Latest Developments in the Treatment of Invasive Aspergillosis

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Latest Developments in the Treatment of Invasive
Aspergillosis

• William J. Steinbach, MD
• Assistant Professor of Pediatrics, Molecular
  Genetics, and Microbiology
• Pediatric Infectious Diseases
• Duke University Medical Center
• Durham, NC USA

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Possible Areas for Improving Outcome in IA

• Understanding IA epidemiology
• Host factors Underlying concomitant diseases
• Immunosuppression / Corticosteroids
• Antifungal prophylaxis
• Early diagnosis
• Early therapy
• Antifungal resistance
• Antifungal therapies
• Immune reconstitution, Immunotherapy

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Invasive Aspergillosis Incidence1990-1998 at
FHCRC
Allograft recipients
Autograft recipients
14
12
10
8
Incidence ()
6
4
2
0
1990
1991
1992
1993
1994
1995
1996
1997
1998
Year
Marr KA, et al. Clin Infect Dis. 200234909-917.
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Invasive Aspergillosis Epidemiology

• 1990-1998 data from 533 total cases of IA
• 1990 1998
• Autologous HSCT lt1 5.3
• Allogeneic HSCT ? 4 ? 12
• 1993-95 1996-98
• Non-fumigatus Aspergillus 18.3 33.7
• Average median survival of 29 days after
  diagnosis
• Marr KA, et al. Clin Infect Dis 200234909-17
• Wald A, et al. J Infect Dis 19971751459-66.

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Probability of Developing Proven or Probable IA
among patients alive at day 40
Overall P  0.001
Marr KA, et al. Blood 20021004358-4366.
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Corticosteroids as a Risk Factor

• Pharmacologic doses of hydrocortisone (10-6 M),
  equivalent to 20 mg IV
• In vitro mean specific growth rate of A.
  fumigatus at 37 C increased by 40 (p0.0001)
• A. fumigatus doubling time increased to 48
  minutes
• Ng TTC, et al. Microbiology 19941402475-79

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Host Susceptibility VariationsDifferent Inbred
Mouse Strains
Resistant BalbC/ByJ, AKR/J, Balb/C, 129/SVJ,
C57BL/6
Sensitive CAST/Ei, C3H/HEJ, A/J, DBA/2J
Intermediate MRL/MPJ, NZW/LAC
Zaas AK, et al. 7th European Conference on
Fungal Genetics, 2004
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Antifungal Therapyfor Invasive Aspergillosis
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A. terreus Infection

• Murine model
• Amphotericin B resistance confirmed
• Graybill JR, et al. Antimicrob Agents Chemother
  2004483715-19.
• Review of 28 in vitro analyses, 9 animal models,
  and 60 previously reported clinical cases
• AmB resistance shown in vitro and in vivo
• Steinbach WJ, et al. Antimicrob Agents Chemother
  2004483217-25.
• Multicenter retrospective analysis of 83 cases
  (1997-2002)
• Mortality at 12 weeks decreased in those who
  received voriconazole (HR 0.29 95 CI,
  0.15-0.56) vs. AmB
• Steinbach WJ, et al. Clin Infect Dis
  200439192-8.

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Aspergillosis Survival with Amphotericin B by
Site of Infection
1.0
0.9
0.8
Sinusitis (n17)
0.7
0.6
Multi-site (n11)
Cumulative Survival Rate
0.5
Aspergilloma (n10)
0.4
0.3
0.2
Pulmonary (n83)
0.1
CNS or Disseminated (n35)
0.0
0
30
60
90
120
150
180
210
240
270
300
330
360
Days
Lin et al. Clin Infect Dis. 200132358-366.
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Outcomes Research Treatment PracticesPatterson
TF, et al. Medicine 200079250-260

• IA cases after 1990, most from 1994-1995 (595
  total cases of IA)
• Asked for recent case records, non-sequential
• Lipid formulations of AmB investigational, so few
  received
• Outcome data from 34 patients with L-AmB excluded
  because patients were in other clinical trials
• Few Combinations Used AmB 5-FC (2)
• AmB Rifampin (2)
• AmB Itraconazole (3)
• Outcomes
• AmB Itraconazole AmB ? Itraconazole
• Pts treated 31 10 16
• All pts CR 25 40 39
• All pts PR 7 17 15

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Outcomes Research Treatment Practices Denning
DW, et al. J Infect 199837173-180.

