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Antimicrobial Agents and Chemotherapy, January 1999, p. 169-171, Vol. 43, No. 1
Department of Pathology, University of Iowa College of
Medicine, Iowa City, Iowa1;
Mycotic
Diseases Branch, Centers for Disease Control and Prevention, Atlanta,
Georgia2;
Mycology Reference Laboratory,
Center for Medical Mycology, Department of Dermatology, Case Western
Reserve University and University Hospitals of Cleveland, Cleveland,
Ohio3;
University of California San
Francisco, San Francisco, California4; and
Uganda Cancer Institute, Kampala, Uganda5
Received 5 June 1998/Returned for modification 18 September
1998/Accepted 9 October 1998
We investigated the in vitro activity of voriconazole compared to
those of fluconazole and itraconazole against 566 clinical isolates of
Cryptococcus neoformans from Africa (164) and the United
States (402). Isolates were obtained from cerebrospinal fluid (362),
blood (139), and miscellaneous sites (65). Voriconazole (MIC at which
90% of the isolates are inhibited [MIC90], 0.12 to 0.25 µg/ml) was more active than either itraconazole (MIC90, 0.5 µg/ml) or fluconazole (MIC90, 8.0 to 16 µg/ml)
against both African and U.S. isolates. Isolates inhibited by Among the community-acquired
opportunistic fungal pathogens, perhaps the most important and
certainly the single most common agent of serious infection is
Cryptococcus neoformans (8). A rare disease prior
to the onset of the AIDS epidemic, cryptococcosis is a leading
mycological cause of morbidity and mortality among AIDS patients
(8, 13). Although precise estimates of the incidence of
cryptococcal disease are not available, it is thought to affect 6 to
10% of patients with AIDS in the United States and 15 to 30% in
sub-Saharan Africa (13, 17). Recent data from the Centers
for Disease Control and Prevention (CDC) suggested that, in
metropolitan areas with a high concentration of human immunodeficiency
virus-infected persons, the incidence may be as high as five cases per
100,000 population (8). C. neoformans var.
neoformans is now the most common cause of meningitis at many large hospitals caring for AIDS patients (6, 8). A recent prospective study in Zimbabwe found that C. neoformans var. neoformans accounted for 45% of all
laboratory-proven cases of meningitis in adults (9).
Current treatment regimens for cryptococcal meningitis have remained
focused on amphotericin B, with or without flucytosine (6, 13, 17,
18, 22, 24). The toxicity of this regimen is well known. Although
fluconazole is better tolerated, it is used primarily as maintenance
therapy in AIDS patients, and concerns regarding the development of
fluconazole-resistant strains of C. neoformans have
been raised (3, 5, 13, 16, 18, 24). Among the available
alternative therapeutic agents, itraconazole has been found to be less
effective than either amphotericin B or fluconazole in the treatment of
cryptococcal meningitis in HIV-infected patients (22). Given
these limitations, investigation of the activity of newer antifungal
agents against C. neoformans is indicated.
Voriconazole is a new monotriazole antifungal agent with potent in
vitro activity against several fungal pathogens including Candida spp., C. neoformans, and
Aspergillus spp. (1, 2, 7, 11, 12, 15, 20).
Although the activity of voriconazole against C. neoformans looks promising (7, 15), the number of
clinical isolates included in the previous studies is limited and there
is a lack of comparative data for isolates from countries other than
the United States.
In this study, we evaluated the in vitro activities of voriconazole,
fluconazole, and itraconazole against 566 clinical isolates of
C. neoformans including 402 isolates from the United
States and 164 isolates from Africa. The in vitro susceptibility
testing method employed was a microdilution method performed according to the guidelines set forth by the National Committee for Clinical Laboratory Standards (NCCLS) (14, 23).
A total of 566 recent clinical isolates of C. neoformans var. neoformans from the United States (402 isolates) and from Africa (164 isolates) were selected for this study.
