Changes in susceptibility to posaconazole in clinical isolates of  Candida albicans

Li, Xin; Brown, Nathaniel; Chau, Andrew S.; López-Ribot, José L.; Ruesga, María Teresa; Quindós, Guillermo; Mendrick, Cara; Hare, R S; Loebenberg, David; DiDomenico, Beth; McNicholas, Paul M.

doi:10.1093/jac/dkh027

Cited by 90 publications

(67 citation statements)

References 23 publications

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“…Posaconazole is known to bind more extensively to the target enzyme, 14␣-demethylase, of C. albicans than does fluconazole, due in part to the presence of a long hydrophobic side chain that serves to stabilize the binding of posaconazole to the target, making it less susceptible to the effect of point mutations in the ERG11 gene (3,50). Indeed, Li et al (17) demonstrated that isolates of C. albicans, from a patient with OPC, that were resistant to fluconazole and voriconazole but susceptible to posaconazole all had the same five missense mutations in ERG11 that specifically reduced the binding of fluconazole and voriconazole to the target enzyme. Furthermore, subsequent isolates obtained during the course of posaconazole therapy had all acquired an additional mutation, leading to the disruption of the binding of the posaconazole side chain within the hydrophobic channel of the enzyme (17).…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, Li et al (17) demonstrated that isolates of C. albicans, from a patient with OPC, that were resistant to fluconazole and voriconazole but susceptible to posaconazole all had the same five missense mutations in ERG11 that specifically reduced the binding of fluconazole and voriconazole to the target enzyme. Furthermore, subsequent isolates obtained during the course of posaconazole therapy had all acquired an additional mutation, leading to the disruption of the binding of the posaconazole side chain within the hydrophobic channel of the enzyme (17). Thus, in order for C. albicans to exhibit resistance to posaconazole, there is a requirement for mutational events affecting the target enzyme that are over and above those necessary to produce resistance to fluconazole and voriconazole.…”

Section: Resultsmentioning

confidence: 99%

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Selection of a Surrogate Agent (Fluconazole or Voriconazole) for Initial Susceptibility Testing of Posaconazole against Candida spp.: Results from a Global Antifungal Surveillance Program

Pfaller¹,

Messer²,

Boyken³

et al. 2008

J Clin Microbiol

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There are currently no FDA-approved broth microdilution antifungal susceptibility testing products or interpretive breakpoints for susceptibility testing of the new triazole posaconazole. Fluconazole and voriconazole are in the same triazole class as posaconazole, have CLSI-approved interpretive MIC breakpoints, and are available on some commercially available MIC panels. We investigated whether one or both of these agents may be useful as a surrogate marker for posaconazole susceptibility. Fluconazole, voriconazole, and posaconazole MIC results for 10,807 isolates of Candida spp. were analyzed to validate a potential surrogate marker for posaconazole activity against indicated species. For illustrative purposes, we applied the voriconazole MIC breakpoints to posaconazole (susceptible, <1 g/ml; susceptible dose dependent, 2 g/ml; resistant, >4 g/ml) and compared these MIC results and categorical interpretations with those of fluconazole and voriconazole by using regression statistics and categorical agreement. For all 10,807 isolates, the absolute categorical agreement was 91.1% (0.1% very major errors [VME], 1.2% major errors [ME], and 7.6% minor errors [M]) using fluconazole as the surrogate marker and 97.7% (0.3% VME 0.1% ME, and 1.9% M) using voriconazole as the surrogate. The results with fluconazole improved to a categorical agreement of 93.7% (0.1% VME, 0.2% ME, and 6.0% M) when results for Candida krusei (not indicated for fluconazole testing) were omitted. Either fluconazole or voriconazole MIC results may serve as surrogate markers to predict the susceptibility of Candida spp. to posaconazole.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Selection of a Surrogate Agent (Fluconazole or Voriconazole) for Initial Susceptibility Testing of Posaconazole against Candida spp.: Results from a Global Antifungal Surveillance Program

Pfaller¹,

Messer²,

Boyken³

et al. 2008

J Clin Microbiol

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“…Multiple studies have demonstrated strain-level discrimination for automated rep-PCR with the DiversiLab system, including mycobacteria (2) and fungi of both Aspergillus (15) and Candida spp. (3,23). The medical and economic benefit of a highly integrated, comprehensive infection control program that includes routine genotyping has been previously demonstrated (14).…”

