2. Antifungal treatment: Past and Present Malcolm Richardson PhD, FIBiol, FRCPath University of Helsinki

3. Introduction The global and local incidence of systemic fungal infection

4. Trends in the Incidence of Documented Fungal Infections 19801981198219831984198519861987198819891990 0 1 2 3 4 5 6 7 % USA GERMANY Adapted data from Beck-Sague J Infect Dis 1993 and Groll et al. J Infect 1996

5. Incidence of Invasive Mycotic Infections in a General Population 1992-1993 No. of cases per million per year CANDIDA species albicans non-albicans CRYPTOCOCCUS ASPERGILLUS Agents of ZYGOMYCOSIS MALASSEZIA FURFUR 73 37 36 66 12 1.7 <1 Case-fatality for first episode 34% 38% 30% 13% 23% 30% Rees JR et al. Clin Infect Dis 1998

6. Focus on invasive aspergillosis

7. Days after transplant 102030405060708090100110120130140150160170 180>180 Cases 20181614121086420 Wald et al. J Infect Dis 1997;175:1459 Aspergillus: Time to diagnosis of aspergillosis after BMT Neutropenia Graft versus host disease

8. Late onset of IA in BMT patients at a university hospital 93 allogeneic and 149 autologous pts 20 month period 0% IA autologous 15.1% allogeneic: overall incidence 5.8% Median time to occurrence: 92 days No de novo cases prior to engraftment Survival 100 days from diagnosis 29% Conclusions –shift towards late occurrence –outpatient environment surveillance Grow et al., BMT 2002; 29: 15-19

9. Invasive fungal infections in pediatric bone marrow transplant recipients: single center experience of 10 years 148 BMT 12/73 (16%) infection: allogeneic 6/75 (8%) infection: autologous 15/18 died, in 12 IFI as cause of death 48 suspected infections allogeneics: severe GVHD major risk factor steroid dose associated with IFI Hovi et al. Bone Marrow Transplantation 2000; 26: 999-1004.

10. Mortality of Proven and Probable Aspergillus Infections in Bone Marrow Transplantation 0102030405060708090100 CONNEALLY B.M.T. 1990 DENNING R.I.D. 1990 HERTENSTEIN Ann. Hemat. 1994 MEYERS Sem. Oncol. 1990 n = 1500 n = 303 n = 2121 n = 123 Case mortality rate Four different studies of BMT recipients evaluated for Aspergillus infections

11. Risk periods for mycosis following HSCT Granulocytes (log 10 1x 10 6 /L) 0.1 1 10 36 37 38 39 40 41 Temperature °C DaysMonths-7071421126912-14628810WeeksTransplant ENGRAFTMENT PRE- TRANSPLANT EARLY POST- ENGRAFTMENT LATE POSTENGRAFTMENT - Stem cells acute GvHD low IgG neutropenianeutropeniacorticosteroidscorticosteroids chronic GvHD

12. Assessment of risks following HSCT Granulocytes (log 10 1x 10 6 /L) 0.1 1 10 36 37 38 39 40 41 Temperature °C DaysMonths-7071421126912-14628810WeeksTransplant ENGRAFTMENT PRE- TRANSPLANT EARLY POST- ENGRAFTMENT LATE POST- ENGRAFTMENT treatment Disease likelihood Prophylaxis remote High risk Host factors High risk Host factors Empirical possible Persistent fever Mucositis Persistent fever Mucositis Pre-emptive Probable disease Clinical features Clinical features Mycological evidence features Mycological evidence features Specific proven Tissue evidence Tissue evidence

13. Diagnosis of invasive aspergillosis Urgent need for early and sensitive diagnosis

14. Growth of Aspergillus 1-2 mm per hour

15. Diagnosis of aspergillosis Infectious Disease Physician Clinician Microbiologist Pharmaceutical Industry Pathologist

16. Clinicians response to laboratory diagnosis Whats the point? A positive result will only confirm my hunch and a negative result will not make me change the treatment Im going to give anyway.

17. Clinical haste answer Microbiology question

18. Rx within 96h - 3 complete resolution - 3 partial response Rx delayed >2w - 11/11 died - 7 diagnosed at PM Why do we need new diagnostic methods? Early initiation of therapy critical Aisner et al Ann Intern Med 1977; 86: 539-43

19. 1970 Clinical diagnosis of IA not made in 68% with evidence at autopsy Young, Medicine 1970; 49: 147-173 1996 68% patients with autopsy proven IA received no treatment Groll, J. Infect 1996; 33: 23-32 Little progress in diagnosis of invasive aspergillosis Little progress in diagnosis of invasive aspergillosis

20. Clinical manifestations are non-specific Conventional diagnostic tests insensitive, positive late in infection Inability to perform invasive diagnostic procedures Why the lack of progress?