The collection included 362 isolates from cerebrospinal fluid cultures,
139 from blood cultures and 65 isolates from miscellaneous clinical
sources (pleural fluid, tissue, urine, etc.). The U.S. isolates were
obtained from AIDS patients located in California, Iowa, Texas, and
Georgia. Approximately 300 of these isolates were collected as part of a population-based survey of cryptococcal disease conducted by the CDC,
and the epidemiologic characteristics of some of these isolates have
been described previously (4, 5). The African isolates were
obtained from AIDS patients with cryptococcal meningitis who were seen
in a clinic in Kampala, Uganda. Identification was confirmed by
standard methods (4, 10). All isolates were of the
neoformans variety, as determined by growing cells on
canavanine-glycine-bromthymol blue agar (10). Isolates were
stored frozen at Standard powders of voriconazole and fluconazole were supplied by
Pfizer Pharmaceuticals Group, Central Research Division (Groton,
Conn.). Itraconazole was obtained from the Janssen Research Foundation
(Beerse, Belgium). Stock solutions were prepared in water (fluconazole)
or dimethyl sulfoxide (voriconazole and itraconazole). Antifungal
agents were diluted as described in NCCLS document M27-A
(14) with RPMI 1640 medium (Sigma, 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 Broth microdilution MICs were determined by the NCCLS method (14,
23). The final concentrations of the antifungal agents ranged
from 0.007 to 8 µg/ml for voriconazole and itraconazole and 0.125 to
128 µg/ml for fluconazole. 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. The microdilution trays were incubated at 35°C. The MIC endpoints were read visually
following 48 and 72 h of incubation and were defined for the three
azoles as the lowest concentration that produced an 80% reduction in growth (prominent decrease in turbidity) compared with that of the
drug-free growth control (5, 11, 14, 23). All isolates grew
in the test system, and MIC results read at 48 and 72 h were in
complete agreement. Thus, the 48-h MIC data is reported herein.
C. parapsilosis ATCC 22019 and C. krusei ATCC 6258 were used as quality control organisms and were
included each time that a set of isolates was tested (11,
14).
The isolates were generally susceptible to all three triazoles, and
only minor differences were observed between the African and the U.S.
isolates (Table 1). Overall, voriconazole
was the most active agent (MIC at which 90% of the isolates are
inhibited [MIC90], 0.12 µg/ml), followed by
itraconazole (MIC90, 0.5 µg/ml) and fluconazole
(MIC90, 16 µg/ml). Fluconazole had MICs of
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
In Vitro Activities of Voriconazole, Fluconazole, and
Itraconazole against 566 Clinical Isolates of Cryptococcus
neoformans from the United States and Africa
ABSTRACT
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16 µg
of fluconazole per ml were almost all (99%) inhibited by 
1 µg of
voriconazole per ml. These results suggest that voriconazole may be
useful in the treatment of cryptococcosis.
TEXT
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20°C in 20% glycerol 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.
70°C until they were used in the study.
8 µg/ml
for 84% (475 of 566) of the C. neoformans isolates
tested (94% of the African isolates and 80% of the U.S. isolates), 16 to 32 µg/ml for 15.5% (88 of 566) of these isolates (6% of the African isolates and 19% of the U.S. isolates), and 64 µg/ml for
0.5% (3 of 566) of these isolates (0% of the African isolates and
0.7% of the U.S. isolates).
TABLE 1.
In vitro susceptibilities of 566 clinical isolates of
C. neoformans to voriconazole and itraconazole
stratified by fluconazole susceptibility category
Among the isolates inhibited by 8 µg of fluconazole per ml,
voriconazole was more potent than itraconazole against both U.S. (MIC90, 0.06 versus 0.5 µg/ml, respectively) and African
(MIC90, 0.12 versus 0.5 µg/ml, respectively) strains. All
475 of these isolates were inhibited by 0.25 µg of voriconazole per
ml, and 73% (71% of African isolates and 74% of U.S. isolates) were
inhibited by 0.25 µg of itraconazole per ml.
