ANKARA, FEBRUARY 2007

EVIDENCE Clinical Management of Invasive Fungal Infections: An Evidence-Based Approach

According to Odds

INCREASE IN FUNGAL INFECTIONS less mortality from other causes -underlying disease -better antibacterial therapy higher age better diagnostic tools more complex interventions We are prepared to go further but have to pay a price

MORTALITY DUE TO INVASIVE MYCOSES McNeil et al MORTALITY DUE TO INVASIVE MYCOSES McNeil et al. Clin Infect Dis 2001;33:641-7 0,2 0,4 0,6 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 Rate per 100,000 population United States, 1980-1997 Mycoses other than Candida albicans

DEVELOPMENT OF FUNGAL INFECTIONS OVER TIME 0,5 1 1,5 2 2,5 3 3,5 Incidence (%) 1999 2000 2001 2002 2003 Aspergillus Candida Andamento annuale dell’incidenza delle infez fungine. other yeasts other moulds

LETHALITY OF THE VARIOUS INVASIVE FUNGAL INFECTIONS number of cases Aspergillus Zygomycetes Fusarium Candida Cryptococcus Trichosporon 100 200 300 400 42% 33% 61% 53% 50% 29% Mortalità nei non trapiantati cases casualties

BASIC RISK FACTORS FOR FUNGAL INFECTIONS OPPORTUNISTS! immuno- suppression epidemiologic exposure technical / anatomic factors Adapted from RH Rubin, Boston

COURSE OF DEFENSE SYSTEMS UNDER MODERN THERAPEUTIC REGIMENS T-cell function Commensal flora Humoral immunity Granulocytes There are different treatment modalities that would fit different clinical situations. However, there is a lot of confusion amongst investigators on the meaning of the labels for the treatments antibiotics Mucosa time

PACE OF DEVELOPMENT OF NEW ANTIFUNGAL AGENTS isavuconazole caspofungin anidulafungin micafungin voriconazole posaconazole PACE OF DEVELOPMENT OF NEW ANTIFUNGAL AGENTS 1960 1970 1980 1990 2000 Adapted from Rex & Edwards, 1997 AmBisome fluconazole Amphocil Abelcet itraconazole ketoconazole miconazole 5-flucytosine terbinafine Amphotericin B Nystatin Griseofulvin 1950

WHAT’S NEW? micafungin anidulafungin voriconazole caspofungin posaconazole micafungin voriconazole anidulafungin caspofungin amphotericin B flucytosine fluconazole itraconazole

A B C I II III RECOMMENDATIONS SOLID CLINICAL EVIDENCE RANDOMISED TRIAL CONSISTENT SERIES EXPERT / CONSENSUS SOLID CLINICAL EVIDENCE REASONABLE CLINICAL EVIDENCE TRIVIAL CLINICAL EVIDENCE

A B C I II III RECOMMENDATIONS early start of antifungal treatment lipid ampho B for primary treatment ampho B followed by itraconazole biological response modifiers // surgery early start of antifungal treatment

487 FUNGAL INFECTIONS IN TRANSPLANT RECIPIENTS Pappas et al 487 FUNGAL INFECTIONS IN TRANSPLANT RECIPIENTS Pappas et al. ICAAC, Chicago 2003; abstr M-1010 Pneumocystis Endemic Crypto Aspergillus and other moulds Candida

FUNGAL INFECTIONS IN TRANSPLANT RECIPIENTS Pappas et al FUNGAL INFECTIONS IN TRANSPLANT RECIPIENTS Pappas et al. ICAAC, Chicago 2003; abstr M-1010 Candida species

POPULATION WITH INVASIVE CANDIDIASIS Diagnosed while alive eligible for clinical trial Invasive candidasis

COMPARISON OF RESULTS FROM CLINICAL TRIALS ON CANDIDAEMIA response mortality Fluconazole 400 mg/day Amphotericin B Caspofungin Micafungin Anidulafungin Voriconazole 72% 79% 62% 74% 76% 65% 39% 40% 30% 23% 36%

