Phage Therapy for Bone and Joint Infections: Challenges, Biological Dynamics, and Therapeutic Prospects in the Era of Antimicrobial Resistance
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsDear Authors.
The manuscript is very interesting and I suggestions by improve the manuscript.
review
abstract section:
Línea 24. PLease the names of the genus and species should be written in italics.
Introduction section
line 91-104. Please include the limits of the page therapy as the host cultivable and that the phage to be lytic and not lysogenic cycle and to be prophages.
Line 106. Please eliminate the sentence initial, because the idea is understood in the next paragraph it is repetitive.
Lines 114, 120, 214, 222,247, 271,303, 330. Please the word “in vitro” or “in vivo” should not be written in italics.
Lines 304. PLease write “S. aureus” in italics.
lines 197-203.please check it, this paragraph is repetitive, it was described previously.
Line 246. please check it, here describe an applied formulation, I suggest to add in paragraph previous a description of examples of formulation application is a limiting.
line 246-251. PLease describe the examples of phages used by treatment of the bacterias mentioned in this paragraph, because it is mentioned the phages in general, could be helped add the specific phages described.
subsection 4.3
lines.315-316. Please eliminate this paragraph. It was described previously as the focus innovator.
line 322. Please do you use the “”amplified” as synonym to “replicate” the word correct is replicate the virus and after purifying it.
line 381. please the “Staphylococcus aureu” should be written in italics.
figure 1.Please increase the size by more clearly.
Line 397. Please could be added the details technique concentrations names, kind phage and dose used in the cases described.
Line 477. ESKAPE please add the meaning and define and after use the abbreviation.
Line 522, 571. please write it in italics “Staphylococcus aureus” “Pseudomonas aeruginosa”
Lines 555-564. Please check it, this paragraph describes information that is repetitive in the paragraph of the lines 565-581and 588- 597, here is present repetitive information please check it.
Author Response
Reviewer 1
Answers for reviewer 1:
Dear reviewer
Thank you very much for your helpful and important comment which was taken into consideration and responded to below and marked on the manuscript in blue/yellow.
Comment 1: Línea 24. PLease the names of the genus and species should be written in italics.
Answer: Suggested changes were made and marked with yellow (page 1).
Comment 2: line 91-104. Please include the limits of the page therapy as the host cultivable and that the phage to be lytic and not lysogenic cycle and to be prophages.
Answer: Suggested changes were made and marked with blue (page 3).
Comment 3: Line 106. Please eliminate the sentence initial, because the idea is understood in the next paragraph it is repetitive.
Answer: Suggested changes were made and marked with blue (page 3).
Comment 4: Lines 114, 120, 214, 222, 247, 271, 303, 330. Please the word “in vitro” or “in vivo” should not be written in italics.
Answer: Suggested changes were made and marked with blue.
Comment 5: Lines 304. PLease write “S. aureus” in italics.
Answer: Suggested changes were made and marked with yellow in Page 9.
Comment 6: lines 197-203.please check it, this paragraph is repetitive, it was described previously.
Answer: Suggested changes were made and marked with blue (page 6).
Comment 7: Line 246. please check it, here describe an applied formulation, I suggest to add in paragraph previous a description of examples of formulation application is a limiting.
Answer: Suggested changes were made and marked with blue (page 8).
Comment 8: line 246-251. PLease describe the examples of phages used by treatment of the bacterias mentioned in this paragraph, because it is mentioned the phages in general, could be helped add the specific phages described.
Answer: Suggested changes were made and marked with blue (page 8).
Comment 9: lines.315-316. Please eliminate this paragraph. It was described previously as the focus innovator.
Answer: Suggested changes were made and marked with blue (page 10).
Comment 9: line 322. Please do you use the “”amplified” as synonym to “replicate” the word correct is replicate the virus and after purifying it.
Answer: Suggested changes were made and marked with blue (page 10).
Comment 10: line 381. please the “Staphylococcus aureu” should be written in italics.
Answer: Suggested changes were made and marked with yellow (page 110).
