New(er) Antifungal Drugs and Management of Fungal Infections

1. New(er) Antifungal Drugs and Management of Fungal Infections Dr. Yasser Hussain SKMCH & RC

2. The Patient • 17 year old female • NHL diagnosed two weeks ago • Cytotoxic therapy ten days ago • Feeling unwell for two days • Fever for 24 hours • HR 90/min; BP 100/60 mmHg; RR 28 / min • Exam normal

3. Investigations • CBC • ANC 600 cells • Rest normal

4. Clinical Course • Empiric Rx • Ceftazidime 2 grams every 8 hours • One day later • Fever spikes continued • 48 hours • Still febrile • Abdominal ultrasound – normal • 72 hours • Positive blood cultures for GNR • Oxidase negative • 96 hours • E. coli identified • Sensitive to PipTazobactam, Carbapenems, Amikacin • Resistant to Cephalosporins, Gentamycin

5. Clinical Course - contd • Day 5 to 7 • PipTazobactam started • Patient defervesced • Day 8 • New fever spike • ANC = 0.1 • Slight phlebitis noticed • Repeat blood cultures done • Vancomycin added • PipTazobactam switched to Imipenem • Day 9 • Fever continued without change • CXR repeated

7. Day 10 • Amphotericin B added • Slight discoloration of ala nasi noted Day 12

9. Candidemia at SKMCH & RC • Blood cultures • Jan 1995 - Mar 2005 • 53 grew candida • Mortality 35%

10. Anidulafungin Caspofungin Ravucon XMP Sordarins Micafun Voricon Posacon Medical Mycology:The Last 50 Years # of drugs L-AmB ABCD ABLC Terbinafine Amphotericin B (1958) Itraconazole Griseofulvin Fluconazole Ketoconazole Miconazole Nystatin 5-FC Global antifungal market will be $9 billion in 2009

11. POLYENES Amphotericin B, Nystatin AZOLES Imidazoles: Ketoconazole.. Triazoles: Fluconazole, Itraconazole, Voriconazole, Posaconazole, Ravuconazole ALLYLAMINES Terbinafine, Butenafine MORPHOLINE Amorolfine FLUORINATED PYRIMIDINE Flucytosine ECHINOCANDINS Caspofungin, Anidulafungin, Micafungin PEPTIDE-NUCLEOSIDE Nikkomycin Z TETRAHYDROFURAN DERIVATIVES Sordarins, Azasordarins OTHER Griseofulvin Structural Classification

12. Membrane function:Ampho-B, Nystatin Cell wall synthesis:Echinocandins Nucleic acid synthesis:5-FC Nuclear division:Griseofulvin Ergosterol synthesis:Azoles, Allylamines Anti Fungal Drug Targets Georgopapadakou NH, Walsh TJ. Science. 1994 Apr 15;264(5157):371-3.

13. Membrane disrupting agents Amphotericin B, nystatin Ergosterol synthesis inhibitors Azoles, allylamines, morpholine Nucleic acid inhibitor Flucytosine Anti-mitotic (spindle disruption) Griseofulvin Glucan synthesis inhibitors Echinocandins Chitin synthesis inhibitor Nikkomycin Protein synthesis inhibitors Sordarins, azasordarins Mode of Action

14. Ergosterol synthesis

15. Azoles, allylamines & morpholines inhibit specific ENZYMES Clin Microbiol Rev 1998; 11: 382

16. Fungal cell Cell membrane and cell wall Mannoproteins b-(1,6)-glucan b-(1,3)-glucan Chitin Phospholipid bilayer of cell membrane b-(1,3)-glucan synthase Ergosterol Ergosterol Synthesis Pathway DNA/RNA Synthesis Squalene

17. PolyenesAmphotericin B

18. Amphotericin B Ergosterol Cell membrane Ca++ Binding to ergosterol, Intercalation of cell membrane Ca++ Na+ Na+ K+ K+ Leakage of intracellular cations and proteins

19. Amphotericin B - Activity • Blasto, Cocci, Histo, C. neoformans, Sporothrix species • C. albicans and most other Candida species (except C. lusitaniae, C. guilliermondii) • Aspergillus (terreus) • Zygomycetes (Mucor species) • Malassezia Furfur • Fusarium • Tricosporon species • P boydii Excellent Variable Resistant

20. Lipid formulations of Amphotericin • Types • ABLC-Albecet (1995) • ABCD- Amphotec (1996) • L-AmB- Ambisome (1997) • Increased daily dose (10 fold) • High tissue especially RE organs • Decreased infusion associated side effects • 1 mg/kg D-AmB = 5 mg/kg LFAB • Nephrotoxicity • D-AmB > ABCD > ABLC > L-AmB • Cost: • L-AmB > ABLC > ABCD > D-AmB