21. New approaches to diagnosis Nucleic acid amplification Radiology Serology Non-culture

22. Diagnosis: Chest CT scan – air crescent sign

23. Diagnosis: Chest CT scan – halo sign © Fungal Research Trust

24. HRCT Scans Halo signAir crescent sign Kuhlman 1987 Chest 92: 95-99; Caillot 2001 J Clin Oncol 19: 253-9

25. Improved diagnosis of IA using early thoracic CT scans 37 haematology patients: 23 histologically proven IA 14 highly probable 14 highly probable Early CT scan: Halo sign 13% 92% Time to diagnosis 7 1.9 days Caillot (1997) J Clin Oncol;15:139-147 Clinical signs: cough 92% chest pain 76% hemoptysis 54% Mycology: BAL positive 69% Asp ag on BAL 83% Attributable mortality: 50% 17% Pre 1991Post 1991

26. Combined approach in IPA - early CT scanning and LAB Ellis et al, Abst 2103, ASH 2001 1998-2000 244 pts 53/244 (21.7%) ARNF Plain CXR & chest CT d.4 ARNF then weekly Amb. 1-3mg/kg at start of ARNF increasing to 5mg/kg on Dx 21/53 had probable IPA (40%)

27. Ellis et al, Abst 2103, ASH 2001 CT findings: Halo signs in 20 pts Consolidation in 1 pt At first pos CT - CXR normal in 6/21 - nonspecific changes 15/21 ARNF to CT Dx median 10d (1-20) 5 pts mean 2.2d (1-5) Halo signs in 6 pts at first CT scan Response rate 17/21 (81%) Crude mortality 9/21 (43%) IPA attributable mortality 9.5% LAB administered at mean time of 7.2d (1-15) of ARNF Mean dose of LAB 4.4mg/kg (1.5-10) for 24d (4-57)

28. Non-culture approaches to fungal diagnosis Cell wall components Cytoplasmic antigens Metabolites Genomic DNA sequences CandidaAspergillusDetection Mannans 1,3- -D-glucans chitin Enolase HSP-90 arabinitol C-14 lanosterol demethylase Chitin synthase Actin Aspartate proteinase Ribosomal RNA genes Galactomannan 1,3- -D-glucans chitin D-mannitol C-14-lanosterol demethylase Alkaline protease Mitochondrial DNA HSP-90 Ribosomal RNA genes LA ELISA RIA Amebocyte lysate assay Spectrophotometry PCR GLC Mass spectroscopy ELISA Immunoblot

29. Rat monoclonal antibody EB- A2 + peroxidase Sandwich ELISA for Aspergillus galactomannan 1234 Rat monoclonal antibody EB- A2 Galactomannan Chromoge n

30. 450 alloSCT recipients + 347 children Prospectively screened 2x/week Platelia Aspergillus ELISA (BioRad) pPositive cutoff > 1.5 2 consecutive positive results required GM ELISA: diagnosis & prediction of IPA 4y prospective study Sulahian, Cancer 2001;91:311-8

31. Proven IA22 17 (81.4)5 * (18.6) Probable IA2222 (100)0 No IA40610 (2.5)396 (97.5) Proven IA55 (100)0 Probable IA44 (100)0 No IA33834 (10.1)304 (89.9) Sulahian, Cancer 2001;91:311-8 * 5 pts were persistently negative (3-32 samples/pt) Patients No. of ptspos. (%)neg. (%) BMT patients Paediatr patients

32. Sensitivity Specificity BMT88.6%97.5% Paediatric100%89.9% Overall90.5%94% GM detection preceded: radiological signs in 31/48 (64.6%) by mean of 8.4days clinical signs in 18/48 (39.6%) by mean of 6.9days Good diagnostic value when increasing titre on 2 consecutive samples Repeated negative = strong argument against IA False positives! Sulahian, Cancer 2001;91:311-8

33. GM screening: prospective validation prospective screening 2x/Week 191 haematology pts (362 episodes) itraconazole or low dose AmB prophylaxis Platelia Aspergillus ELISA (BioRad) Positive cutoff > 1.0 2 consecutive positive results required Maertens, Blood 2001;97:1604-10

34. Positivity preceded: antifungals in 18/29 by 6d (1-27d) [coincided with 4] sampling day of first positive culture in 27/29 by 10.5d (1-100d) development of new pul. infiltrates in 19/28 by 5d (1-27d) definitive diagnosis in 29/30 by 17 d (2-110d) Biopsy proven Probable No IA (30) IFI (3) IA (9) IA (264) Positive 30 0 5 5

35. all 24 patients with persisting/rising titres died 6 patients cleared GM - 4 survived & 2 died antigen titres may correspond with clinical outcome could reduce antifungal use from 43% - 12% - but lack of species specificity a concern Maertens, Blood 2001;97:1604-10 Sensitivity 89.7%Specificity 98.1% PPV 87.5%NPV 98.4%

