1. Treatment of Fungal infections in Hematologic Malignancies
George Samonis M.D. PhD Professor of Medicine The University of Crete

2. Challenges of Diagnosing Opportunistic Infections at the Bedside
At the bedside of a patient with an opportunistic infection, the clinician is often more concerned with treating signs and symptoms or diagnosing a syndrome than identifying and treating the causative pathogen, which may be of bacterial, viral, or fungal origin. 2

3. Challenges of Diagnosing Opportunistic Infections at the Bedside
In this presentation, we will focus on diagnostic challenges and treatment approaches in the management of invasive fungal infections. 3

4. Usual fungal infections in immunocompromised patients
Candidiasis
Aspergillosis
Mucormycosis
Fusariosis
Cryptococcosis

5. Risk factors for development of IFIs
Neutropenia
Lymphopenia
Corticosteroids
Immunosuppressives
Chemotherapy
Bone Marrow Transplantation
Broad-spectrum antibiotics
Mucositis
Parenteral alimentation
Central venous catheters (CVCs)
Hospital construction

32. Increased Incidence of Mould Infection
Aspergillus spp
13.0%
11.4%
11.0%
6.0%
4.0%
A meta-analysis by Martino and Subira showed that a trend toward an increased incidence of infections after allogeneic HSCT caused by invasive mould infections, mostly Aspergillus. Relevant studies showed that the incidence of invasive candidiasis in these patients was demonstrated to be less than 5%.
Martino R, Subira M. Invasive fungal infection in hematology: new trends. Ann Hematol. 2002;81:
Wingard 1987
O’Donnell 1994
Morrison 1994
Baddley
2001
Martino
2002
Martino R, Subira M. Ann Hematol. 2002;81:

33. Distribution of IA in the Post-Engraftment Phase of HSCT
53%
30%
Incidence of IA in HSCT
17%
In a study that determined risks for IA in 1682 patients who received HSCTs between 1993 and 1998 at the Fred Hutchinson Cancer Research Center, 30% were diagnosed earlier than 40 days after stem cell transplantation and 53% were diagnosed between days 40 and 180. An additional 17% of infections developed more than 6 months after transplantation. This study confirmed a trend to later-onset IA in HSCT recipients (40 to 180 days post transplant).
Marr KA, Carter RA, Boeckh M, et al. Invasive aspergillosis in allogeneic stem cell transplant recipients: changes in epidemiology and risk factors. Blood. 2002;100:
<40 (n=57)
(n=99)
>180 (n=31)
Number of Days Post HSCT
Marr KA et al. Blood. 2002;100:

34. Incidence of Aspergillosis in HSCT Recipients Is Growing
1-Year Cumulative Incidence of Aspergillosis at FHCRC* (%) 14
Allograft recipients
Autograft recipients 12 10 8
Incidence (%) 6 4
Over the past 2 decades, infections caused by moulds, particularly Aspergillus spp., have become increasingly more common in HSCT recipients. The incidence of aspergillosis was evaluated at the Fred Hutchinson Cancer Research Center in HSCT recipients between 1992 and 1998.* Results from this study demonstrated that the incidence of aspergillosis in allograft recipients began to increase in 1992 and remained elevated though In autograft recipients, the incidence of invasive aspergillosis increased substantially after 1997, jumping from 1.1% in previous years to 5.3% in 1998.
Marr KA, Carter RA, Crippa F, et al. Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis. 2002;34: 2
1990
1991
1992
1993
1994
1995
1996
1997
1998
Year
Data from 1990 through 1992 were obtained from another study.
*FHCRC, Fred Hutchinson Cancer Research Center
Adapted from Marr KA et al. Clin Infect Dis. 2002;34:

35. Diminished T-cell function
Invasive Aspergillosis Risk Increases During the Post-Engraftment Period
IA Risk
IA Risk
Neutropenia
Immunosuppression:
GVHD
Corticosteroids
Diminished T-cell function
There is a bimodal distribution of risk for IFI during HSCT. Early risk for IA is associated with the neutropenic period, but the greatest risk period occurs late after transplantation in the setting of graft versus host disease (GVHD). This risk is particularly pronounced in non-myeloablative transplant regimens. In these regimens the duration of neutropenia is truncated, shifting the risk of IFI to the post-engraftment phase. In nonmyeloablative transplant, the strategy of using a graft versus tumor effect invariably leads to higher degrees of GVHD. This GVHD, and the immunosuppressive therapies used to manage it, place these patients at very high risk for IFI particularly due to moulds such as Aspergillus.1,2
Pre-engraftment
Post-engraftment
Marr KA. Oncology. 2001;15: Hagen EA et al. Clin Infect Dis. 2003;36:9-15.
Marr KA. Antifungal prophylaxis in hematopoietic stem cell transplant recipients. Oncology. 2001;15:15-19.
Hagen EA, Stern H, Porter D, et al. High rate of invasive fungal infections following nonmyeloablative allogeneic transplantation. Clin Infect Dis. 2003;36:9-15.

36. Aspergillus-Related Mortality in Allogeneic HSCT Remains Relatively High
87.0%
71.0%
68.0%
56.0%
31.6%*
The Aspergillus-associated mortality in HSCT recipients is between 32% and 87%. There has been a slight downward trend in associated mortality, perhaps due to coinciding with multiple changes in transplantation practices, including use of nonmyeloablative conditioning regimens, receipt of peripheral blood stem cells, more prompt diagnosis of IA, and the introduction of broad-spectrum triazoles and echinocandins.5 However, 32% associated mortality is still unacceptably high.1-5
Lin 20011
Cornet 20022
Thursky 20043
Cordonnier 20064
Upton 20075
Studies used crude mortality rate or attributable mortality rates. *Crude mortality rate at 4 months post IA diagnosis.
1. Lin SJ et al. Clin Infect Dis. 2001;32: Cornet M et al. J Hosp Infect. 2002;51: Thursky K et al. Bone Marrow Transplant. 2004;34: Cordonnier C et al. Clin Infect Dis. 2006;42: Upton A et al. Clin Infect Dis. 2007;44:
Lin SJ, Schranz J, Teutsch SM. Aspergillosis case-fatality rate: systemic review of the literature. Clin Infect Dis. 2001;32:
Cornet M, Fleury L, Maslo C, et al. Epidemiology of invasive aspergillosis in France: a six-year multicentric survey in the Greater Paris area. J Hosp Infect. 2002;51:
Thursky K, Byrnes G, Grigg A, et al. Risk factors for post-engraftment invasive aspergillosis in allogeneic stem cell transplantation. Bone Marrow Transplant. 2004;34:
Cordonnier C, Ribaud P, Hebrecht R, et al. Prognostic factors for death due to invasive aspergillosis after hematopoietic stem cell transplantation: a 1-year retrospective study of consecutive patients at French transplantation centers. Clin Infect Dis. 2006;42:
Upton A, Kirby KA, Carpenter P, et al. Invasive aspergillosis following hematopoietic cell transplantation: outcomes and prognostic factors associated with mortality. Clin Infect Dis. 2007;44:

37. The Majority of IFIs Are Identified Post-mortem
Pre-mortem
Post-mortem
33%†
How Can We Better Identify Patients With IFI During Life?
12.3%*
Identification of IFIs pre-mortem is significantly lower than the true incidence. In patients with hematologic malignancies, pre-mortem IFI incidence was 12.3%. Moulds were the predominant pathogens and 90% of the moulds were Aspergillus spp.1 When patients with hematologic malignancy who underwent autopsy exam at MD Anderson Cancer Center from were reviewed, prevalence of IFI at autopsy was 33%. Again, moulds were the predominant pathogens. Only 25% of the IFIs seen on autopsy were diagnosed pre-mortem.2 `
Pagano L, Caira M, Candoni A, et al. The epidemiology of fungal infections in patients with hematologic malignancies: the SEIFEM-2004 study. Haematologica 2006;91:
Chamilos G, Luna M, Lewis RE, et al. Invasive fungal infections in patients with hematologic malignancies in a tertiary care cancer center: an autopsy study over a 15-year period ( ) Haematologica. 2006;91;
Only 1/4 Diagnosed Pre-mortem
Pagano 20061
Chamilos 20062
*Incidence of moulds and yeasts in AML patients (7.9% due to moulds).
†Prevalence of invasive moulds and Candida (22% due to moulds).
1. Pagano L et al. Haematologica. 2006;91: Chamilos G et al. Haematologica. 2006;91:

38. Invasive Aspergillosis Role of Early Diagnosis & Therapy
Have We Made
Progress??

39. Non-Culture Based Diagnosis of Invasive Aspergillosis
Galactomannan
Sandwich ELISA (Platelia)
PCR
18s ribosomal DNA
Multi-copy or single target genes
b-D-glucan
Amebocyte Limulus lysate
Chromogenic (Glucatell, FungiTec G)
Kinetic (Wako)

40. Early diagnosis and treatment of invasive aspergillosis
Impact of early diagnosis of IA in patients with acute leukemia:
90% mortality when treatment instigated ≥ 10 days after first clinical or radiological sign of disease
40% mortality when treatment is instigated early
Serial HR CT scanning:
early and systematic high resolution CT scan in high-risk patients improves outcome
Survival (%)
IA: CT Scanning
100
Systematic CT 75
Non-Systematic CT 50 25
P = (Logrank Test) 50
100
150
200
Days After IPA
(von Eiff M, et al. Ann Hematol. 1995) (Reprinted with permission from Caillot D, et al. J Clin Oncol. 1997)

41. Hospital mortality (%) Delay in start of antifungal treatment (hours)
Relationship between hospital mortality and the timing of antifungal treatment 35 30 25 20
Hospital mortality (%) 15 10
This study provides further evidence that delayed treatment results in increased mortality.1
There is a need to focus on improved diagnosis of fungal infections, so that they can be treated early and adequately to reduce mortality.
Morrell M, et al. Delaying the empiric treatment of Candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality. Antimicrob Agents Chemother 2005; 49:3640–3645. 5
< 12
12–24
24–48
> 48
Delay in start of antifungal treatment (hours)
Morrell M, et al. Antimicrob Agents Chemother 2005; 49:3640–5

42. Patients with Satisfactory Treatment Response categorized by Baseline CT Findings
62%
52%
42%
41%
29%
16%
*Note: Required positive mycology
Greene R et al. ECCMID 2003

43. Utility of Galactomannan Detection in BAL Samples
# pt
160
Sens
(%)
Spec
PPV
NPV
Serum 47 93 73 82
BAL 85
100 88
GM detection in CT-based BAL fluid has a high PPV
for diagnosing IPA early in untreated patients
Becker et al. Br J Haematol 2003; 121: 448

44. Treatment definitions
Prophylactic therapy: Use of antifungals from chemotherapy until prolonged febrile neutropenia
Chance of infection: remote
Empirical therapy: Use of antifungals from febrile neutropenia to culture and/or tissue evidence of fungal infection
Chance of infection: possible
Preemptive therapy: Use of antifungals based on early clinical and/or laboratory markers of invasive disease
Chance of infection: probable

45. Lack of Consensus on the Use of Empirical Antifungal Therapy
Pros
Persistent or recurring fever of unknown origin >38C
Reduces mortality
Addresses diagnostic concerns
Persistent neutropenia Absolute neutrophil count <500 cells/mm3
Cons
Development of resistance
Toxicity
Cost
There is a lack of consensus on the value of empirical antifungal therapy. It can help reduce the morbidity and mortality associated with many fungal infections and it addresses concerns about diagnostic difficulties. However, shortcomings include over treatment and emerging resistance, potential toxicity, and increased treatment costs when patients get therapy who don’t need it. Newer diagnostic tools are needed to more accurately and quickly identify patients in greatest need of antifungal therapy.1,2
Wingard JR. Empirical antifungal therapy in treating febrile neutropenic patients. Clin Infect Dis. 2004;39(suppl):S38-S43.
Walsh TJ, Pappas P, Winston DJ, et al, for the National Institute of Allergy and Infectious Diseases Mycoses Study Group. Voriconazole compared with liposomal amphotericin B for empirical antifungal therapy in patients with neutropenia and persistent fever. N Engl J Med. 2002;346:
Broad-Spectrum antibiotics >96 h
Wingard JR. N Engl J Med. 2002;346:

46. Antifungal treatment evolution
AMB deoxycholate
5-fluocytosine
1st generation azoles (ketoconazole, miconazole)
2nd generation triazoles (fluconazole, itraconazole)
Lipid and liposomal formulations of AMB
Extended spectrum triazoles (voriconazole, posaconazole)
Echinocandins (caspofungin, micafungin, anidulafungin)

