Inter-laboratory variability of caspofungin MICs for Nakaseomyces glabrata isolates – an Irish tertiary hospital experience
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Background. Nakaseomyces glabrata , formerly Candida glabrata , is an opportunistic yeast and emerging cause of human infections. The use of broth microdilution (BMD) methodologies for caspofungin (CSP) antifungal susceptibility testing (AFST) against N. glabrata is reported to be prone to high inter-laboratory variation. We aimed to compare CSP MICs of N. glabrata isolates from our institution with those obtained by the Reference Laboratory for the same isolates.
Methods. All clinically significant N. glabrata isolates from 2019 to 2021 inclusive were reviewed. AFST was performed locally using the VITEK2 system with the AST-YS08 card, while E-tests were performed at the Mycology Reference Laboratory (MRL), and agreement between these two methods was evaluated – categorical and essential.
Results. Forty-one isolates were reviewed during the study period – 30 from blood cultures, seven from intra-operative theatre specimens and four from sterile site drain fluids. Despite an essential agreement of 100 % within ±2 log 2 dilutions, marked discrepancies were noted in interpretative breakpoints between assays with 17 Minor and 16 Major category errors. Categorical agreement was 19.5 %, with the VITEK2 over-estimating resistance. A Mann–Whitney U-test assessed the relationship of MICs across the AFST modalities, and a statistically significant difference was noted, P <0.01, with a higher mean rank for VITKEK2 outputs.
Conclusion. While the VITEK2 system is highly applicable, its performance for CSP AFST is unreliable and potentially results in the mis-classification of susceptible isolates as highlighted in our study. The use of VITEK2 AST-YS08 micafungin as a sentinel echinocandin should be explored and/or the evaluation of CSP-specific E-tests as utilized by the MRL. These methods appear more consistent and less prone to the variation seen with BMD for CSP.
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This is a study that would be of interest to the field and community.
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The reviewers have raised some more minor concerns about this study, in particular, its limitations and similarities with the conference presentation. Authors are advised to clearly state the limitations of this study and preferably site the conference presentation where relevant. Also, please include following statement in the declaration section; “This paper was first presented as a poster at the Microbiology Society’s Annual Conference in 2023.
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Comments to Author
The manuscript has been updated and previous comments addressed sufficiently on the whole. Some minor typographical errors remain throughout, require proof read. Table 1 and table 2 columns are reversed and are confusing for the reader to make direct comparisons. Recommend this be addressed. The methodological rigour is poor but given that it is a retrospective study cannot be addressed for this manuscript without entirely re-reviewing, and is pitched as a comparison of methods which addresses this. The data is small in quantity which is a significant limiting factor, but for this particular study is all that is available. A recommendation is to expand the sites to include others and thus introducing additional samples. Presentation, and communication is ok, discussion supported by the findings but …
Comments to Author
The manuscript has been updated and previous comments addressed sufficiently on the whole. Some minor typographical errors remain throughout, require proof read. Table 1 and table 2 columns are reversed and are confusing for the reader to make direct comparisons. Recommend this be addressed. The methodological rigour is poor but given that it is a retrospective study cannot be addressed for this manuscript without entirely re-reviewing, and is pitched as a comparison of methods which addresses this. The data is small in quantity which is a significant limiting factor, but for this particular study is all that is available. A recommendation is to expand the sites to include others and thus introducing additional samples. Presentation, and communication is ok, discussion supported by the findings but limited impact.
Please rate the manuscript for methodological rigour
Satisfactory
Please rate the quality of the presentation and structure of the manuscript
Satisfactory
To what extent are the conclusions supported by the data?
Partially support
Do you have any concerns of possible image manipulation, plagiarism or any other unethical practices?
No
Is there a potential financial or other conflict of interest between yourself and the author(s)?
No
If this manuscript involves human and/or animal work, have the subjects been treated in an ethical manner and the authors complied with the appropriate guidelines?
Yes
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The reviewers have highlighted major concerns with the work presented. Please ensure that you address their comments. The language used is poor, which can cause ambiguity at times. Please carefully rewrite it. We offer a discounted translation service, Editage (https://www.editage.com/; see https://www.microbiologyresearch.org/prepare-an-article#13 for more information). The reviewers raise concerns regarding the scientific rigour and experimental design of the work.
