2 Latest Developments in the Treatment of Invasive Aspergillosis William J. Steinbach, MDAssistant Professor of Pediatrics, Molecular Genetics, and MicrobiologyPediatric Infectious DiseasesDuke University Medical CenterDurham, NC USA
3 Possible Areas for Improving Outcome in IA Understanding IA epidemiologyHost factors: Underlying & concomitant diseasesImmunosuppression / CorticosteroidsAntifungal prophylaxisEarly diagnosisEarly therapyAntifungal resistanceAntifungal therapiesImmune reconstitution, Immunotherapy
4 Invasive Aspergillosis Incidence 1990-1998 at FHCRC Allograft recipientsAutograft recipients1412108Incidence (%)642199019911992199319941995199619971998YearMarr KA, et al. Clin Infect Dis. 2002;34:
5 Invasive Aspergillosis Epidemiology data from 533 total cases of IAAutologous HSCT <1 % 5.3%Allogeneic HSCT 4% 12%Non-fumigatus Aspergillus 18.3% 33.7%Average median survival of 29 days after diagnosisMarr KA, et al. Clin Infect Dis 2002;34:909-17Wald A, et al. J Infect Dis 1997;175:
6 Probability of Developing Proven or Probable IA among patients alive at day 40 Overall P = 0.001Marr KA, et al. Blood 2002;100:
7 Corticosteroids as a Risk Factor Pharmacologic doses of hydrocortisone (10-6 M), equivalent to 20 mg IVIn vitro mean specific growth rate of A. fumigatus at 37° C increased by 40% (p=0.0001)A. fumigatus doubling time increased to 48 minutesNg TTC, et al. Microbiology 1994;140:
8 Host Susceptibility Variations: Different Inbred Mouse Strains Resistant: BalbC/ByJ, AKR/J, Balb/C, 129/SVJ, C57BL/6Sensitive: CAST/Ei, C3H/HEJ, A/J, DBA/2JIntermediate: MRL/MPJ, NZW/LACZaas AK, et al. 7th European Conference on Fungal Genetics, 2004
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 casesAmB resistance shown in vitro and in vivoSteinbach 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. AmBSteinbach WJ, et al. Clin Infect Dis 2004;39:192-8.
11 Aspergillosis Survival with Amphotericin B by Site of Infection 1.00.90.8Sinusitis (n=17)0.70.6Multi-site (n=11)Cumulative Survival Rate0.50.4Aspergilloma (n=10)0.30.2Pulmonary (n=83)0.1CNS or Disseminated (n=35)0.0306090120150180210240270300330360DaysLin 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-sequentialLipid formulations of AmB investigational, so few receivedOutcome data from 34 patients with L-AmB excluded because patients were in other clinical trialsFew Combinations Used: AmB + 5-FC (2%)AmB + Rifampin (2%)AmB + Itraconazole (3%)Outcomes:AmB Itraconazole AmB ItraconazolePts 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 ptsAmB Lipid AmB Itraconazole 5-FC75% 36% 40% 12%Six month outcomes for IPA:Alive w/o IA Alive w/ IA ExpiredAmB 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 VoriconazoleFluconazole pre-exposure attenuates Itraconazole/ Voriconazole fungicidal activity, but no effect in AmBXTT growth rates pre-exposed/no fluconazole were sameLiu 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 AmBSuggests a preferential role for azole-Caspofungin sequential combinations over azole-AmB regimensKontoyiannis DP, et al. Diag Microbiol Infect Dis 2003;47:415-9.
