Prevencion y Tratamiento de Aspergilosis Invasiva
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8/17/2015 Treatment and prevention of invasive aspergillosis
http://www.uptodate.com.wdg.biblio.udg.mx:2048/contents/treatment-and-prevention-of-invasive-aspergillosis?topicKey=ID%2F2459&elapsedTimeMs=0&source=search_result&searchTerm=galactomannan&select… 1/20
Official reprint from UpToDate www.uptodate.com ©2015 UpToDate
AuthorKieren A Marr, MD
Section EditorCarol A Kauffman, MD
Deputy EditorAnna R Thorner, MD
Treatment and prevention of invasive aspergillosis
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jul 2015. | This topic last updated: May 20, 2015.
INTRODUCTION — Aspergillus species are ubiquitous and exposure to their spores is frequent, but invasive aspergillosis is uncommon and occurs
primarily in immunocompromised hosts. Neutropenia and glucocorticoid use are the most common predisposing factors. The infecting species is most
commonly Aspergillus fumigatus, but other species, including A. flavus, A. terreus, and A. niger, also cause disease. The effective management of
invasive aspergillosis includes strategies to optimize prevention and early antifungal treatment, immunomodulation, and, in some cases, surgery.
The treatment and prevention of invasive aspergillosis will be reviewed here. The clinical features and diagnosis of invasive aspergillosis are discussed
separately; treatment of the other manifestations of Aspergillus infection is also presented elsewhere. (See "Epidemiology and clinical manifestations of
invasive aspergillosis" and "Diagnosis of invasive aspergillosis" and "Epidemiology and clinical manifestations of pulmonary aspergillosis and invasive
disease in HIV-infected patients" and "Diagnosis and treatment of invasive pulmonary aspergillosis in HIV-infected patients" and "Fungal rhinosinusitis" and
"Allergic bronchopulmonary aspergillosis" and "Treatment of chronic pulmonary aspergillosis".)
The epidemiology and prophylaxis of invasive fungal infections in patients with hematologic malignancies and hematopoietic cell transplant recipients are
also discussed in greater detail separately. (See "Prophylaxis of invasive fungal infections in adults with hematologic malignancies" and "Prophylaxis of
invasive fungal infections in adult hematopoietic cell transplant recipients".)
GUIDELINES — The Infectious Diseases Society of America (IDSA) released guidelines for the treatment of invasive aspergillosis in 2008. The American
Thoracic Society (ATS) published guidelines for treatment of fungal infections in adult pulmonary and critical care patients in 2011; the ATS
recommendations for the management of invasive aspergillosis are generally similar to those of the IDSA [1].
Our recommendations agree with the recommendations in the IDSA and ATS with regard to voriconazole being an essential element of therapy for most
patients. These guidelines recommend monotherapy with voriconazole for initial therapy of invasive aspergillosis. However, based on data that became
available after the publication of both sets of guidelines, we suggest consideration of combination therapy with voriconazole plus an echinocandin for
patients with confirmed invasive aspergillosis (ie, diagnosed by culture, galactomannan antigen, or histopathology) and as salvage therapy for patients who
do not respond to voriconazole monotherapy [2]. Some experts continue to prefer monotherapy with voriconazole for initial therapy of invasive aspergillosis,
as the data to support combination therapy remain controversial.
ANTIFUNGAL THERAPY
Choice of regimen — Three classes of antifungal agents are available for the treatment of aspergillosis: polyenes, azoles, and echinocandins.
Appropriate therapy for aspergillosis depends upon the host’s immune status, organ function (kidney and liver), and prior therapies.
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Initial therapy
Salvage therapy — For salvage therapy in patients who do not respond to monotherapy with either voriconazole or liposomal amphotericin B, we
suggest the use of a combination antifungal regimen. In such patients, we suggest adding an echinocandin, such as caspofungin, micafungin, or
anidulafungin, to voriconazole or to liposomal amphotericin B. There are no clinical data to support the use of amphotericin B with triazoles for combination
therapy, and we acknowledge that many cases of failure are due to immunologic failure rather than drug failure. (See 'Echinocandins' below and
'Voriconazole and an echinocandin' below.)
Multiple members of the A. fumigatus species complex exhibit high MICs to azoles (eg, A. lentulus), and A. fumigatus stricto sensu can acquire
resistance to azoles by mutations in the drug target; however, these infections do not appear to be common in the United States. In patients with
documented infection who do not respond to initial monotherapy, not only should a combination therapy be given, but antifungal resistance testing should
For initial therapy of invasive aspergillosis diagnosed by culture, galactomannan antigen, or histopathology, we suggest combination therapy with
voriconazole and an echinocandin [2]. However, some experts prefer monotherapy with voriconazole because of the absence of definitive data. (See
'Voriconazole and an echinocandin' below.)
●
For patients who are intolerant of voriconazole due to severe reactions, we would choose either a lipid formulation of amphotericin B (eg, AmBisome
or Abelcet) or isavuconazole, which was approved by the US Food and Drug Administration (FDA) in 2015. The decision of which agent to choose
depends on organ dysfunction, toxicities, and tolerability. For patients with severe hepatotoxicity or when there is concern for drug interactions
between azoles (as a class) and other agents, we typically switch to a lipid formulation of amphotericin B. Although we do not have a lot of
experience with isavuconazole, we would consider using it instead of voriconazole or a lipid formulation of amphotericin B in patients who have renal
dysfunction and cannot receive intravenous (IV) voriconazole due to its cyclodextrin vehicle (see "Pharmacology of azoles", section on
'Voriconazole'). Neurologic and visual toxicities associated with voriconazole are frequently transient with early dosing; a change in therapy should be
made only with persistent or particularly severe symptoms. (See 'Lipid formulations' below and 'Isavuconazole' below.)
●
If an invasive mold infection is suspected but the diagnosis of invasive aspergillosis has not been established, particularly in those who have recently
received voriconazole, one should consider treating empirically with a lipid formulation of amphotericin B in order to provide antifungal activity against
both aspergillosis and mucormycosis, since the Mucorales are intrinsically resistant to voriconazole [3,4]. When the diagnosis is uncertain, it should
be pursued aggressively even after empiric therapy has been initiated. If the diagnosis of aspergillosis is established, we suggest switching to
voriconazole plus an echinocandin. However, as noted above, some experts prefer monotherapy with voriconazole. (See "Diagnosis of invasive
aspergillosis" and "Mucormycosis (zygomycosis)".)