Section: Discussionmentioning

confidence: 99%

Microbial DNA Typing by Automated Repetitive-Sequence-Based PCR

Healy¹,

Huong²,

Bittner³

et al. 2005

J Clin Microbiol

322

217

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Repetitive sequence-based PCR (rep-PCR) has been recognized as an effective method for bacterial strain typing. Recently, rep-PCR has been commercially adapted to an automated format known as the DiversiLab system to provide a reliable PCR-based typing system for clinical laboratories. We describe the adaptations made to automate rep-PCR and explore the performance and reproducibility of the system as a molecular genotyping tool for bacterial strain typing. The modifications for automation included changes in rep-PCR chemistry and thermal cycling parameters, incorporation of microfluidics-based DNA amplicon fractionation and detection, and Internet-based computer-assisted analysis, reporting, and data storage. The performance and reproducibility of the automated rep-PCR were examined by performing DNA typing and replicate testing with multiple laboratories, personnel, instruments, DNA template concentrations, and culture conditions prior to DNA isolation. Finally, we demonstrated the use of automated rep-PCR for clinical laboratory applications by using isolates from an outbreak of Neisseria meningitidis infections. N. meningitidis outbreak-related strains were distinguished from other isolates. The DiversiLab system is a highly integrated, convenient, and rapid testing platform that may allow clinical laboratories to realize the potential of microbial DNA typing.

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“…In terms of strain level differentiation, too few strains, and no strains that were clonal, were incorporated for comparison; therefore no conclusions can be drawn about its utility for strain typing fungi (8). At least two studies report the utility of the DiversiLab system for typing Candida albicans strains that have developed resistance to azoles, but the studies were not designed to compare rep-PCR to other techniques (4,10). Finally, in an analysis of both outbreak-and non-outbreak-associated Neisseria meningitidis isolates of various serogroups, the DiversiLab system had excellent serogroup and strain level discrimination (9).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2005

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Rapid and sensitive methods for accurate strain delineation are essential for monitoring and preventing transmission of methicillin-resistant Staphylococcus aureus (MRSA). Pulsed-field gel electrophoresis (PFGE) has been the standard technique for strain typing most bacterial species including MRSA. The goal of this study was to compare the performance of the DiversiLab microbial typing system (Bacterial BarCodes, Inc., Houston, TX) (rep-PCR) to that of PFGE for typing MRSA isolates from five well-defined outbreaks. The DiversiLab rep-PCR assay is a rapid, semiautomated method based on PCR amplification of specific regions between noncoding repetitive sequences in the bacterial genome. rep-PCR was performed according to the manufacturer's recommendations, and the results were analyzed and dendrograms were generated using the DiversiLab analysis software (version 2.1.66a). PFGE was performed and interpreted according to published procedures. rep-PCR results using similarity indices (SI) of 80%, 85%, and 90% were compared to PFGE analysis. In addition, intra-and interrun reproducibility was determined for rep-PCR. Overall, correct assignment to outbreak versus nonoutbreak clusters occurred for 91 of 109 isolates (85% agreement) when using a SI of 85%. For each specific outbreak, concordance between rep-PCR and PFGE ranged from 73% to 100%. There were 18 discrepant results (17%). Fourteen isolates were unique by PFGE, but they were placed in clusters by rep-PCR; the other 4 were placed in clusters different from those assigned by PFGE. Intra-and interrun reproducibility was excellent. Times to results were 12 to 24 h for rep-PCR compared to 2 to 4 days for PFGE. Rapid, standardized results and excellent reproducibility make rep-PCR a valuable tool for use in MRSA investigations. However, since rep-PCR was less discriminatory than PFGE, we recommend that it be used to screen isolates, followed by testing isolates which share the same rep-PCR pattern with a more sensitive method, such as PFGE or multilocus sequence typing.

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Changes in susceptibility to posaconazole in clinical isolates of Candida albicans

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

Cited by 90 publications

References 23 publications

Selection of a Surrogate Agent (Fluconazole or Voriconazole) for Initial Susceptibility Testing of Posaconazole against Candida spp.: Results from a Global Antifungal Surveillance Program

Selection of a Surrogate Agent (Fluconazole or Voriconazole) for Initial Susceptibility Testing of Posaconazole against Candida spp.: Results from a Global Antifungal Surveillance Program

Microbial DNA Typing by Automated Repetitive-Sequence-Based PCR

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

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