Fluoroquinolones and Other Antibiotics Redeemed for Cystitis—A Swedish Nationwide Cohort Follow-Up Study (2006–2018)

Round 1

Reviewer 1 Report

Overall

I think the English and the formatting can be improved. I do not think the paragraphs are aligned and the narration seems to be lacking for the reader. Mainly the flow of the article is missing. I have highlighted and asked them to either change or break the sentences.

Study subject and its relevance

I think the authors are commenting on the use of antimicrobials in uncomplicated cystitis. They seem to be pointing toward the guidelines that discouraged the use of fluroquinolones for uncomplicated cystitis. I think in the current time, this is a good topic to pick up.

Introduction

I feel here they can mention about antimicrobial resistance trends in the world. Fluroquinolone resistance can also be mentioned in the study population or in Sweden. For example, here in the United States, in the last 10 years FLQ resistance has increased by 25%. Additionally, the authors can also mention about the ADEs (adverse drug effects) from fluroquinolones.

Research Question:

Null hypothesis : Authors can alter it to by stating the primary objective as a null hypothesis. “National guidelines did not impact antimicrobial choices amongst health care providers for cystitis”. Additionally Secondary objectives stated by the authors seem to be satisfactory.

Materials and Methods

I did not find any critique with the methods. This study was designed to my satisfaction.

Comments for author File: Comments.pdf

Author Response

Overall

I think the English and the formatting can be improved. I do not think the paragraphs are aligned and the narration seems to be lacking for the reader. Mainly the flow of the article is missing. I have highlighted and asked them to either change or break the sentences.

Response: We thank you for your time and valuable comments that identified several opportunities to strengthen our work. We considered all your proposed changes and several amendments have been made, accordingly. The introduction section, in particular, has now been revised and improved.

Study subject and its relevance 

I think the authors are commenting on the use of antimicrobials in uncomplicated cystitis. They seem to be pointing toward the guidelines that discouraged the use of fluroquinolones for uncomplicated cystitis. I think in the current time, this is a good topic to pick up.

Response: Thank you.

Introduction 

I feel here they can mention about antimicrobial resistance trends in the world. Fluroquinolone resistance can also be mentioned in the study population or in Sweden. For example, here in the United States, in the last 10 years FLQ resistance has increased by 25%. Additionally, the authors can also mention about the ADEs (adverse drug effects) from fluroquinolones.

Response: We have expanded this part of the introduction but deliberately not mentioned specific resistance rates in countries but rather in general terms. It is, however, now mentioned (see paragraph 2 in the introduction section) that FLQ resistance has passed the resistance threshold (20%) for empirical treatment in several countries. We have also added specific ADEs for FLQ in this part of the introduction (paragraph 2).

Research Question:

Null hypothesis : Authors can alter it to by stating the primary objective as a null hypothesis. “National guidelines did not impact antimicrobial choices amongst health care providers for cystitis”. Additionally Secondary objectives stated by the authors seem to be satisfactory.

Response: We have revised the research question at the end of the introduction and added more details.

Materials and Methods

I did not find any critique with the methods. This study was designed to my satisfaction.

Response: Thank you.

Reviewer 2 Report

Overall consideration

This is an interesting manuscript regarding Its content. This includes adjustment by socio-demographic factors, and particularly social determinants of health. This is highly relevant and not enough studied in medical literature. Despite, there are some reanalysis and major changes to perform.

Major Changes/reanalysis

Taking into account that prescription of antibiotic X and not Y is not random and depends, at least, on: a) objective/subjective criteria of the physician that prescribes the antibiotic and b) trends on prescription across years, it makes necessary to adjust, at least, by this trend including the year of prescription as continuous variable.

Change the order of section to improve the readability of the manuscript. 1) Introduction; 2) Materials and methods; 3) Results and 4) Conclusions and discussion.

Minor changes

Lines 226 to 228 must be located and rewritten on study design section or elsewhere before the statistical analysis section.

Given that model 1, 2 and 3 are described on statistical analysis section, it could be desirable to include results from models 1 and 2 in a supplementary table (S2).

Tables. Table 2

Reduce the number of p-value decimals, from 4 to 3.

For educational level, given that the reference category is >=12 years, 10-11 years must be located before <=9.

Author Response

Overall consideration

This is an interesting manuscript regarding Its content. This includes adjustment by socio-demographic factors, and particularly social determinants of health. This is highly relevant and not enough studied in medical literature. Despite, there are some reanalysis and major changes to perform.

Response: We thank you for your time and valuable comments that identified several opportunities to strengthen our work.

Major Changes/reanalysis

Taking into account that prescription of antibiotic X and not Y is not random and depends, at least, on: a) objective/subjective criteria of the physician that prescribes the antibiotic and b) trends on prescription across years, it makes necessary to adjust, at least, by this trend including the year of prescription as continuous variable.

Response: Thank you for this suggestion and we agree with these comments. Therefore, we have now revised the analyses and results (including an updated version of table 2). The main results were more or less unchanged (please see the last paragraph of the results section and the second paragraph of the discussion section).

Change the order of section to improve the readability of the manuscript. 1) Introduction; 2) Materials and methods; 3) Results and 4) Conclusions and discussion.

Response: Please note that the current order is in accordance with journal guidelines.

Minor changes

Lines 226 to 228 must be located and rewritten on study design section or elsewhere before the statistical analysis section.

Response: This has now been revised and added under study design.

Given that model 1, 2 and 3 are described on statistical analysis section, it could be desirable to include results from models 1 and 2 in a supplementary table (S2).

Response: Thank you for noticing this. This has now been revised.

Tables. Table 2. Reduce the number of p-value decimals, from 4 to 3. For educational level, given that the reference category is >=12 years, 10-11 years must be located before <=9.

Response: The table has been revised accordingly.

Reviewer 3 Report

The overall manuscript is well written succinct and precise; nonetheless, I think the authors should make some adjustments:

1. I think the introduction section needs to contextualize more the aim of the study for example when to use narrow-spectrum antibiotics or the other types the pro and cons of those antibiotics etc.
2. Line 50, “we aimed 50 to study what specific antibiotics were redeemed and if the same factors could be associated with fluoroquinolone treatment”. It is written in the introduction, but in the conclusion section, it is not clear, at least to me, whether the aim of the work was achieved or not and why.
3. The manuscript is concise and accurate but I think the authors should pay more attention to explaining certain details.  

Author Response

The overall manuscript is well written succinct and precise; nonetheless, I think the authors should make some adjustments:

Response: We thank you for your time and valuable comments that identified several opportunities to strengthen our work.

1. I think the introduction section needs to contextualize more the aim of the study for example when to use narrow-spectrum antibiotics or the other types the pro and cons of those antibiotics etc.

 

Response: The introduction section has now been revised. We have included more information on the resistance and adverse effects of fluroquinolone antibiotics, and pros of the narrow-spectrum antibiotics (i.e., pivmecillinam and nitrofurantoin). [Third paragraph in the introduction section].

2. Line 50, “we aimed 50 to study what specific antibiotics were redeemed and if the same factors could be associated with fluoroquinolone treatment”. It is written in the introduction, but in the conclusion section, it is not clear, at least to me, whether the aim of the work was achieved or not and why.

Response: Thank you for noticing this. We have reviewed the aim in the introduction section to make it more clear, and expanded this section as well as the conclusion in accordance with your comment.

3. The manuscript is concise and accurate but I think the authors should pay more attention to explaining certain details.  

Response: We have added more information on specific details, especially in the introduction section to make the research question clearer.

Round 2

Reviewer 2 Report

Thanks for the feedback. It was a pleassure.