PONE-D-23-12797Antibiotic prescription patterns in patients with suspected Urinary Tract Infections in EcuadorPLOS ONE

Dear Dr. Jimbo,

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 submit your revised manuscript by Sep 28 2023 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: https://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,

Kwame Kumi Asare, Ph.D

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at 

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and 

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. In the ethics statement in the Methods, you have specified that participant consent was obtained. Please provide additional details regarding how this consent was documented and witnessed, and state what participants consented to

3. We noticed you have some minor occurrence of overlapping text with the following previous publication(s), which needs to be addressed:

https://www.tandfonline.com/doi/abs/10.1080/00325481.2017.1246055?journalCode=ipgm20

https://www.ncbi.nlm.nih.gov/books/NBK557569/

https://www.sciencedirect.com/science/article/abs/pii/S0009898117302292?via%3Dihub

In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed.

4. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide.

5. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please delete it from any other section. 

6. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. 

[Note: HTML markup is below. Please do not edit.]

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

**********

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

Reviewer #1: Yes

Reviewer #2: I Don't Know

**********

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: No

**********

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

**********

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 have attached my review as an attached document

This is an interesting cross-sectional study in patients with suspected UTI treated in outpattientcenters and 2nd level hospital in Ecuador during 2019. A total of 507 patients could be retrospectively included. According to the ICD-10 three diagnoses were possible (% of patients): N10-pyelonephritis (11.64%), N300-cystitis (6,51%), N390-UTI not further specified (81.85%). The authors described carefully the prescirbers and the patients and analysed the associated factors for inappropriate antibiotic presciption thereafter.

The antibiotics prescribed were listed in Table 2 according to the 3 UTI diagnoses above, which obviously were the main results for judgment of appropriate or non appropriate antibiotic prescription. Of course, the main problem of such a study is the fact, that about 82% of UTI diagnoses could not be further specified concerning site, complicated/uncomplicated UTI and severity. For local resistance the authors presented some data, which of course are of interest for all three categories, because by far most patients were treated empirically and only in 10% of patients urina culture results were available.

In order to consider all these aspects at a glance Table 2 should be slightly reconstructed.

The new table is attached

Now you could discuss more specifically especially for the first two groups, what is appropriate and what is not appropriate. Unfortunately N390 is a black box exept general recommendations and considerations about local resistance, because it is not known, how many complicated UTI incl pyelonephritis cases are included in each antibiotic prescription. In summary: the reader has problems to comprehend, which antibiotic under which consideration you consider appropriate or inappropriate. Of course, nitrofurantoin and oral fosfomycin would be the preferred antibiotics for uncomplicated cystitis. Fluoroquionolones should not more prescribed at all for UTI unless for specific complicated UTI, e.g. prostatitis. Still, we do not know, what cases are included in N390.

Reviewer #2: The authors present an interesting and up-to-date cross-sectional look at UTI prescription patterns in Ecuador. The overall results certainly seem to be consistent with my own observations from clinical practice, and add the interesting observation that prescriber age, lack of use of POC testing, and care by a generalist may be associated with increased risk of an inappropriate prescription - all information that may be useful for antimicrobial stewardship programs.

I do think a few points need to be addressed before proceeding with publication:

1) The extremely high prescription rate (99%) and specific wording of inclusion criteria (p6, line 127) leave me wondering - was treatment expressly part of inclusion criteria? (I don't think this is a problem per se - just worth clarifying as the question of appropriate antibiotic treatment is quite different than appropriate evaluation of urinary symptoms).

2) Regarding the included list of ICD10 codes (p 6 line 130-131): These codes certainly capture the more certain diagnoses. However, prior research has suggested variable performance in diagnosis-specific vs symptomatic/syndromic ICD10 codes for identifying patients evaluated for UTI (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7558992/). Would suggest the authors provide some citation or justification for the specific list chosen. If current list is kept, may need to add to limitations some statement that this ICD10 code list does risk some selection bias in targeting patients. For example, if patients with "dysuria" were also included, it is possible the rate of inappropriate treatment might have been even higher.