MICAFUNGIN versus AMBISOME IN CHILDREN WITH INVASIVE CANDIDOSIS Arrieta et al. ICAAC, San Francisco 2006; Abstract M-1308b Double-blind comparison, n = 98 100 Rate of Favorable Response premature 70% 67% 80 76% 73% 60 40 20 2mg/kg/d (n=48) micafungin AmBisome 3 mg/day (n=50)

COMPARISON OF RESULTS FROM CLINICAL TRIALS ON CANDIDAEMIA response mortality Fluconazole 400 mg/day Amphotericin B Caspofungin Micafungin Anidulafungin Voriconazole 72% 79% 62% 74% 76% 65% 39% 40% 30% 23% 36%

COMPARISON OF RESULTS FROM CLINICAL TRIALS ON CANDIDAEMIA response mortality Fluconazole 400 mg/day Amphotericin B Caspofungin Micafungin Anidulafungin Voriconazole 72% 79% 62% 74% 76% 65% 39% 40% 30% 23% 36%

COMPARISON OF RESULTS FROM CLINICAL TRIALS ON CANDIDAEMIA response mortality Fluconazole 400 mg/day Amphotericin B Ambisome Caspofungin Micafungin Anidulafungin Voriconazole 72% 79% 62% 71% 74% 76% 65% 39% 40% 34% 30% 23% 36%

RELATION INITIATION FLUCONAZOLE THERAPY AND OUTCOME OF CANDIDAEMIA Garey et al. Clin Infect Dis 2006; 43:25-31 230 cases of candidaemia start fluconazole day 0 day 2 day 3 day 4

RELATION INITIATION FLUCONAZOLE THERAPY AND OUTCOME OF CANDIDAEMIA Garey et al. Clin Infect Dis 2006; 43:25-31 230 cases of candidaemia start fluconazole day 0 day 2 day 3 day 4

RECOMMENDATIONS FOR TREATMENT OF ACUTE CANDIDIASIS -- 2007 B C I II III First line Fluconazole Ampho B Candins Voriconazole Early start therapy Flu-resistant strains AmphoB formulations Candins Voriconazole Lower doses suffice in less critically ill patients Continue therapy for 2 weeks after disappearance of signs and symptoms Flu-resistance Combination therapy Combination of antifungals Biological response modifiers

FROM TREATMENT OF CHOICE TO CHOICES OF TREATMENT

FROM TREATMENT OF CHOICE TO CHOICES OF TREATMENT

STRATEGY FOR THE TREATMENT OF DISSEMINATED CANDIDIASIS Spellberg et al STRATEGY FOR THE TREATMENT OF DISSEMINATED CANDIDIASIS Spellberg et al. Clin Infect Dis 2006; 42:244-251 Spellberg Filler Edwards flucon azole invasive candidiasis proven / probable (risk of) C.glabrata C.krusei ? NO hemodynamically unstable? NO YES lipid ampho-B voriconazole echinocandin

FUNGAL INFECTIONS IN TRANSPLANT RECIPIENTS Pappas et al FUNGAL INFECTIONS IN TRANSPLANT RECIPIENTS Pappas et al. ICAAC, Chicago 2003; abstr M-1010 Aspergillus species

QUESTIONS REGARDING INVASIVE ASPERGILLOSIS ?? QUESTIONS REGARDING INVASIVE ASPERGILLOSIS Why is there an increase? When will it occur? Where will it strike? When should we treat? What is the best therapy?

STRATEGY vs DRUG SELECTION Treatment checklist azoles lipid formulations polyenes candins combinations diagnostics a plan I FD Treatment checklist azoles lipid formulations polyenes candins combinations diagnostics a plan I FD When? What?

STRATEGY vs DRUG-EFFICACY Treatment checklist azoles lipid formulations polyenes candins combinations diagnostics a plan I FD When? What?

STRATEGY vs DRUG-EFFICACY Treatment checklist azoles lipid formulations polyenes candins combinations diagnostics a plan I FD When?

