Prevencion y Tratamiento de Aspergilosis Invasiva

20
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 Author Kieren A Marr, MD Section Editor Carol A Kauffman, MD Deputy Editor Anna 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. ® ®

description

Prevencion y Tratamiento de Aspergilosis Invasiva, tratamiento, epidemiología

Transcript of Prevencion y Tratamiento de Aspergilosis Invasiva

Page 1: Prevencion y Tratamiento de Aspergilosis Invasiva

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.

®

®

Page 2: Prevencion y Tratamiento de Aspergilosis Invasiva

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… 2/20

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".)

Page 3: Prevencion y Tratamiento de Aspergilosis Invasiva

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… 3/20

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".)

Page 4: Prevencion y Tratamiento de Aspergilosis Invasiva

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… 4/20

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'.)

Page 5: Prevencion y Tratamiento de Aspergilosis Invasiva

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… 5/20

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●

Page 6: Prevencion y Tratamiento de Aspergilosis Invasiva

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… 6/20

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)●

Page 7: Prevencion y Tratamiento de Aspergilosis Invasiva

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… 7/20

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).

Page 8: Prevencion y Tratamiento de Aspergilosis Invasiva

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… 8/20

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

Page 9: Prevencion y Tratamiento de Aspergilosis Invasiva

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… 9/20

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

46

Page 10: Prevencion y Tratamiento de Aspergilosis Invasiva

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&sele… 10/20

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.

Page 11: Prevencion y Tratamiento de Aspergilosis Invasiva

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&sele… 11/20

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'.)

Page 12: Prevencion y Tratamiento de Aspergilosis Invasiva

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&sele… 12/20

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'.)

Page 13: Prevencion y Tratamiento de Aspergilosis Invasiva

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&sele… 13/20

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'.)

Page 14: Prevencion y Tratamiento de Aspergilosis Invasiva

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&sele… 14/20

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

Page 15: Prevencion y Tratamiento de Aspergilosis Invasiva

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&sele… 15/20

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

1. Limper AH, Knox KS, Sarosi GA, et al. An official American Thoracic Society statement: Treatment of fungal infections in adult pulmonary andcritical care patients. Am J Respir Crit Care Med 2011; 183:96.

2. Marr KA, Schlamm HT, Herbrecht R, et al. Combination antifungal therapy for invasive aspergillosis: a randomized trial. Ann Intern Med 2015;162:81.

3. Imhof A, Balajee SA, Fredricks DN, et al. Breakthrough fungal infections in stem cell transplant recipients receiving voriconazole. Clin Infect Dis2004; 39:743.

4. Marty FM, Cosimi LA, Baden LR. Breakthrough zygomycosis after voriconazole treatment in recipients of hematopoietic stem-cell transplants. NEngl J Med 2004; 350:950.

5. Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 2002;347:408.

mucormycosis. A definitive diagnosis should be pursued aggressively, and the regimen should be changed to voriconazole plus an echinocandin if

the diagnosis of invasive aspergillosis is established. (See 'Choice of regimen' above.)

Whenever possible, immunosuppression should be decreased as an adjunct to antifungal therapy for the treatment of invasive aspergillosis. (See

'Immunomodulation' above.)

Surgical debridement is often required for the treatment of Aspergillus rhinosinusitis and may also be indicated in settings in which antifungals cannot

be delivered to large necrotic lesions and/or when there is an imminent threat to vessels. (See 'Role of surgery' above.)

The duration of antifungal therapy depends upon the location of the infection, the patient's underlying disease and need for further

immunosuppression, and the response to therapy. For most immunosuppressed patients, antifungal therapy will continue for months or even years in

some cases. (See 'Duration' above.)

Antifungal resistance should be considered in patients with A. fumigatus who do not respond to voriconazole and in patients infected with certain

Aspergillus species that have reduced antifungal susceptibility profiles (eg, A. terreus, A. calidoustus, A. lentulus, Neosartoria udagawae). (See

'Voriconazole' above and 'Antifungal resistance' above.)

