Journal of Antimicrobial Chemotherapy (2002) 50, 119-123
© 2002 The British Society for Antimicrobial Chemotherapy
In vitro activity of three new triazoles and one echinocandin against Candida bloodstream isolates from cancer patients
1 Department of Microbiology–Infectious Diseases, Hôpital Maisonneuve-Rosemont, 5415 Boulevard l’Assomption, Montréal, Québec H1T 2M4; 2 Department of Microbiology, Health Sciences Center, Winnipeg, Manitoba, Canada
Received 13 July 2001; returned 28 December 2001; revised 21 January 2002; accepted 27 March 2002
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and methodsResults and discussionReferences |
|---|
The in vitro activities of voriconazole, posaconazole, ravuconazole and micafungin were compared with those of fluconazole, itraconazole, ketoconazole, flucytosine and amphotericin B against 164 candidaemia isolates recovered from cancer patients in two Canadian centres. The MIC50 results for ravuconazole, voriconazole, posaconazole and micafungin were 0.01, 0.03, 0.12 and 0.25 mg/L, respectively. The new antifungal agents showed substantial activity against isolates demonstrating in vitro resistance to fluconazole and itraconazole. These results suggest that the newer antifungal agents possess promising activity against invasive Candida isolates, particularly against those with reduced susceptibility to fluconazole and itraconazole.
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and methodsResults and discussionReferences |
|---|
Candida bloodstream infections are important causes of morbidity and mortality in immunosuppressed cancer patients.1 Although fluconazole and itraconazole have been shown to be effective against invasive candidiasis in compromised hosts, emerging resistance gives rise to concerns about their future clinical usefulness.2 Several new investigational triazole agents and new echinocandin-like lipopeptides, which have a unique mode of action by disruption of cell wall glucan formation, may represent promising agents against yeast isolates with primary or secondary resistance to fluconazole and/or itraconazole.3,4 We compare the in vitro activity of three new triazoles, voriconazole, posaconazole and ravuconazole, and one echinocandin-like lipopeptide, micafungin, with that of established agents against Candida from bloodstream infections in cancer patients treated in two different Canadian medical centres.
|
Materials and methods |
|---|
|
TopAbstractIntroductionMaterials and methodsResults and discussionReferences |
|---|
A total of 164 Candida spp. isolates, recovered between 1996 and 2000 from blood cultures of cancer patients treated at Hôpital Maisonneuve-Rosemont (HMR) and the Health Sciences Center (HSC), were selected for testing. Standard antifungal powders of amphotericin B (Nucro Technics, Scarborough, Ontario, Canada), ravuconazole (Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT, USA), flucytosine (ICN Canada, Toronto, Ontario, Canada), ketoconazole, itraconazole (Janssen Research Foundation, Beerse, Belgium), fluconazole, voriconazole (Pfizer Pharmaceuticals, New York, NY, USA), posaconazole (Schering-Plough Research Institute, Kenilworth, NJ, USA) and micafungin (Fujisawa Healthcare, Inc., Osaka, Japan) were supplied by their respective manufacturers. Stock solutions were prepared in dimethyl sulphoxide for ravuconazole, voriconazole, posaconazole, itraconazole, amphotericin B and ketoconazole, or in water in the case of the other antifungal agents. Serial two-fold dilutions were made in RPMI 1640 medium (Sigma, St Louis, MO, USA) buffered to pH 7.0 with 0.165 M morpholinepropanesulphonic acid (MOPS) buffer (Sigma) for all antifungals, with the exception of amphotericin B, for which antibiotic medium 3 plus 2% glucose was used as the test medium to enable a more reliable detection of resistant isolates.5 The final concentration of the solvent did not exceed 1% in any of the wells. Antifungal susceptibility testing was performed by a broth microdilution method according to the guidelines recommended by the NCCLS.6 The final concentrations of the antifungal agents were: 0.006–64 mg/L of flucytosine; 0.008–8 mg/L of amphotericin B, itraconazole, voriconazole, ravuconazole, posaconazole and micafungin; 0.016–16 mg/L of ketoconazole; and 0.25–256 mg/L of fluconazole. Drug- and yeast-free controls were included. The trays were incubated in air at 35°C and MIC endpoints were read after 48 h of incubation. Following incubation, the trays were examined visually and the growth in each well was compared with the growth of the control (drug-free) well. The MIC of amphotericin B was defined as the lowest concentration resulting in a complete inhibition of growth, whereas the MICs of all the other compounds were defined as the lowest concentration that resulted in a prominent decrease in turbidity compared with that of growth-control wells, using the turbidity numerical score proposed by the NCCLS.6 The MIC50 and MIC90 results are the concentrations of each antifungal agent necessary to inhibit 50% and 90% of the isolates, respectively. Candida parapsilosis ATCC 22019, Candida kruseï ATCC 6258 and a fluconazole-resistant Candida albicans were included as quality control isolates.
