This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Pfaller, M. A.
Right arrow Articles by Sheehan, D. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pfaller, M. A.
Right arrow Articles by Sheehan, D. J.

 Previous Article

Clinical Microbiology Reviews, April 2006, p. 435-447, Vol. 19, No. 2
0893-8512/06/$08.00+0     doi:10.1128/CMR.19.2.435-447.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Interpretive Breakpoints for Fluconazole and Candida Revisited: a Blueprint for the Future of Antifungal Susceptibility Testing

M. A. Pfaller,1,2* D. J. Diekema,1,3 and D. J. Sheehan4

Departments of Pathology,1 Epidemiology,2 Medicine, Roy J. and Lucille A. Carver College of Medicine, and College of Public Health, University of Iowa, Iowa City, Iowa,3 Pfizer, Inc., Pfizer Global Pharmaceuticals, New York, New York4

Developing interpretive breakpoints for any given organism-drug combination requires integration of the MIC distribution, pharmacokinetic and pharmacodynamic parameters, and the relationship between in vitro activity and outcome from both in vivo and clinical studies. Previously, the Subcommittee for Antifungal Testing of the Clinical and Laboratory Standards Institute (CLSI [formerly National Committee for Clinical Laboratory Standards]) proposed MIC interpretive breakpoints for fluconazole and Candida spp. These breakpoints were considered to be somewhat weak, because the clinical data supporting them came largely from mucosal infections and there were very few infections involving strains with elevated fluconazole MICs. We readdress the issue of fluconazole breakpoints for Candida by using published clinical and microbiologic data to provide further validation of the breakpoints proposed by the CLSI in 1997. We also address interpretive breakpoints for agar disk diffusion testing of fluconazole. The MIC distribution for fluconazole was determined with a collection of 13,338 clinical isolates. The overall MIC at which 90% of the isolates were inhibited was 8 µg/ml: 91% were susceptible (S) at a MIC of ≤8 µg/ml and 3% were resistant (R) (MIC ≥ 64 µg/ml). Similar results were obtained for 2,190 isolates from randomized clinical trials. Analysis of available data for 1,295 patient-episode-isolate events (692 represented mucosal infections and 603 represented invasive infections) from 12 published clinical studies demonstrated an overall success rate of 77%, including 85% for those episodes in which the fluconazole MIC was ≤8 µg/ml, 67% for those episodes in which the MIC was 16 to 32 µg/ml, and 42% for those episodes with resistant (MIC ≥ 64 µg/ml) isolates. Pharmacodynamic analysis demonstrated a strong relationship between MIC, fluconazole dose, and outcome. A dose/MIC ratio of ~25 was supportive of the following susceptibility breakpoints for fluconazole and Candida spp.: S, MIC ≤ 8 µg/ml; susceptible-dose dependent (SDD), MIC = 16 to 32 µg/ml; R, MIC ≥ 64 µg/ml. The corresponding disk test breakpoints are as follows: S, ≥19 mm; SDD, 15 to 18 mm; R, ≤14 mm.

* Corresponding author. Mailing address: Medical Microbiology Division, C606 GH, Department of Pathology, University of Iowa College of Medicine, Iowa City, IA 52242. Phone: (319) 384-9566. Fax: (319) 356-4916. E-mail: michael-pfaller{at}uiowa.edu.

