Overview of candidiasis, antifungal pharmacology and the role of echinocandins

1. Echinocandins in the ICU Do we really need them ( yet )? Dr. Andrew Ferguson MEd FRCA FCARCSI DIBICM FCCP Assistant Professor of Medicine (Critical Care) and Anesthesia, Dalhousie University Consultant in Anaesthesia and Intensive Care Medicine, Craigavon Area Hospital, United Kingdom

3. EPIDEMIOLOGY

4. Clinically relevant fungi/molds Normal flora: Candida spp . Ubiquitous: Aspergillus spp. Cryptococcus spp. Mucor spp. Endemic geographical: Blastomyces spp. Coccidioides spp. Histoplasma spp . Emerging: Scedesporium spp. Fusarium spp. Trichosporin spp.

6. Candida species distribution Author Year N albicans glabrata parapsilosis tropicalis krusei Pfaller et al 2001-04 > 5000 51-60% 10% 12% 9% 5% Guinea et al 1984-2006 307 43.9% 6.2% 39.7% 5.5% 1.6% Mora-Duarte et al 1997-01 224 35 - 54% 9.2-12.8% 18.3-19.8% 12.8-19.8% 0.9-4% Kuse et al 2003-04 392 43 - 44% 8-11% 13-16% 23-26% 3-4% Reboli et al 2003-04 245 59 - 64% 16-25% 10-14% 9-12% n/a Kullberg et al 1998-03 370 43 - 51% 15-17% 16-18% 13-21% 1-2% Garey et al 2002-05 230 56% 17% 11% 7% 3% Parkins et al 1999-04 207 52% 22% 6% 6% 5% Playford et al 2001-04 183 62% 17.9% 7.8% 5.6% 3.9% Azole S-DD Increased MIC to echinocandin ? clinical significance Azole R

7. Candida Spp. In-vitro Sensitivity S = sensitive I = Intermediate R = Resistant S-DD = Sensitive Dose-dependent Species Fluconazole Itraconazole Posaconazole Voriconazole Ampho B Echinocandins C. albicans S S S S S S C. tropicalis S S S S S S C. parapsilosis S S S S S S (to I?) C. dubliniensis S to S-DD S S S S S C. glabrata S-DD to R S-DD to R S to I S to I S to I S C. krusei R S-DD to R S to I S to I S to I S C. lusitaniae S S S S S to R S

8. Independent risk factors for Candida BSI Schelenz S. Management of candidiasis in the intensive care unit. J Antimicrob Chemother 2008; 61 Suppl 1: i31-i34. Blumberg HM et al . Risk factors for candidal bloodstream infections in surgical intensive care unit patients: the NEMIS prospective multicenter study. Clin Infect Dis 2001; 33: 177-86. Independent Variable Relative risk Odds ratio Abdominal surgery 7.3 Triple lumen CVC 5.4 Acute renal failure 4.2 Parenteral nutrition 3.6 Multiple antibiotics 12.5 Candida elsewhere 10.4 ICU > 7 days 9.8

9. Therapeutic Options Ampho B Deoxycholate Liposomal Ampho B (Ambisome) Ampho B Colloidal Dispersion (ABCD) Ampho B Lipid Complex (ABLC) Itraconazole, Fluconazole, Voriconazole Posaconazole, Ravuconazole Caspofungin , Micafungin, Anidulafungin Flucytosine Polyenes Azoles Echinocandins Antimetabolite

10. Hidden Costs of Therapy Drug Acquisition Costs Adverse Effect Costs Therapy Failure Costs Total Therapy Associated Costs

11. ANTIFUNGAL DRUG TARGETS

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

13. Cell membrane Ergosterol Azole Squalene Ergosterol Synthesis Pathway Toxic sterols Accumulation of toxic sterols in cell membrane Inhibition of 14-  -demethylase Azoles

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

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

16. Cytosine permease Cytosine deaminase Phosphorylation Inhibition of thymidylate synthase FdUMP Conversion to deoxynucleosides Inhibition of DNA synthesis Inhibition of Protein Synthesis FdUMP FUTP Substitution for uracil 5-FC, 5-fluorocytosine; 5-FU, 5-fluorouracil; FdUMP, 5-fluorodeoxyuridine; FUMP, 5-fluorouridine monophosphate; FUDP, 5-fluorouridine diphosphate; FUTP, 5-fluorouridine triphosphate; dUMP, deoxyuridine monophosphate; dTMP, deoxythymidine monophosphate Flucytosine 5-FC 5-FC 5-FU dUMP dTMP 5-FC

17. Fungal Cell Wall Targets Fungal cell Mannoproteins  -(1,6)-glucan  -(1,3)-glucan Chitin Phospholipid bilayer of cell membrane Cell membrane and cell wall Ergosterol  -(1,3)-glucan synthase Squalene DNA/RNA Synthesis AZOLES POLYENES ECHINOCANDINS FLUCYTOSINE Ergosterol Synthesis Pathway

