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Antimicrobial Agents and Chemotherapy, February 1998, p. 313-318, Vol. 42, No. 2
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
In Vitro Activity of a New Oral Triazole,
BMS-207147 (ER-30346)
Joan C.
Fung-Tomc,*
Elizabeth
Huczko,
Beatrice
Minassian, and
Daniel P.
Bonner
Bristol-Myers Squibb Pharmaceutical Research
Institute, Wallingford, Connecticut 06492
Received 25 July 1997/Returned for modification 10 September
1997/Accepted 17 November 1997
 |
ABSTRACT |
The antifungal activity of BMS-207147 (also known as ER-30346) was
compared to those of itraconazole and fluconazole against 250 strains
of fungi representing 44 fungal species. MICs were determined by using
the National Committee for Clinical Laboratory Standards
(NCCLS)-recommended broth macrodilution method for yeasts, which was
modified for filamentous fungi. BMS-207147 was about two- to fourfold
more potent than itraconazole and about 40-fold more active than
fluconazole against yeasts. With the NCCLS-recommended resistant MIC
breakpoints of 
1 µg/ml for itraconazole and of 64 µg/ml for
fluconazole against Candida spp., itraconazole and fluconazole were inactive against strains of Candida krusei
and Candida tropicalis. In contrast, all but 9 (all
C. tropicalis) of the 116 Candida strains
tested had BMS-207147 MICs of <1 µg/ml. The three triazoles were
active against about half of the Candida glabrata strains
and against all of the Cryptococcus neoformans strains
tested. The three triazoles were fungistatic to most yeast species,
except for BMS-207147 and itraconazole, which were fungicidal to
cryptococci. BMS-207147 and itraconazole were inhibitory to most
aspergilli, and against half of the isolates, the activity was cidal.
BMS-207147 and itraconazole were active, though not cidal, against most
hyaline Hyphomycetes (with the exception of Fusarium spp. and Pseudallescheria boydii),
dermatophytes, and the dematiaceous fungi and inactive against
Sporothrix schenckii and zygomycetes. Fluconazole, on the
other hand, was inactive against most filamentous fungi with the
exception of dermatophytes other than Microsporum gypseum.
Thus, the spectrum and potency of BMS-207147 indicate that it should be
a candidate for clinical development.
| |
INTRODUCTION |
In the past two decades, the number
of immunocompromised patients has increased significantly.
Immunocompromised patients include patients with neoplasm on
chemotherapy, organ transplant recipients on immunosuppressive therapy,
and patients infected with human immunodeficiency virus (HIV). More
than 95% of HIV-infected individuals suffer from oropharyngeal
candidiasis (OPC) (7). Since its introduction, fluconazole
(FLU) has been used extensively for the treatment of OPC. Though
Candida albicans remains the most prevalent fungal pathogen
causing human disease, other Candida spp. (such as C. krusei, C. tropicalis, and C. glabrata) have increased in frequency as causative agents of candidiasis. The increased isolation of C. krusei in patients on FLU therapy
is likely due to its intrinsic resistance to FLU.
The only other triazole marketed for systemic fungal infections is
itraconazole (ITR). Unlike FLU, the antifungal spectrum of ITR includes
some strains of C. krusei, C. glabrata,
Aspergillus spp., and other filamentous fungi. While both
triazoles are generally fungistatic to yeasts, ITR is fungicidal to
many strains of aspergilli. Nonetheless, aspergillosis infections
treated with ITR fail in 20 to 40% of cases (1, 8).
The widespread use of triazoles in systemic fungal infections is due to
their broad spectrum and improved safety profile compared to those of
other marketed antifungal drugs. In this study, we report on the in
vitro antifungal and fungicidal activities of the new triazole
BMS-207147 (BMS). This triazole, also known as ER-30346, has been
evaluated previously by Eisai Co. on 90 to 100 strains of yeasts and
aspergilli using either SAAM-F (synthetic amino acid medium, fungal
agar), SDA (Sabouraud dextrose agar) or the microbroth method
recommended by the National Committee for Clinical Laboratory Standards
(NCCLS) (4, 5). In the current study, 250 fungal strains
representing 44 species were tested for their sensitivities to BMS,
ITR, FLU, and amphotericin B (AMB) by the NCCLS-approved macrobroth
susceptibility testing method for yeasts and modified for
filamentous fungi.
| |
MATERIALS AND METHODS |
Test organisms.
