Candida in the ICU, Risk Management and Patient Safety

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript addresses an important and clinically relevant topic: the role of Candida infections in ICU patient safety and risk management. The longitudinal perspective based on decades of clinical experience is valuable; however, several aspects require improvement before the manuscript can be considered for publication.

Major Comments
Study Design and Methodology
The manuscript lacks a clear and structured description of the study design. It appears to be a narrative review combined with retrospective observational insights, but this is not explicitly stated.
There is no clear definition of inclusion/exclusion criteria, sample size, or statistical methods.
The methodology section should be significantly expanded to clarify how data from the different time periods (1978–2000s) were collected, analyzed, and compared.
Results Presentation
Results are embedded within the discussion and historical narrative, making them difficult to follow.
Consider separating Results and Discussion into distinct sections.
Provide clearer tables or summarized data to support mortality comparisons and outcomes.
Figure and Algorithm
The diagnostic–therapeutic algorithm (Figure 1) is central to the manuscript but is not sufficiently explained.
The figure quality and readability should be improved, and a more detailed legend is needed.
Scientific Rigor
Many conclusions are based on historical cohorts without clear statistical validation.
The manuscript would benefit from:
Explicit statistical analysis
Confidence intervals or effect sizes
Clarification of whether findings are hypothesis-generating or evidence-based
Clarity of Definitions
While terminology (e.g., colonization, multifocal candidiasis, invasive candidiasis) is detailed, it is sometimes repetitive and difficult to follow.
A summary table of definitions would improve clarity.

Minor Comments
Introduction
The introduction could be shortened.
Include more recent literature to balance historical perspective.
Referencing
References are generally appropriate but heavily weighted toward older studies.
More recent high-impact studies should be incorporated.

Although the manuscript is structured into conventional sections (Introduction, Methods, Results and Discussion, and Conclusions), the content within these sections does not always align clearly with their intended purpose. In particular: The Methods section lacks a clear and systematic description of study design, data collection, and analysis.
The Results are interwoven with discussion and historical narrative, making it difficult to distinguish objective findings from interpretation.
The Discussion component is not clearly delineated, limiting critical comparison with existing literature. A clearer separation and more structured presentation of each section would significantly improve readability and scientific rigor.

Comments on the Quality of English Language

The manuscript requires English language editing for grammar, clarity, and conciseness.
Some sentences are overly long and difficult to interpret.

Author Response

Study Design and Methodology
The manuscript lacks a clear and structured description of the study design. It appears to be a narrative review combined with retrospective observational insights, but this is not explicitly stated. There is no clear definition of inclusion/exclusion criteria, sample size, or statistical methods. 

We have revised the narrative of the entire manuscript and have added the inclusion/exclusion criteria, as well as the sample size and statistical analysis.

The methodology section should be significantly expanded to clarify how data from the different time periods (1978–2000s) were collected, analyzed, and compared. 

The methodology has been expanded and stratified by study periods.

Results Presentation. Results are embedded within the discussion and historical narrative, making them difficultto follow.Consider separating Results and Discussion into distinct sections.Provide clearer tables or summarized data to support mortality comparisons and outcomes.

The results have been incorporated into the Relevant Sections and 2 tables have been added.

Figure and Algorithm
The diagnostic–therapeutic algorithm (Figure 1) is central to the manuscript but is not sufficiently explained. The figure quality and readability should be improved, and a more detailed legend is 
needed.

Figure 1 has been revised.

Scientific Rigor
Many conclusions are based on historical cohorts without clear statistical validation.

Added to the Introduction.

The manuscript would benefit from: Explicit statistical analysis

Modified to include a results table.

Confidence intervals or effect sizes Clarification of whether findings are hypothesis-generating or evidence-based

Incorporated

Clarity of Definitions. While terminology (e.g., colonization, multifocal candidiasis, invasive candidiasis) is detailed, it is sometimes repetitive and difficult to follow. A summary table of definitions would improve clarity.

The tables and definitions have been incorporated.

Minor Comments
Introduction
The introduction could be shortened. Include more recent literature to balance historical perspective.

Completed

Referencing
References are generally appropriate but heavily weighted toward older studies. More recent high-impact studies should be incorporated.

We have included new references to recent articles.

