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Journal of Clinical Microbiology, March 2001, p. 954-958, Vol. 39, No. 3
Division of Infectious Diseases, Medical
College of Virginia, Virginia Commonwealth University, Richmond,
Virginia 23298-0049
Received 8 August 2000/Returned for modification 22 November
2000/Accepted 14 December 2000
The NCCLS proposed standard M38-P describes standard parameters for
testing the fungistatic antifungal activities (MICs) of established
agents against filamentous fungi (molds); however, standard conditions
are not available for testing their fungicidal activities (minimum
fungicidal or lethal concentrations [MFCs]). This study evaluated the
in vitro fungistatic and fungicidal activities of voriconazole,
itraconazole, and amphotericin B against 260 common and emerging molds
(174 Aspergillus sp. isolates [five species], 23 Fusarium sp. isolates [three species], 6 Paecilomyces lilacinus isolates, 6 Rhizopus
arrhizus isolates, 23 Scedosporium sp. isolates, 23 dematiaceous fungi, and 5 Trichoderma longibrachiatum isolates). MICs were determined by following the NCCLS M38-P broth microdilution method. MFCs were the lowest drug dilutions that resulted
in fewer than three colonies. Voriconazole showed similar or better
fungicidal activity (MFC at which 90% of isolates tested are killed
[MFC90], 1 to 2 µg/ml) than the reference agents for Aspergillus spp. with the exception of Aspergillus
terreus (MFC90 of voriconazole and amphotericin B,
>8 µg/ml). The voriconazole geometric mean (G mean) MFC for
Scedosporium apiospermum was lower (2.52 µg/ml) than
those of the other two agents (5.75 to 7.5 µg/ml). In contrast,
amphotericin B and itraconazole G mean MFCs for R. arrhizus
were 2.1 to 2.2 µg/ml, but that for voriconazole was >8 µg/ml.
Little or no fungicidal activity was shown for Fusarium spp. (2 to >8 µg/ml) and Scedosporium prolificans (>8
µg/ml) by the three agents, but voriconazole had some activity
against P. lilacinus and T. longibrachiatum (G
mean MFCs, 1.8 and 4 µg/ml, respectively). The fungicidal activity of
the three agents was similar (G mean MFC, 1.83 to 2.36 µg/ml) for the
dematiaceous fungi with the exception of the azole MFCs (>8 µg/ml)
for some Bipolaris spicifera and Dactylaria
constricta var. gallopava. These data extend and
corroborate the available fungicidal results for the three agents. The
role of the MFC as a predictor of clinical outcome needs to be
established in clinical trials by following standardized testing
conditions for determination of these in vitro values.
A higher incidence of fungal
infections has been documented since the 1980s with the parallel
emergence of either new fungal pathogens or fungi that were considered
nonpathogenic as etiologic agents of systemic disease, especially in
the immunocompromised host (2, 5, 28, 29, 31, 33). The
last 2 decades also have witnessed an increased resistance to
established antifungal agents (2, 5, 7, 8, 28, 31, 32).
Although amphotericin B remains the "gold standard" for the
treatment of invasive diseases caused by both yeasts and filamentous
fungi (molds), the overall response rate in invasive aspergillosis and
other severe infections is poor in the immunocompromised host (2,
15, 28, 29, 32). Amphotericin B lipid formulations do not appear
to have a superior efficacy in some cases (16, 28, 34). As
a result of these trends, several antifungal agents, mostly triazoles
and echinocandins, are under clinical evaluation. Among the new azoles, voriconazole (UK-109, 496; Vfend [Pfizer Pharmaceuticals, New York,
N.Y.]) is a new triazole that is currently undergoing phase III
clinical trials.