Comment 11: figure 1.Please increase the size by more clearly.
Answer: We thank the reviewer for this observation. To ensure optimal clarity and resolution, Figure 1 has been uploaded separately as a high-quality file, allowing the production team to insert and scale it appropriately according to the journal’s layout specifications. This approach will ensure that the final published version presents the figure at a size that maximizes readability and visual clarity.
Comment 12: Line 397. Please could be added the details technique concentrations names, kind phage and dose used in the cases described.
Answer: Suggested changes were made and marked with blue (page 11).
Comment 13: Line 477. ESKAPE please add the meaning and define and after use the abbreviation.
Answer: Suggested changes were made and marked with blue (page 13 and 19).
Comment 14: Line 522, 571. please write it in italics “Staphylococcus aureus” “Pseudomonas aeruginosa”.
Answer: Suggested changes were made and marked with yellow (page 13, 14).
Comment 15: Lines 555-564. Please check it, this paragraph describes information that is repetitive in the paragraph of the lines 565-581and 588- 597, here is present repetitive information please check it.
Answer: Suggested changes were made and marked with blue (page 17).
Author Response File: 
Author Response.docx
Reviewer 2 Report
Comments and Suggestions for AuthorsThis manuscript reviews the role of bacteriophages as a therapeutic treatment against bacteria such as Staphylococcus aureus in bone and joint infections.
The following comments are made:
- Line 24. Italicize scientific names. Review throughout the text.
- It is necessary to explain how phages are isolated and identified, how they are selected, how their efficacy is assessed, and, most importantly, which phages were used. The phages used could be provided in a table or included in Table 2.
- Explain whether phage treatments are ethically permissible and whether they have passed preclinical trials and the different clinical phases for their use.
- Include a column for side effects in Table 2.
- Also indicate combination therapies with antibiotics. In Table 2 or in a separate table.
- There are very long paragraphs that make the text difficult to read. Separate them for better readability.
Author Response
Reviewer 2
Answers for reviewer 2:
Dear reviewer
Thank you very much for your helpful and important comments which were taken into consideration and responded to below and marked on the manuscript in yellow.
Comment 1: Line 24. Italicize scientific names. Review throughout the text.
Answer: The text was changed according to the comment and marked in yellow throughout the manuscript.
Comment 2: It is necessary to explain how phages are isolated and identified, how they are selected, how their efficacy is assessed, and, most importantly, which phages were used. The phages used could be provided in a table or included in Table 2.
Answer: The text was changed according to the comment, included in Table 2, and marked in yellow throughout the manuscript in page 15-16.
Comment 3: Include a column for side effects in Table 2.
Answer: The demanded information was included in Table 2, and marked in yellow throughout the manuscript in page 15-16.
Comment 4: Also indicate combination therapies with antibiotics. In Table 2 or in a separate table
Answer: The demanded information was included in Table 2, and marked in yellow throughout the manuscript in page 15-16.
Comment 5: There are very long paragraphs that make the text difficult to read. Separate them for better readability
Answer: The text was changed according to the comment and marked in yellow throughout the manuscript.
Author Response File: Author Response.docx
Reviewer 3 Report
Comments and Suggestions for AuthorsThe manuscript presented by the author is devoted to an overview of the use of phage therapy in the treatment of multidrug-resistant infections of bones and joints. The chosen topic is very relevant, as the fight against antibiotic-resistant nosocomial pathogens has become a priority.
In the process of reviewing the manuscript, I had several questions/recommendations:
- Since the author has chosen to discuss exclusively bone and joint infections, it would be appropriate to characterize them in a little more detail – what is the complexity of their therapy? Is infection always associated with the presence of an implant?
2. Section 4.1 (and further on) mentions phage endolysins. Unfortunately, the review does not provide more detailed information about the features of their use, preparation and effectiveness in comparison with full-fledged phages. Can some of the described disadvantages of phage therapy (lack of standardization and decrease in in vivo titer) be eliminated by using phage lysines? The author should have paid more attention to the description of phage lysines in this review, for example, to devote a separate subsection to this.
