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Antimicrobial Agents and Chemotherapy, October 2001, p. 2862-2864, Vol. 45, No. 10
Department of Pathology, University of Iowa
College of Medicine, Iowa City,1 and
The Jones Group/JMI Laboratories, North
Liberty,2 Iowa
Received 11 June 2001/Returned for modification 27 June
2001/Accepted 13 July 2001
Posaconazole is a new investigational triazole with
broad-spectrum antifungal activity. The in vitro activities
of posaconazole were compared with those of itraconazole and
fluconazole against 3,685 isolates of Candida spp.
(3,312 isolates) and C. neoformans (373 isolates)
obtained from over 70 different medical centers worldwide. The MICs of
the antifungal drugs were determined by broth microdilution tests
performed according to the National Committee for Clinical Laboratory
Standards method using RPMI 1640 as the test medium. Posaconazole was
very active against all Candida spp. (MIC at which 90%
of the isolates were inhibited [MIC90], 0.5 µg/ml; 97%
of MICs were The triazole antifungal agents
fluconazole and itraconazole offer several advantages over amphotericin
B, including decreased toxicity and the versatility of oral and
intravenous administration, and they are frequently used in the
treatment of fungal infections due to Candida spp.,
Cryptococcus neoformans, and miscellaneous yeast species
(14). However, failure of fluconazole and
itraconazole therapy has been reported, and acquired or intrinsic
resistance to these agents is well known (12, 16). There
is clearly a need for additional agents with an enhanced potency and
spectrum of activity to improve the treatment of fungal infections.
Posaconazole (Sch 56592) is an investigational triazole antifungal
agent that is presently in Phase III clinical trials. Posaconazole exhibits linear pharmacokinetics and has demonstrated comparable safety
and efficacy to those of fluconazole in both human and animal studies
(3, 7, 8, 10; A. Catanzaro, G. Cloud, D. Stevens, B. Levine, P. Williams, et al., 40th Intersci. Conf. Antimicrob.
Agents Chemother., abstr. 1417, 2000; R. Y. Hachem, I. I. Raad, C. M. Afif, R. Negroni, J. Graybill, et al., 40th Intersci. Conf. Antimicrob. Agents Chemother., abstr. 1109, 2000; L. Nieto, R. Northland, P. Pittisuttithum, C. Firnhaber, S. Jacobson, et al., 40th Intersci. Conf. Antimicrob. Agents Chemother.,
abstr. 1108, 2000; J. A. Vazquez, R. Northland, S. Miller, G. Dickinson, and G. Wright, 40th Intersci. Conf. Antimicrob. Agents
Chemother., abstr. 1107, 2000). In vitro studies have documented a
potency and spectrum of activity similar to those of itraconazole and superior to those of fluconazole against clinically important isolates of Candida spp., C. neoformans,
and Aspergillus spp. (1, 3-5, 8-11).
Because previous in vitro studies have included a limited number of
isolates of various yeast species and have generally been restricted in
terms of the geographic distribution of the tested strains, we
determined the in vitro activities of posaconazole against an
international collection (from more than 70 institutions in 22 nations)
of 3,685 clinical isolates of Candida spp. (14 species,
3,312 isolates) and C. neoformans (373 isolates). The comparison agents tested were the licensed triazole antifungal agents
fluconazole and itraconazole. The in vitro susceptibility testing
method employed was the microdilution broth method described in the
National Committee for Clinical Laboratory Standards (NCCLS) document
M27-A (6).
Organisms.
A total of 3,685 clinical isolates of
Candida spp. (3,312 isolates) and C. neoformans
(373 isolates) obtained from more than 70 different medical centers in
North America, South America, and Europe were tested. The collection of
isolates included 1,992 C. albicans, 421 C. glabrata, 468 C. parapsilosis, 243 C. tropicalis, 70 C. dubliniensis, 20 C. guilliermondii, 12 C. famata, 47 C. krusei,
24 C. lusitaniae, 6 C. kefyr, 4 C. rugosa, 2 C. lambica, and 2 C. inconspicua
isolates and 1 C. lipolytica isolate. The isolates
were all recent clinical isolates and the majority were from blood or
normally sterile body fluids. Only the C. dubliniensis isolates were from mucosal sites. The isolates were identified by
standard methods (15) and were stored as water suspensions until they were used. Prior to testing, each isolate was passaged at
least twice on potato dextrose agar (Remel, Lenexa, Kans.) to ensure
optimal growth characteristics.
