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Antimicrobial Agents and Chemotherapy, May 2000, p. 1242-1246, Vol. 44, No. 5
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
In Vitro Activity of A-192411.29, a Novel Antifungal
Lipopeptide
Angela M.
Nilius,*
Patti M.
Raney,
Dena M.
Hensey-Rudloff,
Weibo
Wang,
Qun
Li, and
Robert K.
Flamm
Infectious Diseases Research, Abbott
Laboratories, Abbott Park, Illinois 60064-3537
Received 2 September 1999/Returned for modification 7 October
1999/Accepted 7 February 2000
 |
ABSTRACT |
A-192411.29 is a novel antifungal agent derived from the structural
template of the natural product echinocandin. The in vitro activity of
A-192411.29 against common pathogenic yeasts was assessed by National
Committee for Clinical Laboratory Standards method M27-A. It
demonstrated broad-spectrum, fungicidal activity and was active against
the most clinically relevant yeasts, such as Candida
albicans, Candida tropicalis, and Candida
glabrata, as well as less commonly encountered
Candida species; in general, its potency on a weight basis
was comparable to that of amphotericin B. It maintained potent in vitro
activity against Candida strains with reduced
susceptibilities to fluconazole and amphotericin B. The in vitro
activity of A-192411.29 against Cryptococcus neoformans was
comparable to its activity against Candida spp. However,
A-192411.29 did not demonstrate complete growth inhibition of
Aspergillus fumigatus by the broth microdilution method
used. A-192411.29 possesses an antifungal profile comparable to or
better than those of fluconazole and amphotericin B against pathogenic
yeasts, including strains resistant to fluconazole or amphotericin B,
suggesting that it may be a therapeutically useful new antifungal drug.
| |
INTRODUCTION |
Serious fungal infections are
increasingly recognized as important causes of morbidity and mortality,
especially among debilitated patients. Immunosuppression due to
malignancy, immunosuppressive and cytotoxic therapies, human
immunodeficiency virus infection, and age as well as procedures which
cause breaks in skin and mucosal barriers and broad-spectrum
antibacterial treatment place patients at risk for fungal infections.
In a recent survey of nosocomial bloodstream isolates,
Candida species, predominately Candida albicans, were the fourth most prevalent group of pathogens and were isolated from 8.0% of all patients with nosocomial bloodstream infections (7). Candida spp. are also identified as critical
pathogens in infections of wounds and sterile body fluids
(10). In human immunodeficiency virus-infected patients,
mucosal infections such as oropharyngitis, esophagitis, and vaginitis
caused by Candida spp. and meningeal, lung, and blood
infections caused by Cryptococcus neoformans are very common
(3, 12). Aspergillosis and other opportunistic mycoses are
also significant infections in immunocompromised patients, although
they are less common than infections with yeasts (2, 3).
Options for treatment of serious fungal infections are primarily
azole-class compounds and amphotericin B. However, the widespread and
prolonged use of azole antifungal agents, especially fluconazole, has
increased the prevalence of azole-resistant strains in patients with
mucosal candidiasis and fungemia (7, 10, 12, 14). The
reduced susceptibility of yeasts to amphotericin B is also identified
as a clinical problem for the treatment of fungemia (13,
15). Moreover, current treatment for opportunistic mold infections is limited to amphotericin B and itraconazole
(19). Thus, new antifungal agents are needed.
A-192411.29 is a novel antifungal agent derived by total synthesis from
the structural template of the natural product echinocandin (Fig.
1) (4; Q. Li,
unpublished data). A-192411.29 inhibited C. albicans
-1,3-glucan synthesis by targeting the fungal
1,3--D-glucan synthase complex and disrupting the
fungal cell wall (D. Frost, unpublished data), a mechanism of
action shared by other members of the lipopeptide class of
antifungal agents such as MK-0991 (capsofungin) (4),
LY-303366 (J. Tang, T. R. Parr, Jr., W. Turner, M. Debono,
L. Lagrandeur, F. Burkhardt, M. Rodriguez, M. Zweifel,
J. Nissen, and K. Clingerman, Program Abstr. 33rd Intersci. Conf.
Antimicrob. Agents Chemother., abstr. 367, p. 186, 1993), and FK-463
(17). A-192411.29 demonstrated in vitro activity equivalent
to that of amphotericin B in early studies and effectively treated
systemic candidiasis in a mouse infection model (J. Meulbroek,
unpublished data). In this report, we describe the antifungal spectrum
and potency of A-192411.29.
| |
MATERIALS AND METHODS |
Strains.