• 1993-1994 (123 total cases of IA)
• Monotherapy in 29 pts, Combination therapy in
  91 pts
• AmB Lipid AmB Itraconazole 5-FC
• 75 36 40 12
• Six month outcomes for IPA
• Alive w/o IA Alive w/ IA Expired
• AmB 14 41 46
• Lipid AmB 23 31 46
• AmB Itra 28 56 15
• Itra 33 17 50
• 61 mortality within 28 days after diagnosis

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Outcomes Research Open Label

• Compassionate use itraconazole (125 patients)
• Complete response 27 Improved 36
• Stevens DA and Lee JY. Arch Intern Med
  19971571857-62.
• Multicenter open label itraconazole (76 patients)
• Complete or partial response 39
• Denning DW, et al. Am J Med 199497135-144.
• Open label ABLC (130 patients)
• Complete or partial response 42
• Walsh TJ, et al. Clin Infect Dis
  1998261383-96.

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Antifungal Pre-Exposure

• Serial passages of 10 clinical isolates to
  fluconazole (x4)
• 4-fold increase in MFC (but not MIC) of
  Itraconazole and Voriconazole
• Fluconazole pre-exposure attenuates Itraconazole/
  Voriconazole fungicidal activity, but no effect
  in AmB
• XTT growth rates pre-exposed/no fluconazole were
  same
• Liu W, et al. Antimicrob Agents Chemother
  2003473592-7.
• In vitro pre-exposure of A. fumigatus to
  Itraconazole or Caspofungin resulted in enhanced
  activity for either, in contrast to antagonistic
  effect of sequential itraconazole then AmB
• Suggests a preferential role for
  azole-Caspofungin sequential combinations over
  azole-AmB regimens
• Kontoyiannis DP, et al. Diag Microbiol Infect
  Dis 200347415-9.

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Aspergillus Antifungal Resistance ?

• Itraconazole resistance described in 1997
• Denning DW, et al. Antimicrob Agents Chemother
  1997411364-68.
• Estimated 2.1 of gt 900 A. fumigatus strains
  resistant to itraconazole
• Moore CB, et al. J Infect 200041203-20.
• 200 sequential A. fumigatus isolates from 26
  immunocompromised patients
• MICs similar pre- and post-treatment with AmB
  (n100) or itraconazole (n91)
• Emergence of resistance while on antifungal
  therapy is likely low
• Genotypic diversity and sequential colonization
  with multiple strains could explain low
  resistance
• Dannaoui, et al. J Med Microbiol
  200453129-134.

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Voriconazole Fungicidal Activity on Hyphae

• Previous in vitro studies examined killing of
  conidia and germinated conidia (sporelings)
• But patients have hyphae growing
• Voriconazole killed hyphae in both time- and
  concentration-dependent fashions
• Kill curve and MTT cell wall viability testing
• Voriconazole had better fungicidal activity
  against A. fumigatus hyphae than AmB at 48 hours
• VCZ 1 ug/ml gt95 killed on agar (AmB 1 ug/ml 70
  killed)
• VCZ 1 ug/ml 99 killed in broth (AmB 1 ug/ml
  82 killed)
• Krishnan S, et al. J Antimicrob Chemother ePub
  April 20005