●
It is important to note that some drugs, especially azoles, interact with chemotherapy used in conditioning regimens, potentially increasing toxicities
(eg, neurotoxicity from vincristine) or reducing the efficacy of certain cytotoxic drugs. Hence, it is wise to initiate these agents subsequent to
cytotoxic therapies and/or administer a non-interacting mold-active antifungal during conditioning chemotherapy.
●
It is important to consider the species of Aspergillus when choosing initial therapy, since antifungal resistance is detected with increasing frequency
and is more likely to occur with certain Aspergillus species. For example, A. calidoustus has high minimum inhibitory concentrations (MICs) to
numerous antifungals and A. terreus has high MICs to amphotericin B. A combination of drugs (eg, voriconazole and an echinocandin) may be
considered for infection caused by these species, and antifungal susceptibility testing may help guide choices of antifungal agents. (See 'Antifungal
resistance' below and "Antifungal susceptibility testing".)
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also be considered. (See 'Antifungal resistance' below.)
Dosing and drug effects
Voriconazole – Voriconazole is available in both intravenous and oral formulations [3,5,6]. The recommended dosing regimen is 6 mg/kg
intravenously every 12 hours on day 1 followed by 4 mg/kg IV every 12 hours thereafter. When the patient is able to take oral medications, one can
consider switching to the oral form. Optimal oral dosing is a matter of controversy. The currently recommended dose of 200 mg orally every 12 hours
has been noted to result in low or even unmeasurable serum concentrations in a substantial proportion of patients, and high concentrations may be
associated with excessive toxicities [7]. The dose of oral voriconazole can be increased to 4 mg/kg orally every 12 hours (or 300 mg orally every 12
hours) in patients with disease progression.
●
We suggest monitoring serum voriconazole trough concentrations in all patients receiving voriconazole for invasive aspergillosis. We suggest
checking a trough concentration five to seven days into therapy. A goal of achieving serum trough concentrations >1 mcg/mL and <5.5 mcg/mL has
been suggested [7], but we prefer concentrations between 2 and 5.5 mcg/mL. Trough concentrations below 1 mcg/mL warrant an increase in the
voriconazole dose and appropriate subsequent monitoring [8]. On the other hand, serum drug concentrations above 5.5 mcg/mL warrant a reduction
in the voriconazole dose because they have been associated with an increased risk of toxicity [7,9]. (See "Pharmacology of azoles", section on
'Serum drug concentration monitoring'.)
Voriconazole is associated with a number of drug interactions, which the clinician should carefully check for when prescribing this medication. The
drug has also been reported to cause visual changes, hallucinations, a prolonged QTc interval, neuropathy, central nervous system (CNS) alterations
(eg, memory loss, difficulty concentrating), alopecia, oral excoriations, and a photosensitivity skin rash that has been linked to squamous cell
carcinoma. (See "Pharmacology of azoles", section on 'Voriconazole'.)
Specific interactions of azole agents with other medications may be determined using the drug interaction tool (Lexi-Interact Online). This tool can be
accessed from the UpToDate online search page or through the individual drug information topics, section on Drug interactions. An overview of the
drug interactions associated with the azoles is presented separately. (See "Pharmacology of azoles", section on 'Drug interactions'.)
Echinocandins – The echinocandins are available as intravenous formulations only. Dosage adjustment is not required in patients with renal
insufficiency, including patients who are receiving hemodialysis or continuous renal replacement therapy (continuous venovenous hemofiltration or
continuous venovenous hemodialysis). The recommended dosing of each echinocandin is:
●
Caspofungin – 70 mg IV loading dose on day 1, followed by 50 mg IV daily thereafter; the daily dose can be increased to 70 mg if the response
is inadequate [10].
•
Micafungin – 100 to 150 mg IV dose daily; no loading dose is required.•
Anidulafungin – 200 mg IV loading dose on day 1, followed by 100 mg IV daily.•
Echinocandins are well tolerated, and all three members of the class have similar types of adverse effects. Serious adverse effects requiring drug
discontinuation occur less frequently with the echinocandins than with other classes of systemic antifungals. Modest asymptomatic elevations of
aminotransferases and alkaline phosphatase are the most frequently reported laboratory abnormalities in healthy volunteers and patients treated with
echinocandins. The pharmacology of the echinocandins is discussed in detail separately. (See "Pharmacology of echinocandins".)
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Duration — The duration of antifungal therapy is dependent upon the location of the infection, the patient's underlying disease, the need for further
immunosuppression, and the response to therapy. Antifungal therapy is generally continued until all signs and symptoms of the infection have resolved
and often longer in patients with persistent immune defects. Radiographic abnormalities should have stabilized and signs of active infection should have
disappeared before treatment is discontinued. For most immunosuppressed patients, antifungal therapy will continue for months or even years in some
cases.
Limited data available from one trial indicate that if combination therapy is chosen for microbiologically documented invasive aspergillosis, the
echinocandin should be given for 10 to 14 days before step-down to voriconazole monotherapy [2].
Efficacy and safety
Monotherapy
Triazoles — Triazole antifungal agents include voriconazole, posaconazole, itraconazole, and fluconazole. Fluconazole has no activity against
Aspergillus spp, and itraconazole has become a second-line agent for aspergillosis.
Voriconazole — Voriconazole should be included in the antifungal regimen in nearly all patients with invasive aspergillosis [12-18]. The best
efficacy data come from the Global Comparative Aspergillus Study, an international, multicenter randomized open-label trial in which voriconazole was
compared with amphotericin B deoxycholate as initial therapy in 277 patients with confirmed or probable invasive aspergillosis [5]. Patients with multiple
underlying diseases were enrolled, although the majority had hematologic malignancies and many had undergone hematopoietic cell transplantation.
Primary therapy with voriconazole (administered at 6 mg/kg IV twice a day on day 1, followed by 4 mg/kg twice daily for at least seven days, with the
option to switch to oral dosing at 200 mg orally twice daily thereafter) was compared with amphotericin B deoxycholate (1 to 1.5 mg/kg IV daily). The
Amphotericin B lipid formulations – The dosing of lipid formulations of amphotericin B is:●
Liposomal amphotericin B (AmBisome) – 3 to 5 mg/kg IV daily (see 'Lipid formulations' below)•
Amphotericin B lipid complex (Abelcet, ABLC) – 5 mg/kg IV daily. This drug has not been evaluated for aspergillosis in large randomized trials
but is approved for use in the setting of salvage therapy.
