Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

• The overall presentation quality is substandard and requires substantial improvement. The manuscript contains numerous typographical errors, formatting problems, inconsistent use of italics (e.g., for bacterial species), duplicated spaces, inconsistent fonts, and misaligned paragraphs. These issues significantly detract from the professionalism and readability of the manuscript and should be comprehensively addressed prior to further consideration.
• Abbreviations (e.g., VAP, NIV, IMV) should only be defined at first mention and not repeatedly in figure captions; consistency should be checked throughout the manuscript.
• All figures need to be improved. Using Figure 1 as one example, the use of “yes/no” bars is unnecessary; a single bar with appropriate statistical annotation would be clearer. The y-axis label is missing, and the figure title is redundant given the caption. Caption needs to be more informative. Similar comments apply to all other figures. 
• The Introduction does not clearly articulate a pediatric-specific knowledge gap. While general background on IMV and NIV is provided, the manuscript does not explicitly define what is unknown regarding antibiotic use and ventilator-associated infections in pediatric patients, nor justify why adult data cannot be extrapolated to PICU populations.
• Stewardship recommendations go beyond what is supported by the data. Local antibiotic practices are presented in a quasi-guideline format without being validated by the study design, risking inappropriate generalization beyond descriptive findings.

 

Comments on the Quality of English Language

There are numerous typos, duplicated spaces, inconsistent italics, font inconsistencies and general formatting inconsistencies that detract from the professionalism of the manuscript.

Author Response

 Dear Reviewer,

We sincerely thank you for your careful reading of our manuscript and for your detailed and constructive comments. We appreciate the time and effort you invested in providing this feedback, which has been invaluable in helping us improve the quality and clarity of our work. We address your comments as follows:

Regarding the overall presentation and formatting, we fully agree with your assessment. The manuscript has undergone comprehensive language and formatting revision. Typographical errors, duplicated spaces, font inconsistencies, paragraph alignment issues have been corrected throughout. These changes were made to enhance readability and ensure a more professional presentation. The only thing we did not change is the italic names of the pahogens as this was editor’s recommendations at initial submission editorial check.

With respect to abbreviations, we have revised the manuscript to ensure that all abbreviations (e.g., VAP, NIV, IMV) are defined only at first mention in the main text and used consistently thereafter. Redundant definitions in figure captions have been removed, and uniformity has been checked across the manuscript.

We also acknowledge the issues raised regarding figure quality. All figures have been revised to improve clarity and consistency. Using Figure 1 as a model, unnecessary “yes/no” bars have been replaced with a clearer graphical representation, appropriate statistical annotations have been added, y-axis labels are now included, and figure titles have been streamlined to avoid redundancy with the captions. Captions have been expanded to be more informative and self-explanatory. Similar improvements were applied to all remaining figures.

Concerning the Introduction, we have rewritten this section to explicitly articulate the pediatric-specific knowledge gap. We now clearly state what remains unknown about antibiotic use and ventilator-associated infections in pediatric populations and provide a stronger rationale for why adult data cannot be directly extrapolated to PICU patients, given differences in immune response, underlying disease profiles, and antimicrobial prescribing practices.

Finally, we appreciate your comment on the stewardship recommendations. We agree that our original wording may have suggested broader clinical guidance than supported by our descriptive study design. We have therefore revised this section to ensure that stewardship-related statements are presented more cautiously and framed as observations and hypotheses rather than practice recommendations. The text now emphasizes that our findings are descriptive and intended to inform future studies rather than serve as prescriptive guidance.

We are grateful for your thoughtful critique, which has significantly strengthened the manuscript. We hope that the revisions adequately address your concerns and improve the overall quality and impact of our work.

