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Antimicrobial Agents and Chemotherapy, September 1999, p. 2236-2239, Vol. 43, No. 9
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
In Vitro Activities of BMS-207147 against Over 600 Contemporary
Clinical Bloodstream Isolates of Candida Species from
the SENTRY Antimicrobial Surveillance Program in North America
and Latin America
D. J.
Diekema,*
M. A.
Pfaller,
S. A.
Messer,
A.
Houston,
R. J.
Hollis,
G. V.
Doern,
R. N.
Jones, and
The SENTRY
PARTICIPANTS GROUP
Medical Microbiology Division, Department of
Pathology, University of Iowa College of Medicine, Iowa City, Iowa
Received 14 May 1999/Returned for modification 25 June
1999/Accepted 15 July 1999
 |
ABSTRACT |
We compared the in vitro activity of BMS-207147, an investigational
triazole, with those of itraconazole and fluconazole against 613 clinical bloodstream isolates of Candida spp. collected
from SENTRY participating hospitals during 1997 and 1998. Overall, BMS-207147 was the most active azole against all Candida
spp. While both BMS-207147 and itraconazole displayed a stepwise
decrease in activity against isolates for which the fluconazole MICs
were elevated, BMS-207147 had two- to fourfold greater activity than itraconazole both against Candida spp. that were
dose-dependently fluconazole susceptible and against those that were
fluconazole resistant.
| |
INTRODUCTION |
BMS-207147 (ER-30346) is a novel
investigational triazole antifungal agent (1, 12) with a
broad spectrum of in vitro activity against Candida,
Aspergillus, and Cryptococcus spp. (2-6, 8,
9, 11). BMS-207147 has recently been demonstrated to be two- to
fourfold more active than itraconazole against bloodstream isolates of
Candida spp. collected from U.S. hospitals between 1992 and
1997 (8). In this study, we compared the activity of
BMS-207147 with those of itraconazole and fluconazole against over 600 bloodstream isolates of Candida spp. collected from medical centers in Canada, the United States, and Latin America during 1997 and
1998. This represents the first evaluation of the in vitro activity of
BMS-207147 against recently collected isolates of Candida
spp. from outside the United States. Special attention was given to a
comparison of BMS-207147 versus itraconazole against Candida
sp. isolates for which the fluconazole MICs are elevated.
| |
MATERIALS AND METHODS |
Organisms.
The SENTRY Antimicrobial Surveillance Program was
established in 1997 to monitor the predominant pathogens and
antimicrobial resistance patterns of nosocomial and community-acquired
infections via a broad network of sentinel hospitals distributed by
geographic location and size. The organisms tested in this study
represented all of the isolates of Candida sp. causing
bloodstream infections at SENTRY centers in the western hemisphere
during 1997 and 1998. Candida sp. isolates were collected
from 22 centers in the United States, 6 in Canada, and 7 in Latin
America. Most of the centers were tertiary-care hospitals.
Each participating center contributed results on consecutive blood
culture isolates of Candida spp. judged to be clinically significant by local criteria. All isolates were saved on agar slants
and sent on a weekly basis to the University of Iowa College of
Medicine (Iowa City) for storage and further characterization by
reference identification and susceptibility testing methods.
Organism identification.
All fungal blood culture isolates
were identified at the participating institution by the routine method
in use at each laboratory. Upon receipt at the University of Iowa, the
isolates were subcultured onto potato dextrose agar (Remel, Lenexa,
Kans.) and CHROMagar Candida medium (Hardy Laboratories, Santa Maria,
Calif.) to ensure viability and purity. Confirmation of species
identification was performed with Vitek and API products (bioMerieux,
St. Louis, Mo.) or by conventional methods, as required. Isolates were
stored as suspensions in water or on agar slants at ambient temperature until needed.
Susceptibility testing.