Antifungal agents.
Standard antifungal powders of
posaconazole (Sch 56592; Schering-Plough), fluconazole (Pfizer), and
itraconazole (Janssen) were obtained from their respective
manufacturers. Stock solutions were prepared in polyethylene glycol
(posaconazole and itraconazole) or water (fluconazole). Serial twofold
dilutions were prepared exactly as outlined in NCCLS document M27-A
(6). Final dilutions were made in RPMI 1640 medium (Sigma,
St. Louis, Mo.) buffered to pH 7.0 with 0.165 M
morpholinepropanesulfonic acid (MOPS) buffer (Sigma). The final
concentration of solvent did not exceed 1% in any well. Aliquots (0.1 ml) of each antifungal agent at a 2× final concentration were
dispensed into the wells of plastic microdilution trays by using a
Quick Spense II system (Dynatech Laboratories, Chantilly, Va.). The
trays were sealed and frozen at Antifungal susceptibility studies.
Broth microdilution
testing was performed in accordance with the guidelines in NCCLS
document M27-A (6) by using the spectrophotometric method
of inoculum preparation, an inoculum concentration of (1.5 ± 1.0) × 103 cells/ml, and RPMI 1640 medium
buffered to pH 7.0 with MOPS. A 100-µl yeast inoculum was added to
each well of the microdilution trays. The final concentrations of the
antifungal agents were 0.007 to 8.0 µg/ml for posaconazole and
itraconazole and 0.12 to 128 µg/ml for fluconazole. The trays were
incubated at 35°C, and MIC endpoints were read after 48 h of
incubation (for both Candida spp. and C. neoformans). Drug-free and yeast-free controls were included.
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.10.2862-2864.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
In Vitro Activities of Posaconazole (Sch
56592) Compared with Those of Itraconazole and Fluconazole against
3,685 Clinical Isolates of Candida spp. and
Cryptococcus neoformans
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results and Discussion
References
1 µg/ml) and C. neoformans (MIC90, 0.5 µg/ml; 100% of MICs were 1 µg/ml).
Candida albicans was the most susceptible species of
Candida (MIC90, 0.06 µg/ml), and
Candida glabrata was the least susceptible
(MIC90, 4 µg/ml). Posaconazole was more active than
itraconazole and fluconazole against all Candida spp.
and C. neoformans. These results provide further
evidence for the spectrum and potency of posaconazole against a large
and geographically diverse collection of clinically important fungal pathogens.
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results and Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results and Discussion
References
70°C until they were used.
Quality control. Quality was controlled by testing the following strains recommended by NCCLS standard M27-A (6): C. parapsilosis ATCC 22019 and C. krusei ATCC 6258 (2).
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RESULTS AND DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results and Discussion
References
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Table 1 summarizes the in vitro
susceptibilities of 3,312 isolates of Candida spp. to
posaconazole, fluconazole, and itraconazole. Overall,
posaconazole was quite active (MIC at which 90% of the isolates
were inhibited [MIC90], 0.5 µg/ml; 97% of
isolates were inhibited by 1 µg/ml). C. albicans and
C. dubliniensis were the most susceptible
(MIC90, 0.06 µg/ml; 99 to 100% of MICs
were 1 µg/ml) and C. glabrata was the least
susceptible (MIC90, 4 µg/ml; 80% of MICs
were 1 µg/ml). Posaconazole was more active than both fluconazole
and itraconazole against all species of Candida. Notably,
100% of C. krusei isolates were inhibited by 0.5 µg of
posaconazole/ml, compared with 72% of isolates being inhibited by
itraconazole.
