Use of Antifungal Drugs in the Year 2006"
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1 Use of Antifungal Drugs in the Year 2006" Jose G. Montoya, MD Associate Professor of Medicine Associate Chief for Clinical Affairs Division of Infectious Diseases Stanford University School of Medicine
2 Fungal Infections cutaneous dermatophytosis and dermatomycosis subcutaneous sporotrichosis systemic endemic opportunistic
3 Endemic Fungal Infections Endemic Fungi Blastomycosis Coccidiodomycosis Histoplasmosis Paracoccidiodomycosis
4 Opportunistic Invasive Fungal Infections Opportunistic Fungi Mycelial Aspergillus Scedosporium Zygomycetes (mucorales) Fusarium Yeasts Candida Cryptococcus
5 Therapeutic Options for Invasive Fungal Infections!IV amphotericin B!conventional!lipid formulations!amphotec, Abelcet, Ambisome!IV/PO fluconazole!iv/po itraconazole!iv/po voriconazole!iv caspofungin!iv micafungin!iv anidulafungin!combination therapy
6 Mechanism of Action of Clinically Available Antifungals Echino Azoles Ampho B
7 Use of Antifungals in Patients with F&N Clinical Settings Primary prophylaxis (HSCT) Empiric treatment for persistently febrile neutropenic patients (4th to 7th day) Treatment for possible invasive fungal infection with evidence of target organ involvement but organism has not been isolated Pathogen directed treatment of invasive disease
8 Primary Prophylaxis (HSCT) fluconazole micafungin fluconazole vs liposomal amphotericin B fluconazole vs voriconazole
9 Results: Treatment Success 1 Proportion of Patients with Treatment Success Micafungin (N=425) Fluconazole (N=457) P-Value (2 tailed) = Time to Treatment Failure (Days Since First Dose of Study Drug)
10 Empiric treatment for persistently febrile neutropenic patients (4th to 7th day) amphotericin B (deoxycholate) liposomal amphotericin B itraconazole caspofungin
11 Empirical Therapy: Summary of Major Studies Comparators Sample Size Randomized Double Blind Primary End Point Met Empirical Therapy Indication Liposomal amphotericin B vs amphotericin B yes yes yes yes Itraconazole vs amphotericin B yes no yes yes Voriconazole vs liposomal amphotericin B yes no no no Caspofungin vs liposomal amphotericin B 4 1,111 yes yes yes yes 1. Walsh TJ et al. N Engl J Med. 1999;340: Boogaerts M et al. Ann Intern Med. 2001;135: Walsh TJ et al. N Engl J Med. 2002;346: Walsh TJ et al. N Engl J Med. 2004;351:
12 Treatment for possible invasive fungal infection with evidence of target organ involvement but organism has not been isolated Local fungal epidemiology Depth and duration of neutropenia Clinical presentation and course Combination therapy Oral therapy for long-term use
13
14 Pulmonary Nodules in Patients with Fever and Neutropenia Current Practice CT of chest: advocated for possible Dx and improved outcome 1,2 Invasive procedures (path + isolation): towards definite or probable Dx BAL: appears to have a relatively low yield when used for fungal stains and culture 3 Lung biopsy (FNA, TBB, OLB, VATS) may have a higher yield but it is often contraindicated because of poor bone marrow function 1 Caillot D. et al. J Clin Oncol 1997;15: Caillot D. et al. J Clin Oncol 2001;19: Reichenberger F. et al Bone Marrow Transplant 1999;24:1195-9
15 Pulmonary Nodules in Patients with Fever and Neutropenia Current Practice Detection of fungal antigens (serum and/or BAL) 1 Galactomanan 2,3 Empiric Antifungal therapy aimed at: Aspergillus spp (including Asp terreus) and/or Mucorales, and/or Scedosporium spp, etc 1 Verweij PE Med Mycol 2005;43:S Maertens J et al. Blood 2001;97: Becker MJ British J Hem 2003; 121: Buchheidt D and Hummel M. Med Mycol 2005;43:S Bretagne S et al. CID 1998; 26:
16 Treatment of Possible Invasive Mould Infectiion in Patients with F&N MONOTHERAPY VORICONAZOLE LIPID FORMULATION OF AMPHO B ITRACONAZOLE COMBINATION VORICONAZOLE + CASPOFUNGIN (ANIDULAFUNGIN, MICAFUNGIN?) VORICONAZOLE + LIPID AMPHO B LIPID AMPHO B + CASPOFUNGIN (ANIDULAFUNGIN, MICAFUNGIN?) ITRACONAZOLE + CASPOFUNGIN (ANIDULAFUNGIN, MICAFUNGIN?) ITRACONAZOLE + LIPID AMPHO B
17 Pathogen directed treatment of invasive disease Aspergillus fumigatus Aspergillus terreus Scedosporium or Pseudalescheria boydii Fusarium spp Mucor spp
18 Ecthyma gangrenosum as a result of P. aeruginosa bacteremia in patient with F&N. Necrotizing vasculitis. GNR invading walls of small arteries and veins Cutaneous Aspergillosis on a previous IV site in a patient with F&N. Hyphal elements invading dermis and Aspergillus fumigatus isolated from fungal culture.