A total of 250 strains from 44 fungal
species were used in this study. Almost all (more than 95%) of the
strains were clinical isolates; the rest were obtained from the
American Type Culture Collection (Rockville, Md.).
Antifungal susceptibility test methods.
All isolates (except
Malassezia furfur) were tested by the reference broth
macrodilution method outlined by the NCCLS (6) and
modified for antifungal testing of filamentous fungi (2). BMS was obtained from Eisai Co., FLU was from Pfizer, ITR was from
Janssen Pharmaceutica, and AMB was from Bristol-Myers Squibb Co.
The interpretative MIC breakpoints for FLU and ITR are obtained from
the NCCLS guidelines (6); these breakpoints were meant as
interpretative guidelines for Candida spp. The
NCCLS-recommended breakpoints for FLU are as follows: 
8 µg/ml,
susceptible; 16 to 32 µg/ml, susceptible-dose dependent (S-DD); and
64 µg/ml, resistant. For ITR, the NCCLS-recommended MIC breakpoints
as follows: 0.13 µg/ml, susceptible; 0.25 to 0.5 µg/ml, S-DD; and
1 µg/ml, resistant. At this point, no interpretative MIC
breakpoints for BMS have been established. For the purpose of
discussion of the MIC results in this report, we will use the ITR
interpretative breakpoints for BMS, given that both compounds achieve
the same peak levels in plasma in dogs (4). As for AMB, no
interpretative MIC breakpoints have been recommended by the NCCLS,
though Candida isolates with AMB MICs of >1 µg/ml appear
resistant in animal models (8). Thus, AMB resistance will be
defined in this study as AMB MICs of 2 µg/ml when the NCCLS RPMI
1640 method is used.
Broth macrodilution for yeasts was performed according to the
guidelines of the NCCLS (
6) and modified for filamentous
fungi by the method of Espinel-Ingroff and Kerkering (
2).
The
agar dilution method used for
Malassezia furfur was
described
previously (
3).
The MIC endpoints by the broth macrodilution method were determined as
recommended by the NCCLS (
6). AMB MICs were defined
as the
lowest drug concentrations which inhibited all visible
growth (i.e.,
100% inhibition). FLU, ITR, and BMS MICs were defined
as the lowest
drug concentrations which inhibited 80% of the growth
in the growth
control tube (as determined by comparison with a
1:5 dilution of the
growth control), except with
Malassezia furfur,
where 100%
growth inhibition was the endpoint.
MFCs.
Minimum fungicidal concentrations (MFCs) were
determined by subculturing 0.1 ml from each tube with no visible growth
in the MIC broth macrodilution series onto drug-free SDA plates, as
previously described (3). Colony counts were determined, and
the MFCs were defined in accordance with the level of decrease in the
number of CFU per milliliter, i.e., MFC99 means a 99%
reduction in the number of CFU of the final inoculum size per
milliliter, MFC95 means a 95% reduction, and
MFC90 means a 90% reduction.
| |
RESULTS |
Comparative in vitro antifungal spectra of BMS, ITR, and FLU.
Of the 116 Candida strains tested, all but 9 strains of
C. tropicalis were susceptible to BMS at MICs of 0.5
µg/ml (Table 1). Likewise, eight
strains of C. tropicalis and four strains of C. krusei were resistant to ITR (MICs of 1 µg/ml) compared to
eight C. tropicalis and six C. krusei strains
being resistant to FLU (MICs of 64 µg/ml). Based on
MIC90s, only C. tropicalis strains were
considered resistant to BMS, whereas C. tropicalis and
C. krusei were resistant to ITR and FLU. Nonetheless,
whereas the MIC90s of BMS to C. albicans and
Candida parapsilosis were 0.03 to 0.06 µg/ml, the BMS
MIC90 for C. krusei was 10-fold higher (at 0.5 µg/ml). This suggests that while BMS was active against C. krusei, it was intrinsically less active against this species. C. krusei is considered intrinsically resistant to FLU. All
of the yeast strains tested were susceptible to AMB.