Fungal stains were from the Abbott Laboratories
clinical isolate collection or were purchased from the American Type
Culture Collection (Manassas, Va.). Quality control strains
Candida parapsilosis ATCC 22019, Candida krusei
ATCC 6258, and C. albicans ATCC 90028 were included in each
test as recommended by the National Committee for Clinical Laboratory
Standards (NCCLS).
Antifungal agents.
A-192411.29 and fluconazole were
synthesized at Abbott Laboratories. Amphotericin B was purchased from
Bristol-Meyers Squibb (Wallingford, Conn.). A-192411.29 was dissolved
in either dimethyl sulfoxide or distilled H2O, amphotericin
B was dissolved in dimethyl sulfoxide, and fluconazole was dissolved in
distilled H2O.
Susceptibility tests.
Susceptibility determinations for
yeasts were made by the broth microdilution method as described in
NCCLS document M27-A (8). Yeasts used as inocula for the
tests were grown overnight on Sabouraud dextrose agar (Becton Dickinson
Microbiology Systems, Cockeysville, Md.) at 35°C; C. neoformans, however, was grown for 48 h. Tests were performed
in RPMI 1640 (Gibco BRL, Gaithersburg, Md.) buffered to pH 7.0 with
0.165 mol of morpholinepropanesulfonic acid (MOPS; Sigma Chemical Co.,
St. Louis, Mo.) per liter. A-192411.29 and amphotericin B MICs were
determined to be the lowest drug concentration that inhibited visible
fungal growth. Fluconazole MICs were determined to be the lowest drug
concentration that inhibited fungal growth by at least 80% compared
with the growth in drug-free medium. For determination of medium
effects, buffered RPMI 1640 supplemented with 20 g of glucose per
liter, yeast nitrogen broth (pH 7.0; Difco Laboratories, Detroit,
Mich.) supplemented with 5 g of glucose per liter, antibiotic
medium 3 (Becton Dickinson Microbiology Systems), and Sabouraud
dextrose broth (Difco Laboratories) were substituted for the buffered
RPMI 1640 recommended by NCCLS in document M27-A (6). For
determination of inoculum effects, NCCLS document M27-A (6)
was followed, except that strains were suspended to a turbidity
equivalent to that of a 0.5 McFarland standard in 0.9% (wt/vol) NaCl
and were further diluted in 0.9% NaCl to achieve the desired inoculum
levels. Inoculum densities were verified by determining the number of
viable colonies per milliliter on the Sabouraud dextrose agar after
serial dilutions in 0.9% NaCl.
For
C. albicans, fluconazole MICs were determined by the
Etest method on RPMI 1640 buffered to pH 7.0 with 0.165 mol of MOPS
per
liter and supplemented with 20 g of glucose per liter and
15 g of Bacto Agar (Difco Laboratories) per liter by following
the
manufacturer's directions (Antifungal susceptibility testing
of
yeasts, technical guide 4, AB Biodisk, Solna, Sweden, 1997;
Media for
antifungal susceptibility testing of yeasts and moulds,
Etest customer
information sheet no. 5, AB Biodisk, Solna, Sweden).
Fluconazole Etest
strips were purchased from AB Biodisk (Piscataway,
N.J.). The tests
were incubated at 35°C for 24 to 48 h. MICs were
determined at
the intersection of the ellipse that demarcates
significantly reduced
growth by use of the printed scale (
11;
Antifungal
susceptibility testing of yeasts, technical guide 4,
AB Biodisk, Solna,
Sweden).
The susceptibilities of the
A. fumigatus isolates were
determined by the broth microdilution method. Cultures were grown on
Sabouraud dextrose agar at 35°C until sporulation occurred, typically
72 h. Stock spore suspensions were harvested with yeast nitrogen
broth (pH 7.0) supplemented with 5 g of glucose per liter and
25%
(vol/vol) glycerol and were stored at 4°C until use. The numbers
of
CFU per milliliter were determined by plating serial dilutions
of the
stock suspension on Sabouraud dextrose agar. Before inoculation
for the
susceptibility tests, the spore suspensions were diluted
to achieve
2 × 10
4 to 2 × 10
5 CFU/ml in yeast
nitrogen broth plus 0.5% glucose (pH 7.0) and
were incubated for
24 h at 35°C to germinate the spores. Serial
twofold dilutions
of antibiotics were made in yeast nitrogen broth
plus 0.5% glucose in
100-µl volumes and were inoculated with 100
µl of the germinated
spore suspensions. Incubation was for 72
h at 35°C. MICs were
determined as the lowest concentration that
inhibited visible fungal
growth.
