2 DisclosuresClinical Trials funding support (antifungal agents): Pfizer, Astellas, Merck, Schering-PloughClinical Trials funding support (outside of mycology): Glaxo, ViroPharma, Advanced Biologics, AdamasNot a ConsultantNot on a Speaker’s Bureau
3 Objectives Amphotericin as antifungal prophylaxis Merits, ProblemsEchinocandins as antifungal prophylaxisUndefined areas in practice
4 Amphotericin routes Oral Nebulization or nasal spray IV ICU Selective digestive tract decontaminationRadiotherapy lung cancer patientsNebulization or nasal sprayLung transplantHSCTIV
5 Standard careSDD 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 radiotherapyTrend toward higher esophageal volumesOlderWorse median Karnofsky IndexMore often received induction chemotherapyStart of symptoms day 21 (median, range 14-44)5 patients developed esophagitis grade 120 patients 60 Gy (range 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).
7 NasalBottle design to prevent aspiration of nasal secretions back into the bottleEach nostril 5x/dayCompliance a problemIrritating to nasal mucosa: tolerance a problemReduction in surveillance CFUs, but not in invasive disease
8 Bronchial Anastamosis Courtesy of Jordan Dunitz, MD
14 271 patients407 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 IPA6 of 139 patients in the liposomal amphotericin B groupodds ratio, 0.26; 95% CI, ; P=.005On-treatment analysis13 of 97 patients receiving placebo developed IPA2 of 91 receiving liposomal amphotericin Bodds ratio, 0.14; 95% CI, ; P=.007
18 Nebulization: meritsDirected delivery to the lungs, good distribution throughout lung airwaysAchieves high local concentrationHalf-life in lung of 4.8 daysNot associated with a decline in PFTsAvoids undesirable systemic effects and drug interactionsLipid formulationsPenetrate the lung betterHave a longer half-lifeAdminister at long intervalsNo demonstrated resistance
19 Nebulization: problems Some increased risk ofTransient coughNauseaAftertasteDeoxycholate detergent may have adverse effects on surfactantBreakthrough invasive diseasePulmonaryCerebral
20 Nebulization: undefined areas Many type of nebulizersOnly a few dosages studiedNo data regardingLong term efficacyRepeated use efficacyComparison to systemic antifungalsSynergy with systemic antifungalsLack of standardization of administration procedures and dosesThese are not treatment data
21 IV Potential systemic toxicity Amphotericin accumulates in the reticulo-endothelial systemEven 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
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.
25 CID 2004;39:1407-16 (van Burik et al.) Randomized, double-blind Phase III study72 centers in the US and CanadaPatient population:HCT candidates 6 months of ageAutologous HCT for heme malignancies onlyCID 2004;39: (van Burik et al.)
26 Assess non-inferiority of micafungin to fluconazole over 10% Treatment successTreatment differenceMicafungin340 / 425(80%)+6.5%P= (95% CI, 0.9% to 12%)Fluconazole336 / 457(73.5%)Assess non-inferiority of micafungin to fluconazole over 10%Treatment successAbsence 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
27 Time to Treatment Failure Proportion of Patients with Treatment SuccessP-Value (2 tailed) = 0.025Days Since First Dose of Study Drug
28 2 (Pulmonary aspergillosis) P=0.07 Micafungin compared with FluconazoleBreakthrough fungal infectionAspergillus*ProvenProbableCandidaFusariumZygomycetesDeathDeath due to FIMicafungin7/425(1.6%)1418/425(4.2%)1 (Zygomycetes)Fluconazole11/457(2.4%)743226 / 457(5.7%)2 (Pulmonary aspergillosis)
32 Liver transplantOpen-label trial of 71 adult liver transplant recipientsCaspofungin for at least 21 days2 IFI: Mucor and Candida albicans surgical wound infections6 discontinued: drug-related altered liver function8 patients died, 6 during caspofungin administration and 2 during follow-up period, but none were attributed to IFI or caspofungin toxicityTransplantation 2009 Feb 15;87(3):424-35
33 Echinocandins: undefined areas Limited amount of published data:Randomized trialsObservational cohortsSpecific patient populationsBy diseaseBy ageCan trials with one drug be extrapolated to other drugsDosage
34 Summary Amphotericin as antifungal prophylaxis Merits, ProblemsEchinocandins as antifungal prophylaxisUndefined areas in practice