47. Cellular Targets of Antifungal Therapy
Echinocandins:
Target cell wall synthesis
Polyenes:
Target membrane function
This figure identifies the cellular targets of each main class of antifungal agents
Polyenes target fungal membrane function
Polyenes bind to ergosterol, a sterol that is an important component of the fungal membrane1
The most significant difference between fungal and human cell membranes is the type of sterol present
Ergosterol is the primary sterol in the fungal membrane and cholesterol is the primary sterol in the human cell membrane
Polyene binding to ergosterol causes pores or channels to form in the fungal membrane, causing increased membrane permeability, leakage, and cell death
Azoles target ergosterol synthesis1,2
Azoles inhibit synthesis of ergosterol by binding to 14- sterol demethylase, an enzyme required for ergosterol biosynthesis
Inhibiting ergosterol synthesis causes abnormal fungal cell membrane formation and accumulation of toxic ergosterol precursors
Echinocandins target cell wall synthesis1
Echinocandins inhibit the synthesis of glucan, a major structural polymer in the cell wall, by blocking the enzyme  1,3-glucan synthase
Inhibiting glucan synthesis compromises cell wall integrity
1. Balkis MM, Leidich SD, Mukherjee PK, Ghannoum MA. Mechanisms of fungal resistance: an overview. Drugs. 2002;62:
2. Sheehan DJ, Hitchcock CA, Sibley CM. Current and emerging azole antifungal agents. Clin Microbiol Rev. 1999;12:40-79.
Azoles: Target ergosterol synthesis

48. Fluconazole: Not a good choice for
empirical therapy in certain patients
Pts on azole prophylaxis
Pts with sinusitis or pneumonia
Pts with prolonged neutropenia (e.g. leukemia)
Pts with history of invasive aspergillosis (IA) or positive
surveillance cultures for Aspergillus spp.
Pts at institutions undergoing construction

49. L-AMB vs. AMB for empirical therapy of febrile neutropenia
Ambisome AMB
Patients
343
344
Acute Leukemia
168
165
Success 50 49
BFI (%) *
3.2
7.8
Infusion Fever (%) † 17 44
Nephrotoxicity (%) 19 34
* p= † p<0.001
Walsh NEJM 1999; 340:764

50. Polyene Therapy for Invasive Aspergillosis
Response %
Historical
Control
23%
DAMB
29%
ABCD
18%
L-AMB
52%
ABLC
42%
Note: ABLC=amphotericin B lipid complex; L-AmB=liposomal amphotericin B; ABCD=amphotericin B colloidal dispersion; D-AMB=amphotericin B deoxycholate
Hiemenz JW et al. Blood 1995;86(suppl 1):849a; Leenders ACAP et al. Br J Haem 1998;103:205; Bowden RA et al. Clin Infect Dis 2002;35:

51. Number of days of Therapy Probability of Survival
Comparative Aspergillosis Study: Better Outcomes & Survival of Voriconazole
Number of days of Therapy
Probability of Survival
Amphotericin B arm
Voriconazole arm
Hazard ratio = 0.60
95% CI (0.40, 0.89)
Outcomes at wk 12
Vori AmB
Survival % 57.9%
Response 56.8% 31.6%
Poor efficacy of AmB prior “gold standard”
Vori recommended for primary therapy
Questions?
Role of Other Licensed Antifungal therapy
Lipid for primary therapy
Efficacy in high risk
Combinations
Herbrecht R et al NEJM 2002;347:408-15

52. Voriconazole vs. Ambisome in febrile neutropenia
LAMB (N=422) P
Composite success
26%
31% NS
Breakthrough fungal
infections
1.9% 5%
0.002
Survival rate
87%
90%
Toxicity-related withdrawal
13%
10%
Nephrotoxicity (SCr>1.5)
11%
19%
<0.001
Visual changes
4.3%
0.5%
Walsh et al. N Engl J Med. 2002; 346:

53. Voriconazole: need for monitoring

54. Voriconazole Treatment

55. Subtherapeutic Voriconazole - Omeprazole

56. Posaconazole Posaconazole: broad spectrum of activity
only oral formulation
variable absorption
variable bioavailability
Established for prophylaxis in acute leukemia and HSCT