Although the manuscript is structured into conventional sections (Introduction, Methods, Results and Discussion, and Conclusions), the content within these sections does not always align clearly with their intended purpose. In particular: The Methods section lacks a clear and systematic description of study design, data collection, and analysis. The Results are interwoven with discussion and historical narrative, making it difficult to distinguish objective findings from interpretation.
The Discussion component is not clearly delineated, limiting critical comparison with existing literature. A clearer separation and more structured presentation of each section would significantly improve readability and scientific rigor.

Changes have been made.

Reviewer 2 Report

Comments and Suggestions for Authors

Comments to authors

1. The authors are to be commended for their efforts in preparing this manuscript. The topic has the potential to highlight the diagnostic importance of endogenous candidiasis in clinical settings, particularly in the ICU. However, the current manuscript relies on a very limited dataset, with only three cases included for analysis. This significantly limits the strength of the conclusions. In particular, the term “endogenous candidiasis” is used, but it is unclear how the authors have established the endogenous origin of these infections. The manuscript does not describe whether molecular typing, colonization surveillance, or other microbiological methods were employed to confirm the source of infection. Without such evidence, attributing these cases to an endogenous origin remains speculative.
2. The stated objectives related to risk management and patient safety are important and clinically relevant. However, the data presented are insufficient to adequately support or fulfil these objectives. A more robust evidence base is needed to substantiate the conclusions and recommendations. Furthermore, the manuscript would benefit from inclusion of more recent literature. Comparing current evidence with older reports would significantly strengthen the scientific validity and relevance of the discussion.
3. Consideration of emerging and clinically important Candida species such as auris, C. parapsilosis, and C. glabrata would improve the comprehensiveness and contemporary relevance of the manuscript.

Author Response

The authors are to be commended for their efforts in preparing this manuscript. The topic has the potential to highlight the diagnostic importance of endogenous candidiasis in clinical settings, particularly in the ICU. However, the current manuscript relies on a very limited dataset, with only three cases included for analysis. This significantly limits the strength of the conclusions. In particular, the term “endogenous candidiasis” is used, but it is unclear how the authors have established the endogenous origin of these infections. The manuscript does not describe whether molecular typing, colonization surveillance, or other microbiological methods were employed to confirm the source of infection. Without such evidence, attributing these cases to an endogenous origin remains speculative.

Endogenous candidiasis was defined based on infection surveillance and the exclusion of other sources of infection. Molecular typing was not performed, as this technique was not available at the time the studies were conducted. 

The stated objectives related to risk management and patient safety are important and clinically relevant. However, the data presented are insufficient to adequately support or fulfil these objectives. A more robust evidence base is needed to substantiate the conclusions and recommendations. Furthermore, the manuscript would benefit from inclusion of more recent literature. Comparing current evidence with older reports would significantly strengthen the scientific validity and
relevance of the discussion.

It has been added

Consideration of emerging and clinically important Candida species such as auris, C. parapsilosis, and C. glabrata would improve the comprehensiveness and contemporary relevance of the manuscript.

No cases of Candida auris were identified; however, Candida glabrata was consistently the second most frequent species after Candida albicans across all three studies. Regarding Candida parapsilosis, an outbreak was detected and identified as having an exogenous origin, and the source was successfully eradicated.

 

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript provides a valuable long-term perspective (1978–early 2000s plus later series) on Candida in the ICU and argues for using colonization/multifocality together with an immunoparalysis/MODS framework (SOFA) to identify patients for early antifungal therapy. The patient-safety angle is compelling. However, to meet standards for publication as an evidence-based, reproducible work the manuscript needs focused revisions, primarily to methods, results, ethics, citation balance, and presentation.