36. Micro-arrays: The New Direction....

37. Diagnosis tomorrow

39. Defining systemic fungal infection

40. Defining systemic fungal infectious disease Host factor Clinical feature Mycology

41. Definite invasive fungal disease Host factor Clinical features MycologyTissue+++ Invasive Fungal Infections Cooperative Group

42. Histopathological evidence of IA

43. Probable invasive fungal infective disease Host factor Clinical features Mycology++ Invasive Fungal Infections Cooperative Group

44. Possible invasive fungal disease Host factor Clinical features Mycology+ OR Invasive Fungal Infections Cooperative Group

45. MycologyMycology Culture of mould from aspirate, BAL or sputum Mould seen in sinus aspirate Aspergillus antigen in BAL, CSF or blood Fungal elements seen in sterile body fluids Invasive Fungal Infections Cooperative Group PCR in BAL, CSF or blood

46. Host factors Host factorNeutropeniaNeutropenia >4 days unexplained fever despite broad spectrum antibiotics Graft versus host disease >3 weeks corticosteroids 38°C and: 38°C and: prior mycosisprior mycosis AIDSAIDS immunosuppressivesimmunosuppressives >10 days neutropenia>10 days neutropenia 38°C and: 38°C and: prior mycosisprior mycosis AIDSAIDS immunosuppressivesimmunosuppressives >10 days neutropenia>10 days neutropenia Invasive Fungal Infections Cooperative Group

47. When to treat? FUO New pulmonary infiltrates Antigenaemia Culture DNA- aemia Antibody

48. Therapeutic window of antifungal agents ergosterol nucleic acid synthesis glucan synthesis chitin synthesis nucleic acid synthesis cholesterol protein synthesis mannan synthesis human fungus

49. Mode of action of antifungals ergosterol polyenes eg amphotericin B polyenes azoles eg fluconazole azoles squalenes lanosterol K + Mg 2+ allylamines eg terbinafine allylamines acetyl-Co-A nucleosides eg 5-flucytosine nucleosides nucleic acid synthesis pneumocandins eg caspofungin pneumocandins glucan synthesis nikkomycinsnikkomycins chitin synthesis azasordarinsazasordarins protein synthesis

50. ravuconazole anidulafungin posaconazole micafungin Caspofungin Adapted from Rex & Edwards, 1997 Licensed antifungal agents: the pace quickens 10 20 195019601970198019902000 voriconazole Nyotran AmBisome Amphotec Abelcet itraconazole Griseofulvin fluconazole Amphotericin B Nystatin ketoconazole miconazole 5-flucytosine terbinafine

51. FungusAMB FCZ ITZ CZ PCZ RCZ CF MF AF Candida albicans Candida tropicalis Candida parapsilosis Candida krusei Candida glabrata Cryptococcus neoformans Histoplasma capsulatum Blastomyces dermatitidis Coccidiodes immitis Paracoccidiodes brasiliensis Pneumocystis carinii Aspergillus fumigatus Mucor spp Rhizopus spp Fusarium spp FungusAMB FCZ ITZ CZ PCZ RCZ CF MF AF Candida albicans Candida tropicalis Candida parapsilosis Candida krusei Candida glabrata Cryptococcus neoformans Histoplasma capsulatum Blastomyces dermatitidis Coccidiodes immitis Paracoccidiodes brasiliensis Pneumocystis carinii Aspergillus fumigatus Mucor spp Rhizopus spp Fusarium spp Comparative spectrum of activity

52. Antifungal strategies Prophylaxis Pre-emptive use Early empiric use Targeted treatment

53. Prophylaxis: Key issues 1 Which patients should benefit from prophylaxis? What is the best drug and what is the appropriate dose? What is the impact of prophylaxis on clinical practice re the use of empirical amphotericin B/AmBisome?

54. Prophylaxis: Key issues 2 Is prior prophylaxis a risk factor for subsequent IFI caused by resistant pathogens? What is the approach for those patients with a previously documented fungal infection who need to undergo BMT? What is the indication for growth factors?

55. Prophylactic Therapy Data on the efficacy of prophylaxis are not definitive. There is no clear benefit of prophylaxis in many cases.