3) On sample size calculations (p 6 lines 138-141): Though the formula was nicely provided, I am still uncertain how exactly this was used to choose sample size. Please clarify if possible - which outcome was this powered on, and what was the targeted power or precision?

4) On cohort selection (p 6 line 144): Related to the sample size calculations, how was the cohort actually selected? Was it a random sample to meet goal sample size? Or consecutive cases? All cases?

5) On assessment of antibiotic appropriateness: From a stewardship perspective, appropriateness may refer to whether indication, antibiotic selection, or duration were reasonable. In this case, it looks like appropriateness is adjudicated solely on whether an indication was appropriate. If so, please stage explicitly.

6) On stepwise selection method (p 7, line 164): A few more details would be helpful to understand model selection:

- What were the candidate variables considered and how were these selected?

- I note comorbidity is only included as a yes/no variable- was any consideration given to inclusion of just comorbidities associated with urinary symptoms?

- What rules were used in the stepwise selection and what parameter was used to assess "best performing" model?

7) "First level of health care" (p 9, line 173, but also other places throughout text): Not all readers may be familiar with this term. Please define at first use.

8) Text density on p 9: In general, many of the descriptive statistics on p 9 could best be left in the tables so as not to be redundant or text heavy.

9) Clarity on p 10, line 200-201:

- Does this mean >1 bacterium per HPF was considered a positive result for microscopic bacteria? If so, this seems overly sensitivity and prone to over-calling UTI.

- "Gram negative stain bacteria in all cases" - I am uncertain about the intended meaning of this line. Please reword if possible.

10) On variable selection: I notice prescriber age was converted to a binary variable splitting at age 40. Was there an a priori reason for this selection?

- If there is not a good reason for this split point, was prescriber age assessed as either a continuous variable or ordinal groups like patient age was?

11) Assessment for collinearity: It comes to mind that certain providers - by nature of their specialty - might be associated with particular patient types. Did the authors assess their regression models for the possibility of collinearity among included variables?

12) Caution with epidemiologic wording on p 13, line 254: Would be careful about stating "Our data show that almost 90% of cases develop in women" as this study was a cross sectional one aimed at assessing UTI prescribing appropriateness - and is not actually an epidemiologic survey. E.g., it did not actually assess relative incidence in men/women.

- Would reword to say something akin to: "Nearly 90% of patients seeking evaluation for UTI were women..." etc

13) Use of terms "firstline" or "secondline": A bit of a technicality, but the guideline cited (Gupta et al 2011) uses the term "recommended" rather than firstline. Consider rewording for consistency.

14) Regarding emphasis of conclusions:

- Suggest rewording abstract to refer to appropriate or inappropriate (rather than "adequate") prescription rate

15) Causality assessed in p 17, line 347-348: Can the authors provide specific evidence for their statement that uncertainty from insufficient diagnostic capacity influenced treatment in their study? I think this is an important point - and could be strengthened if they could list for example what proportion of their prescribers had access to UA, culture, etc?

**********

6. 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: Yes: Nicholas A. Turner MD MHSc

**********

[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.

Attachments

Attachment

Submitted filename: 23-05-07-Jimbo 2023 subm Pone-Review-23-05-07-Jimbo 2023 subm-PONE-D-23-12797-Antibiotic prescription patterns in patients with susp UTI in Ecuador.docx

PONE-D-23-12797R1Antibiotic prescription patterns in patients with suspected Urinary Tract Infections in EcuadorPLOS ONE

Dear Dr. Jimbo,

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 submit your revised manuscript by Oct 21 2023 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: https://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,

Kwame Kumi Asare, Ph.D

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.

[Note: HTML markup is below. Please do not edit.]