Time-kill analysis.
C. albicans CCH442 was grown
overnight at 35°C on Sabouraud dextrose agar. Isolated colonies were
selected and suspended in 0.9% NaCl to a turbidity equivalent to that
of a 0.5 McFarland standard. Flasks that contained RPMI 1640 buffered
with 0.165 mol of MOPS per liter to pH 7.0 plus test antibiotics at
four times the MIC or no antibiotic (growth control) were prepared. The
flasks were inoculated with the yeast suspension to a final concentration of approximately 105 CFU/ml. The cultures
were incubated at 35°C with shaking for up to 24 h. At the
indicated times, aliquots were removed and the numbers of viable
colonies per milliliter were determined on Sabouraud dextrose agar
after serial dilutions in 0.9% NaCl.
| |
RESULTS AND DISCUSSION |
In vitro activity of A-192411.29.
The in vitro activity of
A-192411.29 was assessed against 124 strains of yeast (Table
1). A-192411.29 was as active as
amphotericin B against 41 strains of C. albicans; all
strains were inhibited by 
1 µg/ml. A-192411.29 was also as active
as amphotericin B against Candida glabrata, Candida
tropicalis, C. krusei, Candida lusitaniae,
and Candida stellatoidea; all 64 isolates were inhibited by
4 µg/ml. C. parapsilosis, Candida kefyr, and
Candida guillermondii were also inhibited by A-192411.29 at
4 µg/ml, although amphotericin B was slightly more active than
A-192411.29 against these species. Although there was variation in
susceptibility to A-192411.29 in the group of strains tested, with MICs
ranging from 0.25 to 4 µg/ml, no highly resistant strains were
detected. Therefore, A-192411.29 demonstrates broad-spectrum and potent
antifungal activity against pathogenic Candida spp.
A-192411.29 was highly active against fluconazole-resistant
Candida spp. A-192411.29 was as potent against
fluconazole-resistant
C. albicans strains as it was against
fluconazole-susceptible
strains. The MICs at which 90% of strains are
inhibited (MIC
90s)
for A-192411.29, as determined by the
broth microdilution method,
were 0.5 and 1 µg/ml for
fluconazole-resistant and -susceptible
strains, respectively, with
corresponding fluconazole MIC
90s of
>256 and 0.38 µg/ml,
respectively, as determined by the Etest
method. Similarly,
C. glabrata and
C. krusei strains that demonstrated
reduced fluconazole susceptibilities were highly susceptible to
A-192411.29. As determined by the broth microdilution methods,
the MIC
90s of A-192411.29 were 2 µg/ml for both species,
while
the fluconazole MIC
90s were >128 µg/ml for
C. glabrata and >32
µg/ml for
C. krusei.
As the current NCCLS method is unable to adequately identify
amphotericin B resistance, we independently determined the
susceptibility
of
C. albicans to amphotericin B by testing
in antibiotic medium
3 (
15). The amphotericin B MIC for one
resistant strain in our
collection was 64 µg/ml in antibiotic medium
3, while the MIC
range for 31 other strains was 0.12 to 0.25 µg/ml.
The MIC of
A-192411.29 for this amphotericin B-resistant strain of
C. albicans by the NCCLS methodology was 1 µg/ml and was
indistinguishable
from the MICs of A-192411.29 for the amphotericin
B-susceptible
strains, which ranged from 0.25 to 1 µg/ml.
The in vitro anti-
Candida activities of three other
echinocandin-class antifungal compounds have been evaluated by the
NCCLS
method described in document M27-A (
1,
9,
17,
18,
20).
On the basis of a comparison of the results for M-0991, LY-303366,
and
FK-463 reported in the literature and the results for A-192411.29
presented in this report, A-192411.29 appears to be slightly less
active in vitro (two-to fourfold) than M-0991 and LY-303366 (
1,
9,
18,
20), while FK-463 appears to be more active than
M-0991 and
LY-303366 (
17).
The three isolates of
C. neoformans tested were susceptible
to A-192411.29 at 4 µg/ml (Table
1). In contrast, MK-0991, LY-303366,
and FK-463 have little activity against
C. neoformans in
vitro.
