Skip Navigation



JAC Advance Access published online on December 4, 2003
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkh027
© 2003 by The British Society for Antimicrobial Chemotherapy
This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
53/1/74    most recent
dkh027v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
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 Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Li, X.
Right arrow Articles by McNicholas, P. M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Li, X.
Right arrow Articles by McNicholas, P. M.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 2003 The British Society for Antimicrobial Chemotherapy

Original article

Changes in susceptibility to posaconazole in clinical isolates of Candida albicans

Xin Li 1 , Nathaniel Brown 1 , Andrew S. Chau 1 , José L. López-Ribot 2 , Maria T. Ruesga 3 , Guillermo Quindos 3 , Cara A. Mendrick 1 , Roberta S. Hare 1 , David Loebenberg 1 , Beth DiDomenico 1 , and Paul M. McNicholas 1 *

1 Schering-Plough Research Institute, 2015 Galloping Hill Road, 4700 Kenilworth, NJ 07033;
2 Department of Medicine and Division of Infectious Diseases, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA;
3 Departamento de Immunologia, Microbiologia y Parasitologia, Facultad de Medicina y Odontologia, Universidad del Pais Vasco, Bilbao, Vizcaya, Spain

* Corresponding author. E-mail: paul.mcnicholas{at}spcorp.com.

Received 24 July 2003 ; revised 13 October 2003 ; accepted 19 October 2003

Abstract

Objectives: To characterize the molecular mechanisms responsible for reduced susceptibility to azoles in Candida albicans clinical isolates.

Materials and methods: Seven sequential C. albicans isolates were cultured from an AIDS patient treated with posaconazole for refractory oropharyngeal candidiasis. Expression levels of the CDR1, CDR2 and MDR1 genes, encoding efflux pumps previously implicated in azole resistance, and ERG11, encoding the azole target site, were monitored using northern blot and real-time PCR. The ERG11 genes from all seven isolates were sequenced.

Results: The seven closely related isolates exhibited significant decreases in susceptibility to fluconazole (MIC >= 32 mg/L) and voriconazole (MIC >= 2 mg/L) and progressive decreases in susceptibility to both posaconazole (isolates 1-4 MIC 0.25 mg/L, isolates 5-7 MIC 2 mg/L) and itraconazole (isolates 1-4 MIC 1 mg/L, isolates 5-7 MIC > 8 mg/L). None of the isolates exhibited any significant changes in the expression levels of ERG11 or the efflux pump genes. All seven isolates had multiple mutations in ERG11; isolates one through four each had five missense mutations; four of the resultant amino acid changes were previously associated with azole resistance. The fifth isolate had an additional novel mutation in one copy of ERG11, resulting in a Pro-230 to Leu substitution. This mutation was present in both ERG11 genes in the last two isolates. Select ERG11 genes were expressed in Saccharomyces cerevisiae, the ERG11 allele with all six mutations conferred the highest level of posaconazole resistance.

Conclusions: Multiple mutations in ERG11 are required to confer decreased susceptibility to posaconazole.

Keywords: azoles, drug resistance, ERG11, efflux pumps
Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Am J Health Syst PharmHome page
M. I. Morris
Posaconazole: A new oral antifungal agent with an expanded spectrum of activity
Am. J. Health Syst. Pharm., February 1, 2009; 66(3): 225 - 236.
[Abstract] [Full Text] [PDF]

Home page
 The Annals of PharmacotherapyHome page
E. J Rachwalski, J. T Wieczorkiewicz, and M. H Scheetz
Posaconazole: An Oral Triazole with an Extended Spectrum of Activity
Ann. Pharmacother., October 1, 2008; 42(10): 1429 - 1438.
[Abstract] [Full Text] [PDF]

Home page
 J Antimicrob ChemotherHome page
Y. Xu, L. Chen, and C. Li
Susceptibility of clinical isolates of Candida species to fluconazole and detection of Candida albicans ERG11 mutations
J. Antimicrob. Chemother., April 1, 2008; 61(4): 798 - 804.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Microbiol.Home page
M. A. Pfaller, S. A. Messer, L. Boyken, S. Tendolkar, R. J. Hollis, and D. J. Diekema
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., February 1, 2008; 46(2): 551 - 559.
[Abstract] [Full Text] [PDF]

Home page
 J Med MicrobiolHome page
M. G. Wise, M. Healy, K. Reece, R. Smith, D. Walton, W. Dutch, A. Renwick, J. Huong, S. Young, J. Tarrand, et al.
Species identification and strain differentiation of clinical Candida isolates using the DiversiLab system of automated repetitive sequence-based PCR
J. Med. Microbiol., June 1, 2007; 56(6): 778 - 787.
[Abstract] [Full Text] [PDF]

Home page
 J Med MicrobiolHome page
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]

Home page
 Antimicrob. Agents Chemother.Home page
F. Sabatelli, R. Patel, P. A. Mann, C. A. Mendrick, C. C. Norris, R. Hare, D. Loebenberg, T. A. Black, and P. M. McNicholas
In Vitro Activities of Posaconazole, Fluconazole, Itraconazole, Voriconazole, and Amphotericin B against a Large Collection of Clinically Important Molds and Yeasts.
Antimicrob. Agents Chemother., June 1, 2006; 50(6): 2009 - 2015.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Microbiol.Home page
T. L. Ross, W. G. Merz, M. Farkosh, and K. C. Carroll
Comparison of an Automated Repetitive Sequence-Based PCR Microbial Typing System to Pulsed-Field Gel Electrophoresis for Analysis of Outbreaks of Methicillin-Resistant Staphylococcus aureus
J. Clin. Microbiol., November 1, 2005; 43(11): 5642 - 5647.
[Abstract] [Full Text] [PDF]

Home page
 Antimicrob. Agents Chemother.Home page
A. S. Chau, M. Gurnani, R. Hawkinson, M. Laverdiere, A. Cacciapuoti, and P. M. McNicholas
Inactivation of Sterol {Delta}5,6-Desaturase Attenuates Virulence in Candida albicans
Antimicrob. Agents Chemother., September 1, 2005; 49(9): 3646 - 3651.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Microbiol.Home page
B. T. Page and C. P. Kurtzman
Rapid Identification of Candida Species and Other Clinically Important Yeast Species by Flow Cytometry
J. Clin. Microbiol., September 1, 2005; 43(9): 4507 - 4514.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Microbiol.Home page
M. Healy, J. Huong, T. Bittner, M. Lising, S. Frye, S. Raza, R. Schrock, J. Manry, A. Renwick, R. Nieto, et al.
Microbial DNA Typing by Automated Repetitive-Sequence-Based PCR
J. Clin. Microbiol., January 1, 2005; 43(1): 199 - 207.
[Abstract] [Full Text] [PDF]

Home page
 Antimicrob. Agents Chemother.Home page
A. S. Chau, C. A. Mendrick, F. J. Sabatelli, D. Loebenberg, and P. M. McNicholas
Application of Real-Time Quantitative PCR to Molecular Analysis of Candida albicans Strains Exhibiting Reduced Susceptibility to Azoles
Antimicrob. Agents Chemother., June 1, 2004; 48(6): 2124 - 2131.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.