Caspofungin or Micafungin as Empiric Antifungal Therapy for Persistent Fever and Neutropenia

Condition(s) targeted: Febrile Neutropenia

Phase: N/A

Status: Completed

Sponsored by: Brigham and Women's Hospital

Official(s) and/or principal investigator(s):
David W Kubiak, PharmD, Principal Investigator, Affiliation: Brigham and Women's Hospital

Invasive fungal infections are an important cause of morbidity and mortality in patients with neutropenia who are receiving chemotherapy for cancer. Early diagnosis of these infections is difficult and fever may be the only sign. A delay in treatment while a diagnosis is pursued may lead to increased morbidity and mortality. There are now several echinocandins available with similar in vitro spectrum of activity. Caspofungin is the only echinocandin Food and Drug Administration (FDA) approved for empiric antifungal therapy in febrile neutropenia. Although all echinocandin antifungal agents have similar spectrum of activity, there are limited data on the use of micafungin in patients with persistent fever and neutropenia (FN). In November 2006 the Pharmacy and Therapeutics Committee at Brigham & Women's Hospital / Dana Farber Cancer Institute (BWH/DFCI) switched from caspofungin to micafungin as our formulary echinocandin. Given the limited clinical data on the use of micafungin as empiric antifungal therapy in patients with FN, we sought to evaluate the safety and effectiveness of micafungin, compared with caspofungin, for this indication using a sequential cohort analysis of patients treated before and after the formulary change at Brigham and Women's Hospital.

Official title: Evaluation of Caspofungin or Micafungin as Empiric Antifungal Therapy in Adult Patients With Persistent Febrile Neutropenia: A Retrospective, Observational, Sequential Cohort Analysis

Study design: Observational Model: Cohort, Time Perspective: Retrospective

Primary outcome:

Composite Primary Endpoint: Number of Participants With an Overall Favorable Response to Echinocandin Therapy for Empiric Antifungal Therapy for Persistent Febrile Neutropenia (FN)

Successful Treatment of Any Baseline Invasive Fungal Disease (IFD)

Mortality at Hospital Discharge

Absence of Any Breakthrough Invasive Fungal Disease (IFD)

Lack of an Adverse Drug Event (ADE) Attributable to Echinocandin (EC) Therapy That Led to Discontinuation of Therapy

Secondary outcome:

Duration of Echinocadin Therapy for Persistent Febrile Neutropenia (FN)

Liver Function Tests (LFTs) Elevated During or After Echinocandin Therapy

Specific Type of Adverse Event That Resulted in Echinocandin (EC) Therapy Discontinuation

Duration of Hospitization

Duration of Neutropenia

Detailed description: Objectives This retrospective cohort analysis of converting from caspofungin to micafungin as empiric antifungal therapy for cancer patients who are persistently febrile and neutropenic after receiving broad spectrum antibiotics at Brigham & Women's Hospital / Dana Farber Cancer Institute (BWH/DFCI) is designed to evaluate the following objectives:

- Safety of micafungin in this patient population

- Effective dose of 100 mg daily of micafungin compared to 70mg x1, then 50 mg daily of

caspofungin

- Economic impact of converting or formulary echinocandin from micafungin to caspofungin

Study Design

- Retrospective cohort analysis - limited to medical records

- Data to be collected include the following:

- Demographic information: including: gender, age, race

- Past medical history and admitting diagnoses

- Laboratory results: Liver function tests (LFTs), Including alanine

aminotransferase (ALT), aspartate aminotransferase (AST), Total bilirubin, as well as serum fungal assays: Serum Galactomannan assay, 1. 3-BD Glucan assay

- Concomitant medications and duration of therapy for all systemic: antibiotics and

antifungals

- All invasive breakthrough fungal infection details, including speciation and

outcomes during echinocandin therapy

- Dosing, duration, and adverse events associated with echinocandin therapy

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- All patients admitted to BWH/DFCI who received at least 2 doses of caspofungin with

an Absolute Neutrophil Count (ANC) < 500, for persistent febrile neutropenia from

11/1/2005 - 10/31/2006, as there first antifungal agent.

