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Journal of Clinical Microbiology, June 1998, p. 1578-1583, Vol. 36, No. 6
Istituto di Igiene e Medicina Preventiva,
Received 4 August 1997/Returned for modification 13 September
1997/Accepted 19 February 1998
Three susceptibility testing procedures were compared to determine
fluconazole, itraconazole, and ketoconazole MICs against 47 Candida albicans strains isolated sequentially from the
oral cavities of five AIDS patients undergoing azole therapy. They included the broth microdilution method (BM), performed according to
the National Committee for Clinical Laboratory Standards' tentative standard, the agar dilution method (AD), and the Etest; the latter two
tests were performed both in Casitone agar (AD-Cas and Etest-Cas) and
in RPMI (AD-RPMI and Etest-RPMI). Twenty-four- and 48-h MICs obtained
by AD and Etest were compared with 48-h MICs obtained by BM. The MICs
of all the azoles determined by BM were usually lower than those
obtained by the other methods, mainly due to different reading
criteria. In order to assess the most appropriate way of evaluating the
agreement of MICs obtained by different methods with those produced by
the proposed reference method (BM), we used the mean differences
calculated according to Bland and Altman's method. Comparison of
fluconazole MICs obtained by BM and AD-Cas yielded a mean difference of
3, and the percentages of agreement within ±2 dilutions were 98 and
100% at 24 and 48 h, respectively. For ketoconazole and
itraconazole MICs, lower mean differences were noted, and agreement
ranged from 96 to 100%. Agreement between the AD-RPMI and BM results
was poor for all azoles, and an increase in MICs was always observed
between the 1st- and 2nd-day readings. Similarly, Etest-Cas gave better
agreement with BM than did Etest-RPMI for all the azoles. BM, AD-Cas,
and Etest-Cas each demonstrated a progressive increase in fluconazole MICs against strains isolated sequentially from a given patient, in
accordance with the decreased clinical response to fluconazole.
The rising incidence of fungal
infections and the increasingly frequent use of antifungal agents have
intensified the need for useful and reliable antifungal susceptibility
test methods. Susceptibility testing of antifungal agents is greatly
influenced by a variety of factors (5, 6, 10, 16, 18, 25,
26). After several collaborative studies, the Subcommittee on
Antifungal Susceptibility Tests of the National Committee for Clinical
Laboratory Standards (NCCLS) published a reference method for broth
dilution antifungal susceptibility testing of yeasts which includes the less-expensive and less-cumbersome broth microdilution method (BM)
(13). Another widely used antifungal susceptibility testing procedure is the agar dilution method (AD), which is easy to perform and allows simultaneous testing of a large number of organisms and the
easy detection of microbial contaminants (6, 18, 28).
Recently, several commercially available tests, such as Etest, have
been introduced as alternative methods (4, 7, 14, 15,
22-24). Different media have been used with both AD and Etest
(6, 9, 26).
In the last few years, the application of in vitro antifungal
susceptibility tests for strains of Candida albicans causing thrush or esophagitis in AIDS patients showed higher MICs for isolates
from patients refractory to azole treatment (8, 19). A
progression from low to high MICs during the course of the infection was reported for C. albicans strains isolated sequentially
from the oral cavities of patients with AIDS receiving azole therapy (2, 11, 12, 17, 20). Therefore, in vitro procedures could be
helpful in monitoring antifungal therapy in this population of
patients.
In the study described here, we compared three different methods and
two media (RPMI 1640 and Casitone) for testing fluconazole, itraconazole, and ketoconazole against 47 strains of C. albicans isolated sequentially from the oral cavities of five AIDS
patients undergoing azole treatment in order to verify the validity of AD and Etest.
(This work was presented as a poster at the Congress of the
International Society for Human and Animal Mycology, Salsomaggiore Terme, Italy, 8 to 13 June 1997.)
Sources of isolates.
Forty-seven strains of C. albicans isolated from the oral cavities of five AIDS patients who
had recurrent episodes of oropharyngeal candidosis were used. All the
patients were being treated with azoles. Yeasts were identified at
species level by standard morphological and biochemical methods
(27) and were stocked at Susceptibility testing procedures.