The National Committee for Clinical Laboratory Standards (NCCLS)
Subcommittee on Antifungal Susceptibility Tests has proposed standard
procedures for the antifungal susceptibility testing of molds
(23). Based on data from several studies
(9-11), this document recommends the use of (i) standard
RPMI-1640 broth; (ii) nongerminated conidial inoculum suspensions of
approximately 104 CFU/ml; and (iii) incubation at 35°C
for 24 h (Rhizopus spp.), 48 h
(Aspergillus spp., Fusarium spp., and other
opportunistic molds), and 72 h (Pseudallescheria boydii
[Scedosporium apiospermum]). The determination of MICs by
the M38-P document method requires the visual examination of growth
inhibition as compared to the growth control. As for yeast testing, the
document states that MICs of the azoles correspond to prominent (50%)
inhibition of growth. Some degree of correlation has been documented
between M38-P method results and treatment outcomes in experimental
infections (26); however, the clinical value of the NCCLS
methods for mold testing needs to be established. Although the NCCLS
subcommittee has not proposed testing parameters for the determination
of minimum fungicidal or lethal concentrations (MFCs), the fungicidal
activities of some of the new agents have been evaluated and compared
to those of reference agents by following nonstandardized methods (6, 13, 14, 17, 18, 25, 30, 31). This study evaluated the
fungicidal activities of voriconazole, itraconazole, and amphotericin B
against 260 common and emerging pathogenic molds recovered from clinical specimens during the last 5 years, following MIC
determinations by the NCCLS M38-P broth microdilution method
(23).
(This work was presented in part at the 14th International Society for
Human and Animal Mycology World Congress [Buenos Aires, Argentina, 8 to 12 May 2000].)
Isolates.
The set of isolates evaluated included 30 Aspergillus flavus isolates, 94 Aspergillus
fumigatus isolates, 13 Aspergillus nidulans isolates, 8 Aspergillus niger isolates, 29 Aspergillus
terreus isolates, 5 Fusarium moniliforme isolates, 6 Fusarium oxysporum isolates, 12 Fusarium solani
isolates, 6 Paecilomyces lilacinus isolates, 6 Rhizopus arrhizus isolates, 15 S. apiospermum
isolates, 8 Scedosporium prolificans isolates, 5 Trichoderma longibrachiatum isolates, and 23 dematiaceous
molds (three to six isolates each of Alternaria spp.,
Bipolaris spp., Cladophialophora bantiana, Dactylaria
constricta var. gallopava, and Wangiella
dermatitidis). Each isolate originated from a different patient
and was maintained at Antifungal agents.
The MICs of amphotericin B (Bristol-Myers
Squibb Pharmaceutical Research Institute, Wallingford, Conn.) and
itraconazole (Janssen Pharmaceutica, Titusville, N.J.) as well of the
investigational triazole, voriconazole (Pfizer), were determined by the
broth microdilution method described in the NCCLS M38-P document
(23). The antifungal agents were provided by the
manufacturers as assay powders.
Drug concentration ranges.
Additive drug dilutions were
prepared at 100 times the final concentration in 100% dimethyl
sulfoxide followed by further dilutions (1:50) in the NCCLS standard
RPMI-1640 medium to yield two times the final strength required for the
test. The drugs at their final twofold concentrations (16 to 0.031 µg/ml) were frozen at Inoculum preparations.
Stock inoculum suspensions were
prepared as described in the NCCLS M38-P document (23)
from 7-day-old cultures grown on potato dextrose agar slants and
adjusted spectrophotometrically to optical densities that ranged from
0.09 to 0.3 (82 to 60% transmittance); the stock suspensions contained
mostly conidia. The nongerminated conidial inoculum suspensions were
diluted 1:50 in medium. The final sizes of the stock inoculum
suspensions of most of the isolates tested ranged from 0.5 × 106 to 4.5 × 106 CFU/ml (1,000 to 9,000 CFU in the inoculated well), as demonstrated by quantitative colony
counts on Sabouraud dextrose agar. The density of Bipolaris
species stock inoculum suspensions was lower (2 × 105
to 7 × 105 CFU/ml).
NCCLS broth microdilution method (M38-P document).
On the
day of the test, each microdilution well containing 100 µl of the
diluted (two times) drug concentrations was inoculated with 100 µl of
the diluted (two times) conidial inoculum suspensions (the final volume
in each well was 200 µl). Growth and sterility controls were included
for each isolate tested. C. parapsilosis ATCC 22019 and
A. flavus ATCC 204304 were tested each time a set of
isolates was evaluated, as described above. Microdilution trays were
incubated at 35°C and examined at 48 h for MIC determination. MICs for S. apiospermum were determined after 72 h of
incubation. The MICs were determined by the visual inspection of growth
inhibition as described in the NCCLS M38-P document (23)
and corresponded to either prominent inhibition for azoles (50%
inhibition of growth [MICs-2]) or complete growth inhibition for
amphotericin B and azoles (100% inhibition of growth [MICs-0]).
