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Antimicrobial Agents and Chemotherapy, January 1998, p. 161-163, Vol. 42, No. 1
Department of Pathology, University of Iowa
College of Medicine, Iowa City, Iowa 52242
Received 1 August 1997/Returned for modification 26 September
1997/Accepted 13 October 1997
Voriconazole (formerly UK-109,496) is a new monotriazole antifungal
agent which has potent activity against Candida,
Cryptococcus, and Aspergillus species. We
investigated the in vitro activity of voriconazole compared to those of
fluconazole, itraconazole, amphotericin B, and flucytosine (5FC)
against 394 bloodstream isolates of Candida (five species)
obtained from more than 30 different medical centers. MICs of all
antifungal drugs were determined by the method recommended by the
National Committee for Clinical Laboratory Standards using RPMI 1640 test medium. Overall, voriconazole was quite active against all the
yeast isolates (MIC at which 90% of the isolates are inhibited
[MIC90], Newer azoles such as fluconazole and
itraconazole are frequently used in the treatment of fungal infections
due to Candida spp. They offer potential advantages over
amphotericin B, including reduced toxicity and versatility of oral or
intravenous (fluconazole only) administration. However, acquired or
intrinsic resistance to these compounds is well known, and failure of
azole therapy has been reported (11, 12). There is,
therefore, a clear need for new drugs to improve the treatment of
fungal infections.
Voriconazole (UK-109,496) is a new monotriazole antifungal agent
obtained by modification of the structure of fluconazole (14). It exhibits dose-dependent pharmacokinetics and is
usually well tolerated after oral or intravenous administration
(10). Early clinical studies have suggested that
voriconazole may be effective in the treatment of oropharyngeal
candidiasis and of acute or chronic pulmonary aspergillosis (3, 4,
17). The efficacy of voriconazole in experimental models
of invasive aspergillosis and in the treatment of Aspergillus
fumigatus endocarditis has also been documented (5, 7,
8). Previous in vitro investigations have shown activity against
several fungal pathogens, including Candida spp.,
Cryptococcus neoformans, and Aspergillus spp.
(1, 6, 16). Barry and Brown (2) found that
voriconazole had better in vitro activity than fluconazole
against six Candida species. Ruhnke et al. (15)
also reported good activity of voriconazole against
Candida albicans strains isolated from patients with human immunodeficiency virus infection. However, the number of clinical isolates of Candida spp. included in these studies is
limited, and there is a lack of comparative data for other antifungal
agents.
In this study, we evaluated the in vitro activities of
voriconazole and four other antifungal agents against 394 clinical isolates of Candida spp. The comparison
agents tested were fluconazole, itraconazole, amphotericin B, and
flucytosine (5FC). The in vitro susceptibility testing method employed
was a microdilution adaptation of the guidelines set forth by the
National Committee for Clinical Laboratory Standards (NCCLS)
(9).
Yeast isolates.
A total of 394 recent bloodstream isolates
of Candida spp. obtained from 31 different medical centers
were selected for this study. The isolates included were C. albicans (206 strains), Candida glabrata (77 strains),
Candida tropicalis (54 strains), Candida parapsilosis (40 strains), and Candida krusei (17 strains). All isolates were stored as suspensions in sterile distilled
water at room temperature until the study was performed. Prior to
testing, each isolate was subcultured at least twice on potato dextrose agar plates (Remel, Lenexa, Kans.) to ensure purity and optimal growth.
Antifungal agents.
Standard antifungal powders of
voriconazole and fluconazole were supplied by Pfizer Inc.,
Central Research Division (Groton, Conn.). Amphotericin B, 5FC, and
itraconazole were obtained from their respective manufacturers. Stock
solutions were prepared in water (fluconazole and 5FC), dimethyl
sulfoxide (amphotericin B), and polyethylene glycol
(voriconazole and itraconazole). Antifungal agents were diluted
with RPMI 1640 medium (Sigma Chemical Co., St. Louis, Mo.) which had
been buffered to pH 7.0 with 0.165 M morpholinepropanesulfonic acid
(MOPS) buffer (Sigma), and the mixtures were dispensed into 96-well
microdilution trays. Trays containing an aliquot of 0.1 ml in each well
were sealed and frozen at Antifungal susceptibility testing.
Broth microdilution MICs
were determined by the NCCLS method (9). The final
concentrations of the antifungal agents ranged from 0.015 to 16 µg/ml
for voriconazole, 0.125 to 128 µg/ml for fluconazole, 0.007 to 8 µg/ml for itraconazole, 0.015 to 8 µg/ml for amphotericin B,
and 0.06 to 128 µg/ml for 5FC. The yeast inoculum was adjusted
to a concentration of 0.5 × 103 to 2.5 × 103 CFU/ml in RPMI 1640 medium, and an aliquot of 0.1 ml
was added to each well of the microdilution tray. In each case, the
inoculum size was verified by colony counting. MIC endpoints were
determined after incubation for 48 h in ambient air at
35°C. For amphotericin B this endpoint was defined as the lowest
concentration that completely inhibited growth. For the azole compounds
and 5FC the MIC was defined as the lowest concentration that produced
an 80% reduction of growth compared with that of the drug-free growth
control.
Quality control.
C. parapsilosis ATCC 22019 and
C. krusei ATCC 6258 were used as quality control
organisms and were included each time a set of isolates was tested.
