Changing Face of Fungal Infections: Clinical Considerations to Meet the Challenge

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Advances in Empirical Antifungal Therapy in
Patients with Febrile Neutropenia. Marc A.
Boogaerts
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Fungi 2003 the problem

• The incidence of fungal infections is increasing
• The spectrum of fungal disease is changing
• Selection of fungi is a reality
• Resistance of fungi is on the rise
• Cross resistance is increasingly recognized
• Unit epidemiology is underscored

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INCREASE IN FUNGAL INFECTIONS

• Better diagnosis
• More broadspectrum antibiotics
• Higher age of patient population
• More complex interventions (e.g.transplants)
• More intensive cytotoxic therapy
• More immunosuppressive therapy
• Less mortality from other causes
• More high risk patients

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SYSTEMIC FUNGAL INFECTIONS AND GROUPS AT RISK

• Prolonged deep neutropenia (gt7 dayslt500/mm3)
• Stem Cell Transplants (allogtgtgtauto)
• Solid Organ Transplants
• AIDS patients
• High Risk Environment
• Prolonged antibiotic and/or corticosteroid use

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ANTIFUNGAL STRATEGIES

• Prophylaxis
• Empirical use
• Preemptive use
• Treatment

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WHAT DOES EMPIRICAL or PRE-EMPTIVE MEAN?

• Empirical
• based on observation or experiment , not on
  theory
• regarding sense-data as valid information
• e.g. an empiric a quack doctor"
• Pre-emptive
• to make a bid in an auction high enough to
  prevent further bidding
• to obtain by acting in advance of others
• to occupy public land in order to lay claim to it
  
• to purchase goods before they are formally put on
  sale
• to go on the offensive in order to avert an enemy
  attack
• Oxford Dictionary

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Concepts of antifungal strategies

• Likelihood of Fungal Disease Treatment
• Remote 0-4 Prophylaxis
• Possible 5-15 Empirical
• Probable 15-35 Probable
• Proven 100 Specific

-

Days FUO
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CLINICIANS REASONS FOR EMPIRICAL/PRE- EMPTIVE
ANTIFUNGALS

• History of invasive fungal disease
• Atypical Pulmonary Infiltrate
• Dry Cough and/or pleural rubbing/pain
• Persisting fever in patients, known to be
  colonised
• Second fever spike
• Acute fever with muscular tenderness,rash,
  cutaneous lesions
• Fever with unexplained further increase in CRP
  or alkaline phosphatase

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ARGUMENTS AGAINST LIBERALEMPIRICAL USE OF
ANTIFUNGALS

• Introduces false confidence by reducing
• the urge to establish a correct diagnosis
• Never shown to be unquestionably effective
• Possible additional toxicity in high risk
  patients
• Possible interactions of antifungal with other
  drugs
• Because of toxicity and borderline indication
• lower dosages of antifungals might be used
• Brings in emotions, not science

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Realize cost of strategy
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Will laboratory tests guide treatment?
Treatment
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40
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CT
Temperature (C)
37
36
10
0
Disease likelihood
1
Granulocytes (log10x109/L)
0.1
-7
0
7
14
21
28
35
42
49
56
63
-14
Days after transplant
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ASPERGILLUS ANTIGEN FOR EARLIERDETECTION OF
INVASIVE INFECTION
Antifungal
Indication for CT-scan
Neutropenic fever
1.0
0.5?
0 3 6 9
12 15 20 days
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ANTIFUNGAL STRATEGIES

• Prophylaxis
• Empirical use
• Preemptive use
• Treatment

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FDA-approved drugs for empirical therapy
Drug Dosing regimen used in controlled trials
Amphotericin B deoxycholate 0.6 -1.0 mg/kg/day (IV)
Liposomal amphotericin B 3 mg/kg/day (IV)
Itraconazole 400 mg/day for two days folIowed by 200 mg/day for 5-12 days (IV), folIowed by oral solution 400 mg/day for 14 days
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IN GOD WE TRUST FROM ALL OTHERS WE NEED HARD DATA
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Itraconazole-Empirical Therapy

• An open randomized trial comparing the efficacy
  and safety of intravenous followed by oral
  itraconazole with intravenous amphotericin B for
  empiric therapy in neutropenic patients with
  hematologic malignancy
• Boogaerts et al, Annals of Internal Medicine, 2001

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Itraconazole-Empirical Therapy

• Empirical therapy
• IV itra (7 to 14 days) ? Itra oral solution (14
  days)
• IV ampho B (28 days)
• Patients with haematologic malignancies
• neutropenic (lt0.5 x 109 ANC/l)
• fever of unknown origin (gt38 C)
• 3 - 7 days broadspectrum antibiotics
• Objectives
• Compare efficacy (defervescence)
• Compare efficacy (composite)
• Safety
• Blood levels of itraconazole

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Itraconazole-Empirical Therapy
Time till end of neutropenia
subjects
100
80
60
Randomized group
Itra
40
Ampho B
p 0.590
20
0
0 2 4 6 8 10 12 14
16 18 20 22 24 26
days in phase
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Itraconazole-Empirical Therapy
Global evaluation defervescence
ITR
AMPHO B
60
184
186
40
Response
20
0
Unevaluable
20
Failure
40
60
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Composite Endpoint Overall Response