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Only Three Randomized Clinical Trials ever
completed for the Treatment of Invasive
Aspergillosis
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Global Comparative Aspergillosis Study
(307/602)DRC-Assessed Success at Week 12 (MITT)
76/144
Same outcome in each separate protocol
42/133
Voriconazole arm success 52.8 Amphotericin
arm 31.6 Difference (raw) 21.2, 95 CI
(9.9, 32.6) Difference (adjusted) 21.8, 95 CI
(10.5, 33.0)
Herbrecht R, et al. N Engl J Med 2002
347408-415
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Global Comparative Aspergillosis Study (307/602)
DRC-Assessed Success at Week 12 (MITT)
Overall
Pulmonary
Extra Pulmonary
Allogeneic BMT
Autologous BMT / other hematological (e.g.
leukemia)
Other immunosuppressed state (e.g. SOT, HIV/AIDS)
Neutropenic (ANC lt 500)
Non-Neutropenic (ANC ? 500)
Proven IA
Probable IA
Difference in Success Rates (95 CI)
Herbrecht R, et al. N Engl J Med 2002
347408-415
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Global Comparative Aspergillosis Study (307/602)
Time to Death (MITT)
Voriconazole /- OLAT
Amphotericin B /- OLAT
Probability of Survival
Day 84 survival Voriconazole arm 71
Amphotericin B arm 58 Hazard ratio 0.60 95 CI
(0.40, 0.89)
Number of days of Therapy
Herbrecht R, et al. N Engl J Med 2002
347408-415
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ABCD (6 mg/kg/d) vs. AmB-D (1.01.5 mg/kg/d)

• Prospective, double-blind, randomized, controlled
  clinical trial, risk stratified before
  randomization 1993-1997
• ABCD AmB-D
• Evaluable Patients (n50) (n53)
• Therapeutic response 52 50.9 p0.96
• (complete, partial, or stable)
• Overall Mortality 36 45 p0.4
• Fungal Mortality 32 26 p0.7
• Renal Toxicity 25 49 p0.002
• Median time to renal toxicity 301 d 22 d
  plt0.001
• Intent to Treat (n88) (n86)
• Complete Response 5.7 3.5
• Partial Response 6.8 11.6
• ABCD equivalent efficacy and superior renal
  safety
• Study terminated early due to low accrual
• Bowden R, et al. Clin Infect Dis
  200235359-66.

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Liposomal AmB1 mg/kg/d versus 4 mg/kg/d

• 1 mg/kg/d 4 mg/kd/d p value
• (n41) (n46)
• Clinical CR PR (inc. stable) 64
  48 0.144
• Radiologic CR PR 58 54 0.694
• 6-month survival 43 37
• Overall deaths 59 67
• Overall response rate of 55
• Overall 6-month mortality of 63
• Ellis M, et al. Clin Infect Dis 1998271406-12.

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Switching to Other Licensed Therapies

• Received OLT in Voriconazole vs. AmB
• Initial VCZ 36 (52/144)
• Initial AmB 80 (107/133)
• 159 total patients received OLT
• 38 Lipid AmB formulation
• 33 Itraconazole
• 21 AmB deoxycholate (inc. reduced dose)
• 8 Other antifungals
• Switches due to Intolerance/Insufficient
  response
• VCZ 24 (35/144) after median 12 days (1-83
  days)
• AmB 70 (93/133) after median 9 days (1-74 days)
  (plt0.000001)
• Boucher HW, et al. ICAAC 2003, Abstract M-964

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Use the Best Therapy First

• Patient Success
• 33 (31/93) AmB receiving OLT
• 30 (14/47) AmB followed by lipid AmB (median 13
  days)
• 53 All randomized to VCZ (plt0.01)
• Strategy of Voriconazole followed by OLT for
  intolerance or insufficient response was more
  successful than AmB with OLT (including lipid
  AmB)
• Stresses the importance of initial therapy of
  voriconazole for IA
• Boucher HW, et al. ICAAC 2003, Abstract M-964

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Early Treatment is Critical

• Mortality when treatment started after diagnosis
• lt 10 days 40
• gt 11 days 90
• Von Eiff, et al. Respiration 199562241-7.