58. Posaconazole

59. Echinocandins Latest class of antifungal drugs
 First discovered in 1970s in screening
programs for new antibiotics
 Cell-wall active agents:
nhibition of (1, 3)-β-D glucan synthetase  cell wall glucan depletion 
osmotic instability  cell lysis

60. Echinocandins Formerly known as Pneumocandins due to activity
against Pneumocystis carinii
Rapidly fungicidal against most Candidae including azole-resistant strains
Fungistatic against most Aspergillus spp
Limited or no activity against Fusarium spp and Zygomycetes.
No activity against Cryptococcus neoformans

61. Mechanism of action1-4
Mechanism of action involves a target specific for fungus4
Glucan is essential to fungal cell wall integrity2-4
Without it, fungal cells are osmotically fragile and easily lysed4
inhibitor of 1,3--D-glucan synthase1
Enzyme is present in fungal, but not mammalian, cells1
1- ECALTA® SPC. 2- Odds F.C., Brown A.J.P., Gow N.A.R. Antifungal agents: mechanism of action. Trends Microbiol. 2003;11: Debono M., Turner W.W., LaGrandeur L. et al. Semisynthetic chemical modification of the antifungal lipopeptide echinocandin B (ECB): structure-activity studies of the lipophilic and geometric parameters of polyarylated acyl analogs of ECB. J Med Chem. 1995;38(17): Raasch R.H. Anidulafungin: review of a new echinocandin antifungal agent. Expert Rev Anti Infect Ther. 2004;2:

62.  CNS penetration: poor  Dose: once daily
Echinocandins
IV administration
Long half life
 CNS penetration: poor
 Dose: once daily
 Little infusion related toxicity
 Little or no renal and hepatic toxicity
 Drug-drug interaction limited (cyclosporin)
 Potential combination with other antifungals (AMB or azoles)
Animal data suggest synergistic effect
Echinocandins: Caspofungin Anidulafungin Micafungin

63. Echinocandins : In vitro activity1
Minimum inhibitory concentrations of the echinocandins against Candida species
Anidulafungin
Micafungin*
Caspofungin
Candida species
MIC50
(µg/ml)
MIC90
albicans
0.03
0.06-1
glabrata
0.13
0.03-1
0.06-2
tropicalis
0.06
0.25-1
dubliniensis
0.033
0.5
krusei
0.12-2
0.25-2
lusitaniae
0.25 2
0.5-1
1-2
parapsilosis 1
1-4
guilliermondii ND
2 -> 8
MIC50 or MIC90 = minimum inhibitory concentration for 50% or 90%, respectively, of tested strains; ND = not done.
1- Cappelletty D. et al. Reviews of therapeutics : the echinocandins Pharmacotherapy 2007, 27(3):

64. Caspofungin in Invasive Aspergillosis%
Well-documented disease
Efficacy
High risk pts
Progressive infection
Multiple prior antifungals
Excellent tolerability
Clinical utility
No data for primary therapy
Combination therapy
Optimal dose not known
Maertens J, et al. Clin Infect Dis 2004;39:

65. Efficacy of Caspofungin vs Empirical L-AmB in Neutropenic Patients*
Caspo (556) L-AmB (539)
Composite Success % 33.7%
Success Baseline Infections 14/27 (52%) 7/27 (26%)
Breakthrough Infections (5.2%) 24 (4.5%)
Etiological Agents*
Aspergillus
Candida
Fusarium
Zygomycetes
Other
*Patients may have had more than one organism
Walsh TJ et al, New Eng J Med, 2004;351:

66. Anidulafungin versus Fluconazole for Invasive Candidiasis.
Clinical data
Anidulafungin vs Fluconazole
Reboli A.C. et al.
Anidulafungin versus Fluconazole for Invasive Candidiasis.
N Engl J Med 2007;356:

67. Primary endpoint1 Global success at the end of IV therapy
ECALTA® demonstrated superiority vs fluconazole:
Significantly greater response rate in the anidulafungin group
Difference: 15.4% (95% CI: 3.9% to 27.0%)
Mean (median) duration of IV therapy:
fluconazole: (11) days
anidulafungin: (14) days
1- Reboli A.C., Rotstein C., Pappas P.G. et al. Anidulafungin versus Fluconazole for Invasive Candidiasis.
N Engl J Med 2007;356:

68. Phase III study micafungin vs. L-AmB Study design
Randomisation
(1:1)
Micafungin 100 mg/day*
L-AmB 3 mg/kg/day
Treatment period†
2–4 weeks‡
Post-treatment period
12 weeks
Kuse et al. demonstrated the non-inferiority of micafungin to L-AmB in the treatment of adults with SCIs.
Efficacy was assessed in both the modified intent-to-treat (mITT) and the per-protocol (PP) populations:
In the mITT population, 247 patients received micafungin and 247 patients received L-AmB
In the PP population, 202 patients received micafungin while 190 patients received L-AmB.
Kuse ER, et al. Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised double-blind trial. Lancet 2007; 369:1519–1527.
*2.0 mg/kg/day in patients weighing ≤ 40 kg †Treatment continued until at least one week after resolution of clinical signs and symptoms and obtaining of two sequential negative blood cultures
‡Maximum 8 weeks in chronic disseminated candidiasis, Candida osteomyelitis or Candida endocarditis
Kuse ER, et al. Lancet 2007; 369:1519–27

69. Phase III study micafungin vs. L-AmB Overall treatment success
100
Micafungin
L-AmB
89.6
89.5 80
74.1
69.6
Treatment success rate (%) 60 40
Statistical analysis showed that micafungin was equivalent (non-inferior) to L-AmB on the primary endpoint of treatment success in both the mITT and PP populations.
1. Kuse ER, et al. Micafungin versus liposomal amphotericin B for candidaemia and invasive candidosis: a phase III randomised double-blind trial. Lancet 2007; 369:1519–1527. 20
n =
247
247
202
190
mITT PP
Kuse ER, et al. Lancet 2007; 369:1519–27
mITT = modified intent-to-treat; PP = per-protocol set

70. Phase III study micafungin vs. caspofungin Study design
Patients were stratified by region and APACHE II score (≤ 20 or > 20)
Randomisation
(1:1:1)
Micafungin 100 mg/day
Micafungin 150 mg/day
CAS 50 mg/day*
Treatment period†
Max 4 weeks†
Post-treatment period
6 weeks‡
Pappas et al. compared two doses of micafungin with the standard dose of caspofungin in patients with confirmed SCIs.
The primary efficacy population was the mITT population, which included 191 patients that received micafungin 100 mg/day, 199 patients that received micafungin 150 mg/day and 188 patients that received caspofungin.
Pappas PG, et al. Micafungin versus caspofungin for treatment of candidemia and other forms of invasive candidiasis. Clin Infect Dis 2007; 45:883–893.
*70 mg loading dose on Day 1 †8 weeks in chronic disseminated candidiasis or Candida endophthalmitis; switch to oral fluconazole permitted after 10 days in patients meeting protocol-specified criteria ‡Time from last dose day of protocol-defined antifungal therapy to final evaluation
Pappas PG, et al. Clin Infect Dis 2007; 45:883–93
CAS = caspofungin

71. Phase III study micafungin vs. caspofungin Treatment success80
76.4
71.4
72.3 60
Treatment success rate (%) 40 20
Analysis of the primary efficacy endpoint showed that treatment success rates were comparable between micafungin 100 mg/day, micafungin 150 mg/day and caspofungin, demonstrating similar efficacy across all three treatment arms.
Micafungin was associated with treatment success in both candidaemia and deep invasive Candida infections.
In the statistical analysis, the 95% CIs for the treatment difference between caspofungin and both micafungin 100 and micafungin 150 had lower bounds that were higher than –15%, the predefined limit of non-inferiority, and were therefore both non-inferior to caspofungin.
On the secondary efficacy endpoints, there were no significant differences between the three treatment arms in terms of site of infection or incidence of recurrent invasive fungal infections (relapse) during the post-treatment period.
As the lower daily dose of 100 mg/day was as effective as the higher 150 mg dose, 100 mg/day was selected as the dose of choice for the treatment of adult patients with SCIs.
Pappas PG, et al. Micafungin versus caspofungin for treatment of candidemia and other forms of invasive candidiasis. Clin Infect Dis 2007; 45:883–893.
n = 191
n = 199
n = 188
n =
191
199
188
Micafungin 100 mg/day
Micafungin 150 mg/day
Caspofungin 50 mg/day*
Pappas PG, et al. Clin Infect Dis 2007; 45:883–93
*Loading dose 70 mg; mITT population