•
Lipid formulations of amphotericin B are less likely to cause nephrotoxicity than amphotericin B deoxycholate. Infusion-related reactions and
electrolyte abnormalities are other adverse effects of amphotericin B formulations. (See "Pharmacology of amphotericin B" and "Amphotericin B
nephrotoxicity".)
Isavuconazole – Loading doses of 200 mg of isavuconazole (equivalent to 372 mg of isavuconazonium sulfate) every 8 hours for six doses (48 hours)
via oral (2 capsules) or IV administration, followed by 200 mg once daily orally or IV starting 12 to 24 hours after the last loading dose [11].
Isavuconazole is formulated as the prodrug, isavuconazonium sulfate. (See "Pharmacology of azoles", section on 'Isavuconazole'.)
●
The most common adverse reactions are nausea, vomiting, diarrhea, headache, elevated liver chemistry tests, hypokalemia, constipation, dyspnea,
cough, peripheral edema, and back pain [11]. Isavuconazole may also cause serious side effects including hepatotoxicity, infusion reactions, and
severe allergic and skin reactions. Isavuconazole is associated with shortening of the QT interval, the clinical significance of which remains unclear. It
is contraindicated in patients with familial short QT syndrome. (See "Pharmacology of azoles", section on 'Isavuconazole'.)
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treating clinician had the opportunity to switch the patient to another antifungal agent for drug intolerance or clinical failure. Most of the changes in therapy
were in the amphotericin B deoxycholate arm; patients were most often switched to a lipid formulation of amphotericin B because of intolerance.
The following significant benefits were noted in the voriconazole group compared with the amphotericin B deoxycholate group at 12 weeks:
These findings suggest that voriconazole is superior to amphotericin B deoxycholate in patients with invasive aspergillosis. The relative efficacy of
voriconazole compared with a lipid formulation of amphotericin B is unknown since no comparative studies have been published.
Because predefined definitions used for the Global Comparative Aspergillus Study were different from the consensus definition proposed by the European
Organization for Research and Treatment of Cancer/Mycoses Study Group [19], the data from this trial were reanalyzed after recategorizing patients
according to the consensus definition [20]. After recategorization, response rates still favored voriconazole over amphotericin B.
Voriconazole may also have a role in the setting of central nervous system disease, for which the mortality rate historically has approached 100 percent. In
a retrospective study of 48 patients with definite and 33 patients with probable central nervous system aspergillosis, 31 percent of patients who received
voriconazole survived for a median observation time of 390 days [6]. The vast majority of patients had received antifungal agents other than voriconazole for
a median of 31 days prior to receiving voriconazole.
Posaconazole — Posaconazole is a broad-spectrum triazole that has been approved by the FDA for prophylaxis of fungal infections in
neutropenic patients and for the treatment of mucocutaneous candidiasis. Posaconazole was initially available only as an oral suspension, but, in 2013,
the FDA approved delayed release tablets for the prophylaxis of invasive Aspergillus and Candida infections in patients at high risk for these infections. The
delayed release formulation has higher absorption and relies less on oral intake than the oral suspension. An intravenous formulation was approved in
2014. (See "Pharmacology of azoles", section on 'Posaconazole'.)
The efficacy and safety of the oral suspension of posaconazole as monotherapy was investigated in an open-label, multicenter trial in patients with invasive
aspergillosis and other mycoses who were refractory to or intolerant of conventional antifungal therapy [21]. Data from external control cases were
collected retrospectively as a comparative reference group. The overall success rate was 42 percent for 107 posaconazole recipients and 26 percent for 86
controls. The differences in treatment outcomes were maintained across several prespecified patient subsets (eg, site of infection, underlying disease, and
indication for enrollment, refractory disease versus intolerance of therapy).
Given its spectrum of activity [22-24] and the treatment success observed in the uncontrolled trial described above, posaconazole may be an effective
agent for the treatment of invasive aspergillosis. However, further study is necessary before any formulation of posaconazole can be recommended for
initial therapy of invasive aspergillosis. The most common side effect of posaconazole is gastrointestinal upset [25]. (See "Pharmacology of azoles",
section on 'Posaconazole'.)
Isavuconazole — Isavuconazole was approved by the FDA for the treatment of invasive aspergillosis in March 2015 [26]. Its approval was
A greater likelihood of a complete or partial response (53 versus 32 percent)●
A lower mortality rate (29 versus 42 percent)●
A lesser likelihood of the clinician changing the patient to another antifungal agent because of intolerance or poor response (36 versus 80 percent)●
A lower rate of severe adverse reactions, although 45 percent of patients receiving voriconazole reported transient visual disturbances●
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based on a non-inferiority trial involving 516 patients with proven, probable, or possible invasive fungal disease caused by Aspergillus spp or another
filamentous fungus who were randomly assigned to receive either isavuconazole or voriconazole [11]. All-cause mortality through day 42 in the overall
intention-to-treat population was 18.6 percent in the isavuconazole group and 20.2 percent in the voriconazole group. Similar results were seen in patients
with proven or probable invasive aspergillosis. In the subgroup of patients with proven or probable invasive aspergillosis, overall success at end of treatment
was seen in 35 percent of isavuconazole-treated patients compared with 38.9 percent of voriconazole-treated patients.
Itraconazole — Itraconazole is not a first-line agent for the treatment of invasive aspergillosis, and it should not be used in
immunocompromised patients with invasive disease. Voriconazole has greater intrinsic activity against Aspergillus species, and both the intravenous and
the oral formulations are better tolerated than those of itraconazole.
Oral itraconazole has been used in selected patients with mild immunosuppression and non–life-threatening Aspergillus infection or in patients who had
already been stabilized with amphotericin B. In a multicenter, open-label study of 76 evaluable patients who were treated with itraconazole, only 39 percent
had a complete or partial response [27]. Other drawbacks associated with use of itraconazole include the requirement of an acid environment for
absorption, poor bioavailability, and important drug interactions. (See "Pharmacology of azoles", section on 'Drug interactions'.)
When used for the treatment of aspergillosis, the serum itraconazole concentration should be measured two weeks into therapy. If there is a change in
clinical condition, serum concentrations of itraconazole should be rechecked. (See "Pharmacology of azoles", section on 'Serum drug concentration
monitoring'.)
