Slide1 l.jpg
This presentation is the property of its rightful owner.
Sponsored Links
1 / 57

Latest Developments in the Treatment of Invasive Aspergillosis PowerPoint PPT Presentation


  • 115 Views
  • Uploaded on
  • Presentation posted in: General

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. Possible Areas for Improving Outcome in IA.

Download Presentation

Latest Developments in the Treatment of Invasive Aspergillosis

An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -

Presentation Transcript


Latest developments in the treatment of invasive aspergillosis l.jpg

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


Possible areas for improving outcome in ia l.jpg

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


Invasive aspergillosis incidence 1990 1998 at fhcrc l.jpg

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. 2002;34:909-917.


Invasive aspergillosis epidemiology l.jpg

Invasive Aspergillosis Epidemiology

  • 1990-1998 data from 533 total cases of IA

    19901998

  • Autologous HSCT <1 % 5.3%

  • Allogeneic HSCT  4%  12%

    1993-951996-98

  • Non-fumigatus Aspergillus18.3%33.7%

  • Average median survival of 29 days after diagnosis

    Marr KA, et al. Clin Infect Dis 2002;34:909-17

    Wald A, et al. J Infect Dis 1997;175:1459-66.


Probability of developing proven or probable ia among patients alive at day 40 l.jpg

Probability of Developing Proven or Probable IA among patients alive at day 40

Overall P = 0.001

Marr KA, et al. Blood 2002;100:4358-4366.


Corticosteroids as a risk factor l.jpg

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% (p=0.0001)

  • A. fumigatus doubling time increased to 48 minutes

    Ng TTC, et al. Microbiology 1994;140:2475-79


Host susceptibility variations different inbred mouse strains l.jpg

Host Susceptibility Variations:Different 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


Antifungal therapy for invasive aspergillosis l.jpg

Antifungal Therapyfor Invasive Aspergillosis


A terreus infection l.jpg

A. terreus Infection

  • Murine model

    • Amphotericin B resistance confirmed

      Graybill JR, et al. Antimicrob Agents Chemother 2004;48:3715-19.

  • 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 2004;48:3217-25.

  • 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 2004;39:192-8.


Aspergillosis survival with amphotericin b by site of infection l.jpg

Aspergillosis Survival with Amphotericin B by Site of Infection

1.0

0.9

0.8

Sinusitis (n=17)

0.7

0.6

Multi-site (n=11)

Cumulative Survival Rate

0.5

Aspergilloma (n=10)

0.4

0.3

0.2

Pulmonary (n=83)

0.1

CNS or Disseminated (n=35)

0.0

0

30

60

90

120

150

180

210

240

270

300

330

360

Days

Lin et al. Clin Infect Dis. 2001;32:358-366.


Outcomes research treatment practices patterson tf et al medicine 2000 79 250 260 l.jpg

Outcomes Research: Treatment PracticesPatterson TF, et al. Medicine 2000;79:250-260

  • 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:

    AmBItraconazoleAmB  Itraconazole

    Pts treated 31%10%16%

    All pts CR 25%40%39%

    All pts PR 7%17%15%


Outcomes research treatment practices denning dw et al j infect 1998 37 173 180 l.jpg

Outcomes Research: Treatment PracticesDenning DW, et al. J Infect 1998;37:173-180.

  • 1993-1994 (123 total cases of IA)

  • Monotherapy in 29 pts, “Combination” therapy in 91 pts

    AmBLipid AmBItraconazole5-FC

    75%36%40%12%

    Six month outcomes for IPA:

    Alive w/o IAAlive w/ IAExpired

    AmB14%41%46%

    Lipid AmB23%31%46%

    AmB + Itra28%56%15%

    Itra33%17%50%

  • 61% mortality within 28 days after diagnosis


Outcomes research open label l.jpg

Outcomes Research: Open Label

  • Compassionate use itraconazole (125 patients)

    • Complete response 27%; Improved 36%

      Stevens DA and Lee JY. Arch Intern Med 1997;157:1857-62.

  • Multicenter open label itraconazole (76 patients)

    • Complete or partial response 39%

      Denning DW, et al. Am J Med 1994;97:135-144.

  • Open label ABLC (130 patients)

    • Complete or partial response 42%

      Walsh TJ, et al. Clin Infect Dis 1998;26:1383-96.


Antifungal pre exposure l.jpg

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 2003;47:3592-7.

  • 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 2003;47:415-9.


Aspergillus antifungal resistance l.jpg

Aspergillus Antifungal Resistance ?

  • Itraconazole resistance described in 1997

    Denning DW, et al. Antimicrob Agents Chemother 1997;41:1364-68.

  • Estimated 2.1% of > 900 A. fumigatus strains resistant to itraconazole

    Moore CB, et al. J Infect 2000;41:203-20.

  • 200 sequential A. fumigatus isolates from 26 immunocompromised patients

  • MICs similar pre- and post-treatment with AmB (n=100) or itraconazole (n=91)

  • 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 2004;53:129-134.