The reported MIC
90s for
C. neoformans are
32 µg/ml for MK-0991
(
1), >10.24 µg/ml for LY-303366
(
20), and >64 µg/ml for FK-463
(
17). MK-0991,
LY303366, and FK-463 are possibly poorer inhibitors
of the synthesis of
the glucans present in the
C. neoformans cell
wall such as
-(1,3)-
D-glucan,
-(1-6)-glucan, or
-(1,6)-glucan,
while they are effective inhibitors of the synthesis of
-(1,3)-
D-glucan
found in the cell walls of
Candida spp. (
1,
4,
17,
20).
The similar in vitro
activity of A-192411.29 against
C. neoformans and
Candida spp. suggests that the compound may effectively
inhibit
the synthesis of
C. neoformans cell wall
glucans.
A-192411.29 was fungicidal against clinical isolate
C. albicans CCH442 by time-kill analysis (Fig.
2). The MICs obtained with
the larger
inoculum required to detect fungicidal activity were
0.12 µg/ml for
A-192411.29 and 0.25 µg/ml for amphotericin B.
When the two compounds
were tested at four times their respective
MICs, A-192411.29 caused a
99.2 to 99.8% loss of yeast viability
after 4 h of incubation,
while amphotericin B caused a >99.9%
loss of viability after 1 h
of incubation. Fungicidal activity
is an advantage of fungal cell wall
synthesis inhibitors of the
lipopeptide class like A-192411.29,
MK-0991, LY-303366, and FK-463
(
1,
17,
19,
20). Cell lysis
and subsequent cell death
result from an inability of the weakened cell
wall to maintain
protoplast integrity under the stress between high
internal and
low external osmotic pressures (
4).
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|
FIG. 2.
Time-kill analysis of A-192411.29 and amphotericin B at
antibiotic concentrations equal to four times the MIC for C. albicans CCH 442.  , drug-free control;  , A-192411.29, 0.5 µg/ml;  , amphotericin B, 1 µg/ml.
|
|
A-192411.29 did not have detectable activity against the seven strains
of
A. fumigatus tested by use of pregerminated spores
in
yeast nitrogen broth supplemented with glucose. The MICs, defined
as
complete inhibition of mycelial growth, for the seven strains
were all
>100 µg/ml, while the MICs of amphotericin B ranged from
0.39 to
0.78 µg/ml. Substantially inhibited growth at sub-MICs
of A-192411.29
was not detected visually for any strain tested
by this method.
Significant growth inhibition is reported for
MK-0991 (
1,
5,
8), LY-303366 (
8,
20), and FK-463
(
17) at
sub-MICs by other test methods and is suggested to be
therapeutically
relevant on the basis of data obtained with animal
models. Our method
for susceptibility testing might result in
the lack of detectable in
vitro activity for A-192411.29 against
A. fumigatus.
Alternatively, A-192411.29 might be inherently less
active against
A. fumigatus than MK-0991, LY-303366, and FK-463.
Concurrent
testing of the three lipopeptides by the same in vitro
method,
demonstration of similar microscopic changes in mycelial
morphology as
a result of treatment with the three compounds (
5),
or
evidence of the efficacy of A-192411.29 in an animal model
of invasive
aspergillosis is needed to resolve this
point.
Effect of test method on in vitro activity of A-192411.29.
The
test method can affect the determination of antifungal activity
(15, 16). NCCLS recommends the use of RPMI 1640 buffered to
pH 7.0 with MOPS as the test medium, and this may be supplemented with
20 g of glucose per liter (6). We compared the in vitro activity of A-192411.29 against seven strains of Candida in
RPMI 1640 supplemented with glucose, yeast nitrogen broth supplemented with glucose, antibiotic medium 3, and Sabouraud dextrose broth with
its activity in RPMI 1640 (Table 2). The
addition of glucose to RPMI 1640 did not alter the activity of
A-192411.29. The MICs of A-192411.29 were approximately fourfold higher
in yeast nitrogen broth than in RPMI 1640. In contrast, the MICs of
A-192411.29 were about eightfold lower in antibiotic medium 3 and
Sabouraud dextrose broth than in RPMI 1640. Similar results are
reported for the lipopeptide LY-303366, which is also more active in
antibiotic medium 3 than in RPMI 1640 (9). Amphotericin B
was used as a control, and our results (data not shown) are similar to
those reported previously (15); namely, amphotericin B was
most active in antibiotic medium 3 and Sabouraud dextrose broth and the
amphotericin B-resistant strain was clearly distinguished from the
amphotericin B-susceptible strains in antibiotic medium 3 and Sabouraud
dextrose broth but not in RPMI 1640-based medium.