56. IDSA practice guidelines Candidosis Prophylaxis – neutropenic patients fluconazole 400 mg/d amphotericin B 10-20 mg/d AmBisome 1 mg/kg/d

57. Prophylaxis – Current situation Fluconazole: 200-400 mg daily Itraconazole (capsules, oral solution): 400 mg/day Low-dose amphotericin B: 0.1 to 0.25 mg/kg/day Amphotericin B solution, sprays or inhalants AmBisome: 2 mg/kg, 3 x weekly Full dose AmBisome to protect patients with previous aspergillosis

58. Fluconazole for prophylaxis against rectal colonisation in the very LBWN fluconazole 6 mg/kg or placebo rectal colonisation –C. albicans most common species –15.1% FLU –46% placebo BUT: no difference in rate of invasive candidosis Kicklighter et al. Pediatrics 2001; 107: 293-298

59. Fluconazole for prophylaxis against rectal colonisation in the very LBWN fluconazole 6 mg/kg or placebo rectal colonisation –C. albicans most common species –15.1% FLU –46% placebo BUT: no difference in rate of invasive candidosis Kicklighter et al. Pediatrics 2001; 107: 293-298

60. Effect of prophylactic fluconazole on the clinical spectrum of fungal diseases in BMT recipients with special attention to hepatic candidiasis Autopsy study: 355 patients 50% prophylaxis: 400 mg/kg 40% fungal infection (any site) Decrease in Candida infections: 27% to 8% Increase in Aspergillus infections: 18%- 29% Fungal liver infection: 9% Conclusions: –significant reduction in Candida –increase in aspergillosis van Burk Medicine (Baltimore) 1998; 77: 246-254

61. Fluconazole prophylaxis prevents intra- abdominal candidiasis in high risk surgical patients 49 patients: recurrent gastrointestinal perforations or anastomatic leakages Fluconazole 400 mg/day intervention, or placebo 15 days Primary end-point: intra abdominal Candida infection Colonisation: –15% fluconazole group –62% placebo group Infection: –2/23 fluconazole –7/20 placebo 87% C. albicans All strains susceptible to fluconazole Eggimann et al. Crit Care Med 1999; 27: 1066-1072

62. Adverse consequences of azole prophylaxis Increase in bacteraemia Greater use of amphotericin B No impact on survival Advere effect on neutrophil recovery Higher rate of GvHD Increased mortality Risk of hepatitis Emergence and colonisation by FLU-resistant strains

63. Conclusions - Fluconazole Fluconazole prophylaxis is a double-edged sword Use should not be trivalized Fluconazole attractive: –low toxicity –proven efficacy in systemic candidosis Selection of fluconazole-resistant isolates and species will occur if used broadly and injudiciously

64. Conclusions - Itraconazole Oral solution potentially useful where Aspergillus anticipated: risk assessment Steady state rapidly achieved Topical effect – benefit in OPC Breakthrough infections associated with plasma levels <0.25 mg/l Cross-resistance to ITR 30% of 96 FLU- resistant Candida isolates No ITR resistance in FLU-sensitive isolates

65. Empirical antifungal therapy The concept In high-risk IC patients with persisting or relapsing infectious symptoms, the probability of developing invasive fungal disease is 20-40% The mortality of established fungal disease remains high (40-80%) Diagnostic sensitivity and specificity is poor Early empiric antifungal treatment with amphotericin B (and others) is recommended

66. Implementation of empirical amphotericin B PUO unresponsive to antibacterials Pulmonary infiltrates unresponsive to antibacterials Mucosal candidosis

67. Empiric AMB Ampho lite= 0.1 mg/kg/d Ampho regular= 0.5-0.8 mg/kg/d Ampho super= 1-2 mg/kg/d Ampho mega= 3-5 mg/kg/d or higher

68. Empirical antifungal therapy: Questions asked Optimal timing Optimal dosage Optimal agent Optimal spectum Optimal cost/benefit ratio

69. Empirical therapy FAQs Does empirical therapy reduce the incidence of systemic mycoses? Does empirical therapy improve the prognosis of systemic mycoses? What are the practical guidelines for implementation?

70. IDSA practice guidelines Candidosis Empirical therapy for neutropenic patients with prolonged PUO amphotericin B 0.5-0.7 mg/kg/d AmBisome 3-5 mg/kg/d

71. THE IDEAL EMPIRICAL/PREEMPTIVE STRATEGY +USE ONLY >safe and effective antifungal drugs with spectrum adapted to local ecology and optimally adjusted dosage; booster host defense (CSF) first +INCLUDE ONLY, BUT QUICKLY > patients with high probability of fungal disease, belonging to a well defined high risk category + EXCLUDE CERTAINLY > patients with low risk profile or unlikely to have fungal disease +RELY EXCLUSIVELY ON >optimal batteries of clinical, radiologic and laboratory tests +AVOID ALWAYS >indiscriminate primary prophylaxis +ADOPT >early pre-emptive strategy, secondary prophylaxis HEM/90593M

72. Why do we still use empirical antifungal therapy? Assumptions: –Established invasive infections carry excessive mortality rates –Prophylactic strategies are inefficient –Colonization and disease form an obligatory continuum –Newer diagnostic tools yield « too little, too late » –The « hard » data from the published randomized studies are reliable and form « proof of principle » Emotions and traditions HEM/20283M