RELATION OUTCOME AND STATE OF FUNGAL INFECTION time odds to control the infection evolution of the infection

Pulmonary only Disseminated 40% (n=330) 18% (n=144) Survival IMPORTANCE OF EARLY TREATMENT OF INVASIVE ASPERGILLOSIS Patterson et al. Medicine 2000 Type of infection Survival Pulmonary only Disseminated 40% (n=330) 18% (n=144)

RECOMMENDATIONS IDSA 2000 Stevens et al RECOMMENDATIONS IDSA 2000 Stevens et al. Clin Infect Dis 2000; 30:696-709 A B C I II III Early start of antifungal treatment

>90% no disease 20 40 60 80 100 Empirical therapy PROBABILITY OF DEVELOPING PULMONARY ASPERGILLUS Gerson et al. Ann Intern Med 1984 20 40 60 80 100 Empirical therapy incidence aspergillosis 4-6% PERCENTAGE INFECTED >90% no disease 0 10 20 30 40 50 60 70 80 90 100 DAYS WITH NEUTROPENIA

High-resolution CT-scan Ultrasound Bronchoalveolar lavages DIAGNOSTIC TOOLS ANNO 2007 Sandwich-ELISA galactomannan High-resolution CT-scan Ultrasound Bronchoalveolar lavages Biopsy techniques Glucan-test PCR PET-scanning

empirical antifungals TRADITIONAL EMPIRICAL MANAGEMENT OF INVASIVE ASPERGILLOSIS Maertens et al. Clin Infect Dis 2005;41:1242-1250 136 episodes 19 no fever 117 febrile episodes 30 persistent fever 82 defervesence 11 unexplained relapses 35% 41 candidates empirical antifungals

136 treatment episodes haematological malignancies GALACTOMANAN AND CT-SCAN-GUIDED EARLY TREATMENT OF INVASIVE ASPERGILLOSIS Maertens et al. Clin Infect Dis 2005;41:1242-1250 136 treatment episodes haematological malignancies typical negative 117 febrile episodes daily galactomannan 5 days refractory fever no antifungal 2x >0.5 CT BAL CT anti- fungal

pre-emptive antifungals PRE-EMPTIVE MANAGEMENT OF INVASIVE ASPERGILLOSIS Maertens et al. Clin Infect Dis 2005;41:1242-1250 19 no fever 117 febrile episodes 136 episodes + 82 defervesence 9 cases suspicious CT 10 seropositive 16% 19 cases for pre-emptive antifungals

100% autopsy rate fungal mortality 8% PRE-EMPTIVE MANAGEMENT OF INVASIVE ASPERGILLOSIS: MORTALITY Maertens et al. Clin Infect Dis 2005;41:1242-1250 88 patients 100% autopsy rate Fungal mortality Walsh I 7% Walsh II 8% Walsh III 8% Boogaerts 11% fungal mortality 8%

ESTIMATING TIME FOR INTERVENTION Peter Donnelly & Ben dePauw ESTIMATING TIME FOR INTERVENTION Aspergillus infiltrate antigen Persisting fever + very high risk or a suggestive symptom a suspected sign any positive test day 1 5 7 12 // 28 > 42

?? HOW TO PROCEED?

STRATEGY vs DRUG-EFFICACY Treatment checklist azoles lipid formulations polyenes candins combinations diagnostics a plan I FD When? What?

STRATEGY vs DRUG-EFFICACY Treatment checklist azoles lipid formulations polyenes candins combinations I FD What?

WHAT IS THE BEST ANTIFUNGAL DRUG? ?? For prophylaxis? For empirical purposes? For treatment of established disease?

PROPHYLAXIS EMPIRICAL (PRE-EMPTIVE) THERAPY invasive fungal infection NOT PRESENT invasive fungal infection NOT EXCLUDED invasive fungal infection INCIPIENT By contrast, pre-emptive therapy is initiated when there is evidence of pulmonary disease that is virtually pathognomonic for invasive aspergillosis for instance the halo sign around a lesion or the air-crescent sign indicative of a cavity, or is less specific but none the less consistent with the disease and there is also mycological evidence such as recovery of the fungus in several sputa samples or a single bronchoalveolar lavage or Aspergillus antigen has been detected in plasma.

