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Antimicrobial Agents and Chemotherapy, April 2000, p. 1108-1111, Vol. 44, No. 4
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
Postantifungal Effects of Echinocandin, Azole, and Polyene
Antifungal Agents against Candida albicans and
Cryptococcus neoformans
Erika J.
Ernst,*
Michael E.
Klepser, and
Michael A.
Pfaller
College of Pharmacy, The University of Iowa,
Department of Pathology, The University of Iowa College of
Medicine, Iowa City, Iowa 52242
Received 25 August 1999/Returned for modification 22 December
1999/Accepted 11 January 2000
 |
ABSTRACT |
The postantifungal effect (PAFE) of fluconazole, MK-0991, LY303366,
and amphotericin B was determined against isolates of Candida
albicans and Cryptococcus neoformans. Concentrations
ranging from 0.125 to 4 times the MIC were tested following exposure to the antifungal for 0.25 to 1 h. Combinations of azole and
echinocandin antifungals (MK-0991 and LY303366) were tested against
C. neoformans. Fluconazole displayed no measurable
PAFE against Candida albicans or Cryptococcus
neoformans, either alone or in combination with either
echinocandin antifungal. MK-0991, LY303366, and amphotericin B
displayed a prolonged PAFE of greater than 12 h against
Candida spp. when tested at concentrations above the MIC
for the organism and 0 to 2 h when tested at concentrations below
the MIC for the organism.
| |
TEXT |
As the frequency of fungal
infections increases, there is a need for new antifungal agents and
increased understanding of the pharmacodynamic properties of these
agents. The echinocandin antifungals represent a new class of
antifungal agents that inhibit fungal growth by inhibition of glucan
synthase, an enzyme responsible for fungal cell wall formation. The
activity of these agents has been described as either fungicidal
or fungistatic, depending on the isolate and test conditions (1,
3). Amphotericin B (AMB), the mainstay of therapy for fungal
infections, is described as having concentration-dependent
fungicidal activity (8). In comparison, the azole
antifungal agents are described as exhibiting concentration-independent fungistatic activity (8).
The postantifungal effect (PAFE) is the suppression of fungal growth
that persists after limited exposure to an antifungal agent. This has
been described for the azole antifungals and AMB, but not for the
echinocandin antifungal agents (10, 12). The PAFE may have
clinical relevance to the design of dosing regimens for new antifungal
agents such as the echinocandins. Antimicrobials with long PAFEs may be
given less frequently than antimicrobials with short PAFEs, which may
require more frequent administration.
We sought to determine the PAFEs of echinocandin antifungals
MK-0991 and LY303366 and compare them to the PAFEs of AMB and fluconazole (FLC). Secondarily, we sought to determine if the addition of an echinocandin antifungal would enhance the relatively short PAFE generally observed with FLC.
(This work was presented at the American College of Clinical Pharmacy
Annual Meeting, Phoenix, Ariz., 9 to 12 November 1997.)
Stock solutions of AMB (Sigma Chemical Company, St. Louis, Mo.),
FLC (Pfizer, Inc., New York, N.Y.), MK-0991 (Merck and Co., Inc.,
Rahway, N.J.), and LY303366 (Eli Lilly and Co., Indianapolis, Ind.)
were prepared in RPMI 1640 medium (Sigma) buffered to a pH of 7.0 with 0.165 M morpholinopropanesulfonic acid (MOPS). All antifungals
were solubilized with less than a 1% (vol/vol) final volume of
dimethyl sulfoxide.
One clinical isolate, OY31.5, and one American Type Culture Collection
isolate, 90028, of Candida albicans were selected for study
based upon extensive experience with these isolates in our laboratory.
Two clinical isolates of Cryptococcus neoformans were also
selected for study because of our experience with the growth characteristics of these isolates. All isolates were obtained from the
Molecular Epidemiology and Fungus Testing Laboratory, Department
of Pathology, University of Iowa College of Medicine, Iowa City.
Isolates were stored in sterile water, and each isolate was grown on
potato dextrose agar and subcultured twice prior to testing.