16 Aspergillus Antifungal Resistance ? Itraconazole resistance described in 1997Denning DW, et al. Antimicrob Agents Chemother 1997;41:Estimated 2.1% of > 900 A. fumigatus strains resistant to itraconazoleMoore CB, et al. J Infect 2000;41:200 sequential A. fumigatus isolates from 26 immunocompromised patientsMICs similar pre- and post-treatment with AmB (n=100) or itraconazole (n=91)Emergence of resistance while on antifungal therapy is likely lowGenotypic diversity and sequential colonization with multiple strains could explain low resistanceDannaoui, 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 growingVoriconazole killed hyphae in both time- and concentration-dependent fashionsKill curve and MTT cell wall viability testingVoriconazole had better fungicidal activity against A. fumigatus hyphae than AmB at 48 hoursVCZ 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)76/144Same outcome in each separate protocol42/133Voriconazole 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) OverallPulmonaryExtra PulmonaryAllogeneic BMTAutologous BMT / other hematological (e.g. leukemia)Other immunosuppressed state (e.g. SOT, HIV/AIDS)Neutropenic (ANC < 500)Non-Neutropenic (ANC 500)Proven IAProbable IAHerbrecht 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 +/- OLATAmphotericin B +/- OLATProbability of SurvivalDay 84 survival: Voriconazole arm 71%; Amphotericin B arm 58%Hazard ratio = 0.6095% CI (0.40, 0.89)Number of days of TherapyHerbrecht 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-DEvaluable Patients (n=50) (n=53)Therapeutic response 52% 50.9% p=0.96(complete, partial, or stable)Overall Mortality 36% 45% p=0.4Fungal Mortality 32% 26% p=0.7Renal Toxicity 25% 49% p=0.002Median time to renal toxicity 301 d 22 d p<0.001Intent to Treat (n=88) (n=86)Complete Response 5.7% 3.5%Partial Response 6.8% 11.6%ABCD equivalent efficacy and superior renal safetyStudy terminated early due to low accrualBowden 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) % % 0.144Radiologic CR + PR % % 0.6946-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. AmBInitial VCZ 36% (52/144)Initial AmB 80% (107/133)159 total patients received OLT38% Lipid AmB formulation33% Itraconazole21% AmB deoxycholate (inc. reduced dose)8% Other antifungalsSwitches due to Intolerance/Insufficient responseVCZ 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 Success33% (31/93) AmB receiving OLT30% (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 IABoucher 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.
28 Echinocandin Activity on Aspergillus Hyphal Tip Caspofungin (0.3 ug/ml)-treated, DiBAC-stained A. fumigatus6 hours incubation2,000X magnificationBowman JC, et al. Antimicrob Agents Chemother 2002;46:
29 Caspofungin Salvage Therapy Open, non-comparative, multi-center trial90 patients with IA enrolled (median 51 yrs; 15-73)Efficacy evaluation of 83 patients71 patients (86%) refractory to therapy12 patients (14%) intolerant to therapy45% (37/83) with favorable outcome50% (32/64) with pulmonary IA23% (3/13) with disseminated IAMaertens J, et al. Clin Infect Dis 2004; 39:46 Neutropenic patients with IAFavorable response (35%)42% as primary therapy32% as salvage therapyKartsonis N, et al. 14th ECCMID, Abstract 0422
30 Concentration-Dependent Caspofungin Activity Murine model of pulmonary IASubstantial differences in fungal burden as determined by qPCRLargest reduction in burden by those dosing regimens achieving the highest peak concentrationsHistological apical hyphal damage most at highest doseTrend toward improving survival with maximal dosingParadoxical “Eagle Effect” at highest dose, with an increase in tissue burden (but no decrease in survival)Same effect seen in other cell-wall active antibacterialsWiederhold 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 ResponseInvasive 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 patientsKohno S, et al. Scand J Infect Dis 2004;36:372-9.
32 Posaconazole Monotherapy Multicenter study for salvage therapyIncluded 25 pts with IAEffective in 53% (8/15) at week 4Effective in 85% (6/7) at week 8No mention of patients without complete follow-upHachem RY, et al. ICAAC 2000, Abstract 1109Multi-center study of patients with IA refractory to or intolerant of AmB formulations and itraconazole107 posaconazole, 86 controlsGlobal response rate at end of treatmentPosaconazole 42%Controls 26%Walsh TJ, et al. ASH 2003, Abstract 682
33 Cerebral Aspergillosis 86 patients (9 mo - 81yo) with proven or probable CNS aspergillosisA. fumigatus (n=34); A. nidulans (n=5); Aspergillus spp. (n=24)Underlying diseaseBMT (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 OutcomeComplete / 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 Aspergillosis20 patients from Clinical trials and Compassionate useBone InvolvementSpondylodiscitis (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 patientsSalvage voriconazole therapy in 18/20 patientsMedian duration of voriconazole 83.5 days (4-395 days)Global Clinical OutcomeComplete / 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 potencyMore rapid antifungal effectAdditive or synergistic efficacy effectsLowered dosing or less toxicityReduce risk of emerging resistanceHistoric poor outcomes with monotherapyIncreased penetration / transportInhibit different stages of the same biochemical pathwaySimultaneous inhibition of different fungal targetsCreation of a fungicidal combination
37 1966-2001 Review of Combination Therapy Studies Syn Add Indiff AntagIn vitro (n=28) 36% 24% 28% %In vivo (n=18) 14% 20% 51% %AmB + Itraconazole generally indifferent interactions in vitro, in vivo, and clinically249 cases met combination Rx inclusion criteriaMost common combinations:AmB + Flucytosine (49%)AmB + Itraconazole (16%)AmB + Rifampin (11%)Overall 63% of clinical cases reported improvementSteinbach 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 IFIAmB (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 died3 who survived had immune recoveryStudy terminated early, problems included:IA so far advanced at initiationLow dose AmB usedVerweij PE, et al. Infection 1994;22:81-5.
39 Experimental: Voriconazole + Caspofungin In Vitro48 isolates, Synergy (87.5%) of interactions (FICI < 1.0)Perea S, et al. Antimicrob Agents Chemother 2002;46:In Vivo: Neutropenic guinea pig modelMortality (0/12 animals) and survival time (8 days) SAME in EACH of these arms:VCZ 5mg/kg/dCAS (1 mg/kg/d) + VCZCAS (2.5 mg/kg/d) + VCZFungal burden (CFU) with combination better than untreated controls onlyNumber of organs with positive cultures with combination better than monotherapyKirkpatrick WR, et al. Antimicrob Agents Chemother 2002;46:2564-8
40 Experimental: Ravuconazole + Micafungin Neutropenic rabbit modelSurvivalMicafungin monotherapy (0/8)Ravuconazole monotherapy (2/8)Micafungin + Ravuconazole (9/12)Fungal burden, GM assay, Pulmonary injury, Pulmonary infiltrates all less in the combinationPetraitis V, et al. J Infect Dis 2003;187:
42 Ravuconazole + Micafungin Hyphal Damage UntreatedControlMicafunginRavuconazole +MicafunginRavuconazoleThe spherical chlamydoconidial structures are evidence of the effect of echinocandinsThe focal hyphal disintegration and disruption are compatible with the effects of triazolesOriginal magnification ×630; Insert, ×1000; Scale bar 20 umPetraitis 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;15:292-9Micafungin + existing antifungal in 85 BMT pts39% (28%) complete/partial responseRatanatharathorn V, et al. ASH 2002, Abstract A-2472Open-label Micafungin salvage therapy in 283 patientsIn salvage patients (IA, >7d prior therapy & >7d micafungin)11/49 (22%) allogeneic HSCT responded22/45 (49%) leukemia patients respondedUllman AJ, et al. ECCMID 2003, Abstract 0400Salvage therapy with posaconazolePosaconazole 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 AspergillusImmunosuppressed rat model A. fumigatusAmB 1 mg/kg/dVCZ 6 or 9 mg/kg/dTerbinafine 150 mg/kg/dVCZ 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 survivalCombination reduced fungal counts compared to control and AmBGavalda J, et al. ICAAC 2004, Abstract M-224
45 New Data: Combination Therapy for IA 47 patients with proven/probable IA fromPatients experienced failure of initial therapy with AmB formulationsReceived either voriconazole (n=31) or voriconazole + caspofungin (n=16) as salvage therapyVoriconazole + 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 diagnosisP = .048, calculated from the likelihood ratio test using Cox regressionMarr 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/MSGData presented below for Proven / Probable cases onlyALL 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. comboMunoz 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 + RavuconazolePercentage of further reduction in growth following AmB additionAmB 0.1 ug/ml AmB 0.2 ug/mlCaspo + 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/mlFICI ( ) for each triple combination improved by adding subinhibitory concentration of AmB – additive to indifferent effectO’Shaughnessy EM, et al. ICAAC 2004, Abstract M-249
50 Pediatric Voriconazole Elimination by Linear pharmacokinetics in children following doses of 3 and 4 mg/kg/q12hSingle dose, Open, two center study in UK11 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 yrsHigher elimination capacity on a weight basis than do adult healthy volunteersWalsh 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 concentrationThis is only valid if linear pharmacokinetics maintained throughout full dosage rangeWalsh 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 ongoingPK study (2-12 yo) to evaluate > 4 mg/kg BID dosingEnrolled 48 (39 completed all three PK periods)Doses of 4, 6, 8 mg/kg/q12hEach child received at least two different doses in escalating order, then switched to POOral Suspension (40 mg/ml) – FDA approved 12/24/03, orange flavor
53 Voriconazole for Pediatric Aspergillosis Compassionate Use; 58 IFI including 42 IAMean age 8.2 yrs (9 mo – 15 yrs)Therapeutic responseComplete 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 dailyInitial pediatric (ages 2-17) PK study completed39 patients enrolledData 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 adults50 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 toxicityBeta-phase half-life reduced 32-43% in children, so plasma levels were lowerSubsequent studies in children 2-17 years old evaluating:Load with 70 mg/m2 (max 70 mg/d) on Day 1Then, 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 populationsAspergillus qPCR still debated for diagnosisEchinocandins unlikely to be best monotherapy (fungistatic against Aspergillus)Voriconazole is clearly the best monotherapyVoriconzole primary therapy better than salvage therapyVoriconazole has linear pharmacokinetics in childrenCombination therapy – unprovenReports are often contradictoryPotentially would be best if used as primary therapy