Overall, the density of the inoculum did not significantly affect the
in vitro activity of A-192411.29 against two species
of
Candida. The MICs of A-192411.29 for two strains of
C. albicans ranged from 0.06 to 0.25 µg/ml, with no relationship
between the
MIC and the inoculum density for inocula of
10
3, 10
4, and 10
5 CFU/ml. For a
single strain of
C. krusei, the MICs were 0.5 µg/ml
for
all three inoculum densities. For
C. parapsilosis, there was
a trend to higher MICs with an increased inoculum density; the
MICs
were 1, 2, and 4 µg/ml for inocula of 10
3,
10
4, and 10
5 CFU/ml, respectively, for a single
strain. The activity of amphotericin
B in our study was not affected by
the inoculum density for any
strain.
New antifungal agents are needed because of the importance of fungal
infections in compromised patients, the limitations of
currently
available antifungal agents regarding their spectra
of activity and
toxicities, and the increasing prevalence of pathogens
resistant to the
current antifungal agents. A-192411.29 is a novel
lipopeptide which
acts by inhibiting cell wall synthesis in fungi.
We have demonstrated
that it has broad-spectrum, fungicidal activity
and is active against
the most clinically relevant yeasts, such
as
C. albicans,
C. tropicalis, and
C. glabrata, as well as less
commonly encountered
Candida species. It was also highly
active
against
Candida strains resistant to fluconazole and
amphotericin
B. In contrast to other lipopeptide antifungal compounds
like
MK-0991 (capsofungin) and LY-303366 (
1,
20) and FK-463
(
17),
A-192411.29 was active in vitro against
C. neoformans. However,
unlike the other echinocandins in clinical
development, A-192411.29
did not demonstrate activity against
A. fumigatus in vitro, although
this may be due to differences in the
susceptibility test methods
used. Since A-192411.29 has been effective
as treatment for systemic
and renal infections caused by
C. albicans in animal models (J.
Meulbroek, unpublished data), it may
be a therapeutically useful
new antifungal
agent.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: D47T, AP52,
Abbott Laboratories, Abbott Park, IL 60064-3537. Phone: (847) 937-7706. Fax: (847) 935-0400. E-mail: angela.nilius{at}abbott.com.
| |
REFERENCES |
| 1.
|
Bartizal, K.,
C. J. Gill,
G. K. Abruzzo,
A. M. Flattery,
L. Kong,
P. M. Scott,
J. G. Smith,
C. E. Leighton,
A. Bouffard,
J. F. Dropinski, and J. Balkovec.
1997.
In vitro preclinical evaluation studies with the echinocandin antifungal MK-0991 (L-743,872).
Antimicrob. Agents Chemother.
41:2326-2332[Abstract].
|
| 2.
|
Fraser, R. S.
1993.
Pulmonary aspergillosis: pathologic and pathogenic features.
Pathol. Ann.
28:231-277.
|
| 3.
|
Hood, S., and D. W. Denning.
1996.
Treatment of fungal infections in AIDS.
J. Antimicrob. Chemother.
37(Suppl. B):71-85.
|
| 4.
|
Kurtz, M. B., and C. M. Douglas.
1997.
Lipopeptide inhibitors of fungal glucan synthase.
J. Med. Vet. Mycol.
35:79-86[Medline].
|
| 5.
|
Kurtz, M. B.,
I. B. Heath,
J. Marrinan,
S. Dreikorn,
J. Onishi, and C. Douglas.
1994.
Morphological effects of lipopeptides against Aspergillus fumigatus correlate with activities against (1,3)--D-glucan synthase.
Antimicrob. Agents Chemother.
38:1480-1489[Abstract/Free Full Text].
|
| 6.
|
National Committee for Clinical Laboratory Standards.
1997.
Reference method for broth dilution antifungal susceptibility testing of yeasts; approved standard. M27-A.
National Committee for Clinical Laboratory Standards, Wayne, Pa.
|
| 7.
|
Pfaller, M. A.,
R. N. Jones,
S. A. Messer,
M. B. Edmond, and R. P. Wenzel.
1998.
National surveillance of nosocomial blood stream isolates due to Candida albicans: frequency of occurrence and antifungal susceptibility in the SCOPE program.
Diagn. Microbiol. Infect. Dis.
31:327-332[CrossRef][Medline].
|
| 8.
|
Pfaller, M. A.,
F. Marco,
S. A. Messer, and R. N. Jones.
1998.
In vitro activity of two echinocandin derivatives, LY303366 and MK-0991 (L-743,792) against clinical isolates of Aspergillus, Fusarium, Rhizopus, and other filamentous fungi.