The antifungal agents
used in this study were an intravenous fluconazole preparation
(Diflucan i.v.; Roerig Farmaceutici Italiani, Latina, Italy) and
itraconazole and ketoconazole powders (kindly given by Janssen
Pharmaceutica, Beerse, Belgium). Preliminary experiments showed no
difference between the results obtained with the commercial preparation
of fluconazole and those obtained with pure fluconazole (Pfizer Inc.,
New York, N.Y.). Azole susceptibility testing of all isolates of
C. albicans were performed by three different methods: BM,
AD, and Etest.
(i) BM.
BM was performed according to the NCCLS M27-T
guidelines (13). Briefly, we used RPMI 1640 medium (Sigma
Chemical Co., St. Louis, Mo.) buffered to pH 7.0 with 0.165 M
morpholinepropanesulfonic acid (MOPS; Sigma Chemical Co.). Fluconazole
was diluted to obtain final drug concentrations ranging from 0.125 to
64 µg/ml. Itraconazole and ketoconazole powders were dissolved in
polyethylene glycol 400 (Janssen Chemicals, Beerse, Belgium) and
diluted to obtain final drug concentrations ranging from 0.03 to 8.0 µg/ml for both drugs. Fifty microliters of the inoculum prepared
spectrophotometrically as described elsewhere (13) was added
to each well of the microtiter plates (final inoculum, 0.5 × 103 to 2.5 × 103 CFU/ml). Plates were
incubated at 35°C for 48 h. The MIC was defined as the lowest
concentration at which a prominent decrease in turbidity was observed
(13).
(ii) AD.
AD was performed both in RPMI 1640 buffered to pH
7.0 with MOPS (AD-RPMI) and in phosphate-buffered Casitone agar, pH 7 (AD-Cas) (Casitone [Difco Laboratories, Detroit, Mich.], 9 g;
yeast extract [Difco], 5 g; glucose, 20 g; sodium citrate,
10 g; Bacto Agar [Difco], 18 g; phosphate buffer [pH 7],
1 liter). Fluconazole was diluted in distilled water. Itraconazole and
ketoconazole powders (10 mg of each) were dissolved in 1 ml of solvent
(1 N HCl and ethyl alcohol in a 2:8 ratio) and then diluted with the same solvent mixture to 80 µg/ml. The drug solution was further diluted in distilled water. Twofold dilutions of each drug were added
to RPMI and Casitone agar to obtain final concentrations ranging from
0.06 to 64 µg of fluconazole/ml and from 0.008 to 8 µg of
itraconazole or ketoconazole/ml. Plates containing different antifungal
dilutions and those containing diluents were inoculated by using a
multipoint inoculator. Each pin delivered 1 µl of a yeast suspension
containing 5 × 105 cells/ml from a 24-h culture. The
inoculum size was determined by the count in Burker's chamber. MICs
were recorded as the lowest concentrations of drug that suppressed
visible growth after 24 and 48 h of incubation at 35°C. All
tests were performed in duplicate.
(iii) Etest.
Etest was performed in Casitone (Etest-Cas) and
RPMI agar (Etest-RPMI). Petri plates (150 mm in diameter) containing 60 ml of medium were flooded with a yeast suspension of 5 × 105 cells/ml. Excess fluid was removed with a pipette, and
after moisture was allowed to be absorbed, Etest strips were applied on
each medium. The plates were incubated at 35°C and were read according to the manufacturer's instructions at 24 and 48 h.
Analysis of the results.
All the AD and Etest MICs at 24 and
48 h were compared with the BM MICs at 48 h. Both on-scale
and off-scale results were included in the analysis. MIC results
obtained with the different procedures were compared according to the
measuring agreement method reported by Bland and Altman (3).
Every MIC was logarithmically transformed and deviated to avoid
negative values (log-MIC) (e.g., 1, A total of 1,269 MIC data points were available for
analysis. Table 1 summarizes azole MICs
obtained by the three methods. Generally, MICs obtained by BM were
lower than those obtained by the other methods for all three azole
drugs.