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Comments to Author
The authors tried to interpret the local anonymous results with the gold standard method for testing the Inter-laboratory variability of Caspofungin Minimum Inhibitory Concentrations for Nakaseomyces glabrata isolates. The manuscript is interesting, but I wonder how it could be a review article. Use of retrospective data from own source (not clear in the manuscript) and the flow of the manuscript indicating it should be a "method comparison/research paper". There was a significant variation between the results of the gold standard and the VITEK2 system used in their lab, which is the main message of this manuscript. But the number of isolates (N = 41) used to conclude this is very low and can mislead the protocols. Moreover, the categorical agreement made is missing the category of "complete …
Comments to Author
The authors tried to interpret the local anonymous results with the gold standard method for testing the Inter-laboratory variability of Caspofungin Minimum Inhibitory Concentrations for Nakaseomyces glabrata isolates. The manuscript is interesting, but I wonder how it could be a review article. Use of retrospective data from own source (not clear in the manuscript) and the flow of the manuscript indicating it should be a "method comparison/research paper". There was a significant variation between the results of the gold standard and the VITEK2 system used in their lab, which is the main message of this manuscript. But the number of isolates (N = 41) used to conclude this is very low and can mislead the protocols. Moreover, the categorical agreement made is missing the category of "complete agreement". Moreover, there is a missing reference for EA. The authors also did not apply the correlation/agreement analysis that can support the results statistically. The discussion lacks comparison of results or relevant findings with others. Other comments are below: L21: Please add an opening sentence regarding Nakaseomyces glabrata. L60: "Up to 30% prevalence" Where? Please elaborate this paragraph with global prevalence information and clinical significance including diagnosis and therapeutic costs. L70: Describe different systems of AST methods, which one is gold standard and why, then highlights automated broth-micro dilution systems including its pros and cons L77-78: where the testing was performed and how the data were retrieved? L81: use the reference for VITEK2 system L95: Need references L106 and 109: The table title should have elaborative description L112: Insufficient
Please rate the manuscript for methodological rigour
Poor
Please rate the quality of the presentation and structure of the manuscript
Satisfactory
To what extent are the conclusions supported by the data?
Not at all
Do you have any concerns of possible image manipulation, plagiarism or any other unethical practices?
No
Is there a potential financial or other conflict of interest between yourself and the author(s)?
No
If this manuscript involves human and/or animal work, have the subjects been treated in an ethical manner and the authors complied with the appropriate guidelines?
Yes
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Comments to Author
1) In principle the manuscript presents 52% similarity, being unacceptable. Please, rewrite the entire manuscript and leave that similarity less than 15%. 2) Conclusion: Lines 42-43: I don't understand. Please rewrite. 3) Introduction: The introduction needs to be better discussed. The author reports the resistance of Candida species to antifungals. In another paragraph, he reports the divergence between the in vitro assays. It's meaningless. Please bring information about why there is a difference between in vitro techniques. Discuss the importance of your work. 4) Line 75: Material and Methods (no use "s") 5) Line 99: N. glabrata in italics 6) Results: Please, add a table indicating the clinical origin of the clinical isolates. 7) Results: Add the concentration results for all isolates in table form
Comments to Author
1) In principle the manuscript presents 52% similarity, being unacceptable. Please, rewrite the entire manuscript and leave that similarity less than 15%. 2) Conclusion: Lines 42-43: I don't understand. Please rewrite. 3) Introduction: The introduction needs to be better discussed. The author reports the resistance of Candida species to antifungals. In another paragraph, he reports the divergence between the in vitro assays. It's meaningless. Please bring information about why there is a difference between in vitro techniques. Discuss the importance of your work. 4) Line 75: Material and Methods (no use "s") 5) Line 99: N. glabrata in italics 6) Results: Please, add a table indicating the clinical origin of the clinical isolates. 7) Results: Add the concentration results for all isolates in table form 8) Discussion: Bring more information about results that report differences between techniques. Why this occurs? Bring articles with different results. Discuss further. 9) Conclusion ?
Please rate the manuscript for methodological rigour
Poor
Please rate the quality of the presentation and structure of the manuscript
Poor
To what extent are the conclusions supported by the data?
Partially support
Do you have any concerns of possible image manipulation, plagiarism or any other unethical practices?
No
Is there a potential financial or other conflict of interest between yourself and the author(s)?
No
If this manuscript involves human and/or animal work, have the subjects been treated in an ethical manner and the authors complied with the appropriate guidelines?
Yes
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