Amphotericin B
Amphotericin B deoxycholate — Administration of amphotericin B deoxycholate is associated with severe nephrotoxicity, and treatment
outcomes have been poor. Less toxic options, such as voriconazole or a lipid formulation of amphotericin B, when available, should be used in patients
with aspergillosis.
Lipid formulations — There are three currently marketed lipid formulations of amphotericin B:
The main advantage of the lipid formulations is the ability to administer larger doses of amphotericin B with fewer toxicities. Amphotericin B lipid complex
and liposomal amphotericin B have fewer infusion-related side effects than amphotericin B deoxycholate, but ABCD has similar rates of infusion reactions
as amphotericin B deoxycholate [28]. The lipid formulations, although less toxic, have not been definitively shown to result in better outcomes compared to
conventional amphotericin B. One randomized trial showed that ABCD was not superior to amphotericin B deoxycholate in treating aspergillosis [29].
For the treatment of invasive aspergillosis, the recommended initial dose of liposomal amphotericin B (AmBisome) is 3 to 5 mg/kg IV per day and of
amphotericin B lipid complex (Abelcet) is 5 mg/kg IV per day [13]. A small observational study suggested that using higher doses of lipid formulations of
amphotericin B results in better response rates [30]. However, a randomized trial in 201 patients with confirmed aspergillosis compared the efficacy of 10
mg/kg per day versus 3 mg/kg per day dosing for the first 14 days of treatment, followed by receipt of 3 mg/kg per day [31]. The vast majority of patients
had underlying hematologic malignancies and neutropenia. Patients assigned to the higher dosing arm had a higher rate of nephrotoxicity without any
Liposomal amphotericin B (AmBisome)●
Amphotericin B lipid complex (ABLC, Abelcet)●
Amphotericin B cholesteryl sulfate complex (amphotericin B colloidal dispersion, ABCD, Amphotec)●
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additional clinical benefits. Nevertheless, based on our clinical experience and the experience of other experts, we feel that 3 to 5 mg/kg IV once daily is
the appropriate dose of AmBisome and 5 mg/kg once daily is the appropriate dose of Abelcet for treating invasive aspergillosis.
Echinocandins — The echinocandins include caspofungin, micafungin, and anidulafungin. Caspofungin has been approved by the FDA for the
treatment of invasive aspergillosis in patients who cannot tolerate or who are refractory to standard therapy [32]. The other echinocandins, micafungin and
anidulafungin, are not FDA-approved for the treatment of invasive aspergillosis. However, these agents have activity against Aspergillus spp, and all three
echinocandins are considered to have equivalent efficacy.
The echinocandins should not be utilized for initial monotherapy of invasive aspergillosis. We favor the use of an echinocandin in combination with
voriconazole for initial therapy of confirmed invasive aspergillosis [2]. Echinocandins are also used for salvage therapy, often in combination with another
antifungal drug [33-36]. (See 'Combination therapy' below.)
In a compassionate salvage treatment trial for proven or probable invasive aspergillosis, caspofungin was administered to 83 patients who were intolerant of
standard therapy (15 percent of patients) or whose infection was refractory to standard therapy (85 percent of patients) [37]. Almost all had previously
received an amphotericin B formulation. The overall complete and partial success rate was 45 percent; as expected, the response rates were higher for the
patients who were intolerant of standard therapy compared with those who were refractory (75 versus 40 percent) [38].
Combination therapy — Combination antifungal therapy has been evaluated both as initial therapy and as salvage therapy in patients who have not
responded to their initial regimen [39].
Voriconazole and an echinocandin — Experimental models of aspergillosis have suggested benefit of a variety of antifungal combinations, but
results vary [40-42]. The following observations illustrate the range of findings in clinical studies:
Despite the suggestion of benefit of combination therapy with voriconazole and caspofungin in some studies, there are major limitations to study designs,
limiting conclusions. Historical controls are of limited utility because improvements in early diagnosis and therapy of the underlying condition will impact
outcomes in the cohort treated during a later time period [44]. (See "Diagnosis of invasive aspergillosis".)
A large randomized trial assessed the safety and efficacy of voriconazole with or without anidulafungin for the treatment of invasive aspergillosis in patients
One study evaluated 47 patients with evidence of progressive infection after seven or more days of treatment with an amphotericin B preparation [35].
Thirty-one patients were treated with voriconazole alone; the next 16 patients were given voriconazole plus caspofungin. Using a multivariate model,
at three months, patients who received combination therapy had a significantly lower rate of mortality compared with those who received voriconazole
monotherapy (odds ratio [OR] 0.28, 95% CI 0.28-0.92).
●
In a retrospective analysis of 405 hematopoietic cell transplant (HCT) recipients with probable or proven aspergillosis, there was no difference in
clinical outcomes in the 33 patients treated with voriconazole and caspofungin as primary antifungal therapy compared with those who were treated
with voriconazole monotherapy [12].
●
In another study, 40 solid organ transplant patients who received voriconazole and caspofungin as primary therapy were compared with a historical
control group of 47 patients who received liposomal amphotericin B [43]. Combination therapy was associated with reduced mortality in the subset of
patients with A. fumigatus infection (adjusted hazard ratio [HR] 0.37, 95% CI 0.16-0.84) and in those with renal failure (adjusted HR 0.32, 95% CI
0.12-0.85).
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with hematologic malignancies and/or hematopoietic cell transplant [2]. Results showed a trend toward improved six-week survival (the primary endpoint)
with the combination of voriconazole and anidulafungin compared with voriconazole monotherapy. Among the 277 patients with documented proven or
probable invasive aspergillosis, six-week mortality was 19.3 percent for combination therapy and 27.5 percent for monotherapy, suggesting a trend toward
improved survival with combination therapy (95% CI -19.0 to 1.5). In a post-hoc analysis of 222 patients with probable invasive aspergillosis with
radiographic abnormalities and a positive serum or bronchoalveolar lavage fluid galactomannan antigen, a statistically significant difference in mortality was
observed (16 percent with combination therapy versus 27 percent with voriconazole monotherapy; 95% CI -22.7 to -0.4). Interpretation of the nonsignificant
trend to improved survival and the significant benefit observed on post-hoc analysis elicits some lingering questions about the efficacy of combination
therapy. Based on the observed trends toward improved survival, we favor the use of a combination regimen of voriconazole plus an echinocandin for the
treatment of confirmed invasive aspergillosis that is documented by culture, positive galactomannan assay, or histopathology. However, in the absence of
definitive data, some experts prefer monotherapy with voriconazole. (See 'Initial therapy' above.)