19 Invasive Aspergillosis
20
21 Mycelial Infections in Heart Transplant Patients 54 Heart Transplant Patients with Invasive Aspergillosis Site of disease Lung 31 Disseminated 17 Other 6 Mortality Overall 60% Pulmonary 40% Disseminated 90% CNS 97% Montoya, JG et al. Clin Infect Dis 2001;33:629-40
22 Therapeutic Options for Invasive Aspergillosis Surgical debulking or resection Amphotericin B conventional Lipid formulations Amphotec, Abelcet, Ambisome IV/PO Itraconazole Caspofungin Voriconazole Combination therapy
23 ABLC Lipid Ampho B Clinical Response in Aspergillosis (606 patients) CLEAR Refractory/Intolerant* Walsh * Emergency Use Trial 2 *Complete, partial or stable response Complete or partial response. 1. Walsh TJ, et al. Clin Infct Dis. 1998;26: Hiemenz JW, et al. Blood. 1995;86(suppl 1):849a.
24
25
26 Combination Regimens to consider in Select Group of Patients with IA VORICONAZOLE + CASPOFUNGIN VORICONAZOLE + LIPID AMPHO B LIPID AMPHO B + CASPOFUNGIN ITRACONAZOLE + CASPOFUNGIN ITRACONAZOLE + LIPID AMPHO B
27 Montoya JG et al. Clinical Infectious Diseases 2003; 37: S
28 Development of Cavitation in a 50 yo HxTx Patient Montoya JG et al. Clinical Infectious Diseases 2003; 37: S cm mass in the RLL Cavitation, 11 days later
29 Montoya JG et al. Clinical Infectious Diseases 2003; 37: S Evolution of treated IPA in a 56 yo HxTx Patient 1.5-cm nodule 8 days 59 days
30 Mucormycosis
31
32 Overall Response to ABLC ampho B: (Rates by Site of Infection) 1/1 2/2 12/13 29/45 2/3 46/64 Data on file. Enzon Pharmaceuticals, Inc.
33 Scedosporiosis
34 Schaenman JM et al.journal of Clinical Microbiology Feb;43(2):973-7
35 Fusariosis
36 Fever and Neturopenia 68 yo man with AML 2/ 20/04 BM biopsy reveals AML (M0) 2/23/04 Induction chemotherapy 2/29 Neutropenia 3/3 Febrile. Cefepime initiated 3/7 Left foot edema. Vancomycin added 3/10 Amphotericin B added 3/13 Develops skin lesions
37
38
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40 Infections Caused by Yeasts
41 Candidemia: Surveillance and Control of Pathogens of Epidemiologic Importance (SCOPE) Epidemiology of US nosocomial bloodstream infections (24,179): Surveillance at 49 hospitals during a 7-year period ( ) Infecting Organism Coagulase-negative staphylococci Staphylococcus Enterococci Candida species Escherichia coli Klebsiella species Enterobacter species aureus Pseudomonas species Wisplinghoff H et al. Clin Infect Dis. 2004;39: Isolates, % Crude Mortality Rate, %
42 Shift From albicans to Non-albicans Species 1980s C albicans 76% C albicans 54% Non-albicans 24% Non-albicans 46% 1. Beck-Sagué CM et al. J Infect Dis. 1993;167: Pfaller MA et al. J Clin Microbiol. 2002;40: C glabrata 16% C parapsilosis 15% C tropicalis 10% C krusei 2% Other 3%
43
44 Select Yeasts Encountered in Clinical Practice!Candida!albicans!glabrata!parapsilosis!tropicalis!krusei!lusitaniae!Cryptococcus neoformans
45 Candidemia Removal of catheters Eye exam by ophthalmologist Appropriate antifungal therapy
46 broth microdilution method Candida Susceptibility at Stanford University Medical Center No. (%) Ampho B Fluconazole Itraconazole Voriconazole C. albicans 56 (49) C. glabrata 28 (24) C. parapsilosis 18 (16) Other Candida spp. 13 (11) 100 * * *
47 Approach to Patients with Candidemia removal of catheter(s) ophthalmological exam appropriate antifungal therapy resistance neutropenia clinical presentation caspofungin or anidulafungin (micafungin?) lipid formulation of amphotericin B fluconazole voriconazole
48 QuickTime and a Photo CD Decompressor are needed to use this picture
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