Patients who complete antifungal therapy are at risk for relapse of aspergillosis during periods of increased immunosuppression, particularly if

neutropenia recurs. We recommend reinitiation of antifungal therapy if chemotherapy is reinitiated and the patient is expected to become neutropenic

or if immunosuppression is intensified (Grade 1B). (See 'Secondary prophylaxis for prevention of relapse' above.)

Strategies to prevent advanced disease include prophylactic therapy with a mold-active drug and antigen-based screening (eg, galactomannan) in

high-risk patients. The most effective approach has not been determined and is likely to vary depending on patient characteristics and logistics (eg,

ability to follow antigen assays). (See 'Prevention and early treatment' above.)

Page 16: Prevencion y Tratamiento de Aspergilosis Invasiva

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&sele… 16/20

6. Schwartz S, Ruhnke M, Ribaud P, et al. Improved outcome in central nervous system aspergillosis, using voriconazole treatment. Blood 2005;106:2641.

7. Pascual A, Calandra T, Bolay S, et al. Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safetyoutcomes. Clin Infect Dis 2008; 46:201.

8. Vfend® package insert. Roerig, a Division of Pfizer, Inc. New York, NY, 2008. http://media.pfizer.com/files/products/uspi_vfend.pdf (Accessed onNovember 12, 2008).

9. Howard A, Hoffman J, Sheth A. Clinical application of voriconazole concentrations in the treatment of invasive aspergillosis. Ann Pharmacother 2008;42:1859.

10. Maertens J, Glasmacher A, Herbrecht R, et al. Multicenter, noncomparative study of caspofungin in combination with other antifungals as salvagetherapy in adults with invasive aspergillosis. Cancer 2006; 107:2888.

11. CRESEMBA (isavuconazonium sulfate). Highlights of prescribing information.http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/207500Orig1s000lbl.pdf (Accessed on March 09, 2015).

12. Upton A, Kirby KA, Carpenter P, et al. Invasive aspergillosis following hematopoietic cell transplantation: outcomes and prognostic factorsassociated with mortality. Clin Infect Dis 2007; 44:531.

13. Walsh TJ, Anaissie EJ, Denning DW, et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America.Clin Infect Dis 2008; 46:327.

14. Segal BH, Walsh TJ. Current approaches to diagnosis and treatment of invasive aspergillosis. Am J Respir Crit Care Med 2006; 173:707.

15. Patterson TF, Boucher HW, Herbrecht R, et al. Strategy of following voriconazole versus amphotericin B therapy with other licensed antifungaltherapy for primary treatment of invasive aspergillosis: impact of other therapies on outcome. Clin Infect Dis 2005; 41:1448.

16. Böhme A, Ruhnke M, Buchheidt D, et al. Treatment of fungal infections in hematology and oncology--guidelines of the Infectious Diseases WorkingParty (AGIHO) of the German Society of Hematology and Oncology (DGHO). Ann Hematol 2003; 82 Suppl 2:S133.

17. Talbot GH, Bradley J, Edwards JE Jr, et al. Bad bugs need drugs: an update on the development pipeline from the Antimicrobial Availability TaskForce of the Infectious Diseases Society of America. Clin Infect Dis 2006; 42:657.

18. Spanakis EK, Aperis G, Mylonakis E. New agents for the treatment of fungal infections: clinical efficacy and gaps in coverage. Clin Infect Dis 2006;43:1060.

19. De Pauw B, Walsh TJ, Donnelly JP, et al. Revised definitions of invasive fungal disease from the European Organization for Research and Treatmentof Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group(EORTC/MSG) Consensus Group. Clin Infect Dis 2008; 46:1813.

20. Herbrecht R, Patterson TF, Slavin MA, et al. Application of the 2008 definitions for invasive fungal diseases to the trial comparing voriconazole versusamphotericin B for therapy of invasive aspergillosis: a collaborative study of the Mycoses Study Group (MSG 05) and the European Organization forResearch and Treatment of Cancer Infectious Diseases Group. Clin Infect Dis 2015; 60:713.