BUG efficacy DRUG BUG DRUG INTERRELATIONS PROBABLE & PROVEN FUNGAL DISEASE BUG efficacy DRUG EVIDENCE BUG DRUG

RESPONSE TO TREATMENT FOR ASPERGILLOSIS IN NORMAL PRACTICE Patterson et al. Medicine 2000;79:250-260 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 ampho B 32% P A T I E N S

RECOMMENDATIONS IDSA 2000 Stevens et al RECOMMENDATIONS IDSA 2000 Stevens et al. Clin Infect Dis 2000; 30:696-709 A B C I II III Lipid ampho B in compromised kidneys Ampho B and itraconazole for primary treatment Early start of antifungal treatment Lipid ampho B for primary treatment Ampho B followed by itraconazole Biological response modifiers // surgery

4% in trials !! REPRESENTATIVE !? REFERENCE POPULATION ineligible Diagnosed while alive ineligible Invasive aspergillosis Of all patients with invasive fungal disease only about half will be diagnosed while alive; the others become manifest at autopsy (if done). Of the patients who are diagnosed during life the majority will not meet entry criteria (co-medication, life-expectancy, consent, previous treatment, appropriate diagnostic work-up, etc, for trials. By consequence only very few patients will be enrolled and therefore it is the question whether such a study population can be regarded as representative for the daily clinical situation. Particularly, the value of strategic trials is jeopardized by this phenomenon REPRESENTATIVE !?

EORTC IFICG VORICONAZOLE VERSUS AMPHOTERICIN B FOR INVASIVE ASPERGILLOSIS: SUCCESS AT WEEK 12 Herbrecht et al N Engl J Med 2002; 347:408-415 % 10 20 30 40 50 60 Voriconazole 76/144 (53%) 42/133 (32%) Amphotericin B

Complete response Partial Failure Mortality 44% 22% 34% 18% 38% 44% AMBISOME versus AMPHOTERICIN B in PROVEN AND PROBABLE ASPERGILLOSIS Leenders et al. Brit J Haematol. 1998 AmBisome 5 mg/kg/day n = 32 amphotericin B 1 mg/kg/day n = 34 Complete response Partial Failure Mortality 44% 22% 34% 18% 38% 44% 66% 56%

Invasive mould infections HIGH VERSUS STANDARD DOSE AMBISOME FOR INVASIVE MOULD INFECTIONS Cornely et al. Blood 2005; 106:900a, Abstract 3222 AmBisome 10 mg/kg x 14 followed by 3 mg/kg/day 201 proven & probable Invasive mould infections AmBisome 3 mg/kg/day 94 107 End of treatment Favorable response Survivors 12 weeks 46% 50% 14% 31% nephrotoxicity hypokalaemia 16% 30% 59% 72%

7 proven / 25 probable cases FIRST-LINE THERAPY WITH CASPOFUNGIN FOR PULMONARY ASPERGILLOSIS Candoni et al. Eur J Haematol 2005; 75:227-233 7 proven / 25 probable cases 31 neutropenic at start overall n=32 18 (56%) favorable responses G-CSF + caspofungin 70  50 mg/d hematological malignancies

ASSESSMENT OF EFFICACY PROBABLE & PROVEN FUNGAL DISEASE BUG efficacy DRUG patients failing antifungal therapy special occasions As it is difficult to establish a diagnosis, untreated proven cases of invasive fungal disease are exceptions; the diagnosis comes late and, by consequence, most patients will have been put on antifungal therapy on a basis of clinical suspicion untreated patients

PANDORRA’S BOX OF SALVAGE CASES 3 days stable life-threatening progression creatinine increase renal failure treatment refractory toxicity a single shiver hyperpyrexia intolerance There is, however, a problem; toxicity, tolerance, and even therapy-refractoriness are subject to extremely subjective interpretation. All elements have a wide variation in grading !subjective criteria!