73. Broad spectrum of activity (yeasts and filamentous fungi) Rapidly and highly fungicidal, stable to resistance Potent in vivo activity (even in neutropenia) Both oral and parenteral formulations Low toxicity, minimal drug-drug interactions Good pharmacokinetics (AUC) Good penetration into all tissue compartments Cost effective The ideal antifungal agent HEM/00223M

74. Large studies on empirical antifungal therapy in refractory neutropenic fever YearNAgents Viscoli1996112AmphoB vs Fluco Prentice1997338 AmphoB vs Ambisome Malik1998106AmphoB vs Fluco White1998213 AmphoB vs ABCD Walsh1999687 AmphoB vs Ambisome Winston2000317AmphoB vs Fluco Wingard2000244 Ambisome vs ABLC Boogaerts2001384AmphoB vs Itraco Walsh2002849 Ambisome vs Vorico HEM/20281M

75. Response rates(%) in large studies on empirical antifungal therapy in neutropenic fever (%) Ampho B AmbiFlucoItraco Vorico ABLC/ABCD Viscoli50-52--- Prentice4664---- Malik46-56--- White43----50 Walsh4950---- Winston67-68--- Wingard-----40/33 Boogaerts38--47-- Walsh-31--26- HEM/20282M

76. Success if all of the following occurred: –survival for 7 days post study drug –resolution of fever during neutropenic period –resolution of microbiologically confirmed study entry Fungal infection. –no proven or presumed emergent F.I. on study drug therapy or within 7 days after last dose of study drug –study drug was not prematurely discontinued due to toxicity or lack of efficacy. Composite endpoint HEM/80688M Large studies on empirical antifungal therapy

77. Population –Patients with haematologic malignancies neutropenic (<0.5 x 10 9 ANC/l) fever of unknown origin (>38° C) 3 - 7 days broadspectrum antibiotics Objectives –Compare efficacy and safety –Empirical therapy IV itra (7 to 14 days) Itra oral solution (14 days) IV ampho B (28 days) –Blood levels of itraconazole HEM/80675M Empirical Itraconazole verus AmphoB

78. Empirical Itraconazole versus AmphoB Efficacy analysis p=0.156 p<0.001 p=0.055 0.047/0.052 2-sided 1-sided superiority equivalence test Itra n (%) Ampho n (%) Response88 (48)70 (37) Composite endpoint 99 (53)83 (46) HEM/80690M

79. Itraconazole versus amphotericin B as empirical therapy for persistent fever in neutropenic patients Response Itra group (n=179) Amphoteric in B group (n=181) Differenc e (95% CI) Breakthrough fungal infections, n 55 Candidemia22 Filamentous fungal pneumonia 33 HEM/20268M

80. ItraAmpho- B allp Severe adverse events37 (21.5)65 (36)102 (29)0.003 Possibly drug related93 (48)105 (58)188 (53)0.066 Definitely drug related9 (5)103 (57)112 (32)<0.001 Death16 (9)23 (13)39 (11)0.038 Serious adverse events (including death) 32 (19)46 (25)78 (22)0.123 Permanent stop to study therapy 36 (21)73 (40)109 (31)<0.001 Total172183353 Empirical Itraconazole versus AmphoB Adverse events HEM/80698M

81. Large studies on empirical antifungal therapy Prentice et al., BJH 1997; 98:711 2 studies : 134 adults + 204 children conventional ampho B (c-Amb.) randomizationliposomal ampho B 1 mg/kg/d (I-Amb 1) liposomal ampho B 3 mg/kg/d (I-Amb 3) FUO : > 38°C not responding to 4 d broad-spectrum antibiotics Neutropenia : neutrophils < 0.5 x 10 9 /l HEM/80702M

82. Intention-to-treat analysis : all randomized patients Response:1. < 38°C during 3 consecutive days 2.no fungal infection 3.> 0.5 x 10 9 /l neutrophils Failure :1. addition of systemic antifungal therapy 2.systemic fungal infection Success:c-Amb49 % I-Amb158%p=0.03 I-Amb364% Kaplan Meier analysis : no significant difference in time to defervescence H.G. Prentice et al., BJH,1997; 98:711 HEM/80703M Large studies on empirical antifungal therapy

83. Toxicity Severe drug-related :c-Amb :12% I-Amb :1 % Nephrotoxicity:double S-crea:c-Amb:23% I-Amb3:3% I-Amb1 :0% H.G. Prentice et al., BJH 1997; 98:711 p=0.01 HEM/80704M Large studies on empirical antifungal therapy

84. Walsh et al., NEJM 1999; 340:764 687 patients Conventional ampho B (c-Amb.) randomization Liposomal ampho B 3 mg/kg/d (I-Amb) FUO: fever not responding to 5 days broad-spectrum antibiotics Neutropenia : neutrophils < 0.5 x 10 9 /l HEM/80706M Large studies on empirical antifungal therapy