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Voriconazole as Primary Therapy
Therapy Complete Partial Stable
Failure Total Primary 10
(17) 25 (42) 11 (18) 14
(23) 60 (52) Salvage 6 (11) 15
(27) 13 (23) 22 (39) 56
(48)
Denning DW, et al. Clin Infect Dis
200234563-71.
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Echinocandin Activity on Aspergillus Hyphal Tip

• Caspofungin (0.3 ug/ml)-treated, DiBAC-stained
  A. fumigatus
• 6 hours incubation
• 2,000X magnification

Bowman JC, et al. Antimicrob Agents Chemother
2002463001-3012.
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Caspofungin Salvage Therapy

• Open, non-comparative, multi-center trial
• 90 patients with IA enrolled (median 51 yrs
  15-73)
• Efficacy evaluation of 83 patients
• 71 patients (86) refractory to therapy
• 12 patients (14) intolerant to therapy
• 45 (37/83) with favorable outcome
• 50 (32/64) with pulmonary IA
• 23 (3/13) with disseminated IA
• Maertens J, et al. Clin Infect Dis 2004
  391563-71.
• 46 Neutropenic patients with IA
• Favorable response (35)
• 42 as primary therapy
• 32 as salvage therapy
• Kartsonis N, et al. 14th ECCMID, Abstract 0422

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Concentration-Dependent Caspofungin Activity

• Murine model of pulmonary IA
• Substantial differences in fungal burden as
  determined by qPCR
• Largest reduction in burden by those dosing
  regimens achieving the highest peak
  concentrations
• Histological apical hyphal damage most at highest
  dose
• Trend toward improving survival with maximal
  dosing
• Paradoxical Eagle Effect at highest dose, with
  an increase in tissue burden (but no decrease in
  survival)
• Same effect seen in other cell-wall active
  antibacterials
• Wiederhold NP, et al. J Infect Dis
  20041901464-71.

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Micafungin Monotherapy Open-Label Trial in Japan

• 70 patients at 29 sites 56 pts eval. for
  efficacy (IA 42)
• Disease Response
• Invasive pulmonary (n10) 60
• (8 pts with leukemia or lymphoma 2 neutropenic)
• Max dose 50 mg/d 50 (1/2)
• 75 mg/d 33 (1/3)
• 150 mg/d 80 (4/5)
• Disseminated (n1) 0
• Chronic necrotizing pulmonary (n9) 67
• Pulmonary aspergilloma (n22) 55
• AE related to micafungin reported in 30 of
  patients
• Kohno S, et al. Scand J Infect Dis
  200436372-9.

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Posaconazole Monotherapy

• Multicenter study for salvage therapy
• Included 25 pts with IA
• Effective in 53 (8/15) at week 4
• Effective in 85 (6/7) at week 8
• No mention of patients without complete follow-up
• Hachem RY, et al. ICAAC 2000, Abstract 1109
• Multi-center study of patients with IA refractory
  to or intolerant of AmB formulations and
  itraconazole
• 107 posaconazole, 86 controls
• Global response rate at end of treatment
• Posaconazole 42
• Controls 26
• Walsh TJ, et al. ASH 2003, Abstract 682

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Cerebral Aspergillosis

• 86 patients (9 mo - 81yo) with proven or probable
  CNS aspergillosis
• A. fumigatus (n34) A. nidulans (n5)
  Aspergillus spp. (n24)
• Underlying disease
• BMT (n33) Hem malignancy (n14)
• SOT (n12) Acquired/Cong immunosuppression
  (n15)
• Other (n12)
• Only 13/86 received VCZ primary therapy
• (others with previous antifungal therapy before
  VCZ use)
• Global Clinical Outcome
• Complete / Partial Response 34
• Stable / Failed response 66
• BMT Recipient Response 15
• All Others Response 42-50
• Troke PF, et al. ICAAC 2003, Abstract M-1755