21. Azoles ketoconazole itraconazole fluconazole voriconazole posaconazole ravuconazole

22. Azole Cell membrane Ergosterol Ergosterol Synthesis Pathway Squalene Accumulation of toxic sterols in cell membrane Toxic sterols Inhibition of 14-alpha-demethylase

23. Azoles: Triazoles • Mechanism of action: • Inhibit P-450 dependent 14  sterol demethylase (critical step in synthesis of ergosterol). • Affected cells develop morphologic changes (swelling and cytoplasmic protrusions) • Halt cell division • No membrane leakage (No cell death) • Ease of administration • Limited toxicity • Drug Interactions • Itra > vorico > fluco

24. Fluconazole • Comparable to D-AmB • Candidemia • Disseminated C. albicans • Candida UTI • Mucosal candidiasis • Coccidioidomycosis • Prophylaxis in BMT • Cryptococcal suppression after meningitis in HIV • Emergence of resistance (prophylaxis, treatment) • C. glabrata • C. krusei

25. Itraconazole • Oral capsule (1992) – variable absorption • Oral solution in cyclodextrin (1997) – improved absorption and bioavailability • IV formulation (1999) • Active against • Candida, Cryptococcus, Pseudallescheria boydii • Main indications: • Aspergillus • Blastomyces, Histoplasma • Sequential use after initial course of AmB

26. New Azoles 1. Better against Candida • Including C. glabrata and C. krusei • Plus usual C. albicans, tropicalis, parapsilosis 2. Active against Aspergillus • A. fumigatus (fungicidal?) and A. flavus 3. Others • Fusarium (Vori & Posa. Limited data on Ravu) • Scedosporium (Vori, Posa, Ravu) • Zygomycetes (Posa) Ostrosky IDSA #642, ‘01; Pfaller AAC 46:1723, ‘02; Ghannoum J Chemother 11:34, ’99. Pfaller AAC 46:1032, ‘02; Martin AAC 41:13, ’97; Graybill JAC 42:539, ’98; Petraitiene AAC 45:857; Kirkpatrick JAC 49:353, ’02. Lozano-Chiu AAC 43:589, ’99; Carrillo AAC 45:2151, ’01; Mellinghoff CID 34:1648, ’02; Sun AAC 46:2310, ’02

27. Voriconazole • Dose dependent inhibition • 14 -sterol and • 24 methylene dihydrolanosterol demethylase (> activity against molds) • FDA approval • 2002 – First-line Rx of invasive aspergillosis • 2002 - Salvage therapy for Scedosporium apiospermum and Fusarium species • 2003 - Esophageal candidiasis • 2005 - Candidemia

28. Voriconazole • Forms: IV & PO • IV (200 mg/vial) • PO (50 & 200 mg tablets): 96% bioavailable • Dose • IV: 6 mg/kg q12 x 2 doses, then 4 mg/kg q12h • PO: 200 q12h if > 40kg, 100 q12h if < 40kg • Can increase dose 50% if response is slow Sabo Ann Pharmacother 34:1032, ’00; Voriconazole package insert, May 2002; Voriconazole FDA Advisory Cmte, ‘01

29. Voriconazole • Clearance: P450-based • Mostly metabolized; 2% unchanged in urine • High inTER-subject variability, low inTRA • Initial data: little is removed by standard HD • Special Populations • Initial pedi data: 4 mg/kg ~ 3 mg/kg in adults • Renal failure: Use regular dose, but PO • Hepatic failure: In mild-moderate cirrhosis (Child-Pugh A-B), cut maintenance dose 50% • No data for severe (class C) cirrhosis Sabo Ann Pharmacother 34:1032, ’00; Voriconazole package insert, May 2002; Voriconazole FDA Advisory Cmte, ‘01

30. Voriconazole • What to monitor • Blood levels (?) • Liver enzymes: Rising liver enzymes suggest levels may be high • Renal function (why) • P450 drug interactions • Many!! Sabo Ann Pharmacother 34:1032, ’00; Voriconazole package insert, May 2002; Voriconazole FDA Advisory Cmte, ‘01

32. Adverse Events • Hepatic • Overall rate of 13%. ~ 2-fold more than Flu • Visual • Noted by ~30%. A sense of altered light perception, blurring, or photophobia • Miscellaneous • Photosensitivity (~1%)? Avoid strong sunlight. Sabo Ann Pharmacother 34:1032, ’00; Voriconazole package insert, May 2002; Voriconazole FDA Advisory Cmte, ‘01

33. Voriconazole vs. Amphotericin B for Invasive Aspergillus • Randomized, un-blinded trial • Primary therapy of invasive aspergillosis • Voriconazole (VC) (IV + PO; n= 144) vs. D-AmB (1-1.5 mg/kg/day; n=133) Herbrecht R et al. NEJM 2002;347:408