Clinical Microbiology Reviews, April 2006, p. 435-447, Vol. 19, No. 2
0893-8512/06/$08.00+0     doi:10.1128/CMR.19.2.435-447.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Pfaller, M. A., Diekema, D. J., Gibbs, D. L., Newell, V. A., Bijie, H., Dzierzanowska, D., Klimko, N. N., Letscher-Bru, V., Lisalova, M., Muehlethaler, K., Rennison, C., Zaidi, M., the Global Antifungal Surveillance Group, (2009). Results from the ARTEMIS DISK Global Antifungal Surveillance Study, 1997 to 2007: 10.5-Year Analysis of Susceptibilities of Noncandidal Yeast Species to Fluconazole and Voriconazole Determined by CLSI Standardized Disk Diffusion Testing. J. Clin. Microbiol. 47: 117-123 [Abstract] [Full Text]  
  • Tumbarello, M., Sanguinetti, M., Trecarichi, E. M., La Sorda, M., Rossi, M., de Carolis, E., de Gaetano Donati, K., Fadda, G., Cauda, R., Posteraro, B. (2008). Fungaemia caused by Candida glabrata with reduced susceptibility to fluconazole due to altered gene expression: risk factors, antifungal treatment and outcome. J Antimicrob Chemother 62: 1379-1385 [Abstract] [Full Text]  
  • Pfaller, M. A., Boyken, L. B., Hollis, R. J., Kroeger, J., Messer, S. A., Tendolkar, S., Diekema, D. J. (2008). Validation of 24-Hour Fluconazole MIC Readings versus the CLSI 48-Hour Broth Microdilution Reference Method: Results from a Global Candida Antifungal Surveillance Program. J. Clin. Microbiol. 46: 3585-3590 [Abstract] [Full Text]  
  • Ostrosky-Zeichner, L., Rex, J. H., Pfaller, M. A., Diekema, D. J., Alexander, B. D., Andes, D., Brown, S. D., Chaturvedi, V., Ghannoum, M. A., Knapp, C. C., Sheehan, D. J., Walsh, T. J. (2008). Rationale for Reading Fluconazole MICs at 24 Hours Rather than 48 Hours When Testing Candida spp. by the CLSI M27-A2 Standard Method. Antimicrob. Agents Chemother. 52: 4175-4177 [Abstract] [Full Text]  
  • Andes, D. R., Diekema, D. J., Pfaller, M. A., Marchillo, K., Bohrmueller, J. (2008). In Vivo Pharmacodynamic Target Investigation for Micafungin against Candida albicans and C. glabrata in a Neutropenic Murine Candidiasis Model. Antimicrob. Agents Chemother. 52: 3497-3503 [Abstract] [Full Text]  
  • Baddley, J. W., Patel, M., Bhavnani, S. M., Moser, S. A., Andes, D. R. (2008). Association of Fluconazole Pharmacodynamics with Mortality in Patients with Candidemia. Antimicrob. Agents Chemother. 52: 3022-3028 [Abstract] [Full Text]  
  • Ruan, S.-Y., Chu, C.-C., Hsueh, P.-R. (2008). In Vitro Susceptibilities of Invasive Isolates of Candida Species: Rapid Increase in Rates of Fluconazole Susceptible-Dose Dependent Candida glabrata Isolates. Antimicrob. Agents Chemother. 52: 2919-2922 [Abstract] [Full Text]  
  • Pfaller, M. A., Diekema, D. J., Ostrosky-Zeichner, L., Rex, J. H., Alexander, B. D., Andes, D., Brown, S. D., Chaturvedi, V., Ghannoum, M. A., Knapp, C. C., Sheehan, D. J., Walsh, T. J. (2008). Correlation of MIC with Outcome for Candida Species Tested against Caspofungin, Anidulafungin, and Micafungin: Analysis and Proposal for Interpretive MIC Breakpoints. J. Clin. Microbiol. 46: 2620-2629 [Abstract] [Full Text]  
  • Pfaller, M. A., Diekema, D. J., Gibbs, D. L., Newell, V. A., Ng, K. P., Colombo, A., Finquelievich, J., Barnes, R., Wadula, J., the Global Antifungal Surveillance Group, (2008). Geographic and Temporal Trends in Isolation and Antifungal Susceptibility of Candida parapsilosis: a Global Assessment from the ARTEMIS DISK Antifungal Surveillance Program, 2001 to 2005. J. Clin. Microbiol. 46: 842-849 [Abstract] [Full Text]  
  • Andes, D., Diekema, D. J., Pfaller, M. A., Prince, R. A., Marchillo, K., Ashbeck, J., Hou, J. (2008). In Vivo Pharmacodynamic Characterization of Anidulafungin in a Neutropenic Murine Candidiasis Model. Antimicrob. Agents Chemother. 52: 539-550 [Abstract] [Full Text]  
  • Pfaller, M. A., Messer, S. A., Boyken, L., Tendolkar, S., Hollis, R. J., Diekema, D. J. (2008). Selection of a Surrogate Agent (Fluconazole or Voriconazole) for Initial Susceptibility Testing of Posaconazole against Candida spp.: Results from a Global Antifungal Surveillance Program. J. Clin. Microbiol. 46: 551-559 [Abstract] [Full Text]  