Sincerely,

Guergana Petrova on behalf of the authors

Reviewer 2 Report

Comments and Suggestions for Authors

1. The title is comprehensive.
2. Introduction is well written.
3. What you have written under “Aim” is actually the “Objective of the study”. So, remove the “Aim” and there is no need of any sub heading here.
4. What was the rationale of using age group 0-17? On which basis, this cut off was used?
5. What was the rationale of choosing January, 2021 – February, 2025 study period?
6. Why were patients with a GCS of less than 8 were excluded from the study?
7. Why is inclusion and exclusion mentioned twice (Line 268-278)?
8. When was the ethical approval taken? Mention the letter number. Please upload the approval letter as supplementary file.
9. Line 168 (On which bases, these 7 points were extracted?)

 

Author Response

Dear Reviewer,

We sincerely thank you for your positive assessment of our manuscript and for your thoughtful and constructive comments. We greatly appreciate your time and effort, which have helped us improve the clarity and rigor of our work. We address your comments point by point below.

We thank the reviewer for noting that the title is comprehensive and that the Introduction is well written.

Regarding the “Aim” section, we agree with your observation. The section labeled “Aim” has been revised to “Objective of the study,” and the subheading has been removed, as it was unnecessary.

With respect to the age range of 0–17 years, this cutoff was selected to include the full pediatric population treated in our pediatric intensive care unit, in accordance with national and institutional definitions of pediatric age. Patients aged 18 years and older are managed in adult intensive care units in our hospital and were therefore not eligible for inclusion.

Concerning the study period (January 2021–February 2025), this interval was chosen to capture all eligible patients after the introduction of routine non-invasive ventilation in our PICU and to ensure an adequate sample size for analysis while reflecting current clinical practice.

Regarding the exclusion of patients with a Glasgow Coma Scale (GCS) score below 8, these patients were excluded because impaired consciousness represents a contraindication to non-invasive ventilation and introduces fundamentally different airway management strategies, including mandatory invasive ventilation, which would confound comparisons between respiratory support modalities.

We agree that inclusion and exclusion criteria were inadvertently stated twice (Lines 268–278). This duplication has been removed, and the section has been consolidated for clarity.

With respect to ethical approval, the manuscript has been revised to specify the date and reference number of approval by the Ethics Committee of the Medical University of Sofia. The approval letter has now been uploaded as a supplementary file, as requested.

Regarding Line 168 and the seven extracted principles, we clarify that these points were derived from a retrospective review of patient records and reflect observed prescribing patterns in our center rather than predefined or protocol-driven criteria. This has been explicitly stated in the revised manuscript to avoid misinterpretation as formal recommendations.

Once again, we thank you for your valuable and insightful comments. We believe that the revisions made in response to your suggestions have strengthened the manuscript and improved its clarity and methodological transparency.

Sincerely,       

Guergana Petrova on behalf of the authprs

Reviewer 3 Report

Comments and Suggestions for Authors

The topic of antibiotic stewardship in critically ill children, particularly in the context of non-invasive ventilation, is important and clinically relevant. Your effort to address this understudied area and to share real-world experience from a pediatric ICU is appreciated.

However, after careful consideration, I believe that the manuscript, in its current form, has substantial methodological and conceptual limitations that preclude publication.

The main limitation is the retrospective, single-center design combined with a small sample size (n = 89) and marked heterogeneity between patient groups. The oxygen therapy, NIV, and IMV groups differ significantly in age, underlying diagnoses, and disease severity. These differences represent major confounders that are not adequately controlled for and substantially weaken comparisons between respiratory support modalities. As a result, it is difficult to attribute differences in infection rates or antibiotic use to the mode of respiratory support rather than to baseline patient characteristics.

A further concern relates to the definition and diagnosis of ventilator-associated pneumonia (VAP). Reporting VAP in patients receiving non-invasive ventilation is problematic, as VAP is conventionally defined in the setting of invasive mechanical ventilation. In addition, the use of different microbiological sampling methods (BAL versus upper airway specimens) introduces a significant risk of misclassification and limits the validity of pathogen comparisons across groups.

Although multiple statistical tests are presented, the analytical approach remains largely univariate. The absence of multivariable models adjusting for illness severity, comorbidities, prior antibiotic exposure, and duration of ventilation makes it difficult to draw firm conclusions. Some statistically significant findings are therefore likely driven by confounding rather than true associations.