Fluconazole MICs generated in AD-CAs were always 3 dilutions higher
than those obtained with BM. When
0095-1137/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Comparison of Three Methods for Testing Azole
Susceptibilities of Candida albicans Strains Isolated
Sequentially from Oral Cavities of AIDS Patients
IRCCS Ospedale Maggiore di
Milano,
ABSTRACT
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
70°C in 10% glycerin until
used. Candida krusei ATCC 6258 and Candida
kefyr IP 706 were employed as quality control strains and tested
in each run of the experiments for the three antifungal agents.
0.12 µg/ml; 2, 0.25 µg/ml;
11, 
128 µg/ml). The difference (d) between the log-MIC obtained by
AD or Etest and that obtained by BM for each isolate was calculated,
and the mean of these differences (mean difference, or 
)
was determined. Results for MIC pairs obtained with different
methodologies were considered in agreement when the difference between
d and was within 1 (agreement ± 1 dilution) or 2 (agreement ± 2 dilutions) dilutions. The Mann-Whitney U test was
applied to ascertain the distribution of itraconazole and
ketoconazole MICs for fluconazole-susceptible and -resistant isolates.
A P value of <0.05 was considered statistically
significant.
RESULTS
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
TABLE 1.
Fluconazole, itraconazole, and ketoconazole MICs for 47 clinical isolates of C. albicans obtained by three methods
measured by Bland and
Altman's method was considered, the percentages of agreement within 2 dilutions were 98 and 100% at 24 and 48 h, respectively (Table 2;
Fig. 1). between BM and
AD-Cas was lower (<1.0) for both itraconazole and ketoconazole MICs
than for fluconazole MICs. The percentages of agreement within 2 dilutions were 98 and 96% for itraconazole at 24 and 48 h,
respectively, and 100% for ketoconazole at both 24 and 48 h
(Table 2). AD-RPMI yielded poorer
agreement with BM than did AD-Cas for all azoles (Table 2). In this
medium an increase of MICs was always observed between the 1st- and the 2nd-day readings for all azoles (Table 1).
View larger version (8K):
[in a new window]
FIG. 1.
Difference from mean for fluconazole log-MIC (reading at
48 h). The horizontal line indicates .
TABLE 2.
Agreement of MICs obtained by AD and by Etest with MICs
obtained by NCCLS BM
Similarly, Etest-Cas gave better agreement with BM than did Etest-RPMI for all azoles (Table 2). In general, interpretation of MICs by Etest was more difficult in RPMI than in Casitone due to the marked trailing observed in the former medium with most of the strains tested. The same phenomenon was also observed when selected isolates were tested on RPMI containing 2% glucose.
Overall, AD-Cas showed higher agreement with BM than did Etest-Cas for
all azoles (Table 2). BM, AD-Cas, and Etest-Cas each demonstrated a
progressive increase in fluconazole MICs against strains isolated
sequentially from a given patient, in accordance with the decreased
clinical response to fluconazole (Fig.
2). In order to detect possible
cross-resistance among azoles, we further analyzed the distributions of
itraconazole and ketoconazole MICs for fluconazole-susceptible and
-resistant isolates of C. albicans. Because of the
of 3 dilutions between fluconazole MICs obtained by BM
and by AD-Cas, we arbitrarily chose fluconazole breakpoints of 4 and 32 µg/ml to define isolates susceptible to fluconazole by BM and by
AD-Cas, respectively. When the Mann-Whitney U test was used to
determine the distribution of itraconazole and ketoconazole MICs for
the two groups of isolates, a statistically significant difference was
found with both the methods employed (P = 0.0001) (Fig.
3). A decrease in susceptibility to
itraconazole and ketoconazole was observed in strains that developed
resistance to fluconazole.
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DISCUSSION |
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Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
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Antifungal susceptibility tests, like those for antibacterial agents, may be an important aid in the decisions on starting antifungal treatment and in monitoring the outcome. So far, the use of these particular tests to monitor antifungal therapy has been limited by the lack of reproducibility and uncertain clinical relevance (5, 10). Following the increasing prevalence of fungal infections, new antifungal agents have been introduced and yeast isolates with reduced susceptibility to antifungal agents have been recognized (2, 8, 11, 12, 19, 20). Lately, the long-term use of azoles in the prophylaxis of systemic mycoses for bone marrow transplant patients and in suppressive therapy for AIDS patients has resulted in the selection of isolates that are more resistant to azole therapy (8, 11, 12, 19, 20).