85. Composite endpoint liposomal ampho Bconventional ampho B Success171/343 (50%)169/344 (49%) Breakthrough fungal infections liposomal ampho Bconventional ampho B Proven deep FI 41 (3.2%)27 (7.8%) P=0.009 Walsh et al. 1999 HEM/80705M Large studies on empirical antifungal therapy

86. Empirical voriconazole study: Primary endpoint VoriAmbisome No. of patients415422 Success23.7%30.1% Difference between arms-6.1% (-12%, -0.1%) Voriconazole failed to meet its primary endpoint Walsh et al, 2002 HEM/20284M

87. Empirical voriconazole study: Secondary endpoints VoriconazoleAmbisomedifference Overall stratified23.7%30.1%-6.1% No B/T infection98.1%95.0%+3.1% Survival92.0%94.1%-2.1% No discontinuation90.1%93.4%-3.3% Defervescence33.0%36.0%-3.0% Response in B/L infections46.0%67.0%-20.5% Walsh et al, 2002 HEM/20285M

88. Empirical voriconazole study VoriconazoleAmbisomeDifference (95% CI) High risk 45/143 (32%) 42/141 (30%) +1.7% (-9.0%, 12.4%) Moderate risk 63/272 (23%) 87/281 (31%) -7.6% (-15.2%, - 0.4%) Walsh et al, 2002 Overall response rate Subset analysis by risk of fungal infection HEM/20286M

89. Breakthrough infections Fewer in voriconazole arm than ambisome arm VoriconazoleAmbisome 1.9%5.0% Adjusted for death – FDA analysis VoriconazoleAmbisome 9.2% (38/415)%9.2% (39/422)% Walsh et al, 2002 HEM/20288M

90. Voriconazole vs Liposomal Amphotericin B as antifungal therapy for neutropenia and fever ResponseVoriconazole (n=415) L Ampho B (n=422) P value Infusions related reactions Abnormal vision91 (21.9)3 (0.7)< 0.001 Chest pain1 (0.2)17 (4.0)< 0.001 Abdominal pain1 (0.2)12 (2.8)0.002 Dyspnea3 (0.7)37 (8.8)< 0.001 Flushing14 (3.4)46 (10.9)< 0.001 Sweating3 (0.7)9 (2.1) Urticaria1 (0.2)3 (0.7) Cyanosis02 (0.5) Chills57 (13.7)126 (29.9)< 0.001 Cardiac arrest1 (0.2)0 Nausea39 (9.4)53 (12.6) Infusion related reactions and laboratory abnormalities in patients treated with voriconazole or liposomal amphotericin B T. Walsh, NEJM 2002 HEM/20259M

91. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and PUO Key points overall success rates: –voriconazole: 26% –30.6% liposomal amphotericin B breakthrough infections: –voriconazole: 1.9% –liposomal amphotericin B: 5.0% Walsh et al. NEJM 2002; 346: 225-234.

92. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and PUO Discussion points Q.Where all breakthrough infections proven/definite (wording vague)? Q.What dosage where breakthrough infections? Q.Prophylaxis: ?protocol defined, details vague. Q.Dose-limiting toxicity: will monitoring be prolematic (HPLC)? Walsh et al. NEJM 2002; 346: 225-234.

93. IDSA practice guidelines Candidosis Chronic hepatosplenic candidosis (hepatosplenic candidosis) fluconazole 400-800 mg/d amphotericin B 0.6-0.7 mg/kg/d AmBisome 3-5 mg/kg/d or higher Clinical Infectious Diseases, April 2000

94. IDSA practice guidelines Candidosis Candidaemia/disseminated candidosis amphotericin B 0.7 mg/kg/d AmBisome 3-5 mg/kg/d fluconazole 400-800 mg/kg/d iv itraconazole

95. IDSA Practice guidelines Aspergillosis IPA –amphotericin B: response: 14-83% –AmBisome 66% –iv itraconazole –switching therapy

96. Do surveillance cultures predict patients at greatest risk? Candida: positive cultures do not always predict systemic infection Positive C. tropicalis cultures: greatest risk of infection Aspergillus: ?positive nasal swabs useful in predicting outbreaks of invasive aspergillosis Conclusion: positive surveillance cultures may guide appropriate therapy

97. Treatment of proven infections

98. numberASPERGILLUSCANDIDA FUNGIZONE ® 0.5-1mg/kg/day45%60% ABELCET ® up to 6 mg/kg/day88/27962%52% AMPHOCIL / TEC ® up to 6 mg/kg/day114/6945%47% AMBISOME ® 0.5-5 mg/kg/day45/7366%58% ITRACONAZOLE 400 mg/day 189/59% FLUCONAZOLE up to 800 mg/day/44380% amphotericin Comparison of Success Rate in Proven and Presumed Fungal Infections FUNGIZONE (amphotericin B for injection) is a trademark of Bristol Myers Squibb. ABELCET (amphotericin B lipid complex injection) is a trademark of The Liposome Co., Inc. AMPHOCIL (amphotericin B colloidal dispersion) is a trademark of Sequus Pharmaceuticals, Inc. AMBISOME (amphotericin B liposome for injection) is a trademark of NeXstar Pharmaceuticals.