Diagn. Microbiol. Infect. Dis.
30:251-255[CrossRef][Medline].
|
| 9.
|
Pfaller, M. A.,
S. A. Messer, and S. Coffen.
1997.
In vitro susceptibilities of clinical yeast isolates to a new echinocandin derivative, LY303366, and other antifungal agents.
Antimicrob. Agent Chemother.
41:763-766[Abstract].
|
| 10.
|
Pfaller, M. A.,
S. A. Messer,
A. Houston,
M. S. Rangel-Frausto,
T. Wiblin,
H. M. Blumberg,
J. E. Edwards,
W. Jarvis,
M. A. Martin,
H. C. Neu,
L. Saiman,
J. E. Patterson,
J. C. Dibb,
C. M. Roldan,
M. G. Rinaldi, and R. P. Wenzel.
1998.
National epidemiology of mycoses survey: a multicenter study of strain variation and antifungal susceptibility among isolates of Candida species.
Diagn. Microbiol. Infect. Dis.
31:289-296[CrossRef][Medline].
|
| 11.
|
Pfaller, M. A.,
S. A. Messer,
Å. Karlsson, and A. Bolmström.
1998.
Evaluation of the Etest method for determining fluconazole susceptibilities of 402 clinical yeast isolates by using three different agar media.
J. Clin. Microbiol.
36:2586-2589[Abstract/Free Full Text].
|
| 12.
|
Powderly, W. G.
1994.
Resistant candidiasis.
AIDS Res. Hum. Retrovir.
10:925-929[Medline].
|
| 13.
|
Powderly, W. G.,
G. S. Kobayashi,
G. P. Herzig, and G. Medoff.
1988.
Amphotericin B-resistant yeast infection in severely immunocompromised patients.
Am. J. Med.
84:826-832[CrossRef][Medline].
|
| 14.
|
Price, M. F.,
M. T. LaRocco, and L. O. Gentry.
1994.
Fluconazole susceptibilities of Candida spp. and distribution of species recovered from blood cultures over a 5-year period.
Antimicrob. Agents Chemotherap.
38:1422-1424[Abstract/Free Full Text].
|
| 15.
|
Rex, J. H.,
C. R. Cooper, Jr.,
W. G. Merz,
J. N. Galgiani, and E. J. Anaissie.
1995.
Detection of amphotericin B-resistant Candida isolates in a broth-based system.
Antimicrob. Agents Chemother.
39:906-909[Abstract].
|
| 16.
|
Rex, J. H.,
M. A. Pfaller,
M. G. Rinaldi,
A. Polak, and J. N. Galgiani.
1993.
Antifungal susceptibility testing.
Clin. Microbiol. Rev.
6:367-381[Abstract/Free Full Text].
|
| 17.
|
Tawara, S.,
F. Ikeda,
K. Maki,
Y. Morishita,
K. Otomo,
N. Teratani,
T. Goto,
M. Tomishima,
H. Ohki,
A. Yamada,
K. Kawabata,
H. Takasugi,
K. Sakane,
H. Tanaka,
F. Matsumoto, and S. Kuwahara.
2000.
In vitro activities of a new lipopeptide antifungal agent, FK463, against a variety of clinically important fungi.
Antimicrob. Agents Chemother.
44:57-62[Abstract/Free Full Text].
|
| 18.
|
Vasquez, J. A.,
M. Lynch,
D. Boikov, and J. D. Sobel.
1997.
In vitro activity of a new pneumocandin antifungal, L-743,872, against azole-susceptible and -resistant Candida species.
Antimicrob. Agents Chemother.
41:1612-1614[Abstract].
|
| 19.
|
Warnock, D. W.
1995.
Fungal complications of transplantation: diagnosis, treatment, and prevention.
J. Antimicrob. Chemother.
36(Suppl. B):73-90.
|
| 20.
|
Zhanel, G. G.,
J. A. Karlowsky,
G. A. J. Harding,
T. V. Balko,
S. A. Zelenitsky,
M. Friesen,
A. Kabani,
M. Turik, and D. J. Hoban.
1997.
In vitro activity of a new semisynthetic echinocandin, LY-303366, against systemic isolates of Candida species, Cryptococcus neoformans, Blastomyces dermatitidis, and Aspergillus species.
Antimicrob. Agents Chemother.
41:863-865[Abstract].
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Antimicrobial Agents and Chemotherapy, May 2000, p. 1242-1246, Vol. 44, No. 5
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