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: (No Response)

Reviewer #2: All comments have been addressed

**********

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: This is an interesting cross-sectional study to analyze the antibiotic prescription patterns in adult patients with suspected UTI in Ecuador. The authors used the Electronic Health Records (EHR) of three months during 2021. The diagnosis of UTI in the 507 patients from 15 different centers was taken according to the ICD-10 with the following codes: N10 – acute pyelonephritis (59; 11.64%); N300 – acute cystitis (33; 6.51%) and N390-UTI, site not specified (415; 81.85%). All other data, such as demographics, UTI symptoms, concomitant diseases, urinalysis, urine culture and antibiotic prescription were also taken from the EHR. Although dipsticks tests including leucocytes and nitrites were performed in 74,16% patients (positive in 92,47% of them), urine culture was only available in 10.64% of the patients.

Although the authors did their best to analyze all these informations, the main problem os such a study is the fact that in 81.85% of the patients UTI was not specified and the remaining UTI diagnoses (pyelonephritis and cystitis) could not be categorized whether considered as complicated or uncomplicated. To overcome this problem the authors tried to categorize the different forms of UTI according to symptoms and positive urine test (most likely they mean dipstick test?).

Here is my 1. Question: The reader would like to see a table according to the categories mentioned in Chapter „Assessment of appropriateness of antibiotic prescription“. Because most of the patients had UTI not specified, the authors could state, that they tried to specify the UTIs according to symptoms, comorbidities, gender, and positive urine dipstick tests.

Then probably the five categories mentioned in this chapter could correspond to

1. uncomplicated cystitis in women

2. uncomplicated pyelonephritis in women

3. complicated UTI (obviously in women, because the next category says. „any male“)

4. complicated UTI in male patients

5. Here the reader would like to know, what the authors assumed in case no urine dipstick test was performed or the test was negative besides symptoms were present.

After the authors have clarified the consequence of category 5 (are the patients without or negative dipstick test included or excluded from further analysis or maybe still categorized according to the categories 1-4), the the reader would like to see a similar table as Table 2 with the following UTI categories (according to symptoms and comorbidities):

1. uncomplicated cystitis in women

2. uncomplicated pyelonephritis in women

3. complicated UTI in women

4. UTI in male patients

5. Total

Such a table would be more informative than table 2 according to ICD-10, where 81.85% of patients had UTI, not specified. Therefore such a table should be added.

This problematic (most patients had UTI, not specified9 should be discussed also in limitations.

Urine culture were performed only 10.64%, most in cases with pyelonephritis (ok), but 37.85% also in UTI, not specified. Here the additional table with clinical specification could also be helpful.

Only 62.5% of urine cultures were positive according to the definition used (>100.000 CFU/ml). Here the authors could also discuss, e.g. in chapter limitations, that it is not known whether the patients were pretreated with antibiotics – or that lower CFU/ml can also be significant, especially in uncomplicted cystitis in women [1,2]

In summary, this is a very interesting study, which could be improved by some additional evaluations and even better description of the limitations, which are not the fault of the authors, but because of the data availability in the EHR. Otherwise the conclusions of the authors are understandable and justified.

References

1. Stamm WE, Counts GW, Running KR, Fihn S, Turck M, Holmes KK et al (1983) Diagnosis of coliform infection in acutely dysuric women—NEJM. N Engl J Med. https://doi.org/10.1056/NEJM1 98312013092224

2. Hooton TM, Roberts PL, Cox ME, Stapleton AE (2013) Voided midstream urine culture and acute cystitis in premenopausal women. N Engl J Med. https://doi.org/10.1056/nejmoa1302186

Reviewer #2: I appreciate the authors care in addressing each comment/question raised. I do not have any additional questions.

**********

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: Yes: Nicholas A. Turner

**********

[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-23-12797R2Antibiotic prescription patterns in patients with suspected Urinary Tract Infections in EcuadorPLOS ONE

Dear Dr.  Jimbo,

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 submit your revised manuscript by Nov 24 2023 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: https://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,

Kwame Kumi Asare, Ph.D

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

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

Reviewer #4: (No Response)

**********

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

Reviewer #4: Partly

**********

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

Reviewer #2: Yes

Reviewer #3: I Don't Know

Reviewer #4: No

**********

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

Reviewer #4: No

**********

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

Reviewer #4: 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: No addition comments from prior - I believe the authors have addressed all reviewers' points to the fullest extent possible

Reviewer #3: The manuscript in current form should be acceptable in current shape. The manuscript in current shape is seemed to be properly formatted and incorporated with comments. There is no need for further changes, therefore I recommned this manuscript to be accepted by the editor.