MFC determination.
The in vitro fungicidal activities were
determined for each agent as previously described (13).
Briefly, 20-µl aliquots were subcultured from each well that showed
complete inhibition (100%, or an optically clear well) from the last
positive well (growth similar to that for the growth control well) and
from the growth control (drug-free medium) onto Sabouraud dextrose agar
plates. The plates were incubated at between 28 and 30°C until growth
was seen in the growth control subculture (usually 48 h). The MFC
was the lowest drug concentration that resulted in either no growth or
fewer than three colonies (99.9% killing).
Data analyses.
MIC and MFC ranges and corresponding
geometric mean (G mean) values were obtained for the broth
microdilution method results obtained for each species-drug combination
tested. MICs and MFCs at which 90% of the isolates tested were
inhibited (MIC90 and MFC90, respectively) were
determined for species that comprised MIC-0 versus MIC-2 for triazoles.
The most important role of
antifungal susceptibility testing is to identify isolates that are
potentially resistant to the agent being evaluated. Although the NCCLS
M38-P document states that azole MICs are the lowest drug
concentrations that show a 50% inhibition of growth as compared to the
growth in the control, recent data developed by the NCCLS subcommittee
suggest that the conventional criterion of MIC determination (100% or
complete growth inhibition) could more clearly and reliably detect
azole resistance (A. Espinel-Ingroff, M. S. Bartlett, V. Chaturvedi, K. Hazen, M. A. Ghannoum, M. A. Pfaller, M. G. Rinaldi, and T. J. Walsh, submitted for publication). Because
of that, both criteria (50 and 100% growth inhibition) were used for
the determination of voriconazole and intraconazole MICs. The values
depicted in Table 1 were obtained by
using the 100% inhibition criterion of MIC determination (MIC-0
endpoints). As previously demonstrated for another investigational
triazole, posaconazole (SCH56592) (13), most 50%
inhibition voriconazole and itraconazole MICs were only one to two
dilutions lower than the corresponding 100% MICs. The exceptions were
voriconazole MICs-2 and MICs-0 (1.0 to 2 and >8 µg/ml, respectively)
for one isolate each of F. moniliforme and F. solani and two isolates of S. prolificans as well as
itraconazole MIC-2 and MIC-0 endpoints (0.25 to 1.0 and >8 µg/ml,
respectively) for two isolates of P. lilacinus and T. longibrachiatum. Which of these two criteria of MIC determination
is more clinically relevant is to be elucidated in clinical trials. As
of now, for the two well-documented itraconazole-resistant isolates of
A. fumigatus (8), the MIC-0 was the clinically
relevant value (8; Espinel-Ingroff et al., submitted).
Progression of a disseminated disease caused by T. longibrachiatum has been reported despite antifungal therapy
(either with conventional amphotericin B, its liposomal formulation, or
itraconazole) in appropriate dosages; the corresponding itraconazole
MIC-2 endpoint was 1 µg/ml (28).
0095-1137/01/$04.00+0 DOI: 10.1128/JCM.39.3.954-958.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
In Vitro Fungicidal Activities of Voriconazole,
Itraconazole, and Amphotericin B against Opportunistic Moniliaceous and
Dematiaceous Fungi
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results and Discussion
References
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 testing was performed. The
reference isolate A. flavus ATCC 204304 (23)
and the quality control strain Candida parapsilosis ATCC
22019 (24) were included as control isolates. The latter
strain has well-established microdilution MIC ranges for both the
established and investigational agent evaluated in this study
(4). Reference MIC ranges also have been established for
the isolate of A. flavus based upon repeated testing in a prior study (11), and these ranges are listed in the M38-P
document (23). MIC ranges for both controls were within
established values (4, 23).
70°C until they were needed.
10 isolates; MIC50
and MFC50 were obtained for species represented by fewer
than 10 isolates.
RESULTS AND DISCUSSION
Top
Abstract
Introduction
Materials and Methods
Results and Discussion
References
TABLE 1.