Another yeast species often resistant to FLU is
C. glabrata.
Of the 16
C. glabrata strains tested, 9 (or 56%) have FLU
MICs
of <64 µg/ml (Table
1). Compared to other yeast species, BMS
and ITR were also less active against
C. glabrata; 44 and
38%
of the
C. glabrata strains tested had BMS and ITR MICs
of <1 µg/ml,
respectively.
All 32
C. neoformans strains tested were susceptible to the
three azoles, as were the two
Trichosporon beigelii strains
(Tables
1 and
2). While one of the two
Rhodotorula strains was susceptible
to BMS, they were both
less susceptible to ITR and FLU than to
BMS (Table
2).
Sixteen
Aspergillus strains were tested. All but one strain
each of
Aspergillus niger and
Aspergillus
fumigatus had MICs of
<1 µg/ml to BMS and ITR, respectively
(Table
1). In contrast,
all 16 strains of
Aspergillus were
resistant to FLU. BMS and ITR
were active against other hyaline
Hyphomycetes (
Acremonium strictum,
Paecilomyces variotii, and
Penicillium sp.) but
inactive (MICs
>16 µg/ml) against
Fusarium spp. and 4 of
the 6
Pseudallescheria boydii strains (Tables
1 and
2). FLU
MICs were
64 µg/ml for
Fusarium spp., one of the four
P. variotii strains, and one of
the six
P. boydii
strains tested. AMB MICs that were
2 µg/ml
were observed with one
strain of
Fusarium spp. and in five of
the six strains of
P. boydii.
The 25 dermatophytes were highly susceptible (MICs of
0.13 µg/ml)
to BMS and ITR. The four dermatophytic strains with FLU
MICs of
64
µg/ml belonged to the species
Microsporum gypseum.
ITR MICs were
0.13 µg/ml against all of the dematiaceous fungi
tested (Table
2). BMS, on the other hand, was less active
than ITR
against
Alternaria and
Curvularia spp., with MICs
of
1 to 2 µg/ml. FLU MICs of
64 µg/ml were observed with strains
of
Alternaria spp.,
Exophiala jeanselmei,
Fonsecaea pedrosoi,
and
Phialophora verrucosa.
Cladosporium carrionii,
F. pedrosoi,
and
P. verrucosa strains had AMB MICs of
2 µg/ml.
For the most part, BMS and ITR MICs of
1 µg/ml were inactive
against
Sporothrix schenckii and the zygomycetes
(
Mucor spp.,
an
Absidia strain, and a
Rhizopus strain) (Table
2). AMB MICs
to
S. schenckii and the zygomycetes were
1 µg/ml.
Fungicidal activities of BMS, ITR, FLU, and AMB.
For the five
strains of Candida spp. and one C. glabrata
strain tested, AMB MFC99s were no more than twofold greater
than the MICs (Table 3). The three
triazoles were not fungicidal to Candida spp. One strain of
Candida lusitaniae had a FLU MFC99 of 1 µg/ml.
FLU was not fungicidal to
Cryptococcus neoformans (Table
3).
Even though the MFC
99 and MIC
95s of BMS and ITR
were much higher
than the MICs of these drugs, the MFC
95
values were often <1 µg/ml.
Thus, it appears that ITR and BMS were
often fungicidal to cryptococci
at achievable levels of drug in serum.
BMS and ITR were often fungicidal to aspergilli (Table
4). The MFC
99s,
MFC
95s, and MFC
90s were usually the same,
though these
values differed by 4- to 32-fold in four strains. The BMS
MFC
90s
were <1 µg/ml for 7 of 14
Aspergillus
strains compared to 10 of
the 14 strains with this level of fungicidal
activity with ITR.
The three triazoles were not fungicidal to non-
Aspergillus
filamentous fungi (Table
5).
Susceptibility testing of BMS.
