1. Amphotericin- or Echinocandin-Based Antifungal Prophylaxis Approaches
Jo-Anne Young, MD, FACP, FIDSA

2. Disclosures
Clinical Trials funding support (antifungal agents): Pfizer, Astellas, Merck, Schering-Plough
Clinical Trials funding support (outside of mycology): Glaxo, ViroPharma, Advanced Biologics, Adamas
Not a Consultant
Not on a Speaker’s Bureau

3. Objectives Amphotericin as antifungal prophylaxis
Merits, Problems
Echinocandins as antifungal prophylaxis
Undefined areas in practice

4. Amphotericin routes Oral Nebulization or nasal spray IV
ICU Selective digestive tract decontamination
Radiotherapy lung cancer patients
Nebulization or nasal spray
Lung transplant
HSCT IV

5. Standard care
SDD consisted of 4 days of intravenous cefotaxime and topical application of tobramycin, colistin, and amphotericin B in the oropharynx and stomach.
SOD consisted of oropharyngeal application only of the same antibiotics.

6. Nonrandomized study of lung cancer consecutive patients
20 patients 67 Gy (range Gy) AmB QID from day 8 to the end of radiotherapy
Trend toward higher esophageal volumes
Older
Worse median Karnofsky Index
More often received induction chemotherapy
Start of symptoms day 21 (median, range 14-44)
5 patients developed esophagitis grade 1
20 patients 60 Gy (range Gy) control group
Start of symptoms day 18 (median, range 10-32)
14 patients showed esophagitis grade 1 and 2 patients grade 2 (p < 0.05).

7. Nasal
Bottle design to prevent aspiration of nasal secretions back into the bottle
Each nostril 5x/day
Compliance a problem
Irritating to nasal mucosa: tolerance a problem
Reduction in surveillance CFUs, but not in invasive disease

8. Bronchial Anastamosis
Courtesy of Jordan Dunitz, MD

11. 6 single and 6 double lung recipients
One 7-ml (35 mg) nebulized dose labeled with Technetium

12. Selected system: AeroEclipse nebulizer & DeVilbiss compressor

13. 3.9 + 1.6 mg allograft, 2.1 + 1.1 mg native
mg Left, mg Right

14. 271 patients
407 neutropenic episodes.
Some adverse effects, but none serious, in the liposomal amphotericin B group were reported, most frequently coughing (16 patients vs. 1 patient; P=.002).
Prophylactic inhalation of liposomal amphotericin B significantly reduced the incidence of IPA.

15. Intent-to-treat analysis
18 of 132 patients in the placebo group developed IPA
6 of 139 patients in the liposomal amphotericin B group
odds ratio, 0.26; 95% CI, ; P=.005
On-treatment analysis
13 of 97 patients receiving placebo developed IPA
2 of 91 receiving liposomal amphotericin B
odds ratio, 0.14; 95% CI, ; P=.007

18. Nebulization: merits
Directed delivery to the lungs, good distribution throughout lung airways
Achieves high local concentration
Half-life in lung of 4.8 days
Not associated with a decline in PFTs
Avoids undesirable systemic effects and drug interactions
Lipid formulations
Penetrate the lung better
Have a longer half-life
Administer at long intervals
No demonstrated resistance

19. Nebulization: problems
Some increased risk of
Transient cough
Nausea
Aftertaste
Deoxycholate detergent may have adverse effects on surfactant
Breakthrough invasive disease
Pulmonary
Cerebral

20. Nebulization: undefined areas
Many type of nebulizers
Only a few dosages studied
No data regarding
Long term efficacy
Repeated use efficacy
Comparison to systemic antifungals
Synergy with systemic antifungals
Lack of standardization of administration procedures and doses
These are not treatment data

21. IV Potential systemic toxicity
Amphotericin accumulates in the reticulo-endothelial system
Even a single dose may proved tissue depots for prophylaxis in at-risk pts such as liver transplant
Intermittent high dosing of lipid ampho may be an option to daily azoles or candins

22. Enrollment was discontinued in the SCT group as recommended by the independent data review committee in accordance with the 10% limit of AEs (CTC grade 3-4) fixed by the protocol.

23. Yeasts Molds

25. CID 2004;39:1407-16 (van Burik et al.)
Randomized, double-blind Phase III study
72 centers in the US and Canada
Patient population:
HCT candidates  6 months of age
Autologous HCT for heme malignancies only
CID 2004;39: (van Burik et al.)

26. Assess non-inferiority of micafungin to fluconazole over 10%
Treatment success
Treatment difference
Micafungin
340 / 425
(80%)
+6.5%
P= (95% CI, 0.9% to 12%)
Fluconazole
336 / 457
(73.5%)
Assess non-inferiority of micafungin to fluconazole over 10%
Treatment success
Absence of suspected, proven, or probable invasive fungal infection through the end of prophylaxis period
Absence of a proven or probable invasive fungal infection through the end of the 4-week post-treatment period

27. Time to Treatment Failure
Proportion of Patients with Treatment Success
P-Value (2 tailed) = 0.025
Days Since First Dose of Study Drug

28. 2 (Pulmonary aspergillosis)
P=0.07 Micafungin compared with Fluconazole
Breakthrough fungal infection
Aspergillus*
Proven
Probable
Candida
Fusarium
Zygomycetes
Death
Death due to FI
Micafungin
7/425
(1.6%) 1 4
18/425
(4.2%)
1 (Zygomycetes)
Fluconazole
11/457
(2.4%) 7 4 3 2
26 / 457
(5.7%)
2 (Pulmonary aspergillosis)

29. HSCT candidates  6 months of age
Micafungin Fluconazole
Pediatric <16 yrs 69% (27/39) 53% (24/45)
Adult yrs 81% (313/386) 76% (312/412)
Adult > 64 yrs 97% (32/33) 70% (16/23)

30. High dose micafungin Adult patients
Micafungin 150 mg (n = 52) or Fluconazole 400 mg (n = 52)
Success 94 vs. 88%
Empirical antifungal therapy (P = 0.06) 2/50 (4.0%) micafungin 6/50 (12.0%) fluconazole arm
Int J Hematol Dec;88(5):588-95

32. Liver transplant
Open-label trial of 71 adult liver transplant recipients
Caspofungin for at least 21 days
2 IFI: Mucor and Candida albicans surgical wound infections
6 discontinued: drug-related altered liver function
8 patients died, 6 during caspofungin administration and 2 during follow-up period, but none were attributed to IFI or caspofungin toxicity
Transplantation 2009 Feb 15;87(3):424-35

33. Echinocandins: undefined areas
Limited amount of published data:
Randomized trials
Observational cohorts
Specific patient populations
By disease
By age
Can trials with one drug be extrapolated to other drugs
Dosage

34. Summary Amphotericin as antifungal prophylaxis
Merits, Problems
Echinocandins as antifungal prophylaxis
Undefined areas in practice