- All patients admitted to BWH/DFCI who received at least 2 doses of micafungin with an

Absolute Neutrophil Count (ANC) < 500 for persistent febrile neutropenia from

11/1/2006 - 10/31/2007 as there first antifungal agent

Exclusion Criteria:

- Patients receiving an echinocandin antifungal agent (micafungin or caspofungin) for

an indication other then empiric therapy in febrile neutropenia

- Patients receiving therapy for an active or on-going invasive fungal infection

- Patients who received both caspofungin and micafungin during the same admission

- Patients with an ANC > 500 at when either micafungin or caspofungin was started

- Patients who received another antifungal agent for persistent febrile neutropenia,

e. g., voriconazole, amphotericin B liposome, posaconazole, etc... Before they received an echinocandin (caspofungin or micafungin) will be excluded

Brigham and Women's Hospital, Boston, Massachusetts 02115, United States

Related publications:

Schuler U, Bammer S, Aulitzky WE, Binder C, Böhme A, Egerer G, Sandherr M, Schwerdtfeger R, Silling G, Wandt H, Glasmacher A, Ehninger G. Safety and efficacy of itraconazole compared to amphotericin B as empirical antifungal therapy for neutropenic fever in patients with haematological malignancy. Onkologie. 2007 Apr;30(4):185-91. Epub 2007 Mar 23.

Toubai T, Tanaka J, Ota S, Shigematsu A, Shono Y, Ibata M, Hashino S, Kondo T, Kakinoki Y, Masauzi N, Kasai M, Iwasaki H, Kurosawa M, Asaka M, Imamura M. Efficacy and safety of micafungin in febrile neutropenic patients treated for hematological malignancies. Intern Med. 2007;46(1):3-9. Epub 2007 Jan 1.

Seibel NL, Schwartz C, Arrieta A, Flynn P, Shad A, Albano E, Keirns J, Lau WM, Facklam DP, Buell DN, Walsh TJ. Safety, tolerability, and pharmacokinetics of Micafungin (FK463) in febrile neutropenic pediatric patients. Antimicrob Agents Chemother. 2005 Aug;49(8):3317-24.

Walsh TJ, Teppler H, Donowitz GR, Maertens JA, Baden LR, Dmoszynska A, Cornely OA, Bourque MR, Lupinacci RJ, Sable CA, dePauw BE. Caspofungin versus liposomal amphotericin B for empirical antifungal therapy in patients with persistent fever and neutropenia. N Engl J Med. 2004 Sep 30;351(14):1391-402.

Walsh TJ, Pappas P, Winston DJ, Lazarus HM, Petersen F, Raffalli J, Yanovich S, Stiff P, Greenberg R, Donowitz G, Schuster M, Reboli A, Wingard J, Arndt C, Reinhardt J, Hadley S, Finberg R, Laverdière M, Perfect J, Garber G, Fioritoni G, Anaissie E, Lee J; National Institute of Allergy and Infectious Diseases Mycoses Study Group. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med. 2002 Jan 24;346(4):225-34. Erratum in: N Engl J Med. 2007 Feb 15;356(7):760.

Wingard JR, White MH, Anaissie E, Raffalli J, Goodman J, Arrieta A; L Amph/ABLC Collaborative Study Group. A randomized, double-blind comparative trial evaluating the safety of liposomal amphotericin B versus amphotericin B lipid complex in the empirical treatment of febrile neutropenia. L Amph/ABLC Collaborative Study Group. Clin Infect Dis. 2000 Nov;31(5):1155-63. Epub 2000 Nov 7.

Winston DJ, Hathorn JW, Schuster MG, Schiller GJ, Territo MC. A multicenter, randomized trial of fluconazole versus amphotericin B for empiric antifungal therapy of febrile neutropenic patients with cancer. Am J Med. 2000 Mar;108(4):282-9.

