focus of infection (S-L).
Peritonitis
The IDSA recommends prompt peritoneal dialysis catheter removal
accompanied by systemic antifungal therapy with voriconazole (S-L).
Renal
The IDSA suggests a combined approach of medical and urologic
management for renal aspergillosis (W-L).
Obstruction of one or both ureters should be managed with decompression if
possible and local instillation of AmB deoxycholate.
Parenchymal disease is best treated with voriconazole.
Ear Infections
Noninvasive Aspergillus otitis externa, also called otomycosis, is
treated by thorough mechanical cleansing of the external auditory
canal followed by topical antifungals or boric acid (S-M).
10
Treatment
Breakthrough Infection
The IDSA suggests an individualized approach that takes into
consideration the rapidity and severity of infection and local
epidemiology (W-M).
As principles, the IDSA recommends an aggressive and prompt attempt to
establish a specific diagnosis with bronchoscopy and/or CT-guided biopsy for
peripheral lung lesions.
Documentation of serum azole levels should be verified if TDM is available for
patients receiving mold-active triazoles.
Antifungal therapy should be empirically changed to an alternative class of
antifungal with Aspergillus activity.
Other considerations include reduction of underlying immunosuppression, if
feasible, and susceptibility testing of any Aspergillus isolates recovered from the
patient.
11
In lung transplant recipients not on anti-mold prophylaxis, the
IDSA suggests pre-emptive therapy with an anti-mold antifungal for
asymptomatic patients with Aspergillus colonization of the airways
within 6 months of lung transplantation or within 3 months of receiving
immunosuppression augmentation for rejection (W-M).
12
Treatment
In those who fail therapy, who develop triazole resistance and/or have
adverse events, intravenous micafungin (W-L), caspofungin (W-L), or
amphotericin B (W-L) yield some responses.
Treatment may need to be prolonged.
Surgical resection is an option for some patients with localized
disease unresponsive to medical therapy, including those with pan-
azole resistant A. fumigatus infection or persistent hemoptysis despite
bronchial artery embolization (S-M).
The outcomes from surgery are less favorable than those with single aspergilloma,
and a careful risk assessment prior to surgical intervention is required.
In those with progressive disease, long term, even life-long, antifungal
therapy may be required to control disease (W-L), with continual
monitoring for toxicity and resistance.
Aspergilloma
Asymptomatic patients with a single aspergilloma and no progression
of the cavity size over 624 months should continue to be observed
(S-M).
13
Allergic Syndromes
Allergic Bronchopulmonary Aspergillosis
Elevated Aspergillus IgE and total IgE are recommended to establish
the diagnosis and are useful for screening (S-H).
14
Treatment
16
Treatment
18
Treatment
19
Table 3. Commonly Encountered Drug-Drug Interactions
During Treatment of Aspergillosis
Agent/Class Interaction Comment
Calcineurin inhibitors Significant increase in CNI and mTOR agents
(CNI) and mammalian CNI levels by azole should be reduced (~30
target of rapamycin 50% for CNI and more
inhibitors (mTOR) for rapamycin) at the time
immunosuppressive agents 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 May exacerbate immune
azoles suppression favorable for
fungal growth.
Prolonged co-
administration may elicit
signs of excessive steroid
exposure.
Antiretroviral agents for Variable effects Frequently used in
HIV combination with other
classes of agents.
Monitoring of azole
levels recommended, and
bidirectional drug-drug
interactions are common.
Rifampin/rifabutin Decreased levels of azole Combined use
agents while rifampin/ of voriconazole,
rifabutin levels are posaconazole,
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.
20
Treatment
21
Recommendation Grading
1. 2. 3.
Establish initial Consider lowering or raising Final level of
level of confidence level of confidence confidence
rating
1. Rating the quality
situations
22
Abbreviations
ABLC, amphotericin B lipid complex; ABPA; allergic bronchopulmonary aspergillosis;
AmB, amphotericin B; AML, acute myeloid leukemia; BAL, bronchoalveolar lavage;
CCPA, chronic cavitary pulmonary aspergillosis; CF, cystic fibrosis; CGD, chronic
granulomatous disease; CNI, calcineurin inhibitors; CNS, central nervous system; CSF,
colony-stimulating factor; CT, computed tomography; FEV1, forced expiratory volume
in one second; G-CSF, granulocyte colony-stimulating factor; GI, gastrointestinal;
GM, galactomannan; GM-CSF, granulocyte macrophage colony-stimulating factor;
GU, genitourinary; GVHD, graft versus host diseases; HSCT, hematopoietic stem
cell transplantation HIV, human immunodeficiency virus; IA, invasive aspergillosis;
IFN-, interferon gamma; IDSA, Infectious Diseases Society of America; IPA, invasive
pulmonary aspergillosis; IV, intravenous; MDS, myelodysplastic syndrome; PCR,
polymerase chain reaction; PO, per os; TDM, therapeutic drug monitoring; TBA;
tracheobronchial aspergillosis; TDM, therapeutic drug monitoring; TNF, tumor necrosis
factor
Source
Patterson TF et al. Guidelines for the Diagnosis and Management of Aspergillosis:
2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016 Jun 29.
pii: ciw326. [Epub ahead of print]
Disclaimer
This Guideline attempts to define principles of practice that should produce high-quality patient
care. It is applicable to specialists, primary care, and providers at all levels. This Guideline
should not be considered exclusive of other methods of care reasonably directed at obtaining the
same results. The ultimate judgment concerning the propriety of any course of conduct must be
made by the clinician after consideration of each individual patient situation. Neither IGC,
the medical associations, nor the authors endorse any product or service associated with the
distributor of this clinical reference tool.
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