The Discussion section frequently relies on local “at home” antibiotic protocols and clinical experience, which, while informative, are not sufficiently supported by the study data. This shifts the manuscript away from a data-driven scientific analysis toward a descriptive account of institutional practice. Several conclusions—particularly regarding determinants of antibiotic use and outcomes—appear stronger than warranted by the results.

Finally, the manuscript would benefit from substantial language editing and structural tightening, as grammatical issues and repetition at times obscure the central messages.

In summary, while the research question is relevant and the topic important, the current study design and analysis do not allow for sufficiently robust conclusions. I would encourage you to consider reframing the work as a preliminary descriptive or hypothesis-generating study, or to pursue a redesigned, multicenter study with standardized definitions and multivariable analyses.

I hope these comments are helpful and constructive for the further development of your work.

Author Response

Dear Reviewer,

We sincerely thank you for your thorough, thoughtful, and constructive review of our manuscript. We greatly appreciate your recognition of the clinical relevance of the topic and your careful evaluation of the methodological limitations of our study. Your comments have been extremely helpful in guiding substantial improvements to the manuscript.

We fully acknowledge the limitations related to the retrospective, single-center design, small sample size, and heterogeneity of the patient population. In response, we have revised the manuscript to more clearly emphasize the descriptive and hypothesis-generating nature of the study. Comparisons between respiratory support groups are now presented cautiously, and we explicitly state that observed differences in infection rates and antibiotic use cannot be attributed solely to the ventilation modality but are strongly influenced by baseline patient characteristics and disease severity.

Regarding the definition of ventilator-associated pneumonia (VAP), we agree with your concern. The manuscript has been revised to clarify that VAP was defined and diagnosed exclusively in patients receiving invasive mechanical ventilation. In patients treated with non-invasive ventilation, infectious episodes are now consistently described as lower respiratory tract infections rather than VAP. We have also highlighted the limitations arising from the use of different microbiological sampling methods and their potential impact on pathogen comparisons.

We acknowledge that our statistical analyses were primarily univariate. This has now been explicitly stated as a limitation, and we have strengthened the limitations section to note the absence of multivariable adjustment for important confounders such as illness severity, comorbidities, and prior antibiotic exposure. As a result, statistically significant findings are interpreted more conservatively and framed as associations rather than causal relationships.

We agree that portions of the Discussion relied too heavily on local clinical practice and may have conveyed conclusions stronger than supported by the data. This section has been substantially revised to reduce emphasis on institutional protocols and to focus more closely on what can be inferred from the study results. Stewardship-related statements are now framed as observations and considerations rather than recommendations.

Finally, the manuscript has undergone comprehensive language editing and structural tightening to reduce repetition and improve clarity.

We are grateful for your insightful critique and believe that the revisions have significantly strengthened the manuscript by aligning it more clearly with its appropriate role as a preliminary, descriptive study that can inform future multicenter and prospective research.

Sincerely,
Guergana Petrova on behalf of the authors

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

 

• Figure 1: the p-value and all the numbers in the manuscript should be consistent with the decimal places. Same comments apply throughout the manuscript.
• Abbreviation usage remains only partially addressed. Abbreviations are still redundantly defined in figure captions and appear inconsistently in the Limitations and Materials and Methods sections.
• Figures overall lack consistency in font type and size; several axes and labels are unclear or formatted differently across figures.
• Figure 6: The x-axis should use explicit group names (e.g., Oxygen, NIV, IMV) instead of numerical placeholders (1, 2, 3).
• Figure 7 appears to be a screenshot rather than a properly generated figure and contains a typographical artifact (underscore); it should be redrawn in an editable format.
• Table 1 is not explicitly introduced or explained in the main text and should be clearly referenced and summarized.
• If the authors have the abbreviations at the end as a section, then please include all of them. 
• The local practices approaches can be shortened with more precise language. 

