Therapeutic Failure in Invasive Fungal Infections: Beyond Antifungal Resistance—A Narrative Review
Round 1
Reviewer 1 Report
Authors have produced an extensive and well-crafted review of the literature on how to define and address antifungal therapy failure. The work is therefore noteworthy. However, its size (50 pages, excluding the references and supplementary tables) makes it difficult to read and use. While I found the tables and figures to be very well-designed, the text contains numerous repetitions, both of sections inserted at different points (it is true that the topic is complex) and repetitions of what is well summarized in the tables. In my opinion, this almost intolerably lengthens an otherwise very useful literature review. It is absolutely imperative to reduce the text size to no more than 1/5 of its current length, focusing heavily (if not entirely) on tables and figures, and eliminating all repetitions of concepts scattered throughout the text.
There are also numerosi points that, in my opinion, have been overlooked:
- the presence of hyperfiltration in critically ill patients, which could significantly alter the kinetics of fluconazole (the only antifungal drug significantly eliminated via the kidneys)
- the lack of mention of the reduced susceptibility/resistance of Pichia kudriavzevii (formerly C. krusei) and the failure to mention Saccharomyces among the rare fungi to treat (fungiemias associated with the use of drugs to prevent C. difficile diarrhea)
- isavuconazole is rarely mentioned in the text (only one point, if I'm not mistaken), but this drug is increaingly used and requires TDM, and its activity deserves greater attention
- the kinetic data on drugs for CNS infections are imprecise or incomplete: high-dose micafungin crosses the blood-brain barrier in newborns, while liposomal amphotericin B, isavuconazole, and voriconazole are concentrated in the brain parenchyma, but not found in CSF
- Surgical drainage may be necessary for Aspergillus-related brain abscess.
- The "diagnostic review" is very useful, but there are some shortcomings: if we want to discuss everything, then a section on imaging should also be included (e.g., ultrasound and CT scans in hepatosplenic candidiasis and changes in chest CT scans in aspergillosis in presence of neutrophils recovery. This last aspect is described, but sparsely). To assess galactomannan efficiency, it is necessary to discuss the various tests currently available: ELISA, lateral flow, and chemiluminescence, which give results that are not easily comparable. Conversely, BDG is an unreliable test in pediatrics, and this should be specified, even though the entire review never mentions children, who nevertheless represent a significant population of patients affected by invasive mycoses.
Author Response
Please see the attachment.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
This is a narrative review addressing a topic of great current interest: suboptimal responses to invasive fungal infections, without attributing them solely to antifungal resistance. The manuscript meets the scientific rigor expected of a narrative review.
It is a clear and well-structured work. Its strength lies in the clinical algorithms, checklists, and potential quality indicators used to distinguish between actual and apparent failure, identify modifiable factors, and support clinical decision-making. However, there are details that could be improved:
- In the section on cryptic species, emerging species, and misidentification, the authors mention that: “Among emerging yeasts and species associated with greater therapeutic complexity, Nakaseomyces glabratus (formerly Candida glabrata) and Candidozyma auris (formerly Candida auris) pose important challenges related to identification, antifungal resistance, and epidemiological control” However, I believe the case of fluconazole-resistant C. parapsilosis should be included and discussed in depth.
- Tables 1, 2, 3, 4, and S1: I suggest including references in a table column or specifically in the corresponding cell, rather than in the table title.
- Strictly adhere to the *JoF* guidelines for authors, particularly regarding citations and reference formatting.
Author Response
Please see the attachment
Author Response File: Author Response.pdf
Round 2
Reviewer 1 Report
I still find the paper very (too) long (could be divided in 2-3 papers?), but I admit that is really complente. So, I maintain my reserve on the leght of the paper, but this is not a good reason to stop the pubblication of a good job
Omitting comments on the leght, all the question rised are now answered and the paper is complete. No further question
