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Pharmacist Continuing Education: A Review of Current Treatment Guidelines for Invasive Aspergillosis

24 Jan 2019 10:16 AM | Anonymous

Authors:  Robin Yang, PharmD and Sophia Huynh, PharmD
Mentors: Tyson Lotz, PharmD, MBA and Melissa Mays, PharmD
SSM Health St. Clare Hospital – Fenton, MO

Program Number:
Approval Dates:
Approved Contact Hours: One (1) CE(s) per LIVE session.

Learning Objectives:

  1. Recognize patients at high-risk for invasive aspergillosis
  2. Recall non-pharmacological prevention recommendations made in the 2016 Infectious Disease Society of America Aspergillosis guidelines.
  3. Select and recommend appropriate initial antifungal therapy for invasive aspergillosis.
  4. Compare and contrast differences in adverse effect profiles between antifungal agents.

Aspergillus is a common mold that lives in the environment. A majority of healthy people inhale Aspergillus spores daily without contracting illness.1 Since aspergillosis is not a reportable infection in the United States through the Centers of Disease for Disease Control and Prevention, the exact prevalence is unknown.2 Invasive aspergillosis (IA) is relatively uncommon and represents an infectious burden on immunocompromised patients that can be a major cause of mortality. IA has been found to be the most common fungal infection among stem cell transplant patients and the second-most common among patients with a history of solid organ transplantation from prospective surveillance.3-4 A large prospective study found that one-year survival for patients with invasive aspergillosis was 25% in stem cell transplant patients and 59% in solid organ transplant patients, respectively.3-4

Clinical Manifestations and Diagnosis5
IA primarily involves the sinopulmonary tract, as inhalation is the most common portal of entry and transmission. The onset of clinical presentation may range from days to weeks with symptoms including facial swelling, nose bleeds, fever, cough, and dyspnea. Invasion of the vasculature may manifest effects such as chest pain or hemoptysis. As IA clinical manifestations are nonspecific, it remains difficult to diagnose; thus, utilization of appropriate diagnostic tools is crucial.

Diagnostic Tools
The chest computed tomography (CT) scan is recommended in suspected invasive pulmonary aspergillosis regardless of other chest radiograph results due to its much higher sensitivity in lesion identification. Typical features of invasive pulmonary aspergillosis on CT imaging include nodules, consolidative lesions, wedge-shaped infarcts, and the characteristic feature includes a “halo sign.” The “halo sign” is particularly seen in neutropenic patients and is defined as a nodule greater than 1 centimeter in diameter surrounded by ground-glass opacity. Upon recognition of a halo sign, treatment initiation is warranted as it has demonstrated improvement in clinical response.

Bronchoalveolar lavage (BAL) is an alternative in patients with suspicion of invasive pulmonary aspergillosis and remains a cornerstone diagnostic test for microbiological identification in diffuse interstitial or alveolar lung infiltrates. Cells and other components from bronchial and alveolar spaces are obtained in this relatively safe and well tolerated procedure. However, due to being an invasive procedure, it requires patient consent, sufficient patient respiratory capacity, and no major bleeding diathesis that precludes BAL. Therapy should be initiated if findings return with high suspicion of aspergillosis.

Blood or respiratory fluid cultures can be obtained to aid in the diagnosis of aspergillosis infections. It is a common practice to obtain cultures during suspected infection and any growth can further support treatment. Standard and special fungal stains should be performed simultaneously with fungal-specific media during suspected fungal infection. Aspergillus spp. typically grows on most media in approximately 2-5 days. Therefore, incubation period should be at least 5 days. Despite this, culture yield is low and a negative culture does not definitively exclude the diagnosis of IA.