99. Novel Agents for primary therapy T riazoles Voriconazole (UK 109,496) Vfend Posaconazole (SCH 56592) Ravuconazole (BMS 207147, ER 30346) C andins Caspofungin (MK 0661, LY 743,872) Cancidas Micafungin (FK 463) Anidulafungin (LY 303,366)

100. Voriconazole profile A new broad-spectrum, triazole antifungal agent –Effective in vitro against yeasts and moulds Oral and intravenous formulations Efficacy demonstrated in a broad range of patients and clinical situations Acceptable tolerability

101. Voriconazole Mycological aspects active against Aspergillus species: geometric mean MIC: 0.4 mg/l in vitro activity comparable AMB fungicidal in vitro for a majority of isolates (Oakley et al. JAC 1998; 42: 91-94)

102. Efficacy and safety of voriconazole in the treatment of acute IA Study overview Open, multicentre study 116 patients –proven IA 48 (41%) –probable 68 –voriconazole: as primary therapy 60 (52%) Denning et al. CID 2002: 34: 563-571.

103. Efficacy and safety of voriconazole in the treatment of acute IA Response Assessed by clinical and radiographic change –complete response: 16 (14%) –good responses: 56 (48%) –partial response: 40 (34%) Denning et al. CID 2002: 34: 563-571.

104. Efficacy and safety of voriconazole in the treatment of acute IA Inclusion criteria –Definite (proven) IA: histopathologic evidence of tissue invasion with hyphae morphologically consistent with Aspergillus, or a positive culture from a sterile site –Probable IA: radiologic evidence of acute IA –Probable IA: Aspergillus from respiratory fluids and characteristic radiography. –In profound neutropenia: radiology and clinical features with culture: sufficient for enrollment. Denning et al. CID 2002: 34: 563-571.

105. Efficacy and safety of voriconazole in the treatment of acute IA Discussion points Response compares favourable with itraconazole, cAMB and liposomal AMB Patients with positive histological results but negative cultures were included as definite cases No comment about long treatment duration and host response Denning et al. CID 2002: 34: 563-571.

109. Candins Potent broad spectrum activity Fungicidal Novel mechanism of activity Low potential for developing resistance Well tolerated in humans

110. Caspofungin Member of a new class of antifungals, the echinocandins –Inhibitors of glucan synthesis in the fungal cell wall –Cell wall target absent from mammalian cells Spectrum of activity includes Aspergillus and Candida spp. Unique mechanism of action results in a lack of cross-resistance with azoles and polyenes

111. Caspofungin spectrum of activity Spectrum of activity includes Candida albicans, non-albicans Candida spp., and Aspergillus spp. –Caspofungin is fungicidal for Candida spp. –Caspofungin demonstrates clear activity against Aspergillus spp. In vitro, no cross-resistance to Candida spp. with intrinsic or acquired resistance to fluconazole, amphotericin B, or flucytosine No activity against Cryptococcus neoformans Activity against other fungi less well defined

112. Caspofungin is approved!

113. Caspofungin Clinical Development Program PK and Proof of Concept (I/IIA) OPC/Candida Esophagitis Invasive Infections Caspofungin 70 mg X 1; then 50 mg/d Dose Ranging Caspofungin 35, 50, 70 mg/d III Candida Esophagitis Invasive Candidiasis Empirical Therapy of Febrile Neutropenia Dose Selection 50 mg/d Salvage Aspergillus Pediatrics

114. Caspofungin Salvage Aspergillus Study (Protocol 019) Design Multi-center, open-label, non-comparative study –Caspofungin 70 mg qd X 1, followed by 50 mg qd Diagnostic criteria –Documented invasive aspergillosis, AND –Meet criteria as refractory to or intolerant of standard therapy Definition of response –Favorable response: Complete or Partial Response –Unfavorable response: Failure, Stable disease Cases reviewed by independent Expert Panel

115. n/m Expert Panel Assessment of Outcome Efficacy Analysis Primary: All patients with diagnosis who receive at least 1 dose of caspofungin Secondary: Patients who received > 7 days of caspofungin 26/63 (41.3) 26/52 (50.0) Favorable Response (%)

116. n/m Expert Panel Assessment of Outcome Efficacy Analysis Primary: All patients with diagnosis who receive at least 1 dose of caspofungin Secondary: Patients who received > 7 days of caspofungin 26/63 (41.3) 26/52 (50.0) Favorable Response (%)