72. Micafungin vs Caspofungin in febrile neutropenia

73. Micafungin vs Caspofungin in febrile neutropenia
Conclusions
Micafungin as effective and safe as caspofungin in empirical treatment of fungal infections in patients with febrile neutropenia

74. Empirical micafungin treatment of IFIs in hematologic malignancies

75. Empirical micafungin treatment of IFIs in hematologic malignancies

76. Micafungin vs fluconazole for prophylaxis of invasive fungal infections during neutropenia in hematopoietic stem cell transplantation patients Study endpoints
Primary endpoint: treatment success (absence of proven, probable, or suspected systemic fungal infection until the end of prophylaxis therapy and the absence of a proven or probable systemic fungal infection until the end of the 42-day post-treatment period)
Secondary endpoints included: use of systemic antifungal agents for treatment of suspected fungal infections; frequency of proven or probable fungal infections throughout the post-treatment period; pathogen-based frequency of proven infections
The primary efficacy endpoint was treatment success, defined as absence of proven, probable, or suspected systemic fungal infection until the end of prophylaxis therapy and as the absence of a proven or probable systemic fungal infection until the end of the 4-week post-treatment period.
Secondary efficacy endpoints included: use of systemic antifungal agents for treatment of suspected fungal infections, frequency of fungal colonisation, time to treatment failure and mortality.
Safety analyses included adverse events, results of clinical laboratory tests and vital signs.
van Burik JA, et al. Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation. Clin Infect Dis 2004; 39:1407–1416.
van Burik JA, et al. Clin Infect Dis 2004; 39:1407–16

77. Phase III study micafungin vs. fluconazole Overall treatment success90 80
80.0 70
73.5 60 50
Treatment success (%) 40 30
Overall treatment success with micafungin as antifungal prophylaxis during the post-HSCT neutropenic phase was superior to that of fluconazole (primary efficacy endpoint of overall treatment success: 80% versus 73.5%; p = 0.03).
The treatment difference between micafungin and fluconazole was consistent across both allogeneic and autologous transplants.
van Burik JA, et al. Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation. Clin Infect Dis 2004; 39:1407–1416. 20 10
n =
425
457
Micafungin
Fluconazole
van Burik JA, et al. Clin Infect Dis 2004; 39:1407–16

78. Is combination of antifungals indicated?

79. Randomized blinded trial of high-dose fluconazole plus placebo vs fluconazole plus AMB as therapy for candidemia in non-neutropenic patients .
The combination of fluconazole and AMB was evaluated versus monotherapy with high-dose fluconazole in 219 non-neutropenic patients
No difference in survival between the two groups; however, candidemia cleared more rapidly with combination therapy, suggesting potential use in persistent Candida infections
Rex JH, et al. Clin Infect Dis 2003; 36:1221-8

80. . Efficacy and Toxicity of Caspofungin in Combination with L-AMB as Primary or Salvage treatment of Invasive Aspergillosis in Patients with Hematologic Malignancies Kontoyiannis DP, et al Cancer 2003; 98: 292-9
48 patients with documented or possible IA
The majority (65%) received CAS/L-AMB as salvage therapy for progressive IA despite 7 days of previous L-AMB monotherapy
Overall response rate 42%
No significant toxicity
Factors associated with failure: documented IA, significant steroid use, duration of combination therapy < 14 days
Response rate in patients with progressive documented IA 18%
Conclusions: The CAS/L-AMB combination is a promising preemptive therapy

81. Combination antifungal therapy for invasive aspergillosis
Combination antifungal therapy for invasive aspergillosis Marr KA, et al. Clin Infect Dis. 2004; 39:
Salvage therapy with the combination of voriconazole and caspofungin was associated with reduced mortality, compared with voriconazole monotherapy

84. Br J Haematol. 2004; 126:

85. Conclusions  Patients at high risk may benefit from empirical therapy
 Patients under close surveillance may receive preemptive treatment after early prodromal clues of infection
 No clear drug of choice, decisions should be individualized
 Lipid AMB, voriconazole and echinocangins: high risk pts
 Fluconazole, itraconazole: lower risk pts
 Limited data point out to combination treatments for selected high risk pts

86. Future issues
Should we move from empirical to preemptive therapy based on surrogate markers of early diagnosis of IFIs?
Is sequence of antifungals important?
Which combinations are more effective?