|
Results and discussion |
|---|
|
TopAbstractIntroductionMaterials and methodsResults and discussionReferences |
|---|
The 164 isolates were evenly distributed between the two participating centres, with a similar proportion of C. albicans versus non-albicans Candida species (54% versus 46% for HMR and 50% versus 50% for HSC). The in vitro susceptibilities of the isolates are summarized in Table 1. A broad range of MICs was observed with both the current and the new investigational antifungal agents. Overall, ravuconazole was the most potent agent (MIC90 0.25 mg/L), followed by voriconazole, posaconazole, ketoconazole, itraconazole, amphotericin B (MIC90 1 mg/L), flucytosine (MIC90 4 mg/L), mica-fungin (MIC90 > 8 mg/L) and fluconazole (MIC90 32 mg/L). The in vitro activity of micafungin was less for C. parapsilosis, with an MIC90 of >8 mg/L. Against C. albicans and Candida glabrata, the activity of micafungin was comparable to that of voriconazole and posaconazole, and superior to that of fluconazole. Similarly, the activity of posaconazole against C. albicans, C. glabrata and C. parapsilosis (MIC90s 0.5, 1 and 0.125 mg/L, respectively) was comparable to that of the other new triazoles; however, against Candida tropicalis the MIC90 was >8 mg/L. Table 2 summarizes the in vitro susceptibility results of the 69 strains that were resistant or dose-dependent susceptible to fluconazole and/or itraconazole. For all organisms, the MIC90s of the three investigational triazoles ranged from 1 to 2 mg/L, compared with 8 mg/L for micafungin. Seven strains (three C. albicans, two C. tropicalis, one C. glabrata and one Candida spp.) were resistant to both fluconazole (MIC
64 mg/L) and itraconazole (MIC 1 mg/L). The geometric mean MICs of voriconazole, ravuconazole, posaconazole and micafungin for these strains were 8, 1.49, 4.4 and 1 mg/L, respectively (data not shown).
|
|
In general, compared with the current antifungal agents, the new investigational triazoles and echinocandins have been shown to have increased in vitro potencies against Candida isolates.7–9 In our study, ravuconazole, voriconazole and posaconazole were, respectively, 15-, 10- and four-fold more active than fluconazole against fluconazole- and itraconazole-susceptible isolates, and up to three-fold more active than itraconazole against those same susceptible isolates. The newer triazoles and micafungin showed greater activity against isolates with reduced susceptibility to fluconazole and/or itraconazole, by 12- to 85-fold compared with fluconazole and up to six-fold compared with itraconazole.
There are important pharmacokinetic differences between these various antifungal agents and this, combined with the fact that for the newer agents no susceptibility breakpoints have been established so far, means that the clinical impact of these different in vitro potencies will have to be determined through clinical studies. Substantial variation in the activities of the new antifungals, particularly against non-albicans Candida, are occasionally observed between studies. In our study we observed a limited activity of posaconazole against C. tropicalis, which contrasts with the observations made by Pfaller et al.9 The limited number of C. tropicalis isolates in our study, and the fact that 12 of these 21 isolates had reduced susceptibility to fluconazole and/or itraconazole, may explain this apparent disagreement, since cross-resistance with new triazoles has been documented by Hong-Nguyen & Yu.3 Of the three C. tropicalis isolates with posaconazole MICs > 8 mg/L, two showed fluconazole MICs of 128 and 256 mg/L, respectively. Similarly, micafungin was less active against C. parapsilosis. Lesser activity of echinocandins against C. parapsilosis has previously been observed by others.4,7–9 The clinical relevance of such an observation is presently unknown, since standardization of the susceptibility testing methods to assess the in vitro activity of the echinocandin lipopeptides has not been clearly defined, and breakpoints have not yet been determined. Reproducible interlaboratory results, obtained using the currently recommended NCCLS microdilution method against Candida isolates, have been reported with one of the new echinocandin agents.10 However, NCCLS methodology may not be suitable for this class of antifungals, and correlation between the in vitro and in vivo responses has not yet been established.