PANDORRA’S BOX OF SALVAGE CASES co- medication? PANDORRA’S BOX OF SALVAGE CASES treated with what? how much?? treatment refractory toxicity intolerance evolvement underlying disease?? And to complicate things further: appreciation of the data obtained in salvage trials is only possible if co-medication, previous antifungal therapy and evolution of the underlying disease are taken into account

SALVAGE FOR INVASIVE ASPERGILLOSIS Refractory / intolerant amphotericin B caspofungin n=146 posaconazole n=107 voriconazole n=144 ampho B lipid complex response 40%

CLEAR ???? Retrospective Collection of data on a voluntary basis C.L.E.A.R. PROGRAM ON ABLC BETTER THAN NOTHING? Clin Infect Dis 2005; 40:Supplement 6 Retrospective Collection of data on a voluntary basis Mix of superficial and disseminated infections No discrimination “proven-probable-possible” Own definitions for response / success Variations in dosing regimens CLEAR ????

Response rate improved APPRECIATION Response rate improved from 30 to 60%! Failure rate still 50%……

invasive aspergillosis VORICONAZOLE WITH CASPOFUNGIN AS RESCUE FOR INVASIVE ASPERGILLOSIS Marr et al. Clin Infect Dis 2004; 39:797-802 Observational study with historical controls in 47 BMT recipients ampho B 1 mg/kg kidney: lipid 5 mg/kg Proven/probable invasive aspergillosis progression (time?) intolerance nephrotoxicity 1997-2001 2001- voriconazole n=31 + caspofungin n=16 survival 3 months after diagnosis survival 3 months after diagnosis difference in survival

SURVIVAL AFTER COMBINATION THERAPY FOR ASPERGILLOSIS Marr et al SURVIVAL AFTER COMBINATION THERAPY FOR ASPERGILLOSIS Marr et al. Clin Infect Dis 2005; 40:1074-6 Overall Survival 10 20 30 40 50 60 70 80 90 100 Combination Voriconazole In addition, estimation of a survival rate depends very much on the time point selected; the direct influence of the invasive fungal infection will abate with time but, at the other hand, the presence of a fungus may be a reason to postpone or ameliorate therapy for the underlying disease resulting in a reduced long-term survival rate 30 60 90 120 150 180 210 240 270 300 330 360 days after diagnosis

VORICONAZOLE PLUS CASPOFUNGIN FOR ASPERGILLUS IN SOLID ORGAN TRANSPLANTS Singh et al. Transplantation 2006; 81:320-325 VORICONAZOLE + CASPOFUNGIN LIPID AMPHO B HISTORICAL CONTROLS 2003-2005 multicenter 34 38 compare mortality day 90 26% 50%

47 AmBisome-33 voriconazole SINGLE AGENT OR COMBINATION TO TREAT INVASIVE ASPERGILLOSIS? Kubin et al. ICAAC, San Francisco 2006; Abstract M-899 Retrospective 146 proven/probable primary cases monotherapy n = 124 47 AmBisome-33 voriconazole caspofungin + voriconazole n = 22 RESPONSE 24% 21% 12 wk mortality 55% 46%

improved diagnostic tools over-representation of autopsy cases HISTORICAL CONTROLS Unreliable due to: improved diagnostic tools over-representation of autopsy cases changes in therapy underlying disease changes in doctors!

QUESTIONS REGARDING INVASIVE ASPERGILLOSIS ?? QUESTIONS REGARDING INVASIVE ASPERGILLOSIS Why is there an increase? When will it occur? Where will it strike? When should we treat? What is the best therapy? Which factors dictate outcome?

QUESTIONS REGARDING INVASIVE ASPERGILLOSIS ?? QUESTIONS REGARDING INVASIVE ASPERGILLOSIS Why is there an increase? When will it occur? Where will it strike? When should we treat? What is the best therapy? Which factors dictate outcome?

suppression of fungal growth recovery host defense repair organ damage ELEMENTS TO SUCCESS recovery host defense repair organ damage

CORTICOSTEROIDS AND SURVIVAL OF ASPERGILLOSIS IN HSCT Cordonnier et al CORTICOSTEROIDS AND SURVIVAL OF ASPERGILLOSIS IN HSCT Cordonnier et al. Clin Infect Dis 2006;42:955-963 51 patients with aspergillosis 41 allo HSCT 10 auto S U R V I A L low dose corticosteroids high dose

invasive mould infections MOULD INFECTIONS AND AMBISOME: NEUTROPENIA AND SURVIVAL Cornely et al. 2nd Adv Aspergillosis, Athens 2006; Abstr P122 201 proven & probable invasive mould infections AmBisome 10 mg/kg x 14 followed by 3 mg/kg/day 3 mg/kg / day 20 40 60 80 end of therapy at day 14 neutropenic non-neutropenic % survival