Table 1 summarizes the MICs of
voriconazole, itraconazole, fluconazole, amphotericin B, and
5FC for the 394 clinical isolates of Candida spp. Overall,
voriconazole was highly active (MIC at which 90% of the
isolates are inhibited [MIC90],
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
In Vitro Activities of Voriconazole (UK-109,496) and Four Other
Antifungal Agents against 394 Clinical Isolates of
Candida spp.
ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results & Discussion
References
0.5 µg/ml). Candida albicans was
the most susceptible species (MIC90, 0.06 µg/ml) and
Candida glabrata and Candida krusei were the
least (MIC90, 1 µg/ml). Voriconazole was more active than
amphotericin B and 5FC against all species except C. glabrata and was also more active than itraconazole and
fluconazole. For isolates of Candida spp. with decreased
susceptibility to fluconazole and itraconazole MICs of voriconazole
were also higher. Based on these results, voriconazole has promising
antifungal activity and further in vitro and in vivo investigations are
warranted.
INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results & Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results & Discussion
References
70°C until they were used in the study.
The NCCLS recommendations (9) were followed for the
dilution of each antifungal agent.
RESULTS AND DISCUSSION
Top
Abstract
Introduction
Materials & Methods
Results & Discussion
References
0.5 µg/ml) against all isolates, and C. albicans was the most susceptible
species (MIC90, 0.06 µg/ml). C. glabrata
and C. krusei were the least susceptible to
voriconazole (MIC90, 1 µg/ml); the most highly resistant strains were C. albicans and C. tropicalis strains (MIC, >16 µg/ml). Voriconazole was more
active than amphotericin B and 5FC against all species except
C. glabrata and was also more active than itraconazole
and fluconazole.
TABLE 1.
In vitro susceptibilities of 394 clinical yeast
isolates to voriconazole and other antifungal agents
Among the 394 isolates studied, a total of 18 strains (7 C. albicans, 8 C. glabrata, and 3 C. tropicalis strains) from eight different medical centers were
resistant to both fluconazole (MIC, 
64 µg/ml) and itraconazole
(MIC, 1 µg/ml) (13). MICs of voriconazole for
these strains were >16 µg/ml (seven C. albicans and
two C. tropicalis strains), 8 µg/ml (three
C. glabrata strains), 4 µg/ml (three C. glabrata and one C. tropicalis strain), and 2 µg/ml (two C. glabrata strains).
These results support and extend findings reported previously (1, 2, 12). Like Barry and Brown (2), we found that voriconazole was more active than fluconazole against all Candida isolates tested. In addition, the spectrum of activity was better than that of itraconazole. This enhanced in vitro activity against two species frequently considered refractory to azoles, C. krusei and C. glabrata (MIC90, 1 µg/ml), is remarkable. Although pharmacokinetic studies with animal models have found that levels of voriconazole in serum could range from 1 to 5 µg/ml (5, 7, 8) and similar levels are expected to be achieved in humans, clinical trials are clearly required to prove the utility of voriconazole in infections due to these two species.
Ruhnke et al. (15) used a broth microdilution test following the NCCLS guidelines (9) to determine the in vitro activities of voriconazole and fluconazole against 105 isolates of C. albicans recovered from the oral cavities of human immunodeficiency virus-infected patients. They also observed that voriconazole was more potent in vitro than fluconazole.
The data from standardized and reference in vitro susceptibility
testing indicate that voriconazole is more potent than either itraconazole or fluconazole against all clinical isolates tested. Although others have reported that voriconazole could be active against fluconazole-resistant C. albicans isolates
(2, 15), we were unable to demonstrate this finding, and in
our study the MICs of voriconazole (>16 µg/ml) for
fluconazole-resistant C. albicans isolates tested were
high. Even though greater voriconazole activity was observed
with eight C. glabrata isolates and one C. tropicalis isolate that were resistant to fluconazole, MICs for
these isolates were 2 µg/ml. These data suggest a possible cross-resistance mechanism among highly azole-resistant strains.
The translation of this in vitro activity into clinical efficacy still needs to be established; however, Troke et al. (17) have shown in a guinea pig model of systemic candidiasis that voriconazole efficacy was similar to that of fluconazole or itraconazole in C. albicans infections but that voriconazole was more active when the animal was infected with C. krusei, C. glabrata, or azole-resistant strains of C. albicans. Preliminary clinical data also suggest that voriconazole is efficacious in the treatment of oropharyngeal candidiasis, even that caused by fluconazole-resistant strains (15, 17). In view of the potent in vitro activity demonstrated here as well as the promising early in vivo information, voriconazole warrants further investigation.
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ACKNOWLEDGMENTS |
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Francesc Marco is partially supported by a grant from Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica (SEIMC-Hoechst96) and a Permiso de Ampliación de Estudios from Hospital Clínic, Barcelona, Spain. This study was supported by a grant from Pfizer Pharmaceuticals-Roerig Division.
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FOOTNOTES |
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* Corresponding author. Mailing address: Medical Microbiology Division, Department of Pathology, 606 GH, University of Iowa College of Medicine, Iowa City, IA 52242. Phone: (319) 384-9566. Fax: (319) 356-4916. E-mail: mpfaller{at}blue.weeg.uiowa.edu.
Present address: Microbiology Laboratory, Hospital Clinic,
University of Barcelona, 08036-Barcelona, Spain.
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REFERENCES |
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Results & Discussion
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0066-4804/98/$04.00+0
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