echinocandins in the icu

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

2. Overview

Epidemiology

Antifungal drug targetsand mechanisms

Antifungal resistance mechanisms

Side-effect profiles and drug interactions

Choosing a drug - what is the evidence?

Expert opinions:Echinocandins who/when?

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. 5. Epidemiology of Candida BSI Wisplinghoff Het al.Nosocomial bloodstream infection in US hospitals. Analysis of 24,179 cases From a prospective nationwide surveillance study. Clin Infect Dis 2004; 39: 309-317.

4 thmost common cause of nosocomial BSI, 3 rdof ICU BSI

Represents 8-11% of all nosocomial BSI

HIGHmortality+ attributable mortality 15-25% for candidaemia

Non-albicans increasing, especially in cancer patients

6. Candida species distribution Author Year N albicans glabrata parapsilosis tropicalis krusei Pfalleret al 2001-04 > 5000 51-60% 10% 12% 9% 5% Guineaet al 1984-2006 307 43.9% 6.2% 39.7% 5.5% 1.6% Mora-Duarteet al 1997-01 224 35 - 54% 9.2-12.8% 18.3-19.8% 12.8-19.8% 0.9-4% Kuseet al 2003-04 392 43 - 44% 8-11% 13-16% 23-26% 3-4% Reboliet al 2003-04 245 59 - 64% 16-25% 10-14% 9-12% n/a Kullberget al 1998-03 370 43 - 51% 15-17% 16-18% 13-21% 1-2% Gareyet al 2002-05 230 56% 17% 11% 7% 3% Parkinset al 1999-04 207 52% 22% 6% 6% 5% Playfordet 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 HMet 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. (1,3) glucan synthase glucan synthase inhibitor Inhibition of (1,3) glucan synthase Depletion of (1,3) glucansin cell wall Echinocandins Mannoproteins (1,6)-glucan (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 19. Amphotericin B Resistance

In vivo resistance rare

Mechanisms:

Reduced ergosterol content(ERG2/ERG3 genes)

Altered sterolse.g. fecosterol : reduced affinity

Altered sterol:phospholipid ratio

Stationary growth phase

In vitro has been described with:

C. lusitaniae, C. krusei, C. neoformans

A. terreus, Fusarium spp.

20. Azole Resistance

Primary:C. krusei, Aspergillus, C. glabrata

Secondary:C. albicans, C. dubliniensis

Mechanisms:

Altered target (14- demethylase)

Overexpression of target (14- demethylase)

Energy-dependent efflux systems

Altered sterol and/or phospholipid composition

21. Echinocandin Resistance

Rare but emergingin Candida

FKS1 geneencodes glucan synthase

Mutation => resistance

Decrease sensitivity of glucan synthase

by 1000-fold or more !

? confer cross-resistance

22. ADVERSE-EFFECTS & INTERACTIONS 23. Adverse Effects

* widely varying definitions in literature make comparison very difficult.

much less data available for caspofungin and voriconazole

Product data sheets Girois SBet al.Adverse effects of antifungal therapies in invasive fungal infections: review and meta-analysis. Eur J Clin Microbiol Infect Dis 2005; 24: 119-130. Effect AMB-D L-AMB Fluconazole Voriconazole Caspofungin Fever 34.2% 29.2% 1.4% 5.8% 13-27% Nausea 19.2% 12.2% 2% 5.4% ? Rash 2.9% 2.6% 0 ? ? Bronchospasm 7.2% 2.6% 0 ? ? Nephrotoxicity 33.2%* 14.6%* - 8-21%* 2.7%* Abnormal LFTs 16%* 14%* 2%* 10-18%* 14-18%* Abnormal vision - - - 18.7% - 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. Johns 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):14455. 29. Fluconazole Interactions Gubbins PO. Drug-drug interactions of antifungal agents and implications for patient care.J Invasive Fungal Infect2007;1(4):14455. 30. Voriconazole Interactions Gubbins PO. Drug-drug interactions of antifungal agents and implications for patient care.J Invasive Fungal Infect2007;1(4):14455. 31. Echinocandin Interactions

Caspofungin

Decreased AUC fortacrolimusby 20%, C Max16%

Cyclosporinincreases caspo AUC by 35% - watch LFTs

Use dose of 70 mg/day if receiving concurrent P450 inducers e.g. phenytoin, dexamethasone, rifampicin, carbamazepine

Micafungin

Increased AUC forsirolimusby 21% : monitor

Increased AUC fornifedipineby 18%, C Maxby 41%

Anidulafungin

D egradation in bloodstream organ independent

? increased anidulafungin AUC with cyclosporin

Morris MI. Echinocandins in the management of invasive fungal infections. Part 1. Am J Health-Syst Pharm 2006; 63(18): 1693-1703. 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 Fet al.J Invasive Fungal Infect 2007; 1(2): 429. 34. What we know

Early adequate therapy improves outcome

OR for death with appropriate therapy = 0.46 (p=0.05)

Therapy started day 0 mortality = 15%

Therapy started beyond day 2 mortality = 41%

Wrong drug at wrong time = poor outcome

Parkins MDet al . J Antimicrob Chemother 2007; 60: 613-8.

Garey KWet al . Clin Infect Dis 2006: 43: 25-31.

Morrell Met al . Antimicrob Agents Chemother 2005: 49: 3640-3645.