Both BM and AD have been widely employed in clinical laboratories. Little information is available on the correlation between these two procedures. Since the NCCLS suggests performing the broth procedure in RPMI 1640 buffered with MOPS, we compared the azole MICs obtained by the proposed standard method with those obtained by agar dilution in the same medium and in Casitone medium buffered with phosphate.
Generally, AD MICs were higher than BM MICs. This could be explained by
the different reading criteria considered in the definition of the
endpoints. The different methods of reading will produce a consistent
bias resulting in very poor agreement if the percentage of agreement is
calculated, as usual, on the basis of discrepancies between MIC
endpoints of no more than 2 dilutions. In order to assess the most
appropriate way of evaluating agreement of MICs obtained by different
methodologies, such as AD and BM, data analysis was performed
according to Bland and Altman's method (3). By this method
of analysis, based on the notion that the mean of two measurements is
the best estimate, since the "true" value is not known, it is
possible to remove the consistent bias estimated by .
Interestingly, analysis of our data showed that the MICs of all three azoles determined by AD-Cas were in better agreement with the MICs obtained with BM than were those produced by AD-RPMI. The MICs of all three azoles obtained with AD-RPMI showed a marked increase between the 1st- and the 2nd-day readings. This was rarely observed for the MICs obtained by AD-Cas. A tendency to higher fluconazole MICs in assays with agar dilutions buffered with MOPS compared to those obtained in phosphate- or endomethylene-tetrahydrophthalic acid (EMTA)-buffered media has been reported (28).
Recently, the Etest has been introduced as a means of producing an accurate quantitative MIC result by using an agar diffusion format (4, 9, 24). So far, literature data comparing MICs obtained by Etest with those obtained by macro- or microdilution have shown variable results depending on the antifungal agent and the Candida species tested, as well as on the medium used for testing (4, 9, 21, 24). Sewell et al. (24) reported an agreement of 84% (±2 dilutions) between Etest-RPMI and broth macro- and microdilution methods for fluconazole susceptibility testing of Candida isolates when endpoint determinations were made after 24 h of incubation. Our data demonstrated that fluconazole, ketoconazole, and itraconazole MICs determined by Etest-Cas were in better agreement with the BM MICs than those produced in RPMI.
This study, which compared three different azole susceptibility testing procedures for strains of C. albicans isolated sequentially from the oral cavities of AIDS patients undergoing azole therapy, indicates that AD-Cas and Etest-Cas, as well as BM, can demonstrate progressive increases in fluconazole MICs against yeasts isolated from patients during the course of their oral infections, in accordance with the decrease in clinical response to fluconazole. In addition, all three methods were able to reveal a decrease in susceptibility to itraconazole and ketoconazole for some of the strains that developed resistance to fluconazole, as previously reported (1).
In conclusion, our study indicates that AD-Cas, unlike AD-RPMI, is a suitable method for testing azoles against isolates of C. albicans. AD-Cas produces results that agree with those obtained by BM, provided that an appropriate method is used to calculate the agreement. Etest-Cas can be used as an alternative method to determine azole susceptibility.
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ACKNOWLEDGMENTS |
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This work was supported in part by grants from the IRCCS Ospedale Maggiore di Milano and the Istituto Superiore di Sanità, Roma, Italy (IX AIDS project).
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FOOTNOTES |
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* Corresponding author. Mailing address: Istituto di Igiene e Medicina Preventiva, Università degli Studi di Milano, via F. Sforza 35, 20122 Milan, Italy. Phone: 39 2 55188373. Fax: 39 2 55191561. E-mail: viviani{at}imiucca.csi.unimi.it.
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Journal of Clinical Microbiology, June 1998, p. 1578-1583, Vol. 36, No. 6
0095-1137/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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