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Antimicrobial Agents and Chemotherapy, April 1998, p. 767-771, Vol. 42, No. 4
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
In Vitro and In Vivo Antifungal Activity of
Amphotericin B Lipid Complex: Are Phospholipases Important?
Christine E.
Swenson,1
Walter R.
Perkins,1
Patricia
Roberts,1
Imran
Ahmad,1
Rachel
Stevens,1
David A.
Stevens,2 and
Andrew
S.
Janoff1,*
The Liposome Company, Inc., Princeton, New
Jersey 08540,1 and
Division of
Infectious Diseases, Department of Medicine, Santa Clara Valley Medical
Center and Stanford University, San Jose, California
951282
Received 4 June 1997/Returned for modification 21 July
1997/Accepted 27 January 1998
Amphotericin B lipid complex for injection (ABLC) is a suspension
of amphotericin B complexed with the lipids
L-
-dimyristoylphosphatidylcholine (DMPC) and
L-
-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, or
Candida-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.
*
Corresponding author. Mailing address: The Liposome
Company, Inc., One Research Way, Princeton, NJ 08540. Phone: (609)
452-7061. Fax: (609) 520-8250. E-mail: ajanoff{at}lipo.com.
Antimicrobial Agents and Chemotherapy, April 1998, p. 767-771, Vol. 42, No. 4
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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