EVOLUTION OF ELEMENTS DETERMINING SUCCESS OR FAILURE antifungal condition host defense time

RECOMMENDATIONS FOR ASPERGILLOSIS 2007 B C I II III Voriconazole for first line Liposomal minimal dose 3mg/kg /day Lipid ampho B’s in compromised kidneys Caspofungin rescue Liposomal ampho B for first line Posaconazole as prophylaxis Other ampho B’s, itra for primary treatment Pre-emptive works Early intervention is important Ampho B followed by itraconazole Surgery in selected cases Posaconazole (oral) for rescue Biological response modifiers Combination therapy

STRANGE DUCKS IN THE IMMUNOSUPPRESSED POND Fusarium STRANGE DUCKS IN THE IMMUNOSUPPRESSED POND Mucor/ Rhizopus Pseudallescheria boydii Scedosporium Alternaria

INVASIVE FUNGAL INFECTIONS IN RELATION TO IMMUNE DEFENSE external fungal population our body compromised defense severely compromised

2 4 6 8 10 12 14 16 1985-89 1990-94 1994-99 Zygomycetes Fusarium sp EVOLUTION OF NON-ASPERGILLUS MOULDS IN BMT RECIPIENTS 1985-1999 Marr et al. Clin Infect Dis 2002; 34:909-917 2 4 6 8 10 12 14 16 1985-89 1990-94 1994-99 total number Zygomycetes Fusarium sp Scedosporium

POSACONAZOLE RESCUE FOR ZYGOMYCOSIS Kontoyiannis et al POSACONAZOLE RESCUE FOR ZYGOMYCOSIS Kontoyiannis et al. ICAAC, Washington 2005; Abstract M-974 91 patients ORAL MEDICATION 10 intolerant 81 refractory Rhizopus Mucor Cunninghamella Rhizomucor Absidia N=25 17 8 7 2 52% 76% 75% 28% 100%

49 empirical antifungals MUCORMYCOSIS IN HAEMATOLOGIC PATIENTS: TREATMENT RESULTS Pagano et al. Haematologica 2004; 89:207-214 59 cases 49 empirical antifungals 39 amphotericin B 4 liposomal amphotericin B 30 failures 9 successes – 23% 12 liposomal amphotericin B 8 switches 7 successes – 44% 4 surgery

BUG efficacy DRUG PATIENT BUG DOCTOR PATIENT BUG PATIENT DRUG PATIENT INTERRELATIONS BUG efficacy DRUG damage / defense PATIENT BUG DOCTOR PATIENT concern BUG PATIENT DRUG tolerance / toxicity PATIENT DRUG DOCTOR confidence DRUG DOCTOR

PROPHYLAXIS EMPIRICAL (PRE-EMPTIVE) THERAPY invasive fungal infection NOT PRESENT invasive fungal infection NOT EXCLUDED invasive fungal infection INCIPIENT By contrast, pre-emptive therapy is initiated when there is evidence of pulmonary disease that is virtually pathognomonic for invasive aspergillosis for instance the halo sign around a lesion or the air-crescent sign indicative of a cavity, or is less specific but none the less consistent with the disease and there is also mycological evidence such as recovery of the fungus in several sputa samples or a single bronchoalveolar lavage or Aspergillus antigen has been detected in plasma. Drug A Drug B Drug C

BASIS FOR LOCAL ALGORITMS drug efficacy established STRATEGY SELECTION DEPENDS ON: -physician confidence/experience -diagnostic tools available -patient population Whatever strategy we select, a priori we need to establish the efficacy of a drug against a bug; for this goal a double blind randomized trial, though desirable, is not an absolute prerequisite

WHAT’S NEW? posaconazole micafungin anidulafungin voriconazole caspofungin liposomal amphotericin B amphotericin B

EVIDENCE LEADS PRACTICE

THIS AND FUTURE GENERATIONS