PONE-D-21-09419

Inappropriate antibiotic use in the COVID-19 era: factors associated with inappropriate prescribing and secondary complications. Analysis of the registry SEMI-COVID.

PLOS ONE

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PLOS ONE

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2. Thank you for including your ethics statement: The registry has the approval of the Ethics and Research Committee of the Province of Malaga. Patients were asked for informed consent. When it was not possible to obtain it for biosecurity reasons or because the patient was already discharged, it was collected verbally, leaving evidence in their medical history.

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3, One of the noted authors is a group or consortium SEMI-COVID-19 Network in addition to naming the author group, please list the individual authors and affiliations within this group in the acknowledgments section of your manuscript. Please also indicate clearly a lead author for this group along with a contact email address.

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This research received no external funding and “The APC was funded by the Concejelía de

Sanidad, Comunidad de Madrid.

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Additional Editor Comments:

dear authors follow reviewer suggestions to improve your paper

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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: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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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: The study is well designed and included large patient pool for many centers. Indeed, there was and still is inappropriate antibiotic use in COVID-19 infection, specially it was rampant in the beginning of the pandemic. The methodology is explained in detail; patient selection criteria is made as much elaborated as possible. The result and Tables/Figures are used appropriately.

Few questions and suggestions:

1. The aim or the hypothesis of the study is not clear. It should be clearly outlined in abstract and at the end of background.

2. The primary outcome and secondary outcome should be mentioned. Without Primary and secondary outcomes, it is difficult to interpret authors findings. For example, MV analysis reported in abstract’s result section: February-March 2020 admission (OR 1.54, 95%CI 1.18- 2.00), age (OR 0.98, 95%CI 0.97-0.99), …elevated C-reactive protein levels (OR 1.01 for each mg/L increase, 95% CI 1.00- 1.01) is for inappropriate ATB in comparison to No ATB. (But from background it seems the main purpose or aim of this study is to see Appropriate vs Inappropriate ATB). If the aim and the primary and secondary outcomes are No ATB vs Inappropriate Antibiotics, it should be mentioned. Otherwise it is confusing to interpret the data.

3. “Inclusion criteria: e) all data on antibiotic use during hospitalization available.” The authors in Figure 1 reported that 60 patients were excluded as they did not have antibiotic data on admission. ALL DATA means from since admission to discharge?

This is in contrast to criteria of appropriate prescribing (line 163): … including respiratory bacterial coinfection (at admission time) or superinfection (later on admission) with microbial isolation. If those 60 patients were excluded based on no antibiotic data on admission, then how authors included other patients who got superinfection (later on admission) with microbial isolation (because they might have been not prescribed antibiotic on admission hence lacking antibiotic data on admission).

This needs to be clarified.

4. Mention Table 1 in the parenthesis around line 165-166 where appropriate.

5. In Table 2 and 3, “Inadequate ATB and Adequate ATB” should be replaced with “Appropriate Antibiotics and Inappropriate Antibiotics”. The units for po2, lymphocytes, neutrophils etc. should be mentioned.

6. The odds ratio in line 264 and 268: What were they controlled for? Table for regression analysis?

7. Discussion: The first paragraph should be adjusted after the #2 is addressed.

8. Conclusion: Better to make it shorter. The authors attempted to include too many information that are diluting the main take-home message. (Conclusion should be to the point discussing hypothesis and the result in shortest possible words).

Overall a very good research study. I recommend to consider for publication after revisions.

Reviewer #2: Herein Authors discussed the important concern of antibiotic overprescribing in course of COVID-19 pandemic. I believe that this is a very important topic, often underestimated.

Overall, the manuscript is worth for publication, after few minor revisions:

1) A little bit more information should be given regarding the current literature on secondary bacterial infections in COVID-19;

2) A few lines should be spent regarding the high incidence of inappropriate antibiotic prescription in patients transferred to ICU;

3) In my opinion more emphasis should be place regarding the important spreading of multidrug-resistant bacteria due to inappropriate antimicrobial use and lack of infection control procedures;

4) A few lines regarding the importance of knowledge and practice regarding antimicrobial therapy should be included. I suggest citing this work regarding this aspect (Di Gennaro F, et al. Italian young doctors' knowledge, attitudes and practices on antibiotic use and resistance: A national cross-sectional survey. J Glob Antimicrob Resist. 2020 Dec;23:167-173. doi: 10.1016/j.jgar.2020.08.022).

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Reviewer #1: No

Reviewer #2: No

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Inappropriate antibiotic use in the COVID-19 era: factors associated with inappropriate prescribing and secondary complications. Analysis of the registry SEMI-COVID.

PONE-D-21-09419R1

Dear Dr. Parra,

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.

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Kind regards,

Francesco Di Gennaro

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

congratulations

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 #1: All comments have been addressed

Reviewer #2: 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 #1: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

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 #1: Yes

Reviewer #2: 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 #1: Yes

Reviewer #2: 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 #1: Thank you for adding the primary and secondary outcomes. And also for making changes as per recommendations.

Reviewer #2: (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 #1: No

Reviewer #2: No