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Bone Aspergillosis

• 20 patients from Clinical trials and
  Compassionate use
• Bone Involvement
• Spondylodiscitis (n9) Sternum/Rib (n6)
  Peripheral (n5)
• Immunocompromised (n14)
• Largest population Chronic Granulomatous
  Disease (n5)
• Bone was the only infection site in 10 patients
• Salvage voriconazole therapy in 18/20 patients
• Median duration of voriconazole 83.5 days (4-395
  days)
• Global Clinical Outcome
• Complete / Partial Response 55 (11/20)
• Complete (n4) Partial (n7), Failure (n9)
• Mouas H, et al. Clin Infect Dis 2005401141-7.

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Combination Antifungal Therapyin Invasive
Aspergillosis
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Combination Therapy Rationale

• Widened spectrum and potency
• More rapid antifungal effect
• Additive or synergistic efficacy effects
• Lowered dosing or less toxicity
• Reduce risk of emerging resistance
• Historic poor outcomes with monotherapy
• Increased penetration / transport
• Inhibit different stages of the same biochemical
  pathway
• Simultaneous inhibition of different fungal
  targets
• Creation of a fungicidal combination

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1966-2001 Review of Combination Therapy

• Studies Syn Add Indiff Antag
• In vitro (n28) 36 24 28 11
• In vivo (n18) 14 20 51 14
• AmB Itraconazole generally indifferent
  interactions in vitro, in vivo, and clinically
• 249 cases met combination Rx inclusion criteria
• Most common combinations
• AmB Flucytosine (49)
• AmB Itraconazole (16)
• AmB Rifampin (11)
• Overall 63 of clinical cases reported
  improvement
• Steinbach WJ, et al. Clin Infect Dis 200337
  (suppl 3) S188-224

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Only Clinical Trial of Combination Antifungal
Therapy for Aspergillosis

• 28 neutropenic adult pts with proven IFI
• AmB (0.5 mg/kg/d) (n14)
• AmB 5-FC (n14)
• Survival
• AmB alone 2/14 (mortality 86)
• AmB 5-FC 3/14 (mortality 79)
• 15/18 with invasive aspergillosis died
• 3 who survived had immune recovery
• Study terminated early, problems included
• IA so far advanced at initiation
• Low dose AmB used
• Verweij PE, et al. Infection 19942281-5.

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ExperimentalVoriconazole Caspofungin

• In Vitro
• 48 isolates, Synergy (87.5) of interactions
  (FICI lt 1.0)
• Perea S, et al. Antimicrob Agents Chemother
  2002463039-41
• In Vivo Neutropenic guinea pig model
• Mortality (0/12 animals) and survival time (8
  days) SAME in EACH of these arms
• VCZ 5mg/kg/d
• CAS (1 mg/kg/d) VCZ
• CAS (2.5 mg/kg/d) VCZ
• Fungal burden (CFU) with combination better than
  untreated controls only
• Number of organs with positive cultures with
  combination better than monotherapy
• Kirkpatrick WR, et al. Antimicrob Agents
  Chemother 2002462564-8

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ExperimentalRavuconazole Micafungin

• Neutropenic rabbit model
• Survival
• Micafungin monotherapy (0/8)
• Ravuconazole monotherapy (2/8)
• Micafungin Ravuconazole (9/12)
• Fungal burden, GM assay, Pulmonary injury,
  Pulmonary infiltrates all less in the combination
• Petraitis V, et al. J Infect Dis
  20031871834-43

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Ravuconazole Micafungin
Petraitis V, et al. J Infect Dis
20031871834-43
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Ravuconazole Micafungin Hyphal Damage
Micafungin
Untreated Control
Ravuconazole Micafungin
Ravuconazole

• The spherical chlamydoconidial structures are
  evidence of the effect of echinocandins
• The focal hyphal disintegration and disruption
  are compatible with the effects of triazoles
• Original magnification 630 Insert, 1000
  Scale bar 20 um
• Petraitis V, et al. J Infect Dis
  20031871834-43