  • Pfaller, M. A., Diekema, D. J., Procop, G. W., Rinaldi, M. G. (2007). Multicenter Comparison of the VITEK 2 Antifungal Susceptibility Test with the CLSI Broth Microdilution Reference Method for Testing Amphotericin B, Flucytosine, and Voriconazole against Candida spp.. J. Clin. Microbiol. 45: 3522-3528 [Abstract] [Full Text]  
  • Rautemaa, R., Richardson, M., Pfaller, M., Koukila-Kahkola, P., Perheentupa, J., Saxen, H. (2007). Decreased susceptibility of Candida albicans to azole antifungals: a complication of long-term treatment in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) patients. J Antimicrob Chemother 60: 889-892 [Abstract] [Full Text]  
  • Rodriguez-Tudela, J. L., Almirante, B., Rodriguez-Pardo, D., Laguna, F., Donnelly, J. P., Mouton, J. W., Pahissa, A., Cuenca-Estrella, M. (2007). Correlation of the MIC and Dose/MIC Ratio of Fluconazole to the Therapeutic Response of Patients with Mucosal Candidiasis and Candidemia. Antimicrob. Agents Chemother. 51: 3599-3604 [Abstract] [Full Text]  
  • Odds, F. C., Hanson, M. F., Davidson, A. D., Jacobsen, M. D., Wright, P., Whyte, J. A., Gow, N. A. R., Jones, B. L. (2007). One year prospective survey of Candida bloodstream infections in Scotland. J Med Microbiol 56: 1066-1075 [Abstract] [Full Text]  
  • Collins, C. D., Eschenauer, G. A., Salo, S. L., Newton, D. W. (2007). To Test or Not To Test: a Cost Minimization Analysis of Susceptibility Testing for Patients with Documented Candida glabrata Fungemias. J. Clin. Microbiol. 45: 1884-1888 [Abstract] [Full Text]  
  • Pfaller, M. A., Diekema, D. J., Gibbs, D. L., Newell, V. A., Meis, J. F., Gould, I. M., Fu, W., Colombo, A. L., Rodriguez-Noriega, E., and the Global Antifungal Surveillance Group, (2007). Results from the ARTEMIS DISK Global Antifungal Surveillance Study, 1997 to 2005: an 8.5-Year Analysis of Susceptibilities of Candida Species and Other Yeast Species to Fluconazole and Voriconazole Determined by CLSI Standardized Disk Diffusion Testing. J. Clin. Microbiol. 45: 1735-1745 [Abstract] [Full Text]  
  • Cheng, S., Clancy, C. J., Nguyen, K. T., Clapp, W., Nguyen, M. H. (2007). A Candida albicans Petite Mutant Strain with Uncoupled Oxidative Phosphorylation Overexpresses MDR1 and Has Diminished Susceptibility to Fluconazole and Voriconazole. Antimicrob. Agents Chemother. 51: 1855-1858 [Abstract] [Full Text]  
  • Pfaller, M. A., Diekema, D. J., Procop, G. W., Rinaldi, M. G. (2007). Multicenter Comparison of the VITEK 2 Yeast Susceptibility Test with the CLSI Broth Microdilution Reference Method for Testing Fluconazole against Candida spp.. J. Clin. Microbiol. 45: 796-802 [Abstract] [Full Text]  
  • Pfaller, M. A., Diekema, D. J. (2007). Epidemiology of Invasive Candidiasis: a Persistent Public Health Problem. Clin. Microbiol. Rev. 20: 133-163 [Abstract] [Full Text]  
  • Pfaller, M. A., Messer, S. A., Boyken, L., Rice, C., Tendolkar, S., Hollis, R. J., Diekema, D. J. (2007). Use of Fluconazole as a Surrogate Marker To Predict Susceptibility and Resistance to Voriconazole among 13,338 Clinical Isolates of Candida spp. Tested by Clinical and Laboratory Standards Institute-Recommended Broth Microdilution Methods. J. Clin. Microbiol. 45: 70-75 [Abstract] [Full Text]  
  • Pai, M. P., Turpin, R. S., Garey, K. W. (2007). Association of Fluconazole Area under the Concentration-Time Curve/MIC and Dose/MIC Ratios with Mortality in Nonneutropenic Patients with Candidemia. Antimicrob. Agents Chemother. 51: 35-39 [Abstract] [Full Text]  
  • Pfaller, M. A., Diekema, D. J., Mendez, M., Kibbler, C., Erzsebet, P., Chang, S.-C., Gibbs, D. L., Newell, V. A., the Global Antifungal Surveillance Group, (2006). Candida guilliermondii, an Opportunistic Fungal Pathogen with Decreased Susceptibility to Fluconazole: Geographic and Temporal Trends from the ARTEMIS DISK Antifungal Surveillance Program.. J. Clin. Microbiol. 44: 3551-3556 [Abstract] [Full Text]  
  • Pfaller, M. A., Diekema, D. J., Colombo, A. L., Kibbler, C., Ng, K. P., Gibbs, D. L., Newell, V. A., the Global Antifungal Surveillance Group, (2006). Candida rugosa, an Emerging Fungal Pathogen with Resistance to Azoles: Geographic and Temporal Trends from the ARTEMIS DISK Antifungal Surveillance Program.. J. Clin. Microbiol. 44: 3578-3582 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»