Please consider the following specific changes:

1. State clearly the study types included in the analysis (e.g., prospective observational cohort(s), retrospective audits, case series, post-mortem studies), time periods for each, sites, and inclusion/exclusion criteria. The current text implies several different studies across decades but does not present an explicit methods section with counts by study. Provide a summary table listing each study (period, center, n, study type, inclusion criteria).
2. Describe how colonization and multifocality samples were obtained (sampling schedule, culture methods, processing lab), which culture media and identification methods were used, and how species-level ID and antifungal susceptibility were performed. If identification techniques varied over time, state how this was harmonized.
3. Provide actual numerators/denominators for key outcomes (total patients screened, patients with colonization, multifocal candidiasis, candidemia, endophthalmitis, deaths attributable to Candida). The Results section currently provides ratios and percentages but inconsistent population numbers and p-values without clear description. Add confidence intervals where appropriate and specify statistical tests used.
4. Expand on the methods used to calculate 'attributable mortality' — cite methodology and show matching/adjustment approach if used (propensity, case–control, or other). The reader must be able to judge whether reduction in attributable mortality can be ascribed to the algorithm versus secular trends.
5. Add a dedicated ethics statement: institutional review board/ethics committee approvals for each study/period, whether informed consent was obtained or waived for retrospective components, and how post-mortem samples and records were handled. If historical data pre-date modern IRB conventions, explain what approvals/waivers were obtained retrospectively (or why they were not required). Editors will require this. (Current manuscript lacks an explicit ethics statement.)
6. Figure 1 is useful but add a concise algorithm legend and, importantly, the operational thresholds used to initiate antifungal therapy (e.g., how was multifocal colonization operationalized, number of foci and timing; what SOFA cutoffs triggered action; any additional clinical triggers?). Provide explicit decision points and timelines (e.g., surveillance culture schedule: twice weekly?). This will improve reproducibility.
7. Provide detailed list of antifungals used across study periods, dosing strategies, modifications for renal/hepatic dysfunction, and how species-level results or resistance changed therapy (especially for C. glabrata, C. krusei, and emerging C. auris). Comment on adverse events (e.g., amphotericin nephrotoxicity) with numbers where available. Discuss antifungal stewardship risks and how your algorithm attempted to balance early therapy vs overtreatment.
8. Add citations and brief discussion of contemporary rapid diagnostics and biomarkers (1,3-β-D-glucan, T2Candida, PCR panels), with balanced appraisal of sensitivity/specificity and how they might complement or challenge your culture-based surveillance approach. Also include recent systematic reviews/meta-analyses on early empirical antifungal therapy and outcomes in non-neutropenic ICU patients. Although your historical series is valuable, readers will want to know how your approach fits with modern diagnostics and stewardship principles.
9. Explicitly acknowledge limitations: historical and single-group nature of studies, changing diagnostic/therapeutic landscapes over decades, potential for confounding and secular trends, limited external validity beyond similar ICUs, and risks of overtreatment. State how these limitations affect interpretation of cause–effect claims.
10. Provide one or more tables that summarize patient characteristics, interventions, and outcomes by study/time period. Improve Figure 1 resolution and add a stepwise flowchart with sample sizes at each branch where possible. Clarify units, denominators, and p-values in tables.
11. The manuscript currently cites many of the authors' prior publications (which is understandable given the history). Please balance with independent studies, international guidelines, and recent consensus statements beyond your group to strengthen generalizability and reduce perceived bias.
12. Improve grammar, flow, and remove some colloquial/personal anecdotal phrasing in the Introduction (nice for context but keep tone consistent with a scientific paper). Consider professional copyediting. Example: several sentences read as first-person recollection, keep some history but tighten to scientific narrative.
13. Consider providing anonymized datasets or a supplementary appendix that shows the raw numbers per study (for transparency) and the exact surveillance culture schedule and lab SOPs.
14. Reword conclusions to reflect observational nature and limits, e.g., “Implementation of the described surveillance-guided strategy was associated with reduced attributable mortality in our series” rather than implying definitive causation.

Author Response

State clearly the study types included in the analysis (e.g., prospective observational cohort(s), retrospective audits, case series, post-mortem studies), time periods for each, sites, and inclusion/exclusion criteria. The current text implies several different studies across decades but does not present an explicit methods section with counts by study. Provide a summary table listing each study (period,center, n, study type, inclusion criteria).

Incorporated into the Introduction and the results table.

Describe how colonization and multifocality samples were obtained (samplingschedule, culture methods, processing lab), which culture media and identification methods were used, and how species-level ID and antifungal susceptibility were performed. If identification techniques varied over time, state how this was harmonized.

The sampling schedule and laboratory techniques have been incorporated.