MICs and MFCs for 260 isolates of common and emerging
mold pathogensa
Voriconazole and itraconazole data. During the in vitro evaluations of the new antifungal agents, several studies have investigated their fungicidal activities, mostly against molds (6, 13, 14, 17-19, 25, 30, 31). The fungicidal activity of voriconazole has been evaluated against several species of Aspergillus (6, 17, 19, 30, 31), Fusarium spp. (6, 17), C. bantiana, R. arrhizus, S. apiospermum, W. dermatitidis (17), and, more recently, the dimorphic fungi (18). The present study evaluated some of these species with a larger number of isolates of A. fumigatus, A. flavus, and S. apiospermum and included other clinically important species of Aspergillus. In addition, representative isolates of other rare and common mold species that have been associated with severe infections in the immunocompromised host (5, 22, 28, 29) were evaluated. MFC data of the three agents tested have yet to be published for several of the species listed in Table 1.
Overall, voriconazole MICs and MFCs were within 2 dilutions for most of the species tested, and itraconazole MFCs were usually 3 dilutions higher than the corresponding MICs (Table 1). The exceptions were voriconazole values for A. fumigatus, A. terreus, P. lilacinus, S. apiospermum and for three isolates of D. constricta and one isolate of B. spicifera. MFCs for some isolates of these species were more than 2 dilutions higher than the corresponding MICs. This trend was more evident for isolates of A. terreus, as only 34% (10 of 29 pairs) of the MIC and MFC values were within 2 dilutions. In the present study, the itraconazole G mean MFC for A. terreus was 1.23 µg/ml and that for voriconazole was 6.8 µg/ml. The low in vitro fungicidal activity of voriconazole against A. terreus (G mean MFC > 8 µg/ml) has been previously reported by Sutton et al. (30). The G mean MIC also was substantially lower (0.22 µg/ml) than the G mean MFC in that study, as in the present study (0.63 µg/ml). Oakley et al. (25) also did not find high itraconazole MFCs for seven A. terreus isolates. MFC values for the other Aspergillus species were similar for both triazoles or higher for itraconazole, with the exception that MFCs of itraconazole were lower than those of voriconazole for A. flavus. By time-kill procedures, both triazoles also had fungicidal activity against A. fumigatus (19). Itraconazole does not appear to have either fungistatic or fungicidal activity for the isolates of Fusarium species tested in this study, while four voriconazole MICs and three MFC values for the five isolates of F. moniliforme were below voriconazole concentrations achievable in serum (5 µg/ml) in animals (6). The lack of fungistatic (3, 12, 21, 27) and fungicidal (17) activities of itraconazole has previously been reported for F. solani and F. oxysporum, while voriconazole MICs for F. solani have ranged from 0.25 to 8 (3, 6, 17, 27) and 2 to >8 (12, 21) µg/ml. Low itraconazole and voriconazole MICs (0.25 to >8 and 0.5 to 2 µg/ml, respectively) have been published for of F. oxysporum (3, 6, 27). Data from one of these studies were obtained by an agar dilution method, and the incubation temperature was 28°C instead of 35°C (27). Although the MICs in another study were determined by following similar standard conditions as those used in the present study and as described in the NCCLS M38-P document, the prepared inocula were stored for up to a week prior to testing (3). In contrast, the results in Table 1 were obtained with inocula that were prepared and used the same day. Furthermore, the latter investigators did not report MICs-0 but MICs-2, and they found that the itraconazole G mean MIC increased from 0.5 to >8 µg/ml after 72 h of incubation (3). In the present investigation, voriconazole MICs for F. solani and F. oxysporum ranged from 2 to 4 µg/ml at 24 h (data not shown in Table 1). An increase in MICs after a longer incubation time also has been demonstrated recently with amphotericin B and itraconazole for Paecilomyces spp. (1). Therefore, it is difficult to know whether these differences in itraconazole and voriconazole MIC data for F. oxysporum are the result of either the different populations of isolates tested or the variable testing conditions used. It is noteworthy that voriconazole data for F. moniliforme were substantially lower than those for the other two species (Table 1). Although Clancy and Nguyen (6) examined the fungicidal activity of voriconazole against three F. moniliforme isolates, they listed their voriconazole MFC data (range, 2 to >8 µg/ml) for the species of Fusarium tested as a group and the actual data for each species are unknown. The G mean MFCs and MFC90 (Table 1) demonstrated that voriconazole had fungicidal activity superior to that of itraconazole against P. lilacinus and