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Antimicrobial Agents and Chemotherapy, February 1998, p. 471-472, Vol. 42, No. 2
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
In Vitro Comparative Efficacy of Voriconazole and
Itraconazole against Fluconazole-Susceptible and -Resistant
Cryptococcus neoformans Isolates
M. Hong
Nguyen* and
Christine Y.
Yu
Department of Medicine, Division of
Infectious Disease, University of Florida College of Medicine, and
VA Medical Center, Gainesville, Florida
Received 15 September 1997/Returned for modification 25 September
1997/Accepted 1 December 1997
 |
ABSTRACT |
In vitro susceptibility testing for 50 clinical isolates of
fluconazole-susceptible or -resistant Cryptococcus
neoformans was performed with itraconazole and voriconazole.
Voriconazole was more potent than itraconazole for
fluconazole-susceptible isolates and as potent as itraconazole for
fluconazole-susceptible dose-dependent isolates and for
fluconazole-resistant isolates. For fluconazole-resistant isolates, the
voriconazole and itraconazole MICs ranged from 1 to 2 µg/ml.
| |
TEXT |
Cryptococcus neoformans
is the leading cause of meningitis in human immunodeficiency
virus-infected patients. Amphotericin B is the current standard therapy
but is associated with a high toxicity profile. Fluconazole is better
tolerated, but with increasing reports of fluconazole-resistant
C. neoformans (3), the use of this agent
might be limited in the future. Itraconazole is less effective than
fluconazole in the treatment of cryptococcal meningitis in human
immunodeficiency virus-infected patient (5, 10). For these
reasons, the evaluation of newer antifungal agents against
C. neoformans is clearly indicated.
Voriconazole is a new triazole antifungal agent that has in vitro
activity against Candida isolates, including those that are
resistant in vitro to fluconazole (1, 2, 9). Its activity
against C. neoformans is unknown. Furthermore, the in vitro activity of voriconazole has not been compared with that of
itraconazole against this yeast. The goal of this study was to compare
the in vitro activities of fluconazole, itraconazole, and voriconazole
against 50 clinical isolates of C. neoformans; fluconazole had a wide range of MICs for the isolates studied.
Fifty clinical isolates of C. neoformans obtained from
our clinical microbiology laboratory or from the Fungus Testing
Laboratory at the University of Texas Health Science Center (San
Antonio, Tex.) were tested; previously, fluconazole demonstrated a wide range of MICs for these isolates. Candida albicans ATCC
90028, Candida glabrata ATCC 90030, and C. neoformans ATCC 90113 were incorporated into each set of
experiments as quality control isolates.
The susceptibility testing was performed by a macrodilution method
adhering to the National Committee for Clinical Laboratory Standards
(NCCLS) protocol (7). The stock solutions for fluconazole and voriconazole (Pfizer Central Research, Groton, Conn.) were prepared
in sterile water. Stock solutions for itraconazole (Janssen Research
Foundation, Beerse, Belgium) were prepared in dimethyl sulfoxide. The
concentrations of drugs tested were 0.125 to 64 µg/ml for fluconazole
and 0.015 to 16 µg/ml for itraconazole and voriconazole.
Fluconazole and itraconazole breakpoint values for susceptibility have
not yet been proposed by the NCCLS for C. neoformans; for simplicity, we adapted the breakpoint values proposed by the NCCLS
for Candida spp. to Cryptococcus (8).
The fluconazole, itraconazole, and voriconazole MICs for the ATCC
isolates were 0.5, 0.125, and 0.03 µg/ml, respectively, for ATCC
90028; 16, 0.125, and 0.03 µg/ml, respectively, for ATCC 90030; and
2, 0.06, and 0.125 µg/ml, respectively, for ATCC 90113.
Fluconazole had MICs of 
8 µg/ml for 82% (41 of 50) of the
C. neoformans isolates (fluconazole susceptible), 16 to
32 µg/ml for 14% (7 of 50) of these isolates (susceptible, dose
dependent), and 64 µg/ml for 4% (2 of 50) of these isolates
(resistant). The itraconazole and voriconazole MICs paralleled the
fluconazole MICs: the higher the fluconazole MICs, the higher the
itraconazole and voriconazole MICs (P < 0.001, linear
regression). Itraconazole and voriconazole had MICs of 0.5 µg/ml
for all isolates demonstrating in vitro susceptibility or
susceptibility, dose dependent to fluconazole.
Itraconazole and voriconazole had MICs of 0.125 µg/ml, for 56% (23 of 41) and 88% (36 of 41) respectively, of fluconazole-susceptible isolates and MICs of 0.25 to 0.5 µg/ml for 44% (18 of 41) and 12%
(5 of 41), respectively, of these same isolates. For these isolates,
voriconazole was more potent than itraconazole in vitro: the
voriconazole geometric mean MIC (0.07 µg/ml) was significantly lower
than the itraconazole geometric mean MIC (0.14 µg/ml;
P = 0.001, analysis of variance).
Itraconazole and voriconazole had MICs of 0.125 µg/ml for 43%
(three of seven) and 28% (two of seven), respectively, of susceptible, dose dependent isolates and MICs of 0.25 to 0.5 µg/ml for 57% (four
of seven) and 72% (five of seven), respectively, of these same
isolates. For these isolates, there was no difference between the
voriconazole and itraconazole geometric mean MICs (0.37 and 0.29 µg/ml, respectively).
For fluconazole-resistant isolates, the itraconazole and voriconazole
MICs were either 1 or 2 µg/ml. To our knowledge, this is the first
report documenting such high itraconazole and voriconazole MICs for
C. neoformans isolates. Extrapolating from the known pharmacokinetics of itraconazole, and the clinical experience with
C. albicans where itraconazole MICs of 
1 µg/ml
indicate resistance (8), the itraconazole MICs of 1 or 2 µg/ml observed for fluconazole-resistant isolates might represent
itraconazole resistance for C. neoformans as well.
Although the evaluation of the pharmacokinetics and clinical efficacy
of voriconazole is still in progress, there has been evidence in
animals that voriconazole is better absorbed and can achieve higher and
more prolonged concentrations in serum than can itraconazole (4, 6). For example, in a rat model of invasive aspergillosis, the
maximum concentration of drug in serum after an oral administration of
30 mg/kg was 4.6 µg/ml for voriconazole, compared to only 0.4 µg/ml
for itraconazole (6). This favored pharmacokinetics of voriconazole might explain the better outcome observed in infected rats
treated with voriconazole than in those treated with itraconazole and
might therefore represent an advantage of voriconazole over itraconazole (6).
In summary, voriconazole was more potent than itraconazole in vitro
against fluconazole-susceptible C. neoformans isolates and was as potent as itraconazole against fluconazole-susceptible, dose-dependent and fluconazole-resistant isolates. Given the high oral
bioavailability and the well-tolerated nature of voriconazole, this
drug might become an important addition to the armamentarium of
antifungal agents. It should be stressed, however, that clinical confirmation of these promising in vitro results is needed to elucidate
the role of this new antifungal agent in the management of cryptococcal
infection.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Medicine, University of Florida College of Medicine, P.O. Box 100277, JHMHC, Gainesville, FL 32610. Phone: (352) 379-4027. Fax: (352) 379-4015. E-mail: nguyemt{at}medicine.ufl.edu.
| |
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Antimicrobial Agents and Chemotherapy, February 1998, p. 471-472, Vol. 42, No. 2
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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