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Latest Developments in the Treatment of Invasive Aspergillosis

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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 Incidence 1990-1998 at FHCRC
Allograft recipients Autograft recipients 14 12 10 8 Incidence (%) 6 4 2 1990 1991 1992 1993 1994 1995 1996 1997 1998 Year Marr KA, et al. Clin Infect Dis. 2002;34:

5 Invasive Aspergillosis Epidemiology
data from 533 total cases of IA Autologous HSCT <1 % 5.3% Allogeneic HSCT  4%  12% Non-fumigatus Aspergillus 18.3% 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:

6 Probability of Developing Proven or Probable IA among patients alive at day 40
Overall P = 0.001 Marr KA, et al. Blood 2002;100:

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% (p=0.0001) A. fumigatus doubling time increased to 48 minutes Ng TTC, et al. Microbiology 1994;140:

8 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

9 Antifungal Therapy for Invasive Aspergillosis

10 A. terreus Infection Murine model Amphotericin B resistance confirmed
Graybill JR, et al. Antimicrob Agents Chemother 2004;48: 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: Multicenter retrospective analysis of 83 cases ( ) Mortality at 12 weeks decreased in those who received voriconazole (HR 0.29; 95% CI, ) vs. AmB Steinbach WJ, et al. Clin Infect Dis 2004;39:192-8.

11 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 0.4 Aspergilloma (n=10) 0.3 0.2 Pulmonary (n=83) 0.1 CNS or Disseminated (n=35) 0.0 30 60 90 120 150 180 210 240 270 300 330 360 Days Lin et al. Clin Infect Dis. 2001;32:

12 Outcomes Research: Treatment Practices Patterson TF, et al
Outcomes Research: Treatment Practices Patterson TF, et al. Medicine 2000;79: IA cases after 1990, most from (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
Outcomes Research: Treatment Practices Denning DW, et al. J Infect 1998;37: (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 1997;157: Multicenter open label itraconazole (76 patients) Complete or partial response 39% Denning DW, et al. Am J Med 1994;97: Open label ABLC (130 patients) Complete or partial response 42% Walsh TJ, et al. Clin Infect Dis 1998;26:

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 2003;47: 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.

16 Aspergillus Antifungal Resistance ?
Itraconazole resistance described in 1997 Denning DW, et al. Antimicrob Agents Chemother 1997;41: Estimated 2.1% of > 900 A. fumigatus strains resistant to itraconazole Moore CB, et al. J Infect 2000;41: 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:

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 >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

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

19 Same outcome in each separate protocol
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:

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 < 500) Non-Neutropenic (ANC  500) Proven IA Probable IA Herbrecht R, et al. N Engl J Med 2002; 347: % Difference in Success Rates (95% CI)

21 Probability of Survival Number of days of Therapy
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:

22 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; ABCD AmB-D Evaluable Patients (n=50) (n=53) Therapeutic response 52% 50.9% p=0.96 (complete, partial, or stable) Overall Mortality 36% 45% p=0.4 Fungal Mortality 32% 26% p=0.7 Renal Toxicity 25% 49% p=0.002 Median time to renal toxicity 301 d 22 d p<0.001 Intent to Treat (n=88) (n=86) 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 2002;35:

23 Liposomal AmB 1 mg/kg/d versus 4 mg/kg/d
1 mg/kg/d 4 mg/kd/d p value (n=41) (n=46) Clinical CR + PR (inc. stable) % % 0.144 Radiologic CR + PR % % 0.694 6-month survival % % Overall deaths % % Overall response rate of 55% Overall 6-month mortality of 63% Ellis M, et al. Clin Infect Dis 1998;27:

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) (p< ) 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 (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

26 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.

27 Voriconazole as Primary Therapy
Therapy Complete Partial Stable Failure Total Primary 10 (17%) (42%) (18%) (23%) (52%) Salvage 6 (11%) (27%) (23%) (39%) (48%) Denning DW, et al. Clin Infect Dis 2002;34:

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 2002;46:

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; 39: 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 2004;190:

31 Micafungin Monotherapy Open-Label Trial in Japan
70 patients at 29 sites; 56 pts eval. for efficacy (IA = 42) Disease Response Invasive pulmonary (n=10) 60% (8 pts with leukemia or lymphoma; 2 neutropenic) Max dose mg/d 50% (1/2) 75 mg/d 33% (1/3) 150 mg/d 80% (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.

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 (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 Response 34% Stable / Failed response 66% BMT Recipient Response 15% All Others Response % Troke PF, et al. ICAAC 2003, Abstract M-1755

34 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:

35 Combination Antifungal Therapy in 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 (n=28) 36% 24% 28% % In vivo (n=18) 14% 20% 51% % 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): S

38 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: / (mortality 86%) AmB + 5-FC: 3/ (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.

39 Experimental: Voriconazole + Caspofungin
In Vitro 48 isolates, Synergy (87.5%) of interactions (FICI < 1.0) Perea S, et al. Antimicrob Agents Chemother 2002;46: 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

40 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:

41 Ravuconazole + Micafungin
Petraitis V, et al. J Infect Dis 2003;187:

42 Ravuconazole + Micafungin Hyphal Damage
Untreated Control Micafungin 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:

43 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 lipid 8% (p=0.01) AmB lipid + Itraconazole 16% (p=0.2) 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%) (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

45 New Data: Combination Therapy for IA
47 patients with proven/probable IA from 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 ; p=0.048) Multivariate model, combination with reduced mortality (HR 0.28; 95% CI ; p=0.11) Marr KA, et al. Clin Infect Dis 2004;39:

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 2004;39:

47 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 Combo Mono P value (n=34) (n=10) (n=24) 12 wk Survival 53% 50% 54% Median Survival (d) CR/PR 41% 50% 37.5% Stable 5.9% 0% 8.3% Failure 53% 50% 54% 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 ( ) 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

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 2004;48:

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 2004;48: 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 > 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 (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.

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


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