Voriconazole (MIC90, 0.25 µg/ml) was also more active
than itraconazole (MIC90, 1.0 µg/ml) against the 88 isolates inhibited by 16 to 32 µg of fluconazole per ml. All of these
isolates were inhibited by 0.5 µg of voriconazole per ml, and 75%
(80% of African isolates and 74% of U.S. isolates) were inhibited by
0.5 µg of itraconazole per ml.
Only three isolates, all from the United States, required 64 µg of
fluconazole per ml to inhibit growth in vitro. For these isolates, the
voriconazole MICs were 0.25, 1, and 2 µg/ml and the itraconazole MICs
were 0.5, 0.5, and 1 µg/ml.
These results support and extend findings reported previously (7,
15). Like Nguyen and Yu (15), we found voriconazole to
be more active than either itraconazole or fluconazole against C. neoformans isolates. It is notable that 82% of the
isolates tested were inhibited by 0.12 µg of voriconazole per ml
and 99.6% were inhibited by 0.5 µg/ml. By comparison, 18% were
inhibited by 0.12 µg and 96% were inhibited by 0.5 µg of
itraconazole per ml. Both voriconazole and itraconazole appeared most
active against isolates exhibiting the greatest susceptibility to
fluconazole (MIC of fluconazole, 8 µg/ml). As the fluconazole MICs
increased, so did the MICs of voriconazole and itraconazole; however, a
greater percentage of isolates inhibited by 16 to 32 µg of
fluconazole per ml remained highly susceptible (MIC, 0.12 µg/ml) to
voriconazole (65%) than to itraconazole (0%).
In addition to providing comparative in vitro susceptibility data for
three triazole antifungal agents against a large number of clinical
isolates of C. neoformans, this study also provides for
the first time a comparison of in vitro susceptibilities of U.S. versus
African C. neoformans isolates. Importantly, isolates from both the United States and Africa appear to be quite susceptible to fluconazole and the other triazoles. There was no evidence of
increased resistance to fluconazole among the African isolates, and
over 99% of all isolates were inhibited by concentrations of
fluconazole (32 µg/ml) that are readily achieved by standard dosing
regimens (21).
In summary, we have found voriconazole to be more potent than either itraconazole or fluconazole against clinical isolates of C. neoformans from Africa and the United States. This improved potency plus favorable pharmacokinetics suggests that voriconazole may be useful in the treatment of cryptococcosis among other invasive fungal infections. Appropriate clinical trials are encouraged. Although the majority of isolates of C. neoformans in this study appear to be susceptible to fluconazole and other triazoles, continued surveillance for emerging resistance is warranted on a national and international basis given the broad utilization of fluconazole as primary prophylaxis in patients with AIDS (3, 19).
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ACKNOWLEDGMENTS |
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We thank Kay Meyer for secretarial assistance in the preparation of the manuscript and the members of the CDC Fungal Active Surveillance Group, who contributed isolates to this study. Members include David Stephens, Monica Farley, David Rimland, Wendy Baughman, Chris Lao, Jody Otte, and Christopher Harvey (Atlanta, Ga.); Richard Hamill and Edward A. Graviss (Houston, Tex.); Peter Pappas and Carolynn Thomas (Alabama); and Arthur L. Reingold, Gretchen Rothrock, Pam Daily, and Bharat Pattni (San Francisco, Calif.).
This study was partially supported by a grant from Pfizer Pharmaceuticals Group.
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FOOTNOTES |
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* Corresponding author. Mailing address: Medical Microbiology Division, Department of Pathology, C606 GH, University of Iowa College of Medicine, Iowa City, IA 52242. Phone: (319) 384-9566 or 335-8170. Fax: (319) 356-4916. E-mail: mpfaller{at}blue.weeg.uiowa.edu.
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Antimicrobial Agents and Chemotherapy, January 1999, p. 169-171, Vol. 43, No. 1
0066-4804/99/$04.00+0
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