Transcript New Fungal Drugs

Amphotericinor
Echinocandin-Based
Antifungal Prophylaxis
Approaches
Jo-Anne Young, MD, FACP, FIDSA
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
Objectives
Amphotericin as antifungal prophylaxis
Merits, Problems
Echinocandins as antifungal prophylaxis
Merits, Problems
Undefined areas in practice
Amphotericin routes
Oral
ICU Selective digestive tract decontamination
Radiotherapy lung cancer patients
Nebulization or nasal spray
Lung transplant
HSCT
IV
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.
Nonrandomized study of lung cancer consecutive patients
20 patients 67 Gy (range 61-80 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 51-67.5 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).
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
Bronchial Anastamosis
Courtesy of Jordan Dunitz, MD
6 single and 6 double lung recipients
One 7-ml (35 mg) nebulized dose
labeled with Technetium
Selected system: AeroEclipse nebulizer
& DeVilbiss compressor
3.9 + 1.6 mg allograft, 2.1 + 1.1 mg native
2.8 + 0.8 mg Left, 4.0 + 1.3 mg Right
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.
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, 0.09-0.72; 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, 0.02-0.66; P=.007
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
Nebulization: problems
Some increased risk of
Transient cough
Nausea
Aftertaste
Deoxycholate detergent may have adverse
effects on surfactant
Breakthrough invasive disease
Pulmonary
Cerebral
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
IV
Potential systemic toxicity
Amphotericin accumulates in the reticuloendothelial 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
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.
Yeasts
Molds
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;39:1407-16 (van Burik et al.)
Treatment success
Treatment difference
P=0.03
Micafungin
Fluconazole
340 / 425
336 / 457
(80%)
(73.5%)
+6.5%
(95% CI, 0.9% to 12%)
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
Proportion of Patients
with Treatment Success
Time to Treatment Failure
1
0.9
0.8
0.7
0.6
0.5
Micafungin (N=425)
Fluconazole (N=457)
0.4
0.3
P-Value (2 tailed) = 0.025
0.2
0.1
0
0
10
20
30
40
50
60
70
Days Since First Dose of Study Drug
P=0.07 Micafungin compared with Fluconazole
Micafungin
Fluconazole
Breakthrough fungal infection 7/425
11/457
(1.6%)
(2.4%)
Aspergillus*
1
7
Proven
0
4
Probable
1
3
Candida
4
2
Fusarium
1
2
Zygomycetes
1
0
Death
18/425
26 / 457
(4.2%)
(5.7%)
Death due to FI
1 (Zygomycetes) 2 (Pulmonary
aspergillosis)
HSCT candidates  6 months of age
Micafungin
Pediatric <16 yrs 69% (27/39)
Adult 16-64 yrs 81% (313/386)
Adult > 64 yrs
97% (32/33)
Fluconazole
53% (24/45)
76% (312/412)
70% (16/23)
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. 2008 Dec;88(5):588-95
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
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
Summary
Amphotericin as antifungal prophylaxis
Merits, Problems
Echinocandins as antifungal prophylaxis
Merits, Problems
Undefined areas in practice