35. Treatment related mortality risk 1.Retention of CVC 2.Inadequate initial fluconazole dose 3.Therapy delayed > 48 hrs Labelle AJet 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 36. Therapeutic Problem Areas

New pathogenic fungal species

Slow microbiological diagnosis

Variable drug bioavailability

Drug toxicity & interactions

Resistance or breakthrough infection

Efficacy issues nave assumptions

37. Diagnostic Methods - Candida Guery BPet 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 isNOT100% !! - ? combined therapy Drug Response % Author Caspofungin 73.4 Mora-Duarteet al Ampho B deoxycholate 61.7 Micafungin 89.6 Ruhnkeet al Liposomal Ampho B 89.5 Anidulafungin 75.6 Reboliet al Fluconazole 60.2 Voriconazole 65 Kullberget al Ampho B deoxycholate/fluconazole 71 Fluconazole 70 Rexet al Ampho B deoxycholate 79 39. Comparative in vivo efficacy 40. Making the choice we need to know

Severity of illness

Azole exposure

Comorbidity

Is the patient neutropenic

Patient age

Length of hospital stay

Residence in ICU

Hospital epidemiology of Candida spp.

Presence of CVCs and catheters

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 Chemother2002;46:3634 Antifungal Killing vs. Biofilm- EmbeddedCandidaspp. 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 552excluded 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 51.

Avoid Fluconazole as single empirical drug for patients with severe infections (inferior microbiological eradication)

Superior efficacy for anidulafungin vs fluconazole

Comparable efficacy for caspofungin and micafungin vs amphotericin B formulations

Echinocandinsbetter safety profile than azoles/polyenes

Echinocandinsmay be considered first-line treatment for empirical treatment of candidemia

Liposomal amphotericin Bequally good alternative if organ function permits

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 Conclusions 52. Candidemia & NOT neutropenic

Fluconazole

1 stline if stablewith no azole exposure and no risk for resistant species

Voriconazole downsides

Less predictable pharmacokinetics

More frequent drug interactions and adverse effects

Not totally predictable against fluconazole resistant Candida spp

Liposomal Ampho B

Renal toxicity & infusion side-effects tolerable for many pts

Echinocandins

Consistent success in trials

Very few interactions, once daily dosing

Higher MIC for C. parapsilosis but ? Relevant clinically

53. Candidemia - neutropenic

Strategy not as well defined

Fluconazole

Often already used as prophylaxis if so, avoid

Liposomal Ampho B or echinocandin

Choice based on organ impairment

Voriconazoleif ? coexistent mold infection

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: 857863 57. Guinea Jet al . Empirical treatment of candidemia in intensive care units: fluconazole or broad-spectrum agents? Medical Mycology 2008 DOI 10.1080/13693780802415556

Guidelines from different societies and groups agree that broad-spectrum empirical coverage should be used with ICU patients with suspected invasive candidiasis, but the scientific basis for this recommendation is often weak, non-existent, or based on specific settings

IDSA guidelinesrecommend caspofungin or amphotericin B in cases of invasive candidiasis in unstable patients while fluconazole should be employed for stable patients

58. Guery BP et al. Management of invasive candidiasis and candidemia in adult non-neutropenic intensive care unit patients: Part II. Treatment. Intensive Care Med 2008 DOI 10.1007/s00134-008-1339-6

Patients who are hemodynamically unstable with septic shock or who have signs of severe sepsis require potent therapy, with a broad spectrum agent that has minimum toxicity

To achieve this aim,echinocandins are a preferred first choice Alternatively, lipid formulations of amphotericin B may be used in unstable patients

59. Ruhnke Met al.New options for treatment of candidemia in critically ill patients. Clin Microbiol Infect 2008; 14 Suppl 4: 46-54

Fluconazole may be the drug of first choice in clinically stable patients who are not on azole prophylaxis and with proven fluconazole-susceptible Candida spp

initial broad-spectrum therapy has become a standard approach, especially in unstable patients

caspofungin may be regarded as a first choice drug for severely ill, clinically unstable patients with organ dysfunction, especially patients with neutropenia

No justification to drop fluconazole: safety, overall efficacy, low cost

Azoles may be more better in meningitis, endophthalmitis, and candiduria

Relapse rates of candida esophagitis appear higher with echinocandins

Engl J Med 2007; 356: 24

However, in critically ill patients who are hemodynamically unstable and have candidemia, especially when the infection is associated with previous or concurrent exposure to azoles, echinocandins appear to be the drugs of first choice 61. The Consensus

If youre really sick... echinocandin or L-AMB*

If youve been on azoles... echinocandin or L-AMB*

If you might have aspergillus... voriconazole

If youre stable with likely albicans... fluconazole

Candida on line... echinocandin or L-AMB*

So going back to the original question....

YESwe really do need the echinocandins! 62. 63. 64. Comparison of Caspofungin and Amphotericin B for Invasive Candidiasis Jorge Mora-Duarte, M.D., Robert Betts, M.D., Coleman Rotstein, M.D., Arnaldo Lopes Colombo, M.D., Luis Thompson-Moya, M.D., Juanita Smietana, B.S., Robert Lupinacci, M.S., Carole Sable, M.D., Nicholas Kartsonis, M.D., John Perfect, M.D. and the Caspofungin Invasive Candidiasis Study Group N Engl J Med 2002; 347; 25: 2020-2029

Double-blind trial caspofungin v amphotericin B deoxycholate

224 patients with invasive candidiasis

Successful outcome in 73.4% with caspofungin and 61.7% with ampho B

Less nephrotoxicity with caspofungin

Caspofungin appears at least as effective as ampho B

Caspofungin has considerably less toxicity

Few neutropenic patients in trial - further evaluation needed in this group

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 forEmpiricalAntifungal 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. BuellClinical Infectious Diseases 2007; 45:88393 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 68. Bibliography

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echinocandins in the icu

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