that the latter agent had better activity against R. arrhizus. High itraconazole G mean MICs and MFCs (7.51 to >8 µg/ml) have been reported for 13 P. lilacinus (1, 27), while voriconazole MICs have ranged from 0.5 to 1 µg/ml (27). However, the MFC data in Table 1 are the only available results for this species and agent. The contrasting fungicidal activities of itraconazole and voriconazole for R. arrhizus (G mean MFCs of 2.1 and >8 µg/ml, respectively) also have been demonstrated in a previous study (17). Although most studies have only evaluated the fungistatic activities of these three antifungal agents against the two species of Scedosporium tested in this study, the consensus is that they have different susceptibilities to the two triazoles being discussed. As shown in Table 1 and demonstrated in several studies (7, 20, 27), both voriconazole and itraconazole had very little or no activity against S. prolificans (G mean MICs and MFCs, 6.93 to >8 µg/ml), whereas for S. apiospermum, MICs and MFCs of both triazoles were substantially lower in this (Table 1) and other studies (7, 12, 17, 27). However, a promising role for voriconazole in the treatment of S. apiospermum infections has been suggested, since these infections are usually refractory to treatment with either amphotericin B or other reference agents (16). For isolates of T. longibrachiatum, voriconazole MFCs were below achievable levels in serum, while itraconazole does not appear to have any antifungal activity for this species, when MICs-0 are considered. Both voriconazole and itraconazole had good fungistatic and fungicidal activities against most of the dematiaceous fungi tested in this study. High voriconazole MFCs (>8 µg/ml) were obtained for B. spicifera and D. constricta var. gallopava. Although the susceptibilities of these two species to voriconazole and itraconazole have been previously evaluated, only MICs were obtained (12, 20-22). However, their MIC results are similar (0.03 to 1.0 µg/ml) to those obtained in this study (0.5 to 2 µg/ml). Only one other study has evaluated the fungicidal activities of itraconazole and voriconazole against 10 isolates of C. bantiana (17), and the results of that study are also comparable (MFC90, 1.0 µg/ml) to those in this investigation (Table 1).Amphotericin B data.
As with the triazoles, the majority of
amphotericin B MIC and MFC results were within 1 dilution (Table 1).
Similar to voriconazole data, substantially higher MFCs than MICs were
obtained for A. terreus. Major differences between MICs and
MFCs also were observed for R. arrhizus (G means, 0.36 versus 2.2 µg/ml) and T. longibrachiatum (G means, 0.87 versus 5 µg/ml). In addition to these three species, amphotericin B G
mean MFCs were above 2 µg/ml for F. moniliforme, F. solani, and Scedosporium spp. Additionally, the
amphotericin B range was broad for certain species (e.g., A. fumigatus and S. apiospermum). These results are in
contrast to those obtained with this agent for the yeasts, where MICs
are usually within a narrow range (0.25 to 1.0 µg/ml), regardless of
the species being evaluated, and values above 2 µg/ml are rare
(12). The low fungicidal and fungistatic in vitro
activities of amphotericin B have been demonstrated against A. terreus (25, 30), some Fusarium spp.
(6), P. lilacinus (1), and both
Scedosporium spp. (7, 12, 17, 20, 21). Although
the in vitro fungicidal data for F. moniliforme and F. solani are higher in Table 1 (G mean MFC, >3 µg/ml) than those
in another study (MFC90, 2 µg/ml [6]),
most of these values were 2 µg/ml. Based on clinical data in
patients with candidemia, MICs of 1.0 µg/ml could be predictive of
clinical failure to amphotericin B therapy. Similar correlations have
been documented in trichosporonosis (32). This low in
vitro activity of amphotericin B is consistent with the poor response
to this agent in patients infected with isolates of A. terreus, S. apiospermum, S. prolificans, and
T. longibrachiatum, among others (5, 16, 28,
29).
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ACKNOWLEDGMENT |
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This study was partially supported by a grant from Pfizer Pharmaceuticals.
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FOOTNOTES |
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* Mailing address: Medical Mycology Research Laboratory, Medical College of Virginia/VCU, P.O. Box 980049, 1101 E. Marshall St., Sanger Hall, Room 7049, Richmond, VA 23298-0049. Phone: (804) 828-9711. Fax: (804) 828-3097. E-mail: avingrof{at}hsc.vcu.edu.
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Journal of Clinical Microbiology, March 2001, p. 954-958, Vol. 39, No. 3
0095-1137/01/$04.00+0 DOI: 10.1128/JCM.39.3.954-958.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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