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Clinical Combination Therapy Reports

• Caspofungin L-AmB salvage after previous L-AmB
  (n48)
• Overall response rate 42 Response in
  progressive IA 18
• Kontoyiannis DP, et al. Cancer 200315292-9
• Micafungin existing antifungal in 85 BMT pts
• 39 (28) complete/partial response
• Ratanatharathorn V, et al. ASH 2002, Abstract
  A-2472
• Open-label Micafungin salvage therapy in 283
  patients
• In salvage patients (IA, gt7d prior therapy gt7d
  micafungin)
• 11/49 (22) allogeneic HSCT responded
• 22/45 (49) leukemia patients responded
• Ullman AJ, et al. ECCMID 2003, Abstract 0400
• Salvage therapy with posaconazole
• Posaconazole 29
• AmB lipid 8 (p0.01)
• AmB lipid Itraconazole 16 (p0.2)
• Raad II, et al. IDSA 2004, Abstract 678

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Voriconazole Terbinafine

• Previously reported in vitro synergistic/additive
  effect with terbinafine against Aspergillus
• Immunosuppressed rat model A. fumigatus
• AmB 1 mg/kg/d
• VCZ 6 or 9 mg/kg/d
• Terbinafine 150 mg/kg/d
• VCZ 9 mg/kg/d (41) increased survival over AmB
  (28) (plt 0.05)
• All treatment groups except AmB significantly
  increased survival compared to Terbinafine (13)
• Addition of Terbinafine to VCZ did not improve
  survival
• Combination reduced fungal counts compared to
  control and AmB
• Gavalda J, et al. ICAAC 2004, Abstract M-224

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New DataCombination Therapy for IA

• 47 patients with proven/probable IA from
  1997-2001
• Patients experienced failure of initial therapy
  with AmB formulations
• Received either voriconazole (n31) or
  voriconazole caspofungin (n16) as salvage
  therapy
• Voriconazole Caspofungin with improved 3-month
  survival rate compared to voriconazole
  monotherapy (HR 0.42 95 CI 0.17-1.1
  p0.048)
• Multivariate model, combination with reduced
  mortality (HR 0.28 95 CI 0.28-0.92 p0.11)
• Marr KA, et al. Clin Infect Dis 200439797-802.

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Voriconazole vs. Voriconazole
Caspofungin Kaplan-Meier probability of survival
after diagnosis P .048, calculated from the
likelihood ratio test using Cox regression
Marr KA, et al. Clin Infect Dis 200439797-802.
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Primary Combination Therapy

• Retrospective single center cohort review of
  consecutive patients with IA and an underlying
  hematologic malignancy (Jan 98 July 03)
• Proven (n17) / Probable (n17) / Possible (n11)
  by EORTC/MSG
• Data presented below for Proven / Probable cases
  only
• ALL Combo Mono P value
• (n34) (n10) (n24)
• 12 wk Survival 53 50 54 0.82
• Median Survival (d) 110 102 115 ---
• CR/PR 41 50 37.5 0.5
• Stable 5.9 0 8.3 --
• Failure 53 50 54 0.86
• No differences in survival between primary
  therapy with mono vs. combo
• Munoz LS, et al. ICAAC 2004, Abstract M-1024

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In Vitro Treatment PRIOR to Combination
Antifungal Therapy

• Subinhibitory concentration of AmB against Caspo
  Vori or Caspo Ravuconazole
• Percentage of further reduction in growth
  following AmB addition
• AmB 0.1 ug/ml AmB 0.2 ug/ml
• Caspo VCZ 33 (14-57) 34 (13-59)
• Caspo RVZ 11 (0-30) 28 (16-48)
• Significant for all species except A. terreus for
  Cas/VCZ and A. fumigatus Cas/RVZ at AmB 0.1
  ug/ml
• FICI (0.5-1.9) for each triple combination
  improved by adding subinhibitory concentration of
  AmB additive to indifferent effect
• OShaughnessy EM, et al. ICAAC 2004, Abstract
  M-249