Antifungal susceptibility testing
was performed by the reference broth microdilution method described by
the National Committee for Clinical Laboratory Standards (NCCLS)
(7). Reference powders of fluconazole (Pfizer), itraconazole
(Janssen), and BMS-207147 (Bristol-Meyers Squibb) were obtained from
the respective manufacturers. Stock solutions were prepared in dimethyl
sulfoxide (BMS-207147 and fluconazole) or polyethylene glycol
(itraconazole). Serial twofold dilutions were prepared as outlined by
the NCCLS (7), and final dilutions were made in RPMI 1640 medium buffered to pH 7.0 with 0.165 M morpholinepropanesulfonic acid
(MOPS) buffer (Sigma). Aliquots (0.1 ml) of each antifungal agent at a
2× final concentration were dispensed into the wells of plastic
microdilution trays by using a Quick Spense II system (Dynatech
Laboratories, Chantilly, Va.). The trays were sealed and frozen at
70°C until needed.
A 0.1-ml yeast inoculum (concentration of 1.0 × 10
3
to 5.0 × 10
3 cells/ml) was added to each well of the
microdilution trays (final
concentration of 0.5 × 10
3
to 2.5 × 10
3 cells/ml). The final concentrations of
the antifungal agents
were 0.007 to 8 µg/ml for BMS-207147 and
itraconazole and 0.12
to 128 µg/ml for fluconazole. The BMS-207147
concentrations were
chosen based upon previous studies of the in vitro
activity (
3,
4) and pharmacokinetic profile (
6)
of the drug (i.e., to
ensure that on-scale and clinically relevant
concentrations were
tested). The trays were incubated in air at 35°C,
and MIC endpoints
were read after 48 h of incubation. Drug-free
and yeast-free controls
were included on each tray. Following
incubation, the broth microdilution
trays were examined with a reading
mirror and the growth in each
well was compared with that in the growth
control well. The MIC
of each triazole was defined as the lowest
concentration resulting
in 80% inhibition of growth compared to the
growth control (
7).
The data reported are the MICs of each
antifungal agent necessary
to inhibit 50% (MIC
50) and 90%
(MIC
90) of the isolates
tested.
Interpretive susceptibility criteria for fluconazole and itraconazole
were those published by Rex et al. (
10) and the NCCLS
(
7). Isolates for which the fluconazole MICs were
8
µg/ml
were considered susceptible (S), those for which the MICs were
16 to 32 µg/ml were considered susceptible dependent upon dose
(S-DD), and those for which the MICs were
64 µg/ml were considered
resistant (R). For itraconazole, interpretative breakpoints were
as
follows: S,
0.12 µg/ml; S-DD, 0.25 to 0.5 µg/ml; R,
1 µg/ml.
Quality control.
Quality control was performed by testing
Candida parapsilosis ATCC 22019 and C. krusei
ATCC 6258.
| |
RESULTS |
A total of 634 bloodstream isolates of Candida spp.
were reported by SENTRY centers in the United States, Canada, and Latin America during 1997 and 1998. Of these, 613 were contained within the
six most common species groups (C. albicans, C. glabrata, C. parapsilosis, C. tropicalis,
C. krusei, and C. guilliermondii). The frequency
of isolation of each Candida sp. by year and region is
presented in Table 1.
Table 2 summarizes the in vitro
susceptibilities of the 613 bloodstream isolates of Candida
spp. tested against BMS-207147, itraconazole, and fluconazole. Overall,
the fluconazole resistance of C. albicans was extremely low
(0.9%) and, in particular, no resistance was detected in C. parapsilosis and C. tropicalis. Of 106 C. glabrata bloodstream isolates tested, 5.7% were fluconazole resistant (MIC, 64 µg/ml). For each species of Candida
tested, the MIC50 and MIC90 of BMS-207147 were
two- to fourfold lower than those of itraconazole.
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|
TABLE 2.