Walsh TJ, Finberg RW, Arndt C, Hiemenz J, Schwartz C, Bodensteiner D, Pappas P, Seibel N, Greenberg RN, Dummer S, Schuster M, Holcenberg JS. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group. N Engl J Med. 1999 Mar 11;340(10):764-71.

Ascioglu S, Rex JH, de Pauw B, Bennett JE, Bille J, Crokaert F, Denning DW, Donnelly JP, Edwards JE, Erjavec Z, Fiere D, Lortholary O, Maertens J, Meis JF, Patterson TF, Ritter J, Selleslag D, Shah PM, Stevens DA, Walsh TJ; Invasive Fungal Infections Cooperative Group of the European Organization for Research and Treatment of Cancer; Mycoses Study Group of the National Institute of Allergy and Infectious Diseases. Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis. 2002 Jan 1;34(1):7-14. Epub 2001 Nov 26.

Hughes WT, Armstrong D, Bodey GP, Bow EJ, Brown AE, Calandra T, Feld R, Pizzo PA, Rolston KV, Shenep JL, Young LS. 2002 guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis. 2002 Mar 15;34(6):730-51. Epub 2002 Feb 13.

Vartivarian SE, Anaissie EJ, Bodey GP. Emerging fungal pathogens in immunocompromised patients: classification, diagnosis, and management. Clin Infect Dis. 1993 Nov;17 Suppl 2:S487-91. Review.

Perfect JR, Dodds Ashley E, Drew R. Design of aerosolized amphotericin b formulations for prophylaxis trials among lung transplant recipients. Clin Infect Dis. 2004 Oct 15;39 Suppl 4:S207-10.

Pfaller MA, Boyken L, Hollis RJ, Kroeger J, Messer SA, Tendolkar S, Diekema DJ. In vitro susceptibility of invasive isolates of Candida spp. to anidulafungin, caspofungin, and micafungin: six years of global surveillance. J Clin Microbiol. 2008 Jan;46(1):150-6. Epub 2007 Nov 21. Erratum in: J Clin Microbiol. 2008 Sep;46(9):3184-5.

Kuse ER, Chetchotisakd P, da Cunha CA, Ruhnke M, Barrios C, Raghunadharao D, Sekhon JS, Freire A, Ramasubramanian V, Demeyer I, Nucci M, Leelarasamee A, Jacobs F, Decruyenaere J, Pittet D, Ullmann AJ, Ostrosky-Zeichner L, Lortholary O, Koblinger S, Diekmann-Berndt H, Cornely OA; Micafungin Invasive Candidiasis Working Group. Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised double-blind trial. Lancet. 2007 May 5;369(9572):1519-27.

Yanada M, Kiyoi H, Murata M, Suzuki M, Iwai M, Yokozawa T, Baba H, Emi N, Naoe T. Micafungin, a novel antifungal agent, as empirical therapy in acute leukemia patients with febrile neutropenia. Intern Med. 2006;45(5):259-64. Epub 2006 Apr 3.

Pappas PG, Rotstein CM, Betts RF, Nucci M, Talwar D, De Waele JJ, Vazquez JA, Dupont BF, Horn DL, Ostrosky-Zeichner L, Reboli AC, Suh B, Digumarti R, Wu C, Kovanda LL, Arnold LJ, Buell DN. Micafungin versus caspofungin for treatment of candidemia and other forms of invasive candidiasis. Clin Infect Dis. 2007 Oct 1;45(7):883-93. Epub 2007 Aug 29. Erratum in: Clin Infect Dis. 2008 Jul 15;47(2):302.

Sucher AJ, Chahine EB, Balcer HE. Echinocandins: the newest class of antifungals. Ann Pharmacother. 2009 Oct;43(10):1647-57. doi: 10.1345/aph.1M237. Epub 2009 Sep 1. Review.

Starting date: January 2008
Last updated: August 25, 2010