Comments on the Quality of English Language

The manuscript still contains numerous typographical errors, duplicated punctuation, missing spaces, and formatting issues throughout. Examples include Line 88 (“to PICU”), Line 91 (“of”), Line 101 (“..”), among many others. Please check throughout the manuscript again. 

Author Response

Thank you very much for your careful review and for the constructive comments. We appreciate the time and effort invested in evaluating our manuscript. We have carefully considered each of the points raised and have revised the manuscript accordingly.

We have standardized the presentation of p-values and numerical data throughout the manuscript to ensure consistent use of decimal places.

Aslo the abbreviation usage has been reviewed and corrected. Redundant definitions in figure captions have been removed, and consistency has been improved across the Limitations and Materials and Methods sections.

All figures have been reformatted to ensure uniform font type and size, and axis labels have been clarified for improved readability. As you have suggested especially figures 6 and 7 

 Table 1 is now clearly introduced and referenced in the main text, with an appropriate summary added.

We believe these revisions have improved the clarity, consistency, and overall quality of the manuscript. Thank you again for your valuable feedback.

Reviewer 2 Report

Comments and Suggestions for Authors

Good job

Author Response

We sincerely thank the reviewer for the positive evaluation and encouraging feedback. We greatly appreciate your supportive comments and are pleased that the quality and presentation of the work were well received.

Reviewer 3 Report

Comments and Suggestions for Authors

This revised version of the manuscript represents a clear improvement compared with the initial submission. The overall structure is more coherent, the clinical question is better defined, and the authors have adopted a more cautious tone when interpreting their findings. The effort to acknowledge limitations and avoid overt overstatement is evident and appreciated.

The study addresses an important and clinically relevant topic, namely antibiotic use in critically ill pediatric patients receiving different forms of respiratory support. This remains an area where evidence is limited, and real-world data such as those presented here are valuable. The descriptive nature of the dataset, ethical approval, and transparency regarding limitations all strengthen the work and suggest a thoughtful revision process.

Nevertheless, some issues remain that should be addressed to further improve clarity and scientific rigor. While the manuscript is now more focused, there is still occasional ambiguity regarding the study’s scope, particularly in relation to infection incidence and risk factors. Given the retrospective design and lack of multivariable analysis, the results are best interpreted as descriptive or exploratory, and this framing should be consistently maintained throughout the text.

Clarification of infection-related terminology would also strengthen the manuscript. Ventilator-associated pneumonia and tracheobronchitis are appropriately restricted to invasively ventilated patients, but comparisons with lower respiratory tract infections in non-invasive groups should be approached cautiously and clearly delineated, as these entities are not directly comparable.

Finally, while the language has improved, the manuscript still requires careful editing to address residual grammatical errors, typographical issues, and occasional awkward phrasing. A final round of professional language revision would significantly enhance readability and presentation.

Author Response

Dear reviewer,  we sincerely thank you for the thoughtful and constructive feedback, as well as for recognizing the improvements made in the revised version of our manuscript. We greatly appreciate your positive assessment of the clearer structure, more precise clinical framing, and the more cautious interpretation of our findings. Your acknowledgment of the study’s relevance and the value of the presented real-world data is very encouraging.

We also appreciate the additional suggestions aimed at further strengthening the clarity and scientific rigor of the work. In response, we have carefully reviewed the manuscript to ensure that the study’s scope is consistently presented as descriptive and exploratory, in line with its retrospective design and the absence of multivariable analysis. We have revised sections where ambiguity regarding infection incidence and risk factors could arise, with the aim of improving precision and consistency in interpretation.

We have also clarified the infection-related terminology throughout the manuscript. In particular, we have more clearly delineated the distinction between ventilator-associated pneumonia and tracheobronchitis in invasively ventilated patients and lower respiratory tract infections in non-invasive groups, and we have tempered comparisons to avoid unintended equivalence.

Finally, the manuscript has undergone an additional careful language review to correct residual grammatical and typographical issues and to improve overall readability and flow.

We are grateful for your careful evaluation and valuable recommendations, which have helped us further refine and strengthen the manuscript.