Reviewer #4: Appropriateness of antibiotic prescriptions in UTI is still an interesting argument. The manuscript reads well but it should be presented in a more structured way. My main concerns, anyway, regard data, statistical analysis and presentation of results. Here as follows:

1) Data availability issue: the data are made available by the authors but, in the way they are shared, they are not helpful to reproduce the main analysis. First, a code-book description and explanation of each variable (please rename all variables in English) with the specification of the coding used is missing and it seems that some variables are not provided. Please also specify if they refer to prescribers or patients.

2) In the methods, it should be clarified that the sample does not contain repeated measurements within patients. The main outcome and variables collected should be better specified and defined. In fact, it is not clear if the main outcome is the prescription pattern or the appropriateness of the prescription (I understand the second). This should be better highlighted and each variable listed specifying how it is defined (categorical, continuous ...). Otherwise, a more detailed data description should be provided as Supplemental. Please also refer the reader to the data shared (in a better understandable way).

3) The statistical analysis does not take into account the correlation of patients followed by the same prescriber. In fact, it's not sufficient to adjust for prescribers' characteristics but also to adjust for the prescribers as random effects. That is, instead of a simple multivariable logistic regression, a mixed regression model should be performed. Moreover, the mean(sd) of the number of patients seen by the same prescriber is not reported. In the discussion, lines 303-304, page 15, it's reported that general practitioners and specialists were responsible for almost the same number of diagnoses of UTI but this is not evidenced in the results. Moreover, the authors wrote "bivariate analysis" but this is in fact "univariate regression analysis". Please correct it in line 192, methods and line 272, results

4) The authors have not appropriately addressed the previous reviewers' comment. If a table with the subgroup specification uncomplicated/complicated was not possible due to the lack of information, a subgroup analysis, based on the element/factors which defined appropriateness of prescriptions should be given. In fact, it's not clear how many ciprofloxacin prescriptions, for example, were appropriate or not.

5) Results presentation is not systematic and clear. The authors should present more results in Tables and not in plain text, so that the reader could better follow and understand where reported results come from. In Table 1, please also report the count (%) of the patients with no comorbidities. The reader should catch immediately all relevant information. Please rephrase line 225 on page 11: it is not clear to which % they refer or maybe the authors forgot to report the number % of the second level of care. In Table 1 please correct "Age (SD)" moving (SD) after mean.

6) The discussion should be better rewritten. First, a summary of the main results: please first state the more important ones (related to the outcome) and then the secondary ones. Then, discuss each point (the reader would appreciate if subheading were used). The novelty of this study is not highlighted: the reader does not catch what this study adds to the existing literature. No mention is given about the % range of prescription of each antibiotic (nitrofurantoin, fluoroquinolones...) in the existing literature and in the international context. A range should be provided, since the prescription pattern is a main outcome and the reader should understand how much the % of prescriptions of fluoroquinolones (appropriate/not appropriate) found in the study, for example, differs compared to the range found in the literature.

Moreover, not being able to differentiate between complicated/uncomplicated should be stated among the limitations because this limits the interpretation of the results compared to the literature, since the authors referred to studies of appropriateness for uncomplicated UTI.

7) Minor: line 199 please correct "utilized" with "use". That's sounds better.

**********

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: Nicholas A. Turner

Reviewer #3: Yes: Syed Muhammad Zaigham Abbas Naqvi

Reviewer #4: No

**********

[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-23-12797R3Antibiotic prescription patterns in patients with suspected Urinary Tract Infections in EcuadorPLOS ONE

Dear Dr. Jimbo,

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