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Among the 3,312 Candida spp. isolates studied, a total of 76 were resistant to both fluconazole and itraconazole. The MICs of
posaconazole (0.03 to 
8 µg/ml; mode, 8 µg/ml) were also
elevated with these isolates (82% of MICs were 4 µg/ml) (data not
shown). In contrast, among 32 isolates resistant to fluconazole but not itraconazole, 31 (97%) were inhibited by 1 µg/ml of posaconazole. Isolates inhibited by 16 to 32 µg of fluconazole/ml (dose-dependent susceptibility) were all susceptible to 1 µg of posaconazole/ml.
The in vitro susceptibilities of 373 isolates of C. neoformans to posaconazole, fluconazole, and itraconazole are
shown in Table 2. Fluconazole had MICs of
8 µg/ml for 78% of the C. neoformans isolates
tested, 16 to 32 µg/ml for 21% of the isolates, and 64 µg/ml for
1% of the isolates. Overall, posaconazole and itraconazole demonstrated comparable activities (MIC90,
0.5 µg/ml; 100% of isolates were inhibited by 1 µg/ml);
however, 78% of isolates were inhibited by 0.12 µg of
posaconazole/ml versus only 11% with itraconazole.
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Among the isolates of C. neoformans inhibited by 8 µg of
fluconazole/ml, posaconazole was more potent than itraconazole: 96% of
these isolates were inhibited by 0.25 µg of posaconazole/ml and
68% were inhibited by 0.25 µg of itraconazole/ml. Posaconazole was
also more active than itraconazole against the 73 isolates inhibited by
16 to 32 µg of fluconazole/ml. All of these isolates were
inhibited by 0.5 µg of posaconazole/ml and 75% were inhibited by
0.5 µg of itraconazole/ml. Only three isolates required 64 µg of fluconazole/ml to inhibit growth in vitro. For these
isolates, the posaconazole MICs were 0.12, 0.5, and 1 µg/ml and
the itraconazole MICs were 0.5, 1, and 1 µg/ml.
These findings confirm and extend those reported previously regarding
the antifungal activity of posaconazole (1, 3-5, 8-11). Posaconazole was as active or more potent than
either fluconazole or itraconazole against virtually all of the
Candida spp. and C. neoformans isolates tested.
Posaconazole has been reported to be fungicidal against C. neoformans, filamentous fungi, and some Candida species
(4, 8); however, minimum fungicidal concentration
determinations were not performed in the present study. Similar to what
occurred with fluconazole and itraconazole, some trailing was observed
with posaconazole, but this was minimal and did not interfere with MIC
endpoint determinations. Although the MICs of posaconazole for
Candida spp. isolates that were resistant to fluconazole and
itraconazole were also found to be elevated, those isolates resistant
to fluconazole alone and those for which fluconazole MICs were 16 to 32 µg/ml were susceptible to 1 µg of posaconazole/ml.
Likewise, posaconazole was active against all of the C. krusei isolates tested.
Posaconazole was also more active than either itraconazole or
fluconazole against clinical isolates of C. neoformans. Both posaconazole and itraconazole were most active against isolates with
the greatest susceptibility to fluconazole (MIC, 8 µg/ml). In
addition, we evaluated the activity of posaconazole against isolates
for which fluconazole MICs were increased. As fluconazole MICs
increased, the MICs of both posaconazole and itraconazole did likewise.
However, a greater proportion of isolates for which fluconazole MICs
were 16 to 32 µg/ml remained susceptible at concentrations of 0.5
µg/ml for posaconazole (100%) than for itraconazole (75%). The
three isolates for which fluconazole MICs were 64 µg/ml were all
inhibited by 1 µg of posaconazole/ml, and the posaconazole MICs for
two of the isolates were 0.5 µg/ml.