For salvage therapy in patients who do not respond to monotherapy with either voriconazole or liposomal amphotericin B, we also suggest the use of a
combination antifungal regimen, as discussed above. (See 'Salvage therapy' above.)
Liposomal amphotericin B and an echinocandin — Prior to the availability of voriconazole, there was substantial interest in combination
regimens of liposomal amphotericin B (AmBisome) and caspofungin for invasive aspergillosis. This combination has shown some benefit compared with
liposomal amphotericin monotherapy but has not been studied in randomized trials nor has it been compared with voriconazole-based regimens.
In a small prospective open-label study of 30 patients with hematologic malignancies with probable or, in a few cases, proven invasive aspergillosis, a
combination of liposomal amphotericin B (3 mg/kg IV daily) and caspofungin was compared with monotherapy with high-dose liposomal amphotericin B (10
mg/kg IV daily) for initial therapy [45]. There were significantly more favorable responses (partial or complete) in the combination therapy group (10 of 15
patients versus 4 of 15 patients with liposomal amphotericin B). At 12 weeks, survival rates were 100 percent in the combination therapy group compared
with 80 percent in the amphotericin B monotherapy group.
The combination of liposomal amphotericin B and caspofungin has also been studied in small retrospective studies as a salvage regimen [33,34]. One of
these studies evaluated 48 patients with hematologic malignancy and invasive aspergillosis (23 probable, 25 possible); in two-thirds of patients,
caspofungin was added after failure to respond to at least seven days of liposomal amphotericin [34]. Only 18 percent of these patients responded to
combination therapy.
Amphotericin B and triazoles — There are no clinical data to support the use of amphotericin B with a triazole for combination therapy [46,47].
Animal models of aspergillosis suggest that triazoles may be antagonistic when given concomitantly or sequentially with amphotericin B [46-49]. One
proposed mechanism to explain these observations includes the reduction of amphotericin B binding to fungal membranes due to azole inhibition of the
ergosterol biosynthetic pathway [47]. An alternative mechanism may be the accumulation of azole in the cell membrane, which competitively inhibits the
binding of amphotericin B to ergosterol.
Other — The addition of flucytosine or rifampin to amphotericin B in the treatment of invasive aspergillosis has not been shown to be beneficial.
Antifungal resistance — Some species of Aspergillus are known to have variable susceptibilities to different antifungal drugs. Aspergillus terreus is less
susceptible to amphotericin B in vitro and in animal models, and clinical reports suggest that outcomes are better with use of alternative drugs such as
voriconazole [50]. (See "Pharmacology of amphotericin B" and "Amphotericin B nephrotoxicity".) Some species, such as Aspergillus calidoustus,
Aspergillus lentulus, and Neosartorya udagawae, generally exhibit innately high level resistance to multiple antifungal agents, including amphotericin B and
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voriconazole. The clinical significance of this relative resistance is not well defined, although case series suggest poor outcomes in patients with
documented infection, and infection with these isolates warrants consideration of antifungal resistance testing and/or administration of two antifungal
agents in combination [2,51,52]. (See 'Initial therapy' above and 'Salvage therapy' above.)
Although in vitro resistance among Aspergillus spp has been rare to date, isolates of A. fumigatus that exhibit relative cross-resistance to multiple azoles
have been reported and may be increasing in prevalence in certain countries in Europe [53-57]. Surveillance in the Netherlands revealed the emergence of
a set of mutations in A. fumigatus isolates that confers reduced susceptibility to azoles [53]. An amino acid substitution of leucine for histidine at codon
98, in conjunction with a tandem repeat in the gene promoter, causes resistance to itraconazole and increased minimum inhibitory concentrations to
voriconazole and posaconazole. Among isolates in the surveillance study in the Netherlands (which included several isolates from other countries in
Europe), the annual prevalence between 2000 and 2007 ranged from 1.7 to 6 percent [54,55]. In a surveillance study in the Netherlands, the
TR /Y121F/T289A mutation, a novel cyp51A-mediated resistance mutation causing high-level voriconazole resistance was observed in A. fumigatus
clinical and environmental isolates [58]. It is likely that such resistance has occurred as a result of the widespread use of triazole fungicides in crops in the
Netherlands [59]. Epidemiology of A. fumigatus drug resistance in other countries is not as well evaluated, but resistance in A. fumigatus infection not
responding to azole monotherapy needs to be considered.
IMMUNOMODULATION — Whenever possible, the degree of immunosuppression should be decreased as an adjunct to antifungal therapy for the
treatment of invasive aspergillosis [13]. The worst outcomes occur in patients with persistent, severe immune dysfunction and in those with organ
impairment that limits administration of antifungals. Although the relative contribution of these prognostic indicators is unclear, it is generally accepted that
decreasing immune suppression will result in improved outcomes. Invasive aspergillosis occurs most commonly in the setting of immunosuppression,
particularly chemotherapy-induced neutropenia or glucocorticoid administration for graft-versus-host disease (GVHD). In neutropenic patients, recovery of
bone marrow function is critical to the control of aspergillosis [60]; in the hematopoietic cell transplant recipient with aspergillosis, for example, failure to
engraft will result in death due to this infection.
The high mortality observed in invasive aspergillosis reflects the influence of the underlying disease on outcome and the frequent inability to improve
immunosuppression [61]. The importance of the degree of immunosuppression on outcome was illustrated in an international multicenter retrospective
series of 525 patients with invasive aspergillosis [13]. Complete or partial responses to therapy occurred in significantly fewer patients with severe
immunosuppression compared to those with less marked immunosuppression (28 versus 51 percent). In a detailed review of 400 patients who had
aspergillosis in the setting of hematopoietic cell transplantation or treatment of hematologic malignancy, the most important prognostic factors included
clinical variables that dictated overall immune impairment (GVHD severity and HLA mismatch), relative paucity of multiple cell types (neutropenia,
monocytopenia, and lymphocytopenia), as well as kidney and liver impairment [12].
Colony-stimulating factors — At present, we do not recommend routine use of colony-stimulating factors in neutropenic patients with invasive
aspergillosis [62]. Consideration of the risks and benefits should be made on a case-by-case basis.