MICs of FLC, MK-0991, LY303366, and AMB were determined by using broth
microdilution methods according to National Committee for Clinical
Laboratory Standards guidelines (M27-A) (11). The endpoint
for the MICs of FLC, MK-0991, and LY303366 was 80% inhibition of
growth compared to the control, determined by visual inspection (3, 5). The endpoint for the MIC of AMB was complete
inhibition of visible growth (11). All MICs were measured in
RPMI with MOPS medium (Sigma) and results were read after 48 h of incubation for C. albicans and 72 h of
incubation for C. neoformans in a dark, moist chamber at
35°C.
The method used for determining the PAFE in C. albicans was
based on the methods used for bacteria and our previous experience with
antifungal time-kill methodology (2-4, 6-9). A fungal
suspension was prepared by transfer of three to five colonies of test
isolate from a 48-h-old culture plate into 9 ml of sterile water and
adjusting it to a 0.5 McFarland turbidity standard. One milliliter of
this fungal suspension was added to vials containing culture medium alone or with study drug at concentrations ranging from 0.125 to 4.0 times the MIC. Following an incubation period ranging from 0.25 h
to 1.0 h, colony counts were conducted, and the study drug was
removed by a process of three cycles of repeated centrifugation and
washing with normal saline. After the final centrifugation, the fungal
pellet was resuspended in 10 ml of warm medium, and colony counts were
repeated at 2, 4, 6, 8, 10, 12, and 24 h after the final wash. A
100-µl sample was obtained from the culture vial and diluted with
sterile water, and 30 µl was plated on potato dextrose agar for
colony counting. The lower limit of accurately detectable CFU per
milliliter by these methods is 50 (7). Procedures for
C. neoformans were similar to those used for C. albicans, except the drugs were studied alone and in combination
at only one drug concentration (FLC, two times the MIC; MK-0991, 80 µg/ml; LY303366, 80 µg/ml). A single drug concentration was
selected because the echinocandin antifungals do not demonstrate
appreciable activity alone in vitro against C. neoformans
(MIC, >2 µg/ml). Since FLC did not demonstrate a PAFE against
C. albicans at any concentration tested, a single
concentration was selected for testing against C. neoformans. Isolates of C. neoformans were incubated at
30°C for optimal growth. All experiments were conducted in duplicate.
Plots of averaged colony counts (log10 CFU per milliliter)
versus time were constructed and compared against a growth control. PAFE was calculated as the difference in time required for control and
test isolates to grow 1 log10 following the final cell wash.
Both of the C. albicans isolates were susceptible to the AMB
and FLC (Table 1). The C. neoformans isolates had MICs of 4.0 (susceptible) and >2.0
µg/ml for FLC and the echinocandin antifungals, respectively.
Yeast exposed to FLC for 1 h did not display any measurable PAFE
when tested at concentrations of one to four times the MIC. As a
result, concentrations below the MIC and shorter exposure times were
not used with FLC. In contrast, MK-0991, LY303366, and AMB displayed a
prolonged PAFE (>12 h) following exposure for 1 h at
concentrations greater than or equal to the MIC of the organism (Table
2). At concentrations below the
MIC, exposure to MK-0991 for 1 h resulted in no observable
PAFE. In contrast, C. albicans exposed to LY303366
concentrations below the MIC displayed a prolonged PAFE of greater than
12 h following exposure for 1 h. For the 1-h exposure time
and concentrations below the MIC, the PAFE of AMB ranged from 2 to >12
h. Concentrations above the MICs of MK-0991, LY303366, and AMB resulted
in prolonged PAFEs of >12 h. In order to investigate the effect of
exposure time on the observed PAFE, MK-0991, and AMB were also tested
at 0.25- and 0.5-h exposure times. For yeast exposed to MK-0991 or AMB at concentrations above the MIC for 0.25 h there was a prolonged PAFE of >12 h. The PAFE observed for MK-0991 following an exposure time of 0.5 h was 0 to 2 h for concentrations below the MIC
and >12 h for concentrations above the MIC (Fig.
