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Latest Developments in the Treatment of Invasive Aspergillosis

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Title: Latest Developments in the Treatment of Invasive Aspergillosis


1
(No Transcript)
2
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

3
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

4
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.
5
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.

6
Probability of Developing Proven or Probable IA
among patients alive at day 40
Overall P  0.001
Marr KA, et al. Blood 20021004358-4366.
7
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

8
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
9
Antifungal Therapyfor Invasive Aspergillosis
10
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.

11
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.
12
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

13
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

14
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.

15
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.

16
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.

17
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

18
Only Three Randomized Clinical Trials ever
completed for the Treatment of Invasive
Aspergillosis
19
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
20
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
21
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
22
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.

23
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.

24
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

25
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

26
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.

27
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.
28
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.
29
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

30
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.

31
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.

32
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

33
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

34
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.

35
Combination Antifungal Therapyin Invasive
Aspergillosis
36
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

37
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

38
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.

39
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

40
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

41
Ravuconazole Micafungin
Petraitis V, et al. J Infect Dis
20031871834-43
42
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

43
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

44
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

45
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.

46
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.
47
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

48
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

49
Pediatric Antifungal Data
50
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.

51
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

52
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

53
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.

54
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.

55
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.

56
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

57
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