In vitro susceptibilities to fluconazole, itraconazole,
and BMS-207147 of bloodstream isolates of Candida spp. from
1997 and 1998
|
|
BMS-207147 and itraconazole were compared with respect to the
fluconazole susceptibility categories. These data are presented in
Table 3. As the fluconazole MIC increased
(categorized as S, S-DD, or R), stepwise increases in the
MIC50s and MIC90s of both BMS-207147 and
itraconazole were also noted. However, within each fluconazole
susceptibility category, BMS-207147 still displayed two- to fourfold
greater activity than itraconazole. For example, when all 42 fluconazole S-DD isolates were combined for analysis, BMS-207147 had
twofold greater activity than itraconazole
(MIC50/MIC90, 0.5/1.0 versus 1.0/2.0 µg/ml,
respectively).
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|
TABLE 3.
In vitro susceptibilities of bloodstream isolates of
various species of Candida tested against BMS-207147 and
itraconazole and stratified by fluconazole susceptibility category
|
|
Eleven Candida sp. isolates were fluconazole R (MIC, 64
µg/ml). The BMS-207147 and itraconazole MICs for these strains are listed in Table 4. For eight of these
isolates, the BMS-207147 MIC was two- to eightfold lower than the
itraconazole MIC. Notably, against the two C. krusei
isolates for which the fluconazole MICs were 64 µg/ml, the
BMS-207147 MICs were 0.25 and 0.5 µg/ml, compared to 2.0 µg/ml for
itraconazole. For three fluconazole-R strains (two of C. albicans and one of C. glabrata), the BMS-207147 MIC was equal to or higher than the itraconazole MIC.
| |
DISCUSSION |
These results demonstrate that BMS-207147 has a broader spectrum
of in vitro activity against invasive (bloodstream) isolates of
Candida spp. than either itraconazole or fluconazole. Based upon MIC50s and MIC90s, BMS-207147 consistently
demonstrated 2- to 4-fold greater potency than itraconazole and 16- to
32-fold greater potency than fluconazole against all of the
Candida spp. tested, including C. albicans,
C. glabrata, C. parapsilosis, C. tropicalis, C. krusei, and C. guilliermondii. Furthermore, we found that BMS-207147 retained
twofold greater activity than itraconazole against Candida
sp. bloodstream isolates for which the fluconazole MICs were elevated.
Other investigators have demonstrated the excellent in vitro activity
of BMS-207147 against Candida spp. (3, 4, 6, 8,
9) and other fungal pathogens, including Aspergillus
spp. (2, 3, 6) and cryptococci (4, 6).
BMS-207147 has also been evaluated in vivo in murine models of
disseminated candidiasis (6), pulmonary candidiasis
(5), and oral candidiasis (5). These studies
demonstrated BMS-207147 to be more effective than itraconazole and
comparable in efficacy to fluconazole. Also of interest is that
BMS-207147 appeared to have greater activity than itraconazole or
fluconazole against an experimental model of pulmonary infection due to
fluconazole-resistant C. albicans (5). In these
studies and in other experimental models (11), BMS-207147
was administered orally. Hata et al. found the absorption of BMS-207147
in the mouse to be comparable to that of itraconazole at an equivalent
oral dose (maximum drug concentration in serum, 1.0 µg/ml after
administration of a 10-mg/kg dose) but found the half-life of
BMS-207147 (4.0 h) to be about three times longer than that of
itraconazole (6).
The in vitro data we present suggest that BMS-207147 may be a promising
alternative to currently available triazoles for the treatment of
infections due to Candida spp., including those due to
organisms for which the fluconazole MICs are elevated. Further study of
the safety and pharmacokinetic profiles of BMS-207147 in humans is warranted.
| |
ACKNOWLEDGMENTS |
We thank Kay Meyer for her assistance in the preparation of the
manuscript. We appreciate the contributions of all SENTRY site
participants. The following participants contributed data or isolates
to the study: The Medical Center of Delaware, Wilmington (L. Steele-Moore); Clarion Health Methodist Hospital, Indianapolis, Ind.