• Success, requires all of the following
• Survival for at least 7 days after D/C of study
  medication
• No breakthrough fungal infection during
  neutropenia and for at least 7 days after D/C of
  study medication
• Defervescence during neutropenia
• Not D/C from study medication due to toxicity or
  lack of efficacy prior to recovery from
  neutropenia
• Baseline infections global response assessed as
  complete or partial at end of therapy

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Empirical Itraconazole versus AmphoB
Efficacy analysis
Itra n () Ampho-B n ()
Response 88 (48) 70 (37)
Composite endpoint 99 (53) 83 (46)
p0.156 plt0.001 p0.055
2-sided 1-sided superiority
equivalence test
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Itraconazole versus amphotericin B as empirical
therapy for persistent fever in neutropenic
patients
M. Boogaerts et al, 2001
Response Itraconazole group (n179) Amphotericin B group (n181) Difference (95 CI)
By previous antifungal prophylaxis, n/n () By previous antifungal prophylaxis, n/n () By previous antifungal prophylaxis, n/n () By previous antifungal prophylaxis, n/n ()
Yes 63/132 (48) 48/139 (35) 13.0 (1.6 to 24.8)
No 21/47 (45) 20/42 (48) -3.0 (-23.7 to 17.8)
By duration of fever that did not respond to antibiotic therapy, n/n () By duration of fever that did not respond to antibiotic therapy, n/n () By duration of fever that did not respond to antibiotic therapy, n/n () By duration of fever that did not respond to antibiotic therapy, n/n ()
lt 5 d 32/70 (46) 34/70 (49) -3.0 (-19.4 to 13.7)
³ 5 d 52/109 (45) 34/110 (31) 6.0 (4.0 to 29.5)
By duration of neutropenia, n/n () By duration of neutropenia, n/n () By duration of neutropenia, n/n () By duration of neutropenia, n/n ()
lt 7 d 27/60 (45) 23/58 (40) 5.0 (-12.5 to 23.1)
³ 7 d 56/107 (52) 44/108 (41) 11.0 (-1.6 to 24.8)
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Safety results

• Incidence of gastrointestinal side effects
• similar between treatment groups
• similar for itraconazole recipients during IV and
  oral phases

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Safety results

• Incidence of chills and rigors
• significantly lower in itraconazole group 10 vs
  40 (plt0.0001)
• rigors in itra group not related to infusion of
  study drug
• Most common reasons for withdrawal
• nephrotoxicity and rigors in amphotericin group
• nausea and rash in itraconazole group

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Itraconazole-Empirical Therapy
Creatinine clearance
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Large studies on empirical
antifungal therapy
T. Walsh et al.,1999
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Large studies on empirical
antifungal therapy
Toxicity
Liposomal ltltlt
Conventional
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Empirical Voriconazole Study

• Stratified - High vs Low Risk Neutropenic Fever
• allogeneic transplant or relapsed leukemia vs
  autologous transplant or other neoplasm
• Stratified Systemic antifungal prophylaxis
• Blinded DRC for review of fungal infections
• Seeking to show voriconazole is at least as
  effective as L-AMB in terms of overall response

Walsh et al, New Eng J Med 2002
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Empirical voriconazole study Primary composite
endpoint
Voriconazole Ambisome
No. of patients 415 422
Success 23.7 30.1
Difference between arms -6.1 (-12, -0.1) -6.1 (-12, -0.1)
Voriconazole failed to meet its primary endpoint
Walsh et al, 2002
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Empirical voriconazole study Secondary endpoints
Voriconazole Ambisome difference
Overall stratified 23.7 30.1 -6.1
No Breakthrough infection 98.1 95.0 3.1
Survival 92.0 94.1 -2.1
No discontinuation 90.1 93.4 -3.3
Defervescence 33.0 36.0 -3.0
Response in Baseline infections 46.0 67.0 -20.5
Walsh et al, 2002
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Breakthrough Infections According to Risk and
Prophylaxis (MITT)
p 0.003
Mortality no difference
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DRC Assessment of Global Response of Baseline
Infection at End of Therapy (EOT)
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Voriconazole vs Liposomal Amphotericin B as
antifungal therapy for neutropenia and fever
Voriconazole (n415) Liposomal Ampho B (n422) P value

Abnormal vision 91 (21.9) 3 (0.7) lt 0.001
Chest pain 1 (0.2) 17 (4.0) lt 0.001
Back pain 0 14 (3.3) lt 0.001
Dyspnea 3 (0.7) 37 (8.8) lt 0.001
Anaphylactiod reaction 0 7 (1.7) 0.02
Chills 57 (13.7) 126 (29.9) lt 0.001
Sweating 3 (0.7) 9 (2.1)
Nausea 39 (9.4) 53 (12.6) lt 0.001
Serum creatinine (gt1.5) 43(10.4) 80(19.0) lt0.001
Hypokalemia 68(16.4) 131(31.0) lt0.001
Transaminase ( gt5x) 29(7.0) 34(8.1)
Serum bilirubin 73(17.6) 97(23.0) 0.05