- Section 4.2 also mentions the immobilization of phages in a hydrogel (line 297). What are the advantages of this technology compared to suspension of phages in saline solution? This information would be interesting for a review.
4. Describing the effects of phage therapy, the author points to either a positive effect or a neutral one (absence of a positive effect). Only possible allergic reactions are described as a negative effect on the patient. Is the use of phages in the treatment of resistant bacterial infections really unable to aggravate the situation? Is there any evidence that after the use of phages, the bacterial pathogen increased its virulence (for example, by hiding phage receptors, it increased the thickness of the capsule)?
5. Write the Latin names of the strains in Italic (lines 24, 304, 381, 522, Table 2)
Author Response
Reviewer 3
Answers for reviewer 3:
Dear reviewer
Thank you very much for your helpful and important comments, which were taken into consideration and responded to below, marked in green/yellow on the manuscript.
Comment: 1. Since the author has chosen to discuss exclusively bone and joint infections, it would be appropriate to characterize them in a little more detail – what is the complexity of their therapy? Is infection always associated with the presence of an implant?
Answer: Explanations were added according to the comment and marked in green in the manuscript on page 6.
Comment: 2. Section 4.1 (and further on) mentions phage endolysins. Unfortunately, the review does not provide more detailed information about the features of their use, preparation and effectiveness in comparison with full-fledged phages. Can some of the described disadvantages of phage therapy (lack of standardization and decrease in in vivo titer) be eliminated by using phage lysines? The author should have paid more attention to the description of phage lysines in this review, for example, to devote a separate subsection to this.
Answer: Explanations were added according to the comment and marked in green in the manuscript on page 7.
Comment: 3. Section 4.2 also mentions the immobilization of phages in a hydrogel (line 297). What are the advantages of this technology compared to suspension of phages in saline solution? This information would be interesting for a review.
Answer: The text was changed according to the comment and marked in green in the manuscript on page 9.
Comment: 4. Describing the effects of phage therapy, the author points to either a positive effect or a neutral one (absence of a positive effect). Only possible allergic reactions are described as a negative effect on the patient. Is the use of phages in the treatment of resistant bacterial infections really unable to aggravate the situation? Is there any evidence that after the use of phages, the bacterial pathogen increased its virulence (for example, by hiding phage receptors, it increased the thickness of the capsule)?
Answer: The text was changed according to the comment and marked in green in the manuscript on page 17-18.
Comment: 5. Write the Latin names of the strains in Italic (lines 24, 304, 381, 522, Table 2).
Answer: The text was changed according to the comment and marked in yellow throughout the manuscript.
Author Response File: Author Response.docx
Round 2
Reviewer 1 Report
Comments and Suggestions for AuthorsDear author
The new version manuscript show the all details were attended. these were highlight with color in the new version.
Only I found this details:
Line 274-275. please rewritten in italics names bacteria species. I consider thta this version could be consider for publication.
good luck
Author Response
Reviewer 1
Answers for reviewer 1:
Dear reviewer
Thank you very much for your helpful and important comment, which was taken into consideration and responded to below and marked on the manuscript in purple.
Comment 1: Line 274-275. please rewritten in italics names bacteria species. I consider thta this version could be consider for publication..
Answer: Suggested changes were made and marked with purple (page 7).
Author Response File: Author Response.docx
Reviewer 2 Report
Comments and Suggestions for Authors1. Line 415. Italicize scientific names.
2. Very long paragraphs follow. Break them up for better readability.
Author Response
Dear reviewer
Thank you very much for your helpful and important comments which were taken into consideration and responded to below and marked on the manuscript in purple.
Comment 1: Line 415. Italicize scientific names.
Answer: Probably line 615, once 415 does not have scientific names. The text (line 615) was changed according to the comment and marked in purple on page 14.
Comment 2: Very long paragraphs follow. Break them up for better readability.
Answer: Paragraphs were broken when appropriated.
Author Response File: Author Response.docx