Voriconazole fungicidal activity on hyphae l.jpg

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 >95% 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


Only three randomized clinical trials ever completed for the treatment of invasive aspergillosis l.jpg

Only Three Randomized Clinical Trials ever completed for the Treatment of Invasive Aspergillosis


Slide19 l.jpg

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; 347:408-415


Slide20 l.jpg

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 < 500)

Non-Neutropenic (ANC  500)

Proven IA

Probable IA

% Difference in Success Rates (95% CI)

Herbrecht R, et al. N Engl J Med 2002; 347:408-415


Slide21 l.jpg

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; 347:408-415


Abcd 6 mg kg d vs amb d 1 0 1 5 mg kg d l.jpg

ABCD (6 mg/kg/d) vs. AmB-D (1.0–1.5 mg/kg/d)

  • Prospective, double-blind, randomized, controlled clinical trial, risk stratified before randomization; 1993-1997

    ABCDAmB-D

    Evaluable Patients(n=50)(n=53)

    Therapeutic response52%50.9% p=0.96

    (complete, partial, or stable)

    Overall Mortality36%45% p=0.4

    Fungal Mortality32%26% p=0.7

    Renal Toxicity25%49% p=0.002

    Median time to renal toxicity301 d22 d p<0.001

    Intent to Treat(n=88)(n=86)

    Complete Response5.7%3.5%

    Partial Response6.8%11.6%

  • ABCD equivalent efficacy and superior renal safety

  • Study terminated early due to low accrual

    Bowden R, et al. Clin Infect Dis 2002;35:359-66.


Liposomal amb 1 mg kg d versus 4 mg kg d l.jpg

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

1 mg/kg/d4 mg/kd/dp value

(n=41) (n=46)

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 1998;27:1406-12.


Switching to other licensed therapies l.jpg

Switching to Other Licensed Therapies

  • Received OLT in Voriconazole vs. AmB

    • Initial VCZ 36% (52/144)

    • Initial AmB80% (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) (p<0.000001)

      Boucher HW, et al. ICAAC 2003, Abstract M-964


Use the best therapy first l.jpg

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 (p<0.01)

  • 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


Early treatment is critical l.jpg

Early Treatment is Critical

  • Mortality when treatment started after diagnosis:

    < 10 days 40%

    > 11 days 90%

    Von Eiff, et al. Respiration 1995;62:241-7.


Voriconazole as primary therapy l.jpg

Voriconazole as Primary Therapy

TherapyComplete Partial Stable Failure Total

Primary10 (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 2002;34:563-71.


Echinocandin activity on aspergillus hyphal tip l.jpg

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 2002;46:3001-3012.


Caspofungin salvage therapy l.jpg

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; 39:1563-71.

  • 46 Neutropenic patients with IA

  • Favorable response (35%)

    • 42% as primary therapy

    • 32% as salvage therapy

      Kartsonis N, et al. 14th ECCMID, Abstract 0422


Concentration dependent caspofungin activity l.jpg

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 2004;190:1464-71.


Micafungin monotherapy open label trial in japan l.jpg

Micafungin Monotherapy Open-Label Trial in Japan

  • 70 patients at 29 sites; 56 pts eval. for efficacy (IA = 42)

    DiseaseResponse

    Invasive pulmonary (n=10)60%

    (8 pts with leukemia or lymphoma; 2 neutropenic)

    Max dose 50 mg/d50% (1/2)

    75 mg/d33% (1/3)

    150 mg/d80% (4/5)

    Disseminated(n=1)0%

    Chronic necrotizing pulmonary(n=9)67%

    Pulmonary aspergilloma(n=22)55%

  • AE related to micafungin reported in 30% of patients

    Kohno S, et al. Scand J Infect Dis 2004;36:372-9.


Posaconazole monotherapy l.jpg

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%

      • Controls26%

        Walsh TJ, et al. ASH 2003, Abstract 682


Cerebral aspergillosis l.jpg

Cerebral Aspergillosis

  • 86 patients (9 mo - 81yo) with proven or probable CNS aspergillosis

    • A. fumigatus (n=34); A. nidulans (n=5); Aspergillus spp. (n=24)

  • Underlying disease

    • BMT (n=33); Hem malignancy (n=14)

    • SOT (n=12); Acquired/Cong immunosuppression (n=15)

    • Other (n=12)

  • Only 13/86 received VCZ primary therapy

    (others with previous antifungal therapy before VCZ use)

  • Global Clinical Outcome

    • Complete / Partial Response34%

    • Stable / Failed response 66%

    • BMT Recipient Response15%

    • All Others Response42-50%

      Troke PF, et al. ICAAC 2003, Abstract M-1755


Bone aspergillosis l.jpg

Bone Aspergillosis

  • 20 patients from Clinical trials and Compassionate use

  • Bone Involvement

    • Spondylodiscitis (n=9); Sternum/Rib (n=6); Peripheral (n=5)

  • Immunocompromised (n=14)

    • Largest population: Chronic Granulomatous Disease (n=5)

  • 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 (n=4); Partial (n=7), Failure (n=9)

      Mouas H, et al. Clin Infect Dis 2005;40:1141-7.