37. Voriconazole vs. Liposomal Ampho B for Empiric Antifungal Rx in Febrile Neutropenia • Randomized, multi-center trial in pts with F&N (ANC < 250, 24 hrs before randomization) • Voriconazole (VC) (IV + PO; n=415) vs. L-AmB (3-6 mg/kg; n=422) Pts treated until 3 days post resolution of neutropenia • Results:- • Successful outcome; Composite Outcome score: • Fewer breakthrough fungal infections: VC < L-AmB • Survival for 7 days beyond end of therapy: comparable • No premature discontinuation of drug: comparable • Resolution of fever during neutropenia: comparable • VC with more transient visual changes and hallucinations • Controversial study in which voriconazole could not demonstrate noninferiority to lipid amphotericin B for treatment of febrile neutropenia. Walsh TJ et al. NEJM 2002;346:225

39. Antifungal Prophylaxis in Allogeneic BMT • Multicenter, double-blind, ongoing controlled trial • Fluco vs Vori • Rx for 100 days (180 days if on steroids) • Galactomannan screening and pre-emptive therapy for 2 +ve assays • Primary endpoint: fungus-free survival (FFS)

40. Other Data for Vori • Esophagitis • Vori 200 q12h vs. Flu 400 (day 1) then 200 qd • C. albicans (as expected) - Success: 98% (Vori) and 95% (Flu) • Refractory candida infection • Candidemia: 21, 48% overall response • Other invasive: 34, 41% overall response • EC: 51, 61% overall response Ally, Clin Infect Dis 33:1447, 2001 Ostrosky, 40th IDSA Abstract 352, 2002.

41. Voriconazole in non-neutropenic Candidemia • Randomized, open-label, comparative, multi-center study involving 422 patients • Voriconazole (n = 283) vs amphotericin B followed by fluconazole (n = 139) • Clinical response at the end of therapy and two, six and 12 weeks after end of therapy • Success in the primary endpoint was defined as cured or improved at the 12-week assessment • Results = Vori as effective as amphotericin B followed by fluconazole • FDA label – Jan 2005

42. Fusarium and ScedosporiumResponse to Vori • Fusarium • Primary therapy: 1/2 (50%) • Salvage: 5/13 (38%) • Scedosporium • S. apiospermum: 16/27 (59%) • S. prolificans: 2/8 (25%)

43. Breakthrough Zygomycosis during Voriconazole Therapy • 124 adult Allogeneic BMTs • 4 with Zygomycosis - all receiving or received Voriconazole for GVHD • Historical Controls • Jan 2000 – Aug 2002: 2/370 BMT patients with Zygomycosis • Conclusion • Zygomycetes are resistant to Vori • Selective pressure from prolonged use (median 36 days; range 21 – 99) associated with increased incidence of Zygomycosis Marty FM, et al. N Engl J Med 2004;350(9):950-952

44. Other Newer Azoles • Posaconazole • Structurally related to Itraconazole • Phase III trials • PO formulation • Activity • Zygomecetes, Candida, Aspergillus, Fusariumin vivo, and Cryptococcus • Ravuconazole • Structurally related to Fluconazole and voriconazole • Phase II clinical trials • PO formulation; IV (?) long half life • Activity • Candida spp, Cryptococcus, Aspergillus fumigatus, dermatophytes and dematiaceous fungi. • Others • Albaconazole (UR-9825), CS-758

45. Summary Vori Ravu Posa Candida ++ ++ ++ Cryptococcus ++ ++ ++ Aspergillus ++ + ++ Fusarium ++ ? ++ Scedosporium ++ + + Zygomycetes ++ Cryptococcus data: Pfaller AAC 45:2862, ’01; Yildiran EJCMID 19:317. ’00; Yamazumi AAC 44:2883, ‘00

46. ECHINOCANDINS caspofungin anidulafungin micafungin

47. Mannoproteins ß(1,6)-glucan ß(1,3)-glucan Chitin Phospholipid bilayer of cell membrane ß(1,3) glucan synthase glucan synthase inhibitor Depletion of ß(1,3) glucans in cell wall Inhibition of ß(1,3) glucan synthase

48. Echinocandins • Mechanism of action: • Inhibit -(1,3) D-glucan synthetase • Caspofungin – licensed in 2001 • Micafungin – licensed March 2004 • Activity • C. albicans = C. tropicalis = C. glabrata > C. parapsilosis > C. krusei = C. lusitaniaea. • Aspergillus spp • Pneumocystis carini uses beta-glucan - Pneumocandins (In vitro activity) • Limited activity • Trichosporon • Fusarium spp • Rhizopus • Less beta-glucan  less susceptible • Cryptococcosis • B. dermatidis

49. Echinocandins • Advantages: • Combination with triazoles • Minimal drug interactions • Disadvantages: • Side effects: Fever, phlebitis, headache • Drug interactions (Cyclosporin A) • Absence of CNS penetration • IV only