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A Randomized, Double-Blind, Multicenter Trial of
Caspofungin vs. Liposomal Amphotericin B for
Empirical Antifungal Therapy of Persistently
Febrile Neutropenic Patients
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Study Design(1)

• Blinded, randomized, multicenter study in
  patients with persistent febrile neutropenia
• Caspofungin 50mg daily (after 70 mg d1) vs
  liposomal amphotericin B (L-AMB) 3 mg/kg daily
  (up dosing permitted for lack of efficacy)
• DSMB first study of caspofungin in
  neutropenia
• Blinded Adjudication Committee (BAC) to assess
  evidence of invasive fungal infection according
  to EORTC/MSG criteria

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Study Overview

• 1123 patients enrolled over 31 months
• 116 sites 27 countries
• N 1111 treated
• ? 1095 MITT (98.6)
• ? 901 Evaluable (81.1)
• N 358 adjudicated by independent blinded
  committee

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Primary Analysis MITT
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Primary Analysis MITT
Caspofungin Ambisome
High Risk 43.2 37.7
Moderate Risk 31.0 32.4
Antifungal prophylaxis 33.5 - 35.0 32.9 - 34.5
Increased dose (13) 26 25.7
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Breakthrough Infections (BTI) - MITT
Caspofungin (N556) L-AMB (N539)
Total Patients w/BTI 29 (5.2) 24 (4.5 )
Aspergillus spp. 10 9
Candida spp. 16 14
Other 3 1
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Discontinuation due to Drug-Related Toxicity or
Lack of Efficacy (by investigator)
Completion and Non-endpoint discontinuation Caspofungin 89.7 Ambisome 85.5
Lack of Efficacy Persistent fever Suspected FI 30 (5.4) 6 24 34 (6.3) 9 25
Drug-related AE Clinical Lab 27 (4.9) 24 3 44 (8.2) 35 13
P 0.034
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Drug Related Adverse Events
Caspofungin () Ambisome ()
Fever 17 19.4
Chills 13.8 24.7
Rash 6.2 5.3
Nausea 3.5 11.3
Vomiting 3.4 8.6
Creatinine increase 1.5 5.5
HypoK 7.3 11.8
ALT AST Alk Phosphatase Bilirubine 8.7 7.0 7.0 3.0 8.9 7.6 12 5.2
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Randomized controlled trials on empirical
antifungal therapy in febrile neutropenia
composite endpoints
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Safety profile Current Agents
Parameter Amphotericin B formulations Fluconazole Itraconazole Voriconazole Voriconazole Caspofungin
IRRs Variable L-AmBltABLC ABCDAmB-d No No No Visual disturbances Histamine mediated symptoms
Nephrotoxicity Variable L-AmBltABLC ABCDltAmB-d No (dose adjust in renal failure) No avoid IV formulation in renal failure No avoid IV formulation in renal failure ? avoid IV formulation in renal failure No
Cyclodextrin solubilizing excipient used in IV
formulation accumulates in renal failure. AmB-d
amphotericin B deoxycholate L-AmB Liposomal
amphotericin B ABLC amphotericin B lipid
complex ABCD amphotericin B colloidal
dispersion
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Safety profile Current Agents (contd)
Parameter Amphotericin B formulations Fluconazole Itraconazole Voriconazole Voriconazole Caspofungin
? LFTs Minor Monitor LFTs. Azoles can cause hepatoxicity, but variable Monitor LFTs. Azoles can cause hepatoxicity, but variable Monitor LFTs. Azoles can cause hepatoxicity, but variable Monitor LFTs. Azoles can cause hepatoxicity, but variable CsA warning
Ocular No No No No Dose related visual disturbances (IV and oral) No
Skin hypersensitivity reactions Minor Rash Rash Rash Rash, photo-sensitivity Histamine mediated rash ,fever
CsA cyclosporine LFT liver function test
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Drug interactions and PKCurrent Agents
Parameter Amphotericin B formulations Itraconazole Fluconazole Voriconazole Caspofungin
CYP substrate No 3A4 3A4 2C19 No
CYP inhibited No 3A4, ?serum conc. 2C9/3A4, ?serum conc. 2C9/3A4, ?serum conc. No
CYP inducers No effect ?serum conc. ? serum conc. ? serum conc. No
CsA metabolism No inhibition ?CsA exposure ?CsA exposure (dosesgt200mg) ?CsA exposure 1.7x ?CsA exposure 35
Tacrolimus metabolism No inhibition ?Tacrolimus exposure ?Tacrolimus exposure at higher doses ?Tacrolimus trough 10x Tacrolimus exposure 20
PK Linear Non-Linear Linear Non-linear Linear
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THE IDEAL EMPIRICAL 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
• pre-emptive strategy

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The essence of wisdom is the ability to make the
right decision on the basis of inadequate
evidence Old saying in Finland.