Consistent with these in vitro results, in vivo studies have demonstrated efficacy in treating infections due to Candida spp. and C. neoformans with posaconazole (3, 8; Hachem et al., 40th ICAAC; Nieto et al., 40th ICAAC; Vazquez et al., 40th ICAAC). Pharmacokinetic studies have demonstrated excellent oral bioavailability and peak concentrations in plasma of >5 µg/ml, with sustained levels exceeding 1 µg/ml for the entire dosing interval (7, 9). Thus, the oral dosing regimens result in concentrations of posaconazole in plasma that exceeded the MICs for 97 to 100% of Candida spp. and C. neoformans isolates (Tables 1 and 2).
In summary, we have demonstrated posaconazole to be more potent than fluconazole and itraconazole against significant clinical isolates of Candida spp. and C. neoformans. The emerging in vivo data from experimental models of fungal infection, as well as from clinical trials, appear to support these in vitro data. Posaconazole is a very promising new triazole antifungal agent that merits further clinical investigation.
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ACKNOWLEDGMENTS |
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We thank Kay Meyer and Linda Elliott for secretarial assistance in the preparation of the manuscript.
This study was partially supported by grants from Schering-Plough Research Institute, Pfizer Pharmaceuticals, and Bristol-Myers Squibb (The SENTRY Program).
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FOOTNOTES |
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* Corresponding author. Mailing address: Medical Microbiology Division, C606 GH, Department of Pathology, University of Iowa College of Medicine, Iowa City, IA 52242. Phone: (319) 384-9566. Fax: (319) 356-4916. E-mail: michael-pfaller{at}uiowa.edu.
Present address: 345 Beaver Kreek Centre, North Liberty, IA 52317.
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Antimicrobial Agents and Chemotherapy, October 2001, p. 2862-2864, Vol. 45, No. 10
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.10.2862-2864.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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(2004). Three-Dimensional Models of Wild-Type and Mutated Forms of Cytochrome P450 14{alpha}-Sterol Demethylases from Aspergillus fumigatus and Candida albicans Provide Insights into Posaconazole Binding. Antimicrob. Agents Chemother.
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Li, X., Brown, N., Chau, A. S., Lopez-Ribot, J. L., Ruesga, M. T., Quindos, G., Mendrick, C. A., Hare, R. S., Loebenberg, D., DiDomenico, B., McNicholas, P. M.
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Dannaoui, E., Meis, J. F. G. M., Loebenberg, D., Verweij, P. E.
(2003). Activity of Posaconazole in Treatment of Experimental Disseminated Zygomycosis. Antimicrob. Agents Chemother.
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Ostrosky-Zeichner, L., Rex, J. H., Pappas, P. G., Hamill, R. J., Larsen, R. A., Horowitz, H. W., Powderly, W. G., Hyslop, N., Kauffman, C. A., Cleary, J., Mangino, J. E., Lee, J.
(2003). Antifungal Susceptibility Survey of 2,000 Bloodstream Candida Isolates in the United States. Antimicrob. Agents Chemother.
47: 3149-3154
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Tortorano, A. M., Rigoni, A. L., Biraghi, E., Prigitano, A., Viviani, M. A., the FIMUA-ECMM candidaemia study group,
(2003). The European Confederation of Medical Mycology ECMM) survey of candidaemia in Italy: antifungal susceptibility patterns of 261 non-albicans Candida isolates from blood. J Antimicrob Chemother
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Courtney, R., Pai, S., Laughlin, M., Lim, J., Batra, V.
(2003). Pharmacokinetics, Safety, and Tolerability of Oral Posaconazole Administered in Single and Multiple Doses in Healthy Adults. Antimicrob. Agents Chemother.
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Pfaller, M. A., Diekema, D. J.
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(2002). In Vitro Activities of Ravuconazole and Voriconazole Compared with Those of Four Approved Systemic Antifungal Agents against 6,970 Clinical Isolates of Candida spp.. Antimicrob. Agents Chemother.
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Pfaller, M. A., Diekema, D. J., Messer, S. A., Boyken, L., Huynh, H., Hollis, R. J.
(2002). Clinical Evaluation of a Frozen Commercially Prepared Microdilution Panel for Antifungal Susceptibility Testing of Seven Antifungal Agents, Including the New Triazoles Posaconazole, Ravuconazole, and Voriconazole. J. Clin. Microbiol.
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