18. ANTIFUNGAL DRUG RESISTANCE

22. ADVERSE-EFFECTS & INTERACTIONS

24. Comparative nephrotoxicity

25. Azoles and the P450 System

26. Enzyme inducers and Azole Levels 3A4 2C19 2D6 2C9 1A2 2E1 2A6 2B6 2C8 Fluconazole (~ 50%) Voriconazole (~50%) Isoniazid Rifampicin Phenytoin Carbamezepine Phenobarbital Ritonovir St. John’s Wort Reduction in AUC/C Max

27. Azole Inhibition of CYP P450 Increased serum concentration of Oral hypoglycemics Warfarin Cyclosporin Cyclophosphamide Tacrolimus Sirolimus Phenytoin Carbamezepine Benzodiazepines Calcium channel blockers Statins Isoniazid Rifabutin Quinidine Protease inhibitors (e.g. ritonavir) Busulfan Vincristine Cyclophosphamide Digoxin Loratidine Opioids e.g. alfentanil Taxels Proton pump inhibitors and others… 2C19 polymorphism in 5% caucasians and 20% Asians leads to increased voriconazole levels

28. Itraconazole Interactions Gubbins PO. Drug-drug interactions of antifungal agents and implications for patient care. J Invasive Fungal Infect2007;1(4):144–55.

29. Fluconazole Interactions Gubbins PO. Drug-drug interactions of antifungal agents and implications for patient care. J Invasive Fungal Infect2007;1(4):144–55.

30. Voriconazole Interactions Gubbins PO. Drug-drug interactions of antifungal agents and implications for patient care. J Invasive Fungal Infect2007;1(4):144–55.

32. CHOOSING A DRUG – EVIDENCE

33. Therapy Classification Cultured Candida Colonisation Signs of sepsis ? source Prophylactic Presence of Risk Factors Targeted Prophylactic Targeted Empiric Empiric (No colonisation) Candida Colonisation Targeted Adapted from Grenouillet F et al. J Invasive Fungal Infect 2007; 1(2): 42–9.

35. Treatment related mortality risk 1. Retention of CVC 2. Inadequate initial fluconazole dose 3. Therapy delayed > 48 hrs Labelle AJ et al . Treatment-related risk factors for hospital mortality in Candida bloodstream infections. Crit Care Med 2008; 36: 2967-2972. Retrospective cohort 245 pts with C-BSI 111 in ICU

37. Diagnostic Methods - Candida Guery BP et al . Management of invasive candidiasis and candidemia in adult non-neutropenic intensive care unit patients: Part I. Epidemiology and diagnosis. Intensive Care Med 2008 DOI 10.1007/s00134-008-1338-7 Marker Sensitivity Specificity 1->3  D glucan 70% 87.1% Mannans (antigen + antibody) 80 93 C. Albicans germ tube antibody IFA IgG 84.4 94.7 PCR 90.9 100

38. Clinical Efficacy Against IC NB Response is NOT 100% !! - ? combined therapy Drug Response % Author Caspofungin 73.4 Mora-Duarte et al Ampho B deoxycholate 61.7 Micafungin 89.6 Ruhnke et al Liposomal Ampho B 89.5 Anidulafungin 75.6 Reboli et al Fluconazole 60.2 Voriconazole 65 Kullberg et al Ampho B deoxycholate/fluconazole 71 Fluconazole 70 Rex et al Ampho B deoxycholate 79

39. Comparative in vivo efficacy

41. Echinocandin vs. Biofilm 0 10 20 30 40 50 60 70 80 90 100 0.5 2 16 FLU AMB CAS % Viability (XTT) Antifungal Conc (  g/mL) Ramage et al. Antimicrob Agent Chemother 2002;46:3634 Antifungal Killing vs. Biofilm- Embedded Candida spp. C. parapsilosis has higher MIC to caspo but ? not clinically relevant

42. Treatment of Invasive Candidal Infections: Systematic Review and Meta-analysis Anat Gafter-Gvili, MD; Liat Vidal, MD; Elad Goldberg, MD; Leonard Leibovici, MD; Mical Paul, MD Mayo Clin Proc 2008; 83(9): 1011-1021 575 potentially relevant articles 552 excluded for non-random design 23 for detailed evaluation 2 conference abstracts 10 excluded: 1 RCT of different anidulafungin doses 1 RCT monoclonal antibody to HSP 1 incompatible inclusion criteria 4 duplicate publications 1 RCT preventive therapy ! RCT empirical therapy in neutropenia 1 ongoing no results 15 included in meta-analysis

43. Treatment of Invasive Candidal Infections: Systematic Review and Meta-analysis Anat Gafter-Gvili, MD; Liat Vidal, MD; Elad Goldberg, MD; Leonard Leibovici, MD; Mical Paul, MD Mayo Clin Proc 2008; 83(9): 1011-1021 All-cause mortality: Fluconazole vs other antifungal

44. Treatment of Invasive Candidal Infections: Systematic Review and Meta-analysis Anat Gafter-Gvili, MD; Liat Vidal, MD; Elad Goldberg, MD; Leonard Leibovici, MD; Mical Paul, MD Mayo Clin Proc 2008; 83(9): 1011-1021 Clinical treatment failure: Fluconazole vs other antifungal