Galactomannan assay is recommended as an accurate marker to diagnose IA when used in certain patient populations including hematologic malignancy or hematopoietic stem cell transplant. Studies have demonstrated good sensitivity at approximately 70%. It can be obtained from blood or bronchoalveolar lavage. However, galactomannan is not recommended to be routinely used in solid organ transplant patients or those with chronic granulomatous disease. Studies have shown galactomannan sensitivity in non-neutropenic patients appears to be lower in other groups and decreases to approximately 20% in solid organ transplant patients.

Polymerase chain reaction (PCR) has been highly debated for its clinical utility in diagnosing IA. Due to limited supporting evidence, recommendations to use PCR routinely cannot be made.  IDSA recommends clinicians utilize PCR assays only in conjunction with other diagnostic tools and interpret results accordingly, maintaining awareness of the methodologies and performance characteristics of the specific assay used.

Risk Factors5-6
Patient populations at risk for IA include those with prolonged neutropenia, recipients of allogeneic hematopoietic stem-cell or solid organ transplant, acquired immunodeficiency syndrome, chronic granulomatous disease, recipients of immunosuppression agents, defective nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, coexisting conditions such as diabetes and malnutrition, recipients of high doses of glucocorticoids, and pre-existing structural lung disease (emphysema, previous cavitary tuberculosis, etc.).

Management of Invasive Aspergillosis5
Non-pharmacological Prevention: Adult Recommendations
High-risk patients are recommended to reduce mold exposure, such as avoidance of gardening, spreading compost, or exposure to construction.


Treatment: Adult Recommendations (Algorithm 1)
IDSA guidelines strongly recommend early initiation of the primary treatment with voriconazole as soon as infection is suspected rather than delaying therapy. Treatment duration should encompass a minimum of 6 to 12 weeks, depending on infection severity. Alternative therapies include liposomal/lipid complex Amphotericin B and isavuconazole. Table 1 in the supplementary appendix provides direct comparisons between each antifungal medication, routes of administration, and common adverse effects. Table 2 in the supplementary appendix summarizes dosing, renal dose adjustments, and hepatic dose adjustments between each antifungal agent.

Triazoles are preferred agents for treatment and prevention in patients with or at risk for IA.

Voriconazole has become the primary drug of choice for invasive aspergillosis based on a pivotal randomized, unblinded, controlled trial that compared patients who received voriconazole and amphotericin B deoxycholate for primary therapy of invasive aspergillosis. In this trial, voriconazole demonstrated superior antifungal efficacy through improved survival benefit in patients at week 12 and significantly fewer adverse events.7Since that pivotal trial, the results of multiple cohort studies further support voriconazole compared with other intravenous therapies.

Isavuconazole serves as an alternative primary agent as supported by the results of a phase III, randomized-controlled, non-inferiority trial that compared isavuconazole with voriconazole for suspected mold disease. Isavuconazole demonstrated to be noninferior to voriconazole in efficacy and was well tolerated compared to voriconazole with fewer adverse events during the study.8  However, there is limited data that exists outside of this single study which led to Food and Drug Administration (FDA) approval in 2015 and the cost is also significantly higher as compared to voriconazole.

Posaconazole and itraconazole are considered for salvage therapy. Itraconazole does not exist in an intravenous formulation and capsules require a low gastric pH for absorption. The suspension formulation shows favorable absorption, but has a higher association with gastrointestinal side effects. Posaconazole has primarily only been studied in prophylaxis and steady-state levels may not be achieved for up to a week, limiting its use.

Triazole antifungals have proven to be difficult to initiate in patients with pertinent drug-drug interactions with their other required medications. Clinical judgement should be used to evaluate patients on a case by case basis and establish appropriate monitoring parameters for those who continue concomitant therapy.

Echinocandins include caspofungin, micafungin, and anidulafungin.  

These agents have extensive half-lives, which provides ease with once-daily dosing. This class distributes well into all major organ sites except the eye and does not require renal dose adjustment. However, echinocandins are only available as parenteral administration. Anidulafungin is not approved by the FDA for IA and caspofungin is significantly more expensive than micafungin making micafungin a desirable choice from this class.