In conclusion, ravuconazole, posaconazole, voriconazole and the echinocandin micafungin exhibited good in vitro activity against our bloodstream isolates of Candida from cancer patients. They also demonstrate remarkable in vitro activity against isolates with reduced susceptibility to fluconazole and/or itraconazole. These new antifungal agents may hold promise in the management of invasive candidiasis caused by yeasts with primary and/or secondary resistance to established triazole agents.
|
Acknowledgements |
|---|
We thank Bristol-Myers Squibb, Fujisawa Healthcare, Inc., Janssen-Ortho Pharmaceuticals, Pfizer Pharmaceuticals and Schering-Plough Research Institute for providing the standard antifungal powders used in this study. This work was presented in part at the Fortieth Interscience Conference on Antimicrobial Agents and Chemotherapy, Toronto, Ontario, Canada, 17–20 September 2000, abstract 921.
|
Footnotes |
|---|
* Corresponding author. Tel: +1-514-252-3817; Fax: +1-514-252-3898; E-mail: laverdim{at}courrier.umontreal.ca
|
References |
|---|
|
TopAbstractIntroductionMaterials and methodsResults and discussionReferences |
|---|
1 . Uzun, O. & Anaissie, E. J. (2000). Predictors of outcome in cancer patients with candidemia. Annals of Oncology 12, 1517–21.
2 . Hong-Nguyen, M., Peacock, J. E., Morris, A. J., Tanner, D. C., Nguyen, M. L., Snydman, D. R. et al. (1996). The changing face of candidemia: emergence of non-Candida albicans species and antifungal resistance. American Journal of Medicine 100, 617–23.[Web of Science][Medline]
3
.
Hong-Nguyen, M. & Yu, C. Y. (1998). Voriconazole against fluconazole-susceptible and resistant Candida isolates: in-vitro efficacy compared with that of itraconazole and ketoconazole. Journal of Antimicrobial Chemotherapy 42, 253–6.
4
.
Cuenca-Estrella, M., Mellado, E., Diaz-Guerra, T. M., Monzon, A. & Rodriguez-Tudela, J. L. (2000). Susceptibility of fluconazole-resistant clinical isolates of Candida spp. to echinocandin LY303366, itraconazole and amphotericin B. Journal of Antimicrobial Chemotherapy 46, 475–7.
5 . Rex, J. H., Cooper, C. R., Jr & Mertz, W. G. (1995). Detection of amphotericin B-resistant Candida species in a broth-based system. Antimicrobial Agents and Chemotherapy 39, 906–9.[Abstract]
6 . National Committee for Clinical Laboratory Standards. (1997). Reference Method for Broth Dilution Antifungal Susceptibility of Yeasts: Approved Standard M27-A. NCCLS, Wayne, PA.
7
.
Fung-Tomc, J. C., Huczko, E., Minassian, B. & Bonner, D. P. (1998). In vitro activity of a new oral triazole, BMS-207147 (ER-30346). Antimicrobial Agents and Chemotherapy 42, 313–8.
8
.
Mikamo, H., Sato, Y. & Teruhiko, T. (2000). In vitro antifungal activity of FK 463, a new water-soluble echinocandin-like lipopeptide. Journal of Antimicrobial Chemotherapy 46, 485–7.
9
.
Pfaller, M. A., Messer, S. A., Holler, R. J., Jones, R. N., Doern, G. V., Brandt, M. E. et al. (1998). In vitro susceptibilities of Candida bloodstream isolates to these new triazole antifungal agents BMS-207147, SCH 56592, and voriconazole. Antimicrobial Agents and Chemotherapy 42, 3242–4.
