In Vitro and In Vivo Antifungal Activity of Amphotericin B Lipid Complex: Are Phospholipases Important?

Abstract

Amphotericin B lipid complex for injection (ABLC) is a suspension of amphotericin B complexed with the lipidsl-α-dimyristoylphosphatidylcholine (DMPC) andl-α-dimyristoylphosphatidylglycerol. ABLC is less toxic than amphotericin B deoxycholate (AmB-d), while it maintains the antifungal activity of AmB-d. Active amphotericin B can be released from ABLC by exogenously added (snake venom, bacteria, orCandida-derived) phospholipases or by phospholipases derived from activated mammalian vascular tissue (rat arteries). Such extracellular phospholipases are capable of hydrolyzing the major lipid in ABLC. Mutants of C. albicans that were resistant to ABLC but not AmB-d in vitro were deficient in extracellular phospholipase activity, as measured on egg yolk agar or as measured by their ability to hydrolyze DMPC in ABLC. ABLC was nevertheless effective in the treatment of experimental murine infections produced by these mutants. Isolates of Aspergillus species, apparently resistant to ABLC in vitro (but susceptible to AmB-d), were also susceptible to ABLC in vivo. We suggest that routine in vitro susceptibility tests with ABLC itself as the test material may not accurately predict the in vivo activity of ABLC and that the enhanced therapeutic index of ABLC relative to that of AmB-d in vivo may be due, in part, to the selective release of active amphotericin B from the complex at sites of fungal infection through the action of fungal or host cell-derived phospholipases.

Amphotericin B resistance leads to enhanced proteinase and phospholipase activity and reduced germ tube formation in Candida albicans

“…The Pz (in mm) for AMB-R was 0.382 AE 0.038 that showed very strong presence of phospholipase activity as compared to its parent strain 0.664 AE 0.047 which was relatively strong. The enhanced activity of extracellular phospholipase can be indication of increased resistant of C. albicans towards AMB (Swenson et al 1998).…”

The experience is CLEAR®

“…In comparison, 95% of L-AmB remains associated with the liposome as long as 72 h after dosing [2][3][4][5][6]. This may explain why, when compared with L-AmB, ABLC is more rapidly taken up by the reticuloendothelial system and therapeutic concentrations are more readily found in tissues that are common sites of fungal infection (e.g.…”

“…This may explain why, when compared with L-AmB, ABLC is more rapidly taken up by the reticuloendothelial system and therapeutic concentrations are more readily found in tissues that are common sites of fungal infection (e.g. lung, liver, spleen) [2][3][4][5][6]. Hence, rapid onset of action is anticipated, although such rapid release of amphotericin B from ABLC has not been shown to have superior clinical value.…”

Use of amphotericin B lipid complex in elderly patients

“…17 These characteristics are associated with a lower incidence of nephrotoxicity compared to the conventional formulation of AMB, but with preservation of the broad, potent antifungal activity that is associated with the parent compound. [16][17][18][19][20][21] Several reports have indicated the effectiveness and lower nephrotoxic side effects of amphotericin B lipid complex (ABLC) by showing improvement or stabilization of renal function in ABLC-treated patients who had experienced severe nephrotoxicity associated with or had failed to respond to prior antifungal therapy. [22][23][24] To investigate the safety and effectiveness of ABLC treatment in elderly patients, we conducted a retrospective analysis using a large multicenter database, the Collaborative Exchange of Antifungal Research (CLEAR), which includes data on over 500 patients over 65 years of age and over 2900 patients below or at 65 years of age.…”