Echinocandins can be used in combination with other antifungal agents.    For salvage therapy, the use of monotherapy or combination therapy is appropriate. However, the IDSA recommends against routine use as monotherapy for invasive aspergillosis due to limited data.  The use of echinocandins in combination therapy provides a multimodal approach with differing mechanisms of action.

Additionally, combination therapy is supported by a study comparing therapy with voriconazole plus anidulafungin versus voriconazole alone in a subgroup of patients with hematologic malignancies and hematopoietic cell transplantation diagnosed with invasive aspergillosis did not demonstrate statistical significance, but showed a trend towards increased 6 week survival.9 While there are no strong recommendations regarding combination therapy, the safety and tolerability of echinocandins supports it as a reasonable option to initiate as add-on therapy in severe or refractory disease.

Amphotericin B
Amphotericin B is an appropriate option for initial and salvage therapy of aspergillus infections when a triazole cannot be administered. Currently, two amphotericin formulations, deoxycholate and liposomal derivatives, exist. The deoxycholate formulation should only be reserved for use when alternative agents are unavailable due to its higher risk of adverse effects as compared to the liposomal and lipid complex formulations. Amphotericin B shows activity against most Aspergillus species.  Common adverse effects include infusion-related reactions such as fever, rigors, hypotension and may require premedications for alleviation.10

Summary of Evidence5

  1. Recommend primary treatment of IA with voriconazole.
  2. Early empiric initiation in patients with strongly suspected IA is warranted.
  3. Alternative therapies include isavuconazole or liposomal/lipid complex amphotericin B depending on organ dysfunction, toxicities, and tolerability.
  4. Combination therapy with voriconazole and an echinocandin can be considered in select patients based on severity or refractory to initial treatment.
  5. Primary therapy with an echinocandin is not recommended.
  6. Treatment duration should be a minimum of 6-12 weeks, largely dependent on degree and duration of immunosuppression, site of disease, and evidence of improvement.

Supplementary Appendix

Submit for CE


  1. Barnes PD, Marr KA. Aspergillosis: spectrum of disease, diagnosis, and treatment. Infect Dis Clin North Am. 2006;20(3):545-561, vi.
  2. Centers for Disease Control and Prevention. Aspergillosis statistics. October 12, 2017; https://www.cdc.gov/fungal/diseases/aspergillosis/statistics.html. Assessed November 29th, 2018.
  3. Kontoyiannis DP, Marr KA, Park BJ, et al. Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001-2006: overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database. Clin Infect Dis. 2010;50(8):1091-1100.
  4. Pappas PG, Alexander BD, Andes DR, et al. Invasive fungal infections among organ transplant recipients: results of the Transplant-Associated Infection Surveillance Network (TRANSNET). Clin Infect Dis. 2010;50(8):1101-1111.
  5. Patterson TF, Thompson GR, Denning DW, et al. Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Disease Society of America. Clin Infect Dis. 2016;63(4):e1-e60.
  6. Segal BH. Aspergillosis. N Engl J Med. 2009:360(18):1870-1884. Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002;347(6):408-415.
  7. Maertens JA, Raad II, Marr KA, et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet. 2016;387(10020):760-769.
  8. Marr KA, Schlamm HT, Herbrecht R, et al. Combination antifungal therapy for invasive aspergillosis: a randomized trial. Ann Intern Med. 2016;162(2):81-89.
  9. AmBisome® [package insert]. San Dimas, CA: Gilead Sciences, Inc.; 2012.
  10. VFEND® [package insert]. New York City, NY: Roerig; 2010.
  11. SPORANOX® [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc.; 2017.
  12. Noxafil® [package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp.; 2015.
  13. CRESEMBA® [package insert]. Northbrook, IL: Astellas Pharma US, Inc.; 2015. CANCIDAS® [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2005.
  14. Mycamine® [package insert]. Deerfield, IL: Astellas Pharma US, Inc.; 2007.

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