Combination antifungal therapy in invasive aspergillosis l.jpg

Combination Antifungal Therapyin Invasive Aspergillosis


Combination therapy rationale l.jpg

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


1966 2001 review of combination therapy l.jpg

1966-2001 Review of Combination Therapy

StudiesSynAddIndiff Antag

In vitro (n=28)36%24% 28% 11%

In vivo (n=18)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 2003;37 (suppl 3): S188-224


Only clinical trial of combination antifungal therapy for aspergillosis l.jpg

Only Clinical Trial of Combination Antifungal Therapy for Aspergillosis

  • 28 neutropenic adult pts with proven IFI

    • AmB (0.5 mg/kg/d) (n=14)

    • AmB + 5-FC (n=14)

  • 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 1994;22:81-5.


Experimental voriconazole caspofungin l.jpg

Experimental:Voriconazole + Caspofungin

  • In Vitro

    • 48 isolates, Synergy (87.5%) of interactions (FICI < 1.0)

      Perea S, et al. Antimicrob Agents Chemother 2002;46:3039-41

  • 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 2002;46:2564-8


Experimental ravuconazole micafungin l.jpg

Experimental:Ravuconazole + 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 2003;187:1834-43


Ravuconazole micafungin l.jpg

Ravuconazole + Micafungin

Petraitis V, et al. J Infect Dis 2003;187:1834-43


Ravuconazole micafungin hyphal damage l.jpg

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 2003;187:1834-43


Clinical combination therapy reports l.jpg

Clinical Combination Therapy Reports

  • Caspofungin + L-AmB salvage after previous L-AmB (n=48)

    • Overall response rate 42%; Response in progressive IA 18%

      Kontoyiannis DP, et al. Cancer 2003;15:292-9

  • 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, >7d prior therapy & >7d 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 lipid8% (p=0.01)

    • AmB lipid + Itraconazole 16%(p=0.2)

      Raad II, et al. IDSA 2004, Abstract 678


Voriconazole terbinafine l.jpg

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%) (p< 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


New data combination therapy for ia l.jpg

New Data:Combination Therapy for IA

  • 47 patients with proven/probable IA from 1997-2001

  • Patients experienced failure of initial therapy with AmB formulations

  • Received either voriconazole (n=31) or voriconazole + caspofungin (n=16) as salvage therapy

  • Voriconazole + Caspofungin with improved 3-month survival rate compared to voriconazole monotherapy (HR 0.42; 95% CI 0.17-1.1; p=0.048)

  • Multivariate model, combination with reduced mortality (HR 0.28; 95% CI 0.28-0.92; p=0.11)

    Marr KA, et al. Clin Infect Dis 2004;39:797-802.


Slide46 l.jpg

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 2004;39:797-802.


Primary combination therapy l.jpg

Primary Combination Therapy

  • Retrospective single center cohort review of consecutive patients with IA and an underlying hematologic malignancy (Jan 98 – July 03)

  • Proven (n=17) / Probable (n=17) / Possible (n=11) by EORTC/MSG

  • Data presented below for Proven / Probable cases only

    ALL ComboMonoP value

    (n=34)(n=10)(n=24)

    12 wk Survival53%50%54% 0.82

    Median Survival (d)110102115 ---

    CR/PR41%50%37.5% 0.5

    Stable5.9%0%8.3% --

    Failure53%50%54% 0.86

  • No differences in survival between primary therapy with mono vs. combo

    Munoz LS, et al. ICAAC 2004, Abstract M-1024


In vitro treatment prior to combination antifungal therapy l.jpg

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/mlAmB 0.2 ug/ml

  • Caspo + VCZ33% (14-57%)34% (13-59%)

  • Caspo + RVZ11% (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

    O’Shaughnessy EM, et al. ICAAC 2004, Abstract M-249


Pediatric antifungal data l.jpg

Pediatric Antifungal Data


Pediatric voriconazole l.jpg

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 2004;48:2166-72.


Pediatric voriconazole51 l.jpg

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 2004;48:2166-72.

  • Correct pediatric dosing not fully established, but clearly higher than adult dosing – prompted a second PK study


2 nd pediatric voriconazole pharmacokinetic study l.jpg

2nd Pediatric Voriconazole Pharmacokinetic Study

  • Study completed, data analyses ongoing

  • PK study (2-12 yo) to evaluate > 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


Voriconazole for pediatric aspergillosis l.jpg

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 (n=12) 33%

      • CNS (n=6)50%

      • Disseminated (n=7) 86%

      • Sinusitis (n=7) 29%

      • Bone / Liver / Skin (n=10) 30%

    • Stable 7%

    • Intolerance 10%

    • Failure 40%

      Walsh TJ, et al. Pediatr Infect Dis J 2002;21:240-8.


Pediatric caspofungin l.jpg

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.


Pediatric caspofungin55 l.jpg

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.


Summary l.jpg

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


  • Login