45. Treatment of Invasive Candidal Infections: Systematic Review and Meta-analysis Anat Gafter-Gvili, MD; Liat Vidal, MD; Elad Goldberg, MD; Leonard Leibovici, MD; Mical Paul, MD Mayo Clin Proc 2008; 83(9): 1011-1021 Microbiological failure: Fluconazole vs other antifungal

46. Treatment of Invasive Candidal Infections: Systematic Review and Meta-analysis Anat Gafter-Gvili, MD; Liat Vidal, MD; Elad Goldberg, MD; Leonard Leibovici, MD; Mical Paul, MD Mayo Clin Proc 2008; 83(9): 1011-1021 Adverse event discontinuation: Fluconazole vs other antifungal

47. Treatment of Invasive Candidal Infections: Systematic Review and Meta-analysis Anat Gafter-Gvili, MD; Liat Vidal, MD; Elad Goldberg, MD; Leonard Leibovici, MD; Mical Paul, MD Mayo Clin Proc 2008; 83(9): 1011-1021 All-cause mortality: Echinocandin vs other antifungal

48. Treatment of Invasive Candidal Infections: Systematic Review and Meta-analysis Anat Gafter-Gvili, MD; Liat Vidal, MD; Elad Goldberg, MD; Leonard Leibovici, MD; Mical Paul, MD Mayo Clin Proc 2008; 83(9): 1011-1021 Clinical treatment failure: Echinocandin vs other antifungal

49. Treatment of Invasive Candidal Infections: Systematic Review and Meta-analysis Anat Gafter-Gvili, MD; Liat Vidal, MD; Elad Goldberg, MD; Leonard Leibovici, MD; Mical Paul, MD Mayo Clin Proc 2008; 83(9): 1011-1021 Microbiological failure: Echinocandin vs other antifungal

50. Treatment of Invasive Candidal Infections: Systematic Review and Meta-analysis Anat Gafter-Gvili, MD; Liat Vidal, MD; Elad Goldberg, MD; Leonard Leibovici, MD; Mical Paul, MD Mayo Clin Proc 2008; 83(9): 1011-1021 Adverse event discontinuation: Echinocandin vs other antifungal

54. CHOOSING A DRUG – OPINION

55. When to Treat Pappas PG. The patient with candidemia: treatment choices and algorithms. Current Fungal Infection Reports 2008; 2: 112-119.

56. Ostrosky-Zeichner L, Pappas P. Crit Care Med 2006; 34: 857–863

65. Anidulafungin versus Fluconazole for Invasive Candidiasis Annette C. Reboli, M.D., Coleman Rotstein, M.D., Peter G. Pappas, M.D., Stanley W. Chapman, M.D., Daniel H. Kett, M.D., Deepali Kumar, M.D., Robert Betts, M.D., Michele Wible, M.S., Beth P. Goldstein, Ph.D., Jennifer Schranz, M.D., David S. Krause, M.D., Thomas J. Walsh, M.D., for the Anidulafungin Study Group N Engl J Med 2007; 356(24): 2472-2482 Randomized, double-blind, international, multicenter study. Anidulafungin non-inferior to fluconazole in the treatment of invasive candidiasis

66. Caspofungin versus Liposomal Amphotericin B for Empirical Antifungal Therapy in Patients with Persistent Fever and Neutropenia Thomas J. Walsh, M.D., Hedy Teppler, M.D., Gerald R. Donowitz, M.D., Johan A. Maertens, M.D., Lindsey R. Baden, M.D., Anna Dmoszynska, M.D., Ph.D., Oliver A. Cornely, M.D., Michael R. Bourque, M.S., Robert J. Lupinacci, M.S., Carole A. Sable, M.D. and Ben E. dePauw, M.D., Ph.D. N Engl J Med 2004; 351; 14: 1391-1402 Multinational, double-blind trial 1095 patients, Caspofungin v liposomal AMB Empirical therapy for persistent fever and neutropenia Caspofungin non-inferior to standard therapy Caspofungin less nephrotoxicity and adverse events

67. Micafungin versus Caspofungin for Treatment of Candidemia and Other Forms of Invasive Candidiasis Peter G. Pappas, Coleman M. F. Rotstein, Robert F. Betts, Marcio Nucci, Deepak Talwar, Jan J. De Waele, Jose A. Vazquez, Bertrand F. Dupont, David L. Horn, Luis Ostrosky-Zeichner, Annette C. Reboli, Byungse Suh, Raghunadharao Digumarti, Chunzhang Wu, Laura L. Kovanda, Leah J. Arnold, and Donald N. Buell Clinical Infectious Diseases 2007; 45:883–93 International, randomized, double-blind trial in adults with invasive candidiasis Micafungin (100 mg) v micafungin (150 mg) v caspofungin (70 mg then 50 mg daily) Micafungin non-inferior to caspofungin