Provide actual numerators/denominators for key outcomes (total patients screened, patients with colonization, multifocal candidiasis, candidemia, endophthalmitis, deaths attributable to Candida). The Results section currently provides ratios and percentages but inconsistent population numbers and p-values without clear description. Add confidence intervals where appropriate and specify statistical tests used.

A results table and the statistical tests used have been incorporated.

Expand on the methods used to calculate 'attributable mortality' — cite methodology and show matching/adjustment approach if used (propensity, case–control, or other). The reader must be able to judge whether reduction in attributable mortality can be ascribed to the algorithm versus secular trends.

Revision of the description of attributable mortality and comparison with current results.

Add a dedicated ethics statement: institutional review board/ethics committeeapprovals for each study/period, whether informed consent was obtained or waived for retrospective components, and how post-mortem samples and records were handled. If historical data pre-date modern IRB conventions, explain whatapprovals/waivers were obtained retrospectively (or why they were not required). Editors will require this. (Current manuscript lacks an explicit ethics statement.)

Although the data predate modern regulatory frameworks, with the exception of the first phase, all patients admitted to the ICU had informed consent signed by their legal representative regarding the care to be provided during their ICU stay. This included consideration of potential limitations of diagnostic and therapeutic efforts according to the patient’s clinical evolution. This working methodology was described in the SOFA study that we published. Postmortem studies were always conducted with informed consent from the family, in which the procedure was explained and it was stated that a final report would be provided once all study results were available. This entire approach was highly valued by the Joint Commission during its final evaluation for quality accreditation, which was granted to the Hospital General de Catalunya in 1999, becoming the first center accredited by the Joint Commission in the United States.

Figure 1 is useful but add a concise algorithm legend and, importantly, the operational thresholds used to initiate antifungal therapy (e.g., how was multifocal colonization operationalized, number of foci and timing; what SOFA cutoffs triggered action; any additional clinical triggers?). Provide explicit decision points and timelines (e.g., surveillance culture schedule: twice weekly?). This will improve reproducibility.

The figure legend has been expanded.

Provide detailed list of antifungals used across study periods, dosing strategies, modifications for renal/hepatic dysfunction, and how species-level results or resistance changed therapy (especially for C. glabrata, C. krusei, and emerging C. auris). Comment on adverse events (e.g., amphotericin nephrotoxicity) with numbers where available. Discuss antifungal stewardship risks and how your algorithm attempted to balance early therapy vs overtreatment.

The antifungal agents initially used were fluconazole and amphotericin B in the second phase. In the third phase, lipid complex amphotericin B and liposomal formulations were incorporated according to renal risk. At the time this protocol was designed, no other antifungal alternatives were available. Multifocal disease was always treated, whereas unifocal forms or Candida colonization were never treated, as reflected in the Introduction and the figure. Treatment was discontinued upon clinical improvement and/or negativization of cultures. This aspect is not emphasized, as other therapeutic alternatives are currently available that could not be considered at the time the different studies were conducted.

Add citations and brief discussion of contemporary rapid diagnostics and biomarkers (1,3-β-D-glucan, T2Candida, PCR panels), with balanced appraisal of sensitivity/specificity and how they might complement or challenge your culture-based surveillance approach. Also include recent systematic reviews/meta- analyses on early empirical antifungal therapy and outcomes in non-neutropenic ICU patients. Although your historical series is valuable, readers will want to know how your approach fits with modern diagnostics and stewardship principles.

In this study, no empirical antifungal therapy was administered. Treatment was always initiated after identification of the isolated fungal pathogen. Caspofungin may be a suitable alternative to fluconazole, while amphotericin formulations should be reserved for cases with evidence of azole-resistant yeast or marked clinical instability. The choice of amphotericin formulation should be guided by the patient’s renal risk. The bibliography includes the most recent clinical practice guidelines with therapeutic recommendations.

Explicitly acknowledge limitations: historical and single-group nature of studies, changing diagnostic/therapeutic landscapes over decades, potential for confounding and secular trends, limited external validity beyond similar ICUs, and risks of overtreatment. State how these limitations affect interpretation of cause–effect claims.