Since test factors can
influence the MICs to azoles, we examined a number of test factors
(temperature, inoculum size, pH, duration of incubation, and human
serum) on three yeast strains (data not shown). The MICs of BMS, ITR,
and FLU were not affected by incubation temperature (30, 35, or 37°C)
or pH (3, 4, 5, 6, or 7). The MICs increased no more than fourfold with
an additional 24 h of incubation. Increasing the inocula from
102 to 105 CFU/ml affected BMS MIC the least
(up to 2-fold increase), while up to 16- and 8-fold increases were
observed in ITR MICs and FLU MICs, respectively. In the presence of
50% human serum, the MICs of the three azoles remained essentially
unchanged (4-fold increase) against two strains of C. albicans. Interestingly, with the C. tropicalis strain,
the MICs of the azoles decreased by 8- to 16-fold in the presence of
human serum.
The MIC distribution of BMS and ITR are listed in Table
6. Only 1 of the 24 ITR MICs with
C. parapsilosis ATCC 22019 was
outside the acceptable
quality control range recommended by the
NCCLS. The ITR MICs for
C. krusei ATCC 22492 was within the NCCLS-recommended,
acceptable quality control range. The recommended acceptable quality
control MIC ranges for BMS are 0.015 to 0.06 µg/ml for
C. parapsilosis ATCC 22019 and 0.13 to 0.5 µg/ml for
C. krusei ATCC 22492.
| |
DISCUSSION |
BMS appears to have a broader anticandidal spectrum than ITR and
FLU do. Based on their MIC90s, ITR and FLU were inactive against some strains of C. krusei and C. tropicalis, compared to BMS, which was active against all of the
C. krusei strains tested but was inactive against some
strains of C. tropicalis. Only 40 to 60% of the C. glabrata strains were susceptible or S-DD to the three triazoles.
With the exception of the MIC90s reported by Hata et al.
(4, 5) against C. tropicalis and C. glabrata, our results confirmed their findings. Hata et al. reported MIC90s in the 0.03- to 0.4-µg/ml range for the
three triazoles against C. tropicalis when SAAM-F medium was
used (5) but in the 12.5- to >100-µg/ml range when RPMI
1640 medium was used (4). In both studies by Hata et al.
(4, 5), the BMS MIC90s to C. glabrata
were 0.4 µg/ml versus the >16 µg/ml result obtained in this study.
The three triazoles were active against C. neoformans,
though only BMS and ITR were fungicidal to this yeast species. In this study and the Hata et al. studies (4, 5), BMS was 2- to 4-fold more active than ITR and 40-fold more active than FLU against yeast species.
In this study, BMS and ITR were inhibitory at 1 µg/ml to all but one
of the 16 strains of Aspergillus spp. Similarly, Hata et al.
observed the consistent activity of BMS and ITR against Aspergillus spp. (4, 5). The antiaspergillus
potencies of BMS and ITR are comparable. FLU was inactive against
aspergilli. BMS and ITR were also fungicidal to 50 to 74% of the
Aspergillus strains tested.
The activities of BMS and ITR against other filamentous fungi are
variable compared to FLU, which was inactive against most filamentous
fungi. ITR and BMS were uniformly active against dermatophytes, while
FLU was less active against Microsporum gypseum. Acremonium strictum, Paecilomyces variotii, and
Penicillium sp. were susceptible to BMS and ITR. Though both
ITR and BMS were active against most dematiaceous fungi, ITR appeared
to be somewhat more active than BMS. BMS and ITR were less active
against most strains of Pseudallescheria boydii,
Sporothrix schenckii, and the zygomycetes, and both were generally inactive against Fusarium spp. Unlike
Aspergillus spp., BMS and ITR were not fungicidal to the
other filamentous fungi.
In summary, BMS is a new triazole that is two- to fourfold more potent
than ITR and up to 40-fold more active than FLU against many species of
fungi. Its spectrum includes some yeast strains that are resistant to
FLU. BMS is like ITR in that it is fungicidal to cryptococci and many
strains of aspergilli. The in vitro profile of BMS warrants its
development as a therapeutic agent in humans.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Microbiology-104, Bristol-Myers Squibb Pharmaceutical Research
Institute, 5 Research Pkwy., Wallingford, CT 06492. Phone: (203)
284-6370. Fax: (203) 284-6771. E-mail:
joan_c._fung-tomc{at}ccmail.bms.com.
| |
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Antimicrobial Agents and Chemotherapy, February 1998, p. 313-318, Vol. 42, No. 2
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