Colony-stimulating growth factors enhance neutrophil chemotaxis and phagocytosis and attract neutrophils to the site of inflammation. In clinical studies,
granulocyte colony-stimulating factor (G-CSF) shortens the period of neutropenia following myelosuppressive chemotherapy, leading to shorter
hospitalizations, fewer documented infections, and fewer days of antimicrobial therapy. Despite these positive effects, there is currently no definitive proof
that hematopoietic growth factors decrease mortality from infection, improve the response rate to antibiotics, or improve overall survival. Furthermore, there
is no evidence to support the role of colony-stimulating factors to increase innate neutrophil fungicidal capacity. An in vitro study examined the ability of
granulocyte colony-stimulating factor and interferon-gamma to increase neutrophil oxidative burst and damage Aspergillus hyphae [63]. Both cytokines
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increased oxidative burst: G-CSF by 37 percent and interferon-gamma by 71 percent. Damage to hyphae by neutrophils was also increased by both
cytokines whether or not the hyphae were opsonized; combination of the two cytokines produced an additive effect.
The clinical significance of these observations is uncertain.
Granulocyte transfusions — There are few data to support the use of donor granulocyte transfusions for the management of patients with neutropenia
and invasive aspergillosis [64]. Experience has been limited to situations in which severe disease warranted drastic measures. A randomized trial has
been completed but data have not been reported regarding the potential utility of G-CSF–stimulated community donor granulocyte transfusions for infection
that develops in the setting of neutropenia. (See "Granulocyte transfusions".)
ROLE OF SURGERY — Surgery can be used to debride necrotic tissue and to remove infected tissue in patients with invasive aspergillosis but is helpful
only in a minority of cases. The decision of whether to perform surgery depends on many factors, including the extent and location of the lesion(s), the
degree of resection required, comorbidities, the ability of the patient to tolerate surgery, the potential impact of delay of chemotherapy, and the overall
goals of antineoplastic therapy (eg, curative versus palliative) [13]. As an example, many neutropenic patients have profound thrombocytopenia, which may
complicate or preclude surgery as a therapeutic option.
PREVENTION AND EARLY TREATMENT — Studies performed in the 1990s and early 2000s reported very poor outcomes for invasive aspergillosis.
Mortality rates ranged from 60 to 90 percent and were largely dependent upon the underlying disease [68]. Overall survival has improved but varies
depending upon factors such as duration of neutropenia, dosage of glucocorticoids, liver and kidney function, and site and extent of infection [12,69]. A
Debridement appears to be a useful adjunct for treatment of Aspergillus rhinosinusitis, according to at least one case series [65]. Radical surgical
debridement is required in some cases to achieve cure and sometimes requires multiple surgeries. The need for surgery may depend on the degree
of fungal bone invasion at diagnosis and anticipated risks in the setting of severe thrombocytopenia; we have treated some patients successfully with
medical therapy alone. (See "Fungal rhinosinusitis", section on 'Invasive fungal sinusitis'.)
●
Surgery may also be indicated for settings in which a large degree of necrosis limits antifungal activity and/or there is an imminent threat to vessels
[1]. Examples include endocarditis, extensive necrotic cutaneous lesions, pericardial infection, empyema, invasion of the chest wall from a
contiguous pulmonary lesion, pulmonary lesions in proximity to great vessels or pericardium, infected prosthetic devices, and osteomyelitis [13].
●
Surgical excision of a pulmonary cavity has been performed in patients with a single pulmonary lesion and recurrent hemoptysis or bacterial
superinfection [66]. However, there are risks associated with surgery, as spillage of viable fungus into the pleural cavity can result. We recommend
initial medical therapy of pulmonary aspergillosis with sequential follow-up to determine whether surgery is necessary, except in cases of impending
major bleeding. Most patients with invasive pulmonary aspergillosis do not require surgery. One retrospective series evaluated 41 patients with
hematologic disease complicated by neutropenia and invasive pulmonary aspergillosis [67]. Patients underwent lobectomy (23 patients), wedge
resection (16 patients), or enucleation of a mass lesion (two patients); complication rate and 30-day mortality were both estimated to be 10 percent.
Outcomes were generally good (response rate 80 percent) and were associated with successful treatment of the underlying hematologic malignancy.
In this study, it was not possible to identify which patients benefit most from a surgical approach.
●
While a mortality benefit to surgery for the management of cerebral lesions in combination with antifungal therapy with voriconazole has been
suggested in small studies [6], many patients resolve residual central nervous system disease with current antifungal management and do not
require surgical management.
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great deal of effort has been put into preventing infections by utilizing prophylactic strategies and into treating invasive aspergillosis as early as possible by
either empiric treatment of febrile patients with neutropenia or preemptive treatment based upon results of screening assays (eg, galactomannan, beta-D-
glucan) for infection [70,71].
These issues are briefly reviewed here; more extensive discussions are provided separately. (See "Treatment of neutropenic fever syndromes in adults with
hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)", section on 'Addition of an antifungal agent' and "Prophylaxis of
invasive fungal infections in adult hematopoietic cell transplant recipients" and "Prophylaxis of invasive fungal infections in adults with hematologic
malignancies" and "Prophylaxis of infections in solid organ transplantation", section on 'Antifungal prophylaxis' and "Fungal infections following lung
transplantation", section on 'Invasive fungal infections'.)
Primary prophylaxis — Providing prophylaxis with mold-active drugs can prevent invasive aspergillosis. Which specific patients will benefit from
prophylactic strategies remains ill defined and is partly dependent upon patient characteristics and the epidemiology of invasive fungal infections at
individual institutions.
Results of several randomized trials are summarized as follows:
Positive results from each of these studies are balanced with the potential drawbacks of prophylaxis, including possible toxicities and drug interactions,
costs of the drugs, and the potential generation of microbial resistance. Oral drugs often are poorly absorbed in the setting of gastrointestinal tract
mucositis and/or graft-versus-host disease [79].
The use of anti-mold prophylaxis is discussed in detail separately. (See "Prophylaxis of invasive fungal infections in adults with hematologic malignancies"
and "Prophylaxis of invasive fungal infections in adult hematopoietic cell transplant recipients".)
Empiric therapy — Empiric therapy involves antifungal treatment of febrile patients during periods of neutropenia. This strategy was first introduced as a
Posaconazole was more effective than fluconazole or itraconazole for preventing aspergillosis in patients receiving therapy for acute myeloid leukemia
(absolute reduction in the posaconazole group, -6%, 95% CI -9.7 to -2.5%) and was associated with improved survival [72]. It was also more effective
than fluconazole in allogeneic hematopoietic cell transplant (HCT) recipients with severe graft-versus-host disease (odds ratio [OR] 0.31, 95% CI 0.13
to 0.75) [73].
●
Voriconazole was associated with fewer cases of documented infections caused by Aspergillus species compared with fluconazole (both with
galactomannan antigen monitoring), although these results failed to reach statistical superiority in a study endpoint that included measurement of
survival [74].
●
Itraconazole may be more effective than fluconazole in preventing aspergillosis in patients with leukemia and in hematopoietic cell transplant
recipients [75-77].
●
Inhaled administration of amphotericin B formulations reduced the incidence of aspergillosis in patients with hematologic malignancies who had
prolonged neutropenia (OR 0.26, 95% CI 0.09-0.72) [78].
●
Based upon observational data, inhaled amphotericin B is often used in lung transplant recipients during the early posttransplant period. (See "Fungal
infections following lung transplantation", section on 'Nebulized amphotericin B'.)
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means to prevent invasive fungal infections in the 1980s after it was noted that many patients with fevers had underlying, otherwise undiagnosed, fungal
infections, particularly invasive candidiasis [80]. Such infections were especially common in patients with a long duration of neutropenia who were not
receiving azole prophylaxis.
Empiric antifungal treatment after a defined duration of persistent fever has become standard practice, and multiple drugs have been studied and approved
for this indication. It is important to note that placebo-controlled trials have not been performed to prove the benefit in the era of widespread azole
prophylaxis, and the drugs have potential negative effects (eg, toxicity, cost). This subject is reviewed in more depth elsewhere. (See "Treatment of
neutropenic fever syndromes in adults with hematologic malignancies and hematopoietic cell transplant recipients (high-risk patients)", section on 'Addition
of an antifungal agent'.)
Preemptive therapy — Preemptive therapy is an early treatment strategy that has been proposed as an alternative to empiric therapy. Preemptive
therapy involves initiating antifungal therapy based upon the results of serial screening for aspergillosis. Randomized trials are currently being performed to
assess this approach. Results of studies that have compared preemptive therapy to empiric therapy in allogenic HCT recipients and/or patients with
hematologic malignancies have shown:
Although the results of these studies suggest limited benefit of a preemptive strategy, none of the trials provides definitive conclusions due to study design
issues. Since the safety and efficacy of replacing empiric therapy with preemptive therapy in neutropenic patients has not been established, the latter
approach cannot be recommended.
Secondary prophylaxis for prevention of relapse — Patients who complete antifungal therapy are at risk for reactivation of aspergillosis if neutropenia
recurs. Individuals who are at high risk of relapse, such as those who receive chemotherapy or hematopoietic cell transplantation, require secondary
prophylaxis. Secondary prophylaxis involves the reinitiation of antifungal therapy during periods of increased risk of relapse, such as following
chemotherapy or hematopoietic cell transplantation. Voriconazole has been evaluated as secondary prophylaxis to prevent relapsed aspergillosis [84]. In
patients at increased risk of relapse following the completion of primary treatment, we recommend reinitiation of antifungal therapy with voriconazole or
another mold-active antifungal that the patient responded to and tolerated. (See "Prophylaxis of invasive fungal infections in adults with hematologic
malignancies", section on 'Secondary prophylaxis' and "Prophylaxis of invasive fungal infections in adult hematopoietic cell transplant recipients", section
on 'Secondary prophylaxis'.)
The pathogenesis of relapsed invasive aspergillosis is thought to be due to reactivation of a latent, subclinical infection that had not been fully eradicated.
This may be secondary to the angioinvasive nature of the organism or due to lack of sterilization secondary to poor drug penetration (eg, foreign bodies,
vegetations, or lung or bone sequestra) [60]. Factors that predispose patients to relapsing invasive aspergillosis include site of infection (eg, sinuses), use
A significant reduction in the use of empiric antifungal therapy (32 versus 15 percent) but no difference in mortality among patients who were
assigned to serial galactomannan and polymerase chain reaction (PCR) testing compared with those who were assigned to standard diagnosis [81].
●
No overall clinical or survival benefit to a preemptive strategy that involved serial PCR testing [82].●
No survival benefit of a preemptive strategy that used the serum galactomannan assay in combination with other clinical indicators [83]. Probable or
proven invasive fungal infections were significantly more common among those who received preemptive therapy (9 versus 4 percent), but some of
these infections were due to Candida spp rather than molds. (See "Diagnosis of invasive aspergillosis", section on 'Galactomannan antigen
detection'.)
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of systemic glucocorticoids, lack of remission of underlying hematologic malignancy, duration of neutropenia, and receipt of an unrelated hematopoietic
cell transplant [60]. The recognition that certain variations in innate immunity increase the risk of invasive aspergillosis suggest that at least some of these
infections may represent reinfection due to ongoing high risk of disease; examples include polymorphisms in the genes encoding toll-like receptor-4,
dectin-1, and mannose-binding lectin. (See "Epidemiology and clinical manifestations of invasive aspergillosis", section on 'Risk factors'.)
PROGNOSTIC FACTORS — Invasive aspergillosis is a major cause of death in immunosuppressed patients, particularly following hematopoietic cell
transplantation (HCT) [85]. Historically, the one-year mortality rate after onset of invasive aspergillosis in this population was as high as 80 percent [85].
However, results of more recent studies demonstrate improved outcomes, both with regard to estimated attributable and overall mortality [12,69].
In a United States–based multicenter surveillance study that enrolled patients from 2001 to 2005, the 12-week all-cause mortality among HCT recipients
with invasive aspergillosis was 58 percent [86]. Lower mortality rates have been observed in trials that included patients other than HCT recipients. As an
example, in one trial in which only 29 percent of patients were HCT recipients, the 12-week mortality in patients who received voriconazole was 29 versus
42 percent in those who received amphotericin B deoxycholate [5]. (See 'Voriconazole' above.)