10 . Barry, A. L., Pfaller, M. A., Brown, S. D., Espinel-Ingroff, A., Ghannoum, M. A., Knapp, C. et al. (2000). Quality control limits for broth microdilution susceptibility tests of ten antifungal agents. Journal of Clinical Microbiology 28, 3457–9.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. C. Arendrup, G. Garcia-Effron, W. Buzina, K. L. Mortensen, N. Reiter, C. Lundin, H. E. Jensen, C. Lass-Florl, D. S. Perlin, and B. Bruun Breakthrough Aspergillus fumigatus and Candida albicans Double Infection during Caspofungin Treatment: Laboratory Characteristics and Implication for Susceptibility Testing Antimicrob. Agents Chemother., March 1, 2009; 53(3): 1185 - 1193. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Trofa, A. Gacser, and J. D. Nosanchuk Candida parapsilosis, an Emerging Fungal Pathogen Clin. Microbiol. Rev., October 1, 2008; 21(4): 606 - 625. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Chowdhry and W. L. Marshall Analytical Reviews: Antifungal Therapies in the Intensive Care Unit J Intensive Care Med, May 1, 2008; 23(3): 151 - 158. [Abstract] [PDF]
|
|
|
|
|
|
C. Serena, M. Marine, G. Quindos, A. J. Carrillo, J. F. Cano, F. J. Pastor, and J. Guarro In Vitro Interactions of Micafungin with Amphotericin B against Clinical Isolates of Candida spp. Antimicrob. Agents Chemother., April 1, 2008; 52(4): 1529 - 1532. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Dannaoui, O. Lortholary, D. Raoux, M. E. Bougnoux, G. Galeazzi, C. Lawrence, D. Moissenet, I. Poilane, D. Hoinard, F. Dromer, et al. Comparative In Vitro Activities of Caspofungin and Micafungin, Determined Using the Method of the European Committee on Antimicrobial Susceptibility Testing, against Yeast Isolates Obtained in France in 2005-2006 Antimicrob. Agents Chemother., February 1, 2008; 52(2): 778 - 781. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. M. Rodriguez, M. Ruiz, F. J. Pastor, G. Quindos, A. Carrillo, and J. Guarro In vitro interaction of micafungin and fluconazole against Candida J. Antimicrob. Chemother., July 1, 2007; 60(1): 188 - 190. [Full Text] [PDF]
|
|
|
|
|
|
H. Seifert, U. Aurbach, D. Stefanik, and O. Cornely In Vitro Activities of Isavuconazole and Other Antifungal Agents against Candida Bloodstream Isolates Antimicrob. Agents Chemother., May 1, 2007; 51(5): 1818 - 1821. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Enoch, H. A. Ludlam, and N. M. Brown Invasive fungal infections: a review of epidemiology and management options. J. Med. Microbiol., July 1, 2006; 55(Pt 7): 809 - 818. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Laverdiere, R. G. Lalonde, J.-G. Baril, D. C. Sheppard, S. Park, and D. S. Perlin Progressive loss of echinocandin activity following prolonged use for treatment of Candida albicans oesophagitis J. Antimicrob. Chemother., April 1, 2006; 57(4): 705 - 708. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Cuenca-Estrella, A. Gomez-Lopez, E. Mellado, M. J. Buitrago, A. Monzon, and J. L. Rodriguez-Tudela Head-to-Head Comparison of the Activities of Currently Available Antifungal Agents against 3,378 Spanish Clinical Isolates of Yeasts and Filamentous Fungi Antimicrob. Agents Chemother., March 1, 2006; 50(3): 917 - 921. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-H. Yan, M. R. Marino, R. A. Smith, V. Kanamaluru, E. M. O'Mara, and D. M. Grasela The Effect of Ravuconazole on the Pharmacokinetics of Nelfinavir in Healthy Male Volunteers J. Clin. Pharmacol., February 1, 2006; 46(2): 193 - 200. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Heyn, A. Tredup, S. Salvenmoser, and F.-M. C. Muller Effect of Voriconazole Combined with Micafungin against Candida, Aspergillus, and Scedosporium spp. and Fusarium solani Antimicrob. Agents Chemother., December 1, 2005; 49(12): 5157 - 5159. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Bagg, M P. Sweeney, A. N Davies, M. S Jackson, and S. Brailsford Voriconazole susceptibility of yeasts isolated from the mouths of patients with advanced cancer J. Med. Microbiol., October 1, 2005; 54(10): 959 - 964. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Golan Overview of transplant mycology Am. J. Health Syst. Pharm., April 15, 2005; 62(suppl_1): S17 - S21. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. L Carver Micafungin Ann. Pharmacother., October 1, 2004; 38(10): 1707 - 1721. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Cuenca-Estrella, A. Gomez-Lopez, E. Mellado, G. Garcia-Effron, and J. L. Rodriguez-Tudela In Vitro Activities of Ravuconazole and Four Other Antifungal Agents against Fluconazole-Resistant or -Susceptible Clinical Yeast Isolates Antimicrob. Agents Chemother., August 1, 2004; 48(8): 3107 - 3111. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Takakura, N. Fujihara, T. Saito, T. Kudo, Y. Iinuma, S. Ichiyama, and the Japan Invasive Mycosis Surveillance Study Grou National surveillance of species distribution in blood isolates of Candida species in Japan and their susceptibility to six antifungal agents including voriconazole and micafungin J. Antimicrob. Chemother., February 1, 2004; 53(2): 283 - 289. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||