117. Summary of Caspofungin Efficacy in the Salvage Aspergillus Study Expert Panel determined that 41% of patients had a Complete or Partial Response at the end of caspofungin therapy High prevalence of poor prognostic factors Favorable outcomes seen in all high risk groups –Refractory patients, hematologic malignancies/bone marrow transplant, disseminated disease, corticosteroids, and neutropenia Documented relapse uncommon at 4 week follow-up

118. Therapeutic regimens Nyotran ravuconazole posaconazole itraconazole oral Amphotericin B AmBisome Amphotec Abelcet voriconazole anidulafungin caspofungin micafungin IVOral itraconazole voriconazole itraconazole voriconazole ravuconazole posaconazole

119. Managing mycosis following HSCT Granulocytes (log 10 1x 10 6 /L) 0.1 1 10 36 37 38 39 40 41 Temperature °C DaysMonths-7071421126912-14628810WeeksTransplant ENGRAFTMENT PRE- TRANSPLANT EARLY POST- ENGRAFTMENT LATE POST- ENGRAFTMENT IVoraloralVoriconazoleItraconazolePosaconazoleVoriconazoleItraconazolePosaconazoleVoriconazoleItraconazoleCaspofunginAmBisome

120. 0 36 37 38 39 40 41414141 Temperature (°C) Optimal antifungal management? CultureCulture + TissueTissue + GalactomannanGalactomannan + PCRPCR + Treatment Disease likelihood -7071421283542495663-14 0.1 1 10 Days after transplant Granulocytes (log 10 x10 9 /L) Empirical Possible Prophylaxis Remote Specific Proven Pre-emptive Probable disease

121. DIAGNOSTICS ANTIFUNGALS ALONE OR IN COMBINATION INTERFERON INTERLEUKINS G(M)-CSF SURGERY HYGIENE ISOLATION ELIMINATION OF RISK FACTORS Future Antifungal Strategies

122. Combination therapy Issues Clinical trials supporting combination therapy are sparse No concensus regarding which combinations are synergistic or antagnostic Predicting whether synergy or antagonism will predominate in vivo is extraordinarily difficult Extrapolation from in vitro or animal studies is, at best, tenuous. Antagnostic interactions can be based on mechanisms of action, but not synergy. Lewis & Kontoyiannis Pharmacotherapy 2001; 21: 149S-164S

123. Itraconazole-amphotericin B combinations: MD Anderson experience 67 haematological malignancy patients Definite IA (EORTC/MSG criteria) Failure rate, regardless of regimen: 85% No difference in outcome –monotherapy –combination therapy –adjunctive therapy Major factors: –poor diagnosis tests –extent and duration of immunosuppression

124. Itraconazole-5FC combination therapy Successful in cerebral aspergillosis Anecdotal reports Given relatively poor CNS penetration of echinocandins and some triazoles, combining 5FC with these agents may be warrented in patients in whom disseminated or cerebral aspergillosis is suspected. Lewis & Kontoyiannis Pharmacotherapy 2001; 21: 149S-164S

125. Caspofungin in combination with itraconazole for the treatment of invasive aspergillosis in humans No data on combination of caspofungin + others antifungals 2 cases IA: –ALL: A. terreus: Caspo 50 mg/day + Itra 200 mg t.i.d. po, 8 weeks, no recurrence –Single-lung Tx: A. fumigatus: Itra 400 mg/day po + ABLC 5 mg/kg/day Itra 400 mg/kg/day po + Caspo 70 mg/day No recurrence Rubin et al. CID 2002; 34: 1160-1161

126. Clinical Implications for Today Cryptococcus –Adding 5FC is generally good. +FLU is better? Candida –Can combine fluconazole with AmB But, probably should avoid in endocarditis Candins may render this idea moot Aspergillus –Candin-based combos look like the way to go Keep terbinafine-based combos in mind

127. Todays choices Invasive aspergillosis –amphotericin B desoxycholate: 1-1.5 mg/kg/d –Liposomal amphotericin B: 5 mg/kg/d starting dose –Casopofungin: 50/70 mg/d –Voriconazole: 4 mg/kg bid –Itraconazole: 200-600 mg/d –Second-generation antifungal triazoles (investigational) –Combinations Groll & Walsh. Infect Med 2002; 19: 326-334. (Medscape: www.medscape.com)www.medscape.com Patterson CID 2002; 35: 367-369.

128. Conclusions The echinocandins and new triazoles offer more choice There is too little known about the optimum dosage, the need for monitoring and the potential DRAEs Acquisition costs will be high Flexible administration is now demanded Who should get what and when remains unclear Targeting the drugs will require better identification of those at risk and assessment of that risk Further studies are need to establish the place of these drugs in clinical practice PREVENTION IS BETTER THAN CURE

129. Any questions or comments? malcolm.richardson@helsinki.fi