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Pediatric Antifungal Data
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Pediatric Voriconazole

• Elimination by Linear pharmacokinetics in
  children following doses of 3 and 4 mg/kg/q12h
• Single dose, Open, two center study in UK
• 11 Children ages 2-11 yrs (mean 5.9 yrs)
• Multiple dose, Open, 8 center, two-cohort (ages
  2-6, 6-12)
• 28 children, mean age 6.4 yrs
• Higher elimination capacity on a weight basis
  than do adult healthy volunteers
• Walsh TJ, et al. Antimicrob Agents Chemother
  2004482166-72.

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Pediatric Voriconazole

• Extrapolated plasma pharmacokinetics of pediatric
  doses (5-12 mg/kg/q12h) vs. adult (4 mg/kg/q12h)
• Pediatric dose of approx. 11 mg/kg/q12h is
  equivalent to adult dose of 4 mg/kg/q12h by AUC
  and plasma concentration
• This is only valid if linear pharmacokinetics
  maintained throughout full dosage range
• Walsh TJ, et al. Antimicrob Agents Chemother
  2004482166-72.
• Correct pediatric dosing not fully established,
  but clearly higher than adult dosing prompted a
  second PK study

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2nd Pediatric Voriconazole Pharmacokinetic Study

• Study completed, data analyses ongoing
• PK study (2-12 yo) to evaluate gt 4 mg/kg BID
  dosing
• Enrolled 48 (39 completed all three PK periods)
• Doses of 4, 6, 8 mg/kg/q12h
• Each child received at least two different doses
  in escalating order, then switched to PO
• Oral Suspension (40 mg/ml) FDA approved
  12/24/03, orange flavor

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Voriconazole for Pediatric Aspergillosis

• Compassionate Use 58 IFI including 42 IA
• Mean age 8.2 yrs (9 mo 15 yrs)
• Therapeutic response
• Complete or partial response 43
• Pulmonary IA (n12) 33
• CNS (n6) 50
• Disseminated (n7) 86
• Sinusitis (n7) 29
• Bone / Liver / Skin (n10) 30
• Stable 7
• Intolerance 10
• Failure 40
• Walsh TJ, et al. Pediatr Infect Dis J
  200221240-8.

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Pediatric Caspofungin

• Adult dosing Load 70mg once, then 50mg once
  daily
• Initial pediatric (ages 2-17) PK study completed
• 39 patients enrolled
• Data obtained using a weight-based (1 mg/kg/d)
  and BSA approach (70 mg/m2/d or 50 mg/m2/d)
• Weight-based (1 mg/kg/d) resulted in suboptimal
  plasma concentrations in all children relative to
  adults
• 50 mg/m2/d similar C24hr and increased AUC to
  adult patients (50 mg/d)
• Walsh TJ, et al. ICAAC 2002, Abstract M-896
  Under review.

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Pediatric Caspofungin

• Caspofungin well-tolerated, no discontinuation
  due to toxicity
• Beta-phase half-life reduced 32-43 in children,
  so plasma levels were lower
• Subsequent studies in children 2-17 years old
  evaluating
• Load with 70 mg/m2 (max 70 mg/d) on Day 1
• Then, 50 mg/m2 (max 70 mg/d)
• Walsh TJ, et al. ICAAC 2002, Abstract M-896
  Under review.

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Summary

• Aspergillus epidemiology changing
• GM assay interpretations different in specific
  populations
• Aspergillus qPCR still debated for diagnosis
• Echinocandins unlikely to be best monotherapy
  (fungistatic against Aspergillus)
• Voriconazole is clearly the best monotherapy
• Voriconzole primary therapy better than salvage
  therapy
• Voriconazole has linear pharmacokinetics in
  children
• Combination therapy unproven
• Reports are often contradictory
• Potentially would be best if used as primary
  therapy

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