The main limitations relate to the availability of current therapeutic options and the future potential of emerging molecular diagnostic techniques. Regarding secular trends or external validity beyond similar intensive care units, we believe this does not represent a significant limitation. Evidence supporting this comes from observations during the COVID-19 pandemic: long-stay ICU patients with MODS affected by Candida infections exhibit behavior similar to that observed in our initial cases from the 1970s. New invasive technologies introduced in the ICU may further increase patient risk if they prolong ICU stays, as well as contribute to the emergence of new species such as Candida auris. Notably, Candida glabrata and Candida krusei were already identified in our studies. This comment has been incorporated.

Provide one or more tables that summarize patient characteristics, interventions, and outcomes by study/time period. Improve Figure 1 resolution and add a stepwise flowchart with sample sizes at each branch where possible. Clarify units,denominators, and p-values in tables.

Tables has been added and improved the Fgures resolution

The manuscript currently cites many of the authors' prior publications (which is understandable given the history). Please balance with independent studies, international guidelines, and recent consensus statements beyond your group to strengthen generalizability and reduce perceived bias.

Modified

Improve grammar, flow, and remove some colloquial/personal anecdotal phrasing in the Introduction (nice for context but keep tone consistent with a scientific paper). Consider professional copyediting. Example: several sentences read as first-person recollection, keep some history but tighten to scientific narrative.

It has been reviewd

Consider providing anonymized datasets or a supplementary appendix that shows the raw numbers per study (for transparency) and the exact surveillance culture schedule and lab SOPs.

At present, it is not possible to retrieve this information.

Reword conclusions to reflect observational nature and limits, e.g., “Implementation of the described surveillance-guided strategy was associated with reduced attributable mortality in our series” rather than implying definitive causation.

Modified.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have performed all changes. Thank you!

Comments on the Quality of English Language

The manuscript requires English language editing for grammar, clarity, and conciseness.
Some sentences are overly long and difficult to interpret.

Author Response

The manuscript requires English language editing for grammar, clarity, and conciseness.
Some sentences are overly long and difficult to interpret.

We have reviewed the entire text with a view to improving its clarity and scientific accuracy

Reviewer 2 Report

Comments and Suggestions for Authors

Comments 

1. The manuscript has been revised and now includes adequate information. However, it was submitted under the “Article” category, and it is unclear whether this classification is appropriate. In my opinion, the authors should reconsider the submission category, as it may be more suitable as a “Review” or another format.
2. I agree with the concerns raised by the authors regarding improvements in the diagnosis of invasive candidiasis, particularly those based on non-culture methods. Given the growing body of evidence supporting non-culture–based diagnostic approaches in recent years, the revised manuscript should place greater emphasis on this aspect, including a discussion of the practical implications and challenges associated with implementing these methods in clinical settings.
3. Additionally, there are typographical errors in the supplementary figures (e.g., “profilaxis” and “Respiratori”) that should be corrected.
4. While the supplementary materials provide sufficient descriptions for figures and captions, the authors are encouraged to clearly reference specific figure and table numbers to improve clarity and ease of navigation.

Author Response

The manuscript has been revised and now includes adequate information. However, it was submitted under the “Article” category, and it is unclear whether this classification is appropriate. In my opinion, the authors should reconsider the submission category, as it may be more suitable as a “Review” or another format.

The authors believe that this is an original article rather than a review because, building on previous work, we have conducted a study as such, approaching it as a clinical study with methodology, results, discussion and conclusions, and setting out key avenues for future research. It is not a review

I agree with the concerns raised by the authors regarding improvements in the diagnosis of invasive candidiasis, particularly those based on non-culture methods. Given the growing body of evidence supporting non-culture–based diagnostic approaches in recent years, the revised manuscript should place greater emphasis on this aspect, including a discussion of the practical implications and challenges associated with implementing these methods in clinical settings.

According to the reviewer, this is a study based on clinical diagnostic methods and culture techniques. We refer to the new methods in the discussion and in the conclusions, which we believe may divert attention away from the focus of this article regarding the early diagnosis and treatment of invasive candidiasis

Additionally, there are typographical errors in the supplementary figures (e.g., “profilaxis” and “Respiratori”) that should be corrected.

Corrected

While the supplementary materials provide sufficient descriptions for figures and captions, the authors are encouraged to clearly reference specific figure and table numbers to improve clarity and ease of navigation.

Done

Reviewer 3 Report

Comments and Suggestions for Authors

Accept 

Author Response

OK