(G. Denys); Henry Ford Hospital (C. Staley); Summa Health System,
Akron, Ohio (J. R. Dipersio); Good Samaritan Regional Medical
Center (M. Saubolle); Denver General Hospital, Denver, Colo. (M. L. Wilson); University of New Mexico Hospital, Albuquerque, (G. D. Overturf); University of Illinois at Chicago, (P. C. Schreckenberger); University of Iowa Hospitals and Clinics, Iowa City
(R. N. Jones); Creighton University, Omaha, Nebr. (S. Cavalieri);
Froedtert Memorial Lutheran Hospital-East, Milwaukee, Wis. (S. Kehl);
Boston VAMC, Boston, Mass. (S. Brecher); Columbia Presbyterian Medical
Center, New York, N.Y. (P. Della-Latta); Long Island Jewish Medical
Center, New Hyde Park, N.Y. (H. Isenberg); Strong Memorial Hospital,
Rochester, N.Y. (D. Hardy); Kaiser Regional Laboratory, Berkeley,
Calif. (J. Fusco); Sacred Heart Medical Center, Spokane, Wash. (M. Hoffmann); University of Washington Medical Center, Seattle (S. Swanzy); Barnes-Jewish Hospital, St. Louis, Mo. (P. R. Murray);
Parkland Health & Hospital System, Dallas, Tex. (P. Southern); The
University of Texas Medical School, Houston (A. Wanger); University of
Texas Medical Branch at Galveston (B. Reisner); University of
Louisville Hospital, Louisville, Ky. (J. Snyder); University of
Mississippi Medical Center, Jackson (J. Humphries); Carolinas Medical
Center, Charlotte, N.C. (S. Jenkins); University of Virginia Medical
Center, Charlottesville (K. Hazen); University of Alberta Hospital,
Edmonton, Alberta, Canada (R. Rennie); Health Sciences Centre,
Winnipeg, Manitoba, Canada (D. Hoban); Queen Elizabeth II Health
Sciences Centre, Halifax, Nova Scotia, Canada (K. Forward); Ottawa
General Hospital, Ottawa, Ontario, Canada (B. Toye); Royal Victoria
Hospital, Montreal, Quebec, Canada (H. Robson); Microbiology Laboratory C.E.M.I.C., Buenos Aires, Argentina (J. Smayvsky); Hospital San Lucas
and Olivos Community Hospital, Buenos Aires, Argentina (J. M. Casellas and G. Tome); Lamina LTDA, Rio de Janeiro, Brazil (J. L. M. Sampaio); Unidad de Microbiología Oriente, Santiago, Chile (V. Prado); Hospital Clinico Universidad Católica,
Santiago, Chile (E. Palavecino); Corporación para
Investigaciónes Biológicas, Medellín, Colombia,
(J. A. Robledo); Instituto Nacional de la Nutrición, Mexico
City, Mexico (J. S. Osornio); Laboratorio Medico Santa Luzia,
Florianopolis, Brazil (C. Zoccoli); Instituto DE Doencas
Infecciosas-IDIPA, Sao Paulo, Brazil (H. S. Sader); Centro Medico
de Caracas, San Bernadino, Caracas, Venezuela (M. Guzman); and the
Hospital Maciel, Montevideo, Uruguay (H. Bagnulo).
This study was supported by a research and educational grant from
Bristol-Myers Squibb Company.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Medical
Microbiology Division, C606 GH, Department of Pathology, University of
Iowa College of Medicine, Iowa City, IA 52242. Phone: (319) 384-9951. Fax: (319) 356-4916. E-mail: daniel-diekema{at}uiowa.edu.
| |
REFERENCES |
| 1.
|
Bartroli, J.,
E. Turmo, and M. Alguero.
1998.
New azole antifungals. 3. Synthesis and antifungal activity of 3-substituted-4(3H)-quinozolinones.
J. Med. Chem.
41:1868-1882.
|
| 2.
|
Espinel-Ingroff, A.
1998.
Evaluation of antifungal susceptibility testing parameters for amphotericin B, itraconazole, voriconazole, SCH56592, and BMS-207147 against Aspergillus spp., abstr. J-7, p. 452.
