PONE-D-21-00235

Impact of restriction of over-the-counter sales of antimicrobials on antimicrobial resistance in Escherichia coli from community-onset urinary tract infections in inner São Paulo State, Brazil.

PLOS ONE

Dear Dr. Fortaleza,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please proceed to revise the manuscript paying special attention to the comments provided by reviewer number 2. We look forward to your revised version.

For Lab, Study and Registered Report Protocols: These article types are not expected to include results but may include pilot data. 

Please submit your revised manuscript by Apr 30 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

Monica Cartelle Gestal, PhD

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: I Don't Know

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: I found this manuscript very well written, in a clear and concise manner.

All the findings are very well presented and the analysis of data is well done.

The findings are mostly negative which is very interesting considering how much emphasis is put on controlling antimicrobial drug use as a way to control resistance.

I feel that the manuscript should be accepted without any changes.

Reviewer #2: This is an important study investigating impact of restriction of OTC sales of antibiotics on antimicrobial resistance (AMR). This study attempts to address the most important endpoint in this type of research, but also the most challenging; Preventing increase of AMR is the main objective of regulating sales of antibiotics, but is affected by many other factors. The authors use an innovative methodology for assessing the impact of policy measures on AMR (Interrupted-time-series). However, the study still requires some work before it meets the standards of PLOS ONE. Some points of concern below.

General comments

My main concern about this study is that no data is provided about the total sales of the antibiotics that have been looked at in the study. This makes it challenging/impossible to estimate the relevance of the findings in this study. Other studies have shown that impact of regulating OTC sales of antibiotics varies greatly among countries, regions and types of antibiotics. It is essential to include the total sales volumes of cefazolin, ceftriaxone, ciprofloxacin, TMP-SMX and amikacin for the region of interest in the analysis to be able to interpret the resistance data.

A similar study has been done by Mattos et al. (Journal of Global Antimicrobial Resistance 2017). Please comment on what this study adds to the knowledge we have obtained from this study.

While the study appears to be sound, the language sometimes is unclear (for example, words like ‘straightforward’, ‘in opposite direction’ and ‘relevant’ are used incorrectly), making it difficult to follow. The whole paper needs a quick copy edit.

Title and abstract

The title is appropriate for the content of the article. The abstract is concise and accurately summarizes the essential information of the paper although it could be improved if the authors address the following issues:

• Abstract: Please include aim of the study in Introduction instead of Methods

• Abstract: Please include numbers in results for clarification of the findings. Also, the authors claim that they found an ‘impact’ on cefazolin and amikacin resistance, but this is not necessarily due to reduction of OTC sales and does not correspond with the conclusions drawn in this article.

• Abstract: Conclusion section now only exists of a policy recommendation, but no conclusion is provided based on your results.

Introduction

The introduction covers most important issues regarding banning OTC sales of antibiotics. Some points to consider:

• Unclear what you mean by ‘which have a human development index’. Please elaborate.

• No information is provided on what the actual impact of the new regulation was in the region where this study has been done.

• Further clarification is needed on why antimicrobial resistance is an important outcome, why desired impact on AMR is still uncertain and include more references on reduction of OTC sales of antibiotics in Brazil (see also comment above)

Methods

The Methods section is comprehensive and detailed but there are some points that should be clarified.

• Please explain what resistant tests have been conducted and how resistance was defined in this study.

• Why did the authors choose to analyse these specific antibiotics?

Results

It is unclear (in the first paragraph) what IRR values refer to and, more important, how to interpret these values.

Discussion

• The first paragraph reads like it is unclear whether antibiotics play a role in antimicrobial resistance at all. Moreover, the content of this paragraph seems better suited for the introduction.

• The second paragraph contains the most important text in the discussion. Would suggest to move that up to the first paragraph.

• There is a lot of focus on direct impact of banning OTC sales of antibiotics on AMR in the results sections, but this approach has some limitations since AMR resistance rates evolve and will not change from one day to another. Maybe consider mentioning this as a limitation

Conclusion

The main conclusion is very clear and well formulated. However, new information and references are quoted in the second part of the conclusion that have not been described in the discussion.

Figure

• In figure 1 for amikacin, it seems that the data is not suitable for an ITS because of the large differences between the resistance measurements. These deviating findings require clarification.

• Figure 1: Please consider including units for Resistance at Y-axis

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Reviewer #1: No

Reviewer #2: Yes: Tom G. Jacobs

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PONE-D-21-00235R1

Impact of restriction of over-the-counter sales of antimicrobials on antimicrobial resistance in Escherichia coli from community-onset urinary tract infections in inner São Paulo State, Brazil.

PLOS ONE

Dear Dr. Fortaleza,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

Thanks for your submission, please address the reviewers comments and submit as early as your convenience

==============================

Please submit your revised manuscript by Oct 08 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Monica Cartelle Gestal, PhD

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

Reviewer #3: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: I Don't Know

Reviewer #3: I Don't Know

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4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

Reviewer #3: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

Reviewer #3: No

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: I am happy with the adjustments made by the authors and their responses to the questions. I support publication of this paper in PLOS ONE.

Although, in general, the level of scientific English in the manuscript is appropriate, there are still a few typo's and grammatical errors.

Reviewer #3: Dear Authors the following statements are ambiguous

1. on the conclusion section of the abstract ''At the present study, we found that OTC sales restriction did not

generally impact on antimicrobial resistance. '' = it is better rewritten in a more informative way.

2.the last statement of the first paragraph on the background section ''Laws restricting

or prohibiting OTC sales of antimicrobials have been issued, but their impact is

currently not straightforward. (it is better to paraphrase the phrase -----currently not straightforward)

3.on the first statement of 2nd paragraph of the background section---''The population drivers of antimicrobial resistance are complex''. (it is better to change the phrase population drivers to community drivers)

4.the last statement of the third paragraph of the background section ''Most importantly, the impact on antimicrobial

resistance is uncertain in Brazil and in our region.(better to say---the impact on antimicrobial resistance is uncertain in Brazil generally and in our region specifically)

5. the statement on the discussion section ''Disappointing as our findings may be, they are evidently not an argument against

restricting OTC sales of antimicrobials.'' is ambiguous. I advise the authors to make it more clear.

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: Yes: Tom G Jacobs

Reviewer #3: Yes: Oumer Abdu Muhie

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Impact of restriction of over-the-counter sales of antimicrobials on antimicrobial resistance in Escherichia coli from community-onset urinary tract infections in inner São Paulo State, Brazil.

PONE-D-21-00235R2

Dear Dr. Fortaleza,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Monica Cartelle Gestal, PhD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: I Don't Know

Reviewer #3: I Don't Know

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: Happy with the changes made by the authors. THe manuscript has considerably been improved since their initial submission.

Reviewer #3: (No Response)

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: Yes: Tom G Jacobs

Reviewer #3: Yes: Oumer Abdu Muhie