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