1). AMB displayed no observable PAFE at
the lowest concentration tested (0.125 times the MIC). Because AMB
produced fungicidal activity at all other concentrations tested, the
PAFE could not be determined (Fig. 2). FLC did not display a measurable
PAFE against C. neoformans alone or in combination
with the echinocandin antifungal agents (Fig.
3).
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TABLE 2.
PAFE after 1.0 h of drug exposure time for
concentrations ranging from 0.125 to 4.0 times the MIC for C. albicans OY31.5 and 90028
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FIG. 1.
PAFE of MK-0991 in C. albicans 90028 following 0.5 h of exposure to the drug at various concentrations.
 , control;  , 0.125 times the MIC;  , 0.25 times the MIC;  ,
0.5 times the MIC;  , 1 times the MIC;  , 2 times the MIC;  , 4 times the MIC.
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FIG. 2.
PAFE of AMB in C. albicans 90028 following
0.5 h of drug exposure at various concentrations. , control;
, 0.125 times the MIC; , 0.25 times the MIC; , 0.5 times the
MIC; , 1 times the MIC; , 2 times the MIC; , 4 times the
MIC.
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FIG. 3.
PAFE of FLC, MK-0991, and LY303366 alone and in
combination in C. neoformans 1450. , control; , FLC;
, MK-0991; , LY303366; , FLC plus MK-0991; , FLC plus
LY303366.
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We have investigated the effect of concentration and exposure time on
the PAFEs of three different classes of antifungal agents. FLC did not
produce a measurable PAFE against C. albicans or C. neoformans regardless of concentration. This finding is consistent with previously published reports of the PAFEs of the azole
antifungals, including FLC (10, 12). In contrast, the
echinocandin antifungal MK-0991 displayed long PAFEs which were
dependent on concentration. Concentrations below the MIC produced a
very short PAFE (0 to 2 h) compared to concentrations above the
MIC, which produced consistently prolonged PAFEs of >12 h. The
prolonged PAFE observed was not affected by the exposure time, such
that exposure for 0.25 h to the antifungal produced the same PAFE
as exposure for 1 h. In comparison, LY303366, also an echinocandin
antifungal, generally produced long PAFEs even at concentrations below
the MIC for the organism, with the exception of C. albicans
90028, which at a concentration of 0.125 times the MIC produced no
measurable PAFE. We did not test shorter exposure times with LY303366.
It is possible that the variability in PAFE between these two compounds of the same antifungal class may result from imperfections in determining the MIC for an organism. That is, if the MIC used for
determining the PAFE was 1 doubling dilution higher than the true MIC,
then subinhibitory concentrations may actually be at or above the true
MIC for the organisms, resulting in a longer observed PAFE. The
addition of an echinocandin with FLC did not increase the PAFE against
C. neoformans. AMB produced fungicidal activity at
concentrations above the MIC regardless of the exposure time;
therefore, it was not possible to calculate the PAFE under these
conditions. The observed PAFE with AMB was shorter with concentrations
below the MIC than with higher concentrations. This is consistent with
the previously published reports of the PAFE of AMB (12).
This is the first published study of the PAFE produced by the
echinocandin antifungal agents. Interestingly, the echinocandins and
AMB, both of which have been described as exhibiting fungicidal activity, displayed PAFEs which were prolonged and dose dependent. In
comparison, the azole antifungal FLC, which is fungistatic, does not
produce a measurable PAFE against C. albicans or C. neoformans. The significant PAFEs observed with the echinocandin
antifungal agents may have clinical relevance, but additional animal
studies and human clinical trials are necessary to substantiate these observations.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: The University
of Iowa, College of Pharmacy, S428 Pharmacy Building, Iowa City, IA 52242. Phone: (319) 335-8785. Fax: (319) 353-5646. E-mail:
erika-ernst{at}uiowa.edu.
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Antimicrobial Agents and Chemotherapy, April 2000, p. 1108-1111, Vol. 44, No. 4
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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