In
Abstracts of the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington, D.C.
|
| 3.
|
Espinel-Ingroff, A.,
A. Palacio, and A. Carrillo-Munoz.
1998.
In vitro activity of the new triazole BMS-207147 against Aspergillus spp., Candida spp., and emerging mold pathogens: a comparative study, abstr. F-154, p. 271.
In
Abstracts of the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington, D.C.
|
| 4.
|
Fung-Tomc, J. C.,
E. Huczko,
B. Minassian, and D. P. Bonner.
1998.
In vitro activity of a new oral triazole, BMS-207147 (ER-30346).
Antimicrob. Agents Chemother.
42:313-318[Abstract/Free Full Text].
|
| 5.
|
Hata, K.,
J. Kimura,
H. Miki,
T. Toyosawa,
M. Moriyama, and K. Katsu.
1996.
Efficacy of ER-30346, a novel oral triazole antifungal agent, in experimental models of aspergillosis, candidiasis, and cryptococcosis.
Antimicrob. Agents Chemother.
40:2243-2247[Abstract].
|
| 6.
|
Hata, K.,
J. Kimura,
H. Miki,
T. Toyosawa,
T. Nakamura, and K. Katsu.
1996.
In vitro and in vivo antifungal activities of ER-30346, a novel oral triazole with a broad antifungal spectrum.
Antimicrob. Agents Chemother.
40:2237-2242[Abstract].
|
| 7.
|
National Committee for Clinical Laboratory Standards.
1997.
Reference method for broth dilution antifungal susceptibility testing of yeast. Approved standard M27-A.
National Committee for Clinical Laboratory Standards, Wayne, Pa.
|
| 8.
|
Pfaller, M. A.,
S. A. Messer,
R. J. Hollis,
R. N. Jones,
G. V. Doern,
M. E. Brandt, and R. A. Hajjeh.
1998.
In vitro susceptibilities of Candida bloodstream isolates to the new triazole antifungal agents BMS-207147, Sch 56592, and voriconazole.
Antimicrob. Agents Chemother.
42:3242-3244[Abstract/Free Full Text].
|
| 9.
|
Pfaller, M. A.,
S. A. Messer,
S. Gee,
S. Joly,
C. Pujol,
D. J. Sullivan,
D. C. Coleman, and D. R. Soll.
1999.
In vitro susceptibilities of Candida dubliniensis isolates tested against the new triazole and echinocandin antifungal agents.
J. Clin. Microbiol.
37:870-872[Abstract/Free Full Text].
|
| 10.
|
Rex, J. H.,
M. A. Pfaller,
J. N. Galgiani,
M. S. Bartlett,
A. Espinel-Ingroff,
M. A. Ghannoum,
M. Lancaster,
F. C. Odds,
M. G. Rinaldi,
T. J. Walsh, and A. L. Barry for The Subcommittee on Antifungal Susceptibility Testing of The National Committee for Clinical Microbiology Standards..
1997.
Development of interpretive breakpoints for antifungal susceptibility testing: conceptual framework and analysis of in vitro-in vivo correlation data for fluconazole, itraconazole, and Candida infections.
Clin. Infect. Dis.
24:235-247[Medline].
|
| 11.
|
Shock, K.,
S. Marino,
T. Baumgartner, and V. Andriole.
1998.
Efficacy of a new triazole, BMS-207147, in a model of invasive aspergillosis in immunosuppressed, neutropenic rabbits, abstr. J-54, p. 466.
In
Abstracts of the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington, D.C.
|
| 12.
|
Tsuruoka, A.,
Y. Kaku,
H. Kakinuma,
M. Yanagisawa,
K. Nara, and T. Naito.
1998.
Synthesis and antifungal activity of novel thiazole-containing triazole antifungals. II. Optically active ER-30346 and its derivatives.
Chem. Pharm. Bull.
46:623-630.
|
Antimicrobial Agents and Chemotherapy, September 1999, p. 2236-2239, Vol. 43, No. 9
0066-4804/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
