Intermittent amphotericin?

Amphotericin B (AmB) is a polyene antifungal agent that is frequently used to treat invasive yeast and mold infections and is available in conventional and lipid formulations.  AmB deoxycholate has a long half-life (terminal half-life of 15 days) and distributes into well into the tissues; practitioners in the past have taken advantage of these pharmacokinetic parameters: instead of dosing conventional AmB on a daily basis, it would be dosed on as an alternative-day schedule.  (The package insert recommends a maximum dose of 1 mg/kg IV daily or 1.5 mg/kg IV on alternate days.¹)  Besides the most obvious advantage of giving the medication less frequently, it also meant that patients were going to experience less infusion-related reactions such as fever, chills, hypotension, and phlebitis (no news about decreasing the risk of nephrotoxicity with this alternative dosing).  However, there is scare clinical data available that supports the use of intermittent dosing of AmB deoxycholate, but anecdotal reports suggest that the outcomes are similar (per the 2 people in my group who have actually had anecdotal use of intermittent AmB).

Conventional AmB is well known to be associated with nephrotoxicity, and newer formulations have been developed to decreased the risk of nephrotoxicity; lipid-formulations AmB has become increasingly utilized due to its safety and lower risk of infusion reactions.  Because the half-life of liposomal AmB is also prolonged (100-153 hours), I was asked if there was any clinical data that suggested that alternate-day dosing had similar outcomes as traditional daily dosing.  In theory, dosing liposomal AmB should be possible, unfortunately, there are virtually no studies that explored alternate day dosing for treatment (in humans, at least).  Although it has been suggested that in conventional AmB has concentration-dependent activity, the PK/PD (pharmacokinetic/pharmacodynamic) targets of liposomal AmB may not be the same and further investigation would aid in determining more novel dosing.²  

Some studies suggest high-dose intermittent liposomal AmB is safe and feasible at 7.5-10 mg/kg/dose IV weekly.³ Additionally, there have been limited studies assessing the efficacy of intermittent liposomal AmB for fungal prophylaxis in patients undergoing chemotherapy for hematological malignancies (primarily acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS)) or stem cell transplantation, which have been summarized below.  Overall, the data is conflicting and the study designs are varied and have small numbers; some studies suggest that intermittent liposomal AmB can decrease the risk of IFI in neutropenic patients, but some suggest that there is no difference.  Although azoles, such as voriconazole, appear to be preferred for IFI prophylaxis in hematological malignancy patients (oral formulation, less toxicity), liposomal AmB may be used due to contraindications to azoles; although intermittent dosing is potentially an option for patients requiring longer prophylaxis, it appears that comparative trials between standard and intermittent dosing is needed.

PMID	Patient Population	Intervention	Outcome (IFI)
10197802 (1999)	Adult, n = 161 (auto- or allo-HSCT)	Randomization: LAmB 2 mg/kg IV three times weekly vs. placebo	Suspected: 31/74 vs. 40/87 (NS) Proven: 0/74 vs. 3/87 (NS) (This study suggests that the prophylaxis group had lower fungal colonization rates)
11820258 (2001)	Pediatric, n = 29 (AML, HR-ALL, MDS, severe aplastic anemia, stage IV neuroblastoma, auto-HSCT)	Partial randomization: Prophylaxis (LAmB   1 mg/kg IV three times weekly) vs. “early intervention”	Probable: 5/16 vs. 5/13 (NS) Proven: 0/16 vs. 1/13 (NS)
16766594 (2006)	Adult, n = 140 (232 neutropenic episodes) (expected neutropenia > 10 days or auto-HSCT	Randomization: LAmB 50 mg IV every other day vs. placebo	1st neutropenic episode: Probable and Proven: 5/75 vs. 20/57 (p = 0.001) All episodes: Probable and Proven: 5/110 vs. 22/109 (p < 0.01) (This study suggested the LAmB decreased risk for developing Aspergillosis but not Candidasis)
18430130 (2008)	Adults, n = 30	Randomization: LAmB 3 mg/kg IV daily vs. LAmB 10 mg/kg IV day 1, then 5 mg/kg IV days 3 and 6	Probable and Proven: 3/15 vs. 0/15 (no statistical analysis mentioned)
21895857 (2011)	Pediatric, n = 44 (46 neutropenic episode) (HR-ALL, AML, relapse ALL, AML, HR-NHL, severe aplastic anemia) Historical control, n = 39, (45 cases)	Prophylaxis: LAmB2.5 mg/kg IV twice weekly	Probable: 0/46 vs. 2/45 (p = 0.01) Proven: 0/46 vs. 5/45 (p = 0.01)

1.     Gallis HA, Drew RH, Pickard WW. “Amphotericin B: 30 years of clinical experience.” Reviews Infect Dis. 1990;12:309-29.

2.     Lestner JM, Howard SJ, Goodwin J, et al. “Pharmacokinetics and pharmacodynamics of amphotericin B deoxycholate, liposomal amphotericin B, and amphotericin B lipid complex in an in vitro model of invasive pulmonary aspergillosis.” Antimicrob Agents Chemother. 2010;54:3432-41.

3.     Ellis M. “New dosing strategies for liposomal amphotericin B in high-risk patients.” Clin Microbiol Infect. 2008;14:55-64.