Amphotericin- Amphotericin- or or

Echinocandin-Based Echinocandin-Based Antifungal Prophylaxis Antifungal Prophylaxis

ApproachesApproaches

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 prophylaxisMerits, Problems

Echinocandins as antifungal prophylaxisMerits, Problems

Undefined areas in practice

Amphotericin routes

OralICU Selective digestive tract decontamination

Radiotherapy lung cancer patients

Nebulization or nasal sprayLung 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 patients20 patients 67 Gy (range 61-80 Gy) AmB QID from day 8 to the end of radiotherapy

Trend toward higher esophageal volumesOlderWorse median Karnofsky Index More often received induction chemotherapyStart of symptoms day 21 (median, range 14-44) 5 patients developed esophagitis grade 1

20 patients 60 Gy (range 51-67.5 Gy) control groupStart 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 bottleEach nostril 5x/day

Compliance a problemIrritating 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 analysis18 of 132 patients in the placebo group developed IPA6 of 139 patients in the liposomal amphotericin B groupodds ratio, 0.26; 95% CI, 0.09-0.72; P=.005

On-treatment analysis13 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: meritsDirected delivery to the lungs, good distribution throughout lung airways

Achieves high local concentrationHalf-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: problemsSome 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 nebulizersOnly a few dosages studiedNo data regarding

Long term efficacyRepeated use efficacyComparison to systemic antifungalsSynergy with systemic antifungals

Lack of standardization of administration procedures and dosesThese are not treatment data

IV

Potential systemic toxicityAmphotericin accumulates in the reticulo-endothelial system Even a single dose may proved tissue depots for prophylaxis in at-risk pts such as liver transplantIntermittent 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 Yeasts MoldsMolds

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 BurikCID 2004;39:1407-16 (van Burik et al. et al.))

Treatment success

Treatment difference

Micafungin

340 / 425

(80%)

+6.5%

P=0.03 (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 periodAbsence of a proven or probable invasive fungal infection through the end of the 4-week post-treatment period

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

0 10 20 30 40 50 60 70

Micafungin (N=425)Fluconazole (N=457)

Time to Treatment Failure P

ropo

rtio

n of

Pat

ient

s w

ith T

reat

men

t Suc

cess

P-Value (2 tailed) = 0.025

Days Since First Dose of Study Drug

Breakthrough fungal infection

Aspergillus*ProvenProbable

CandidaFusariumZygomycetes

Death

Death due to FI

Micafungin7/425 (1.6%)

101411

18/425 (4.2%)

1 (Zygomycetes)

Fluconazole11/457 (2.4%)

743220

26 / 457 (5.7%)

2 (Pulmonary aspergillosis)

P=0.07 Micafungin compared with Fluconazole

HSCT candidates 6 months of age

Micafungin Fluconazole

Pediatric <16 yrs 69% (27/39) 53% (24/45)

Adult 16-64 yrs 81% (313/386) 76% (312/412)

Adult > 64 yrs97% (32/33) 70% (16/23)

High dose micafungin

Adult patients Micafungin 150 mg (n = 52) orFluconazole 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 areasLimited amount of published data:

Randomized trials

Observational cohorts

Specific patient populationsBy disease

By age

Can trials with one drug be extrapolated to other drugs

Dosage

Summary

Amphotericin as antifungal prophylaxisMerits, Problems

Echinocandins as antifungal prophylaxisMerits, Problems

Undefined areas in practice