Studies evaluating more homogeneous patient populations, such as those done only in HCT recipients, have shown a measurable increase in survival after
the diagnosis of invasive aspergillosis in recent years [12,87]. However, variables that influence outcome include a complex combination of host factors,
including the underlying disease, as well as the therapies used. Factors predictive of death include disseminated disease, cerebral involvement, persistent
and severe neutropenia, administration of glucocorticoids, receipt of human leukocyte antigen-mismatched stem cells, and uncontrolled graft-versus-host
disease [12,69,88,89]. A delay in diagnosis may also lead to worse outcomes. As mentioned previously, multiple host factors, such as pulmonary function
prior to transplant, and underlying organ (kidney and liver) function impact outcomes. There is some indication that recipients of non-myeloablative (or
reduced intensity) conditioning regimens have relatively better outcomes after infection compared with patients who received myeloablative therapies [12].
Glucocorticoid use has been associated with higher mortality rates among HCT recipients in several studies [12,85-89], but, in one study of solid organ
transplant recipients, glucocorticoid use resulted in a decreased risk of death [86].
Galactomannan assay — The serum galactomannan assay has diagnostic value and may have prognostic value [90-95], as illustrated by the following
studies:
In contrast, in bronchoalveolar lavage fluid samples, neither the detection of galactomannan nor the magnitude of the results correlated with mortality in
allogeneic cell transplant recipients with invasive pulmonary aspergillosis [94]. (See "Diagnosis of invasive aspergillosis", section on 'Bronchoalveolar
lavage fluid'.)
In a review of 27 studies of patients with hematologic malignancies and proven or probable aspergillosis, patients with persistently positive
galactomannan results were significantly more likely to die and to have autopsy-proven aspergillosis than those with a test that normalized in value
[90].
●
Another study demonstrated that both the serum galactomannan value at the time of diagnosis of invasive aspergillosis and the one-week
galactomannan decay were predictive of all-cause mortality [91]. Each enzyme immunoassay (EIA) unit increase in galactomannan at the time of
diagnosis increased the hazard of time to all-cause mortality at six weeks by 25 percent, whereas each galactomannan EIA unit decline during the
week following the initial test decreased the risk of time to all-cause mortality at six weeks by 22 percent. (See "Diagnosis of invasive aspergillosis",
section on 'Galactomannan antigen detection'.)
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INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient
education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have
about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics
patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best
for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also
locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
SUMMARY AND RECOMMENDATIONS
th th
th th
Basics topic (see "Patient information: Invasive aspergillosis (The Basics)")●
Aspergillus species are ubiquitous, but invasive aspergillosis occurs primarily in immunocompromised hosts. Neutropenia and glucocorticoid use are
the most common predisposing factors. Invasive aspergillosis is a major cause of death in immunosuppressed patients, particularly following
hematopoietic cell transplantation (HCT). (See 'Introduction' above and 'Prognostic factors' above.)
●
For initial therapy of patients with confirmed invasive aspergillosis (ie, diagnosed by culture, galactomannan antigen, or histopathology), we
recommend a voriconazole-based regimen rather than an amphotericin B–based regimen (Grade 1A). We also suggest the addition of an
echinocandin to voriconazole for the first one to two weeks of therapy (Grade 2B). However, some experts prefer monotherapy with voriconazole.
(See 'Choice of regimen' above and 'Voriconazole' above and 'Voriconazole and an echinocandin' above.)
●
In patients who are intolerant of voriconazole due to hepatotoxicity or other severe reactions, we suggest switching from voriconazole to a lipid
formulation of amphotericin B (AmBisome or Abelcet) (Grade 2B). The recommended dose of liposomal amphotericin B (AmBisome) is 3 to 5 mg/kg
IV per day and of amphotericin B lipid complex (Abelcet) is 5 mg/kg IV per day. In patients receiving voriconazole and an echinocandin who are
switched from voriconazole to a lipid formulation of amphotericin B, we suggest continuing the echinocandin, although the efficacy of AmBisome plus
an echinocandin has not been proven (Grade 2C). (See 'Choice of regimen' above and 'Lipid formulations' above and 'Liposomal amphotericin B and
an echinocandin' above.)
●
For salvage therapy in patients who do not respond to monotherapy with voriconazole or a lipid formulation of amphotericin B, we suggest
combination therapy with either voriconazole plus an echinocandin (Grade 2B) or a lipid formulation of amphotericin B (AmBisome or Abelcet) plus
an echinocandin (Grade 2C). There are no data to support the use of amphotericin B with a triazole for combination therapy. (See 'Salvage therapy'
above and 'Echinocandins' above and 'Voriconazole and an echinocandin' above.)
●
All patients receiving voriconazole for the treatment of invasive aspergillosis, particularly those receiving oral therapy, should undergo monitoring of
serum voriconazole trough concentrations. We suggest checking a trough concentration five to seven days into therapy. A goal of achieving serum
concentrations >1 mcg/mL and <5.5 mcg/mL has been suggested, but we prefer concentrations between 2 to 5.5 mcg/mL. (See 'Voriconazole'
above.)
●
If an invasive mold infection is suspected and the likelihood of mucormycosis is increased due to recent receipt of voriconazole, we use a lipid
formulation of amphotericin B (AmBisome or Abelcet) rather than voriconazole in order to provide antifungal activity against both aspergillosis and
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●
Surgical debridement is often required for the treatment of Aspergillus rhinosinusitis and may also be indicated in settings in which antifungals cannot
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●
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●
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Disclosures: Kieren A Marr, MD Grant/Research/Clinical Trial Support: Pfizer [Antifungals (Voriconazole, anidulafungin)]; Astellas[Transplant infections (Liposomal amphotericin B, micafungin, isavuconazole)]. Consultant/Advisory Boards: Astellas [Antifungals (Liposomalamphotericin B, micafungin, isavuconazole)]; Merck [Antifungals (Posaconazole)]; Cidara Therapeutics [Antifungals (Antifungals)]; ChimerixTherapeutics [Antivirals (Antivirals)]. Patent Holder: MycoMed Technologies [Aspergillosis (Fungal diagnostics)]. Equity Ow nership/StockOptions: MycoMed Technologies [Aspergillosis (Fungal diagnostics)]. Carol A Kauffman, MD Nothing to disclose. Anna R Thorner, MDNothing to disclose.
Contributor disclosures are review ed for conflicts of interest by the editorial group. When found, these are addressed by vetting through amulti-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content isrequired of all authors and must conform to UpToDate standards of evidence.
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