21. Walsh TJ, Raad I, Patterson TF, et al. Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant ofconventional therapy: an externally controlled trial. Clin Infect Dis 2007; 44:2.

22. Diekema DJ, Messer SA, Hollis RJ, et al. Activities of caspofungin, itraconazole, posaconazole, ravuconazole, voriconazole, and amphotericin Bagainst 448 recent clinical isolates of filamentous fungi. J Clin Microbiol 2003; 41:3623.

23. Torres HA, Hachem RY, Chemaly RF, et al. Posaconazole: a broad-spectrum triazole antifungal. Lancet Infect Dis 2005; 5:775.

Page 17: Prevencion y Tratamiento de Aspergilosis Invasiva

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&sele… 17/20

24. Howard SJ, Lestner JM, Sharp A, et al. Pharmacokinetics and pharmacodynamics of posaconazole for invasive pulmonary aspergillosis: clinicalimplications for antifungal therapy. J Infect Dis 2011; 203:1324.

25. Raad II, Graybill JR, Bustamante AB, et al. Safety of long-term oral posaconazole use in the treatment of refractory invasive fungal infections. ClinInfect Dis 2006; 42:1726.

26. FDA news release. FDA approves new antifungal drug Cresemba. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm437106.htm(Accessed on March 09, 2015).

27. Denning DW, Lee JY, Hostetler JS, et al. NIAID Mycoses Study Group Multicenter Trial of Oral Itraconazole Therapy for Invasive Aspergillosis. Am JMed 1994; 97:135.

28. Hiemenz JW, Walsh TJ. Lipid formulations of amphotericin B: recent progress and future directions. Clin Infect Dis 1996; 22 Suppl 2:S133.

29. Bowden R, Chandrasekar P, White MH, et al. A double-blind, randomized, controlled trial of amphotericin B colloidal dispersion versus amphotericinB for treatment of invasive aspergillosis in immunocompromised patients. Clin Infect Dis 2002; 35:359.

30. Trullas JC, Cervera C, Benito N, et al. Invasive pulmonary aspergillosis in solid organ and bone marrow transplant recipients. Transplant Proc 2005;37:4091.

31. Cornely OA, Maertens J, Bresnik M, et al. Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized trial comparing ahigh-loading dose regimen with standard dosing (AmBiLoad trial). Clin Infect Dis 2007; 44:1289.

32. McCormack PL, Perry CM. Caspofungin: a review of its use in the treatment of fungal infections. Drugs 2005; 65:2049.

33. Aliff TB, Maslak PG, Jurcic JG, et al. Refractory Aspergillus pneumonia in patients with acute leukemia: successful therapy with combinationcaspofungin and liposomal amphotericin. Cancer 2003; 97:1025.

34. Kontoyiannis DP, Hachem R, Lewis RE, et al. Efficacy and toxicity of caspofungin in combination with liposomal amphotericin B as primary orsalvage treatment of invasive aspergillosis in patients with hematologic malignancies. Cancer 2003; 98:292.

35. Marr KA, Boeckh M, Carter RA, et al. Combination antifungal therapy for invasive aspergillosis. Clin Infect Dis 2004; 39:797.

36. Petraitiene R, Petraitis V, Lyman CA, et al. Efficacy, safety, and plasma pharmacokinetics of escalating dosages of intravenously administeredravuconazole lysine phosphoester for treatment of experimental pulmonary aspergillosis in persistently neutropenic rabbits. Antimicrob AgentsChemother 2004; 48:1188.

37. Maertens J, Raad I, Petrikkos G, et al. Efficacy and safety of caspofungin for treatment of invasive aspergillosis in patients refractory to or intolerantof conventional antifungal therapy. Clin Infect Dis 2004; 39:1563.

38. Almyroudis NG, Kontoyiannis DP, Sepkowitz KA, et al. Issues related to the design and interpretation of clinical trials of salvage therapy for invasivemold infection. Clin Infect Dis 2006; 43:1449.

39. Martín-Peña A, Aguilar-Guisado M, Espigado I, Cisneros JM. Antifungal combination therapy for invasive aspergillosis. Clin Infect Dis 2014; 59:1437.

40. Baddley JW, Pappas PG. Antifungal combination therapy: clinical potential. Drugs 2005; 65:1461.

41. Sionov E, Mendlovic S, Segal E. Experimental systemic murine aspergillosis: treatment with polyene and caspofungin combination and G-CSF. JAntimicrob Chemother 2005; 56:594.

42. Vazquez JA. Clinical practice: combination antifungal therapy for mold infections: much ado about nothing? Clin Infect Dis 2008; 46:1889.

43. Singh N, Limaye AP, Forrest G, et al. Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organtransplant recipients: a prospective, multicenter, observational study. Transplantation 2006; 81:320.

Page 18: Prevencion y Tratamiento de Aspergilosis Invasiva

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&sele… 18/20

44. Viscoli C. Combination therapy for invasive aspergillosis. Clin Infect Dis 2004; 39:803.

45. Caillot D, Thiébaut A, Herbrecht R, et al. Liposomal amphotericin B in combination with caspofungin for invasive aspergillosis in patients withhematologic malignancies: a randomized pilot study (Combistrat trial). Cancer 2007; 110:2740.

46. Kontoyiannis DP, Boktour M, Hanna H, et al. Itraconazole added to a lipid formulation of amphotericin B does not improve outcome of primarytreatment of invasive aspergillosis. Cancer 2005; 103:2334.

47. Meletiadis J, Petraitis V, Petraitiene R, et al. Triazole-polyene antagonism in experimental invasive pulmonary aspergillosis: in vitro and in vivocorrelation. J Infect Dis 2006; 194:1008.

48. Sugar AM. Antifungal combination therapy: where we stand. Drug Resist Updat 1998; 1:89.

49. Sugar AM. Overview: antifungal combination therapy. Curr Opin Investig Drugs 2001; 2:1364.

50. Steinbach WJ, Benjamin DK Jr, Kontoyiannis DP, et al. Infections due to Aspergillus terreus: a multicenter retrospective analysis of 83 cases. ClinInfect Dis 2004; 39:192.

51. Balajee SA, Nickle D, Varga J, Marr KA. Molecular studies reveal frequent misidentification of Aspergillus fumigatus by morphotyping. Eukaryot Cell2006; 5:1705.

52. Vinh DC, Shea YR, Sugui JA, et al. Invasive aspergillosis due to Neosartorya udagawae. Clin Infect Dis 2009; 49:102.

53. Snelders E, van der Lee HA, Kuijpers J, et al. Emergence of azole resistance in Aspergillus fumigatus and spread of a single resistancemechanism. PLoS Med 2008; 5:e219.

54. Verweij PE, Mellado E, Melchers WJ. Multiple-triazole-resistant aspergillosis. N Engl J Med 2007; 356:1481.

55. van der Linden JW, Jansen RR, Bresters D, et al. Azole-resistant central nervous system aspergillosis. Clin Infect Dis 2009; 48:1111.

56. Bueid A, Howard SJ, Moore CB, et al. Azole antifungal resistance in Aspergillus fumigatus: 2008 and 2009. J Antimicrob Chemother 2010; 65:2116.

57. Steinmann J, Hamprecht A, Vehreschild MJ, et al. Emergence of azole-resistant invasive aspergillosis in HSCT recipients in Germany. J AntimicrobChemother 2015; 70:1522.

58. van der Linden JW, Camps SM, Kampinga GA, et al. Aspergillosis due to voriconazole highly resistant Aspergillus fumigatus and recovery ofgenetically related resistant isolates from domiciles. Clin Infect Dis 2013; 57:513.

59. Denning DW, Bowyer P. Voriconazole resistance in Aspergillus fumigatus: should we be concerned? Clin Infect Dis 2013; 57:521.

60. Sipsas NV, Kontoyiannis DP. Clinical issues regarding relapsing aspergillosis and the efficacy of secondary antifungal prophylaxis in patients withhematological malignancies. Clin Infect Dis 2006; 42:1584.

61. Karp JE, Burch PA, Merz WG. An approach to intensive antileukemia therapy in patients with previous invasive aspergillosis. Am J Med 1988;85:203.

62. Safdar A. Immunotherapy for invasive mold disease in severely immunosuppressed patients. Clin Infect Dis 2013; 57:94.

63. Salerno CT, Ouyang DW, Pederson TS, et al. Surgical therapy for pulmonary aspergillosis in immunocompromised patients. Ann Thorac Surg 1998;65:1415.

64. Baron O, Guillaumé B, Moreau P, et al. Aggressive surgical management in localized pulmonary mycotic and nonmycotic infections for neutropenicpatients with acute leukemia: report of eighteen cases. J Thorac Cardiovasc Surg 1998; 115:63.

65. Süslü AE, Oğretmenoğlu O, Süslü N, et al. Acute invasive fungal rhinosinusitis: our experience with 19 patients. Eur Arch Otorhinolaryngol 2009;

Page 19: Prevencion y Tratamiento de Aspergilosis Invasiva

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&sele… 19/20

266:77.

66. Herbrecht R, Natarajan-Amé S, Letscher-Bru V, Canuet M. Invasive pulmonary aspergillosis. Semin Respir Crit Care Med 2004; 25:191.

67. Matt P, Bernet F, Habicht J, et al. Predicting outcome after lung resection for invasive pulmonary aspergillosis in patients with neutropenia. Chest2004; 126:1783.

68. Patterson TF, Kirkpatrick WR, White M, et al. Invasive aspergillosis. Disease spectrum, treatment practices, and outcomes. I3 Aspergillus StudyGroup. Medicine (Baltimore) 2000; 79:250.

69. Parody R, Martino R, Sánchez F, et al. Predicting survival in adults with invasive aspergillosis during therapy for hematological malignancies or afterhematopoietic stem cell transplantation: Single-center analysis and validation of the Seattle, French, and Strasbourg prognostic indexes. Am JHematol 2009; 84:571.

70. Groll AH, Tragiannidis A. Recent advances in antifungal prevention and treatment. Semin Hematol 2009; 46:212.

71. Leventakos K, Lewis RE, Kontoyiannis DP. Fungal infections in leukemia patients: how do we prevent and treat them? Clin Infect Dis 2010; 50:405.

72. Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med2007; 356:348.

73. Ullmann AJ, Lipton JH, Vesole DH, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med 2007;356:335.

74. Wingard JR, Carter SL, Walsh TJ, et al. Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infectionafter allogeneic hematopoietic cell transplantation. Blood 2010; 116:5111.

75. Marr KA, Crippa F, Leisenring W, et al. Itraconazole versus fluconazole for prevention of fungal infections in patients receiving allogeneic stem celltransplants. Blood 2004; 103:1527.

76. Winston DJ, Emmanouilides C, Bartoni K, et al. Elimination of Aspergillus infection in allogeneic stem cell transplant recipients with long-termitraconazole prophylaxis: prevention is better than treatment. Blood 2004; 104:1581; author reply 1582.

77. Winston DJ, Maziarz RT, Chandrasekar PH, et al. Intravenous and oral itraconazole versus intravenous and oral fluconazole for long-term antifungalprophylaxis in allogeneic hematopoietic stem-cell transplant recipients. A multicenter, randomized trial. Ann Intern Med 2003; 138:705.

78. Rijnders BJ, Cornelissen JJ, Slobbe L, et al. Aerosolized liposomal amphotericin B for the prevention of invasive pulmonary aspergillosis duringprolonged neutropenia: a randomized, placebo-controlled trial. Clin Infect Dis 2008; 46:1401.

79. Krishna G, Martinho M, Chandrasekar P, et al. Pharmacokinetics of oral posaconazole in allogeneic hematopoietic stem cell transplant recipientswith graft-versus-host disease. Pharmacotherapy 2007; 27:1627.

80. Marr KA. Empirical antifungal therapy--new options, new tradeoffs. N Engl J Med 2002; 346:278.

81. Morrissey CO, Chen SC, Sorrell TC, et al. Galactomannan and PCR versus culture and histology for directing use of antifungal treatment for invasiveaspergillosis in high-risk haematology patients: a randomised controlled trial. Lancet Infect Dis 2013; 13:519.

82. Hebart H, Klingspor L, Klingebiel T, et al. A prospective randomized controlled trial comparing PCR-based and empirical treatment with liposomalamphotericin B in patients after allo-SCT. Bone Marrow Transplant 2009; 43:553.

83. Cordonnier C, Pautas C, Maury S, et al. Empirical versus preemptive antifungal therapy for high-risk, febrile, neutropenic patients: a randomized,controlled trial. Clin Infect Dis 2009; 48:1042.

84. Cordonnier C, Maury S, Pautas C, et al. Secondary antifungal prophylaxis with voriconazole to adhere to scheduled treatment in leukemic patients

Page 20: Prevencion y Tratamiento de Aspergilosis Invasiva

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&sele… 20/20

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.

Conflict of interest policy

and stem cell transplant recipients. Bone Marrow Transplant 2004; 33:943.

85. Marr KA, Carter RA, Crippa F, et al. Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis2002; 34:909.

86. Baddley JW, Andes DR, Marr KA, et al. Factors associated with mortality in transplant patients with invasive aspergillosis. Clin Infect Dis 2010;50:1559.

87. Nivoix Y, Velten M, Letscher-Bru V, et al. Factors associated with overall and attributable mortality in invasive aspergillosis. Clin Infect Dis 2008;47:1176.

88. Ribaud P, Chastang C, Latgé JP, et al. Survival and prognostic factors of invasive aspergillosis after allogeneic bone marrow transplantation. ClinInfect Dis 1999; 28:322.

89. Cordonnier C, Ribaud P, Herbrecht R, et al. Prognostic factors for death due to invasive aspergillosis after hematopoietic stem cell transplantation: a1-year retrospective study of consecutive patients at French transplantation centers. Clin Infect Dis 2006; 42:955.

90. Miceli MH, Grazziutti ML, Woods G, et al. Strong correlation between serum aspergillus galactomannan index and outcome of aspergillosis inpatients with hematological cancer: clinical and research implications. Clin Infect Dis 2008; 46:1412.

91. Koo S, Bryar JM, Baden LR, Marty FM. Prognostic features of galactomannan antigenemia in galactomannan-positive invasive aspergillosis. J ClinMicrobiol 2010; 48:1255.

92. Woods G, Miceli MH, Grazziutti ML, et al. Serum Aspergillus galactomannan antigen values strongly correlate with outcome of invasiveaspergillosis: a study of 56 patients with hematologic cancer. Cancer 2007; 110:830.

93. Nouér SA, Nucci M, Kumar NS, et al. Earlier response assessment in invasive aspergillosis based on the kinetics of serum Aspergillusgalactomannan: proposal for a new definition. Clin Infect Dis 2011; 53:671.

94. Fisher CE, Stevens AM, Leisenring W, et al. The serum galactomannan index predicts mortality in hematopoietic stem cell transplant recipientswith invasive aspergillosis. Clin Infect Dis 2013; 57:1001.

95. Heylen L, Maertens J, Naesens M, et al. Invasive aspergillosis after kidney transplant: case-control study. Clin Infect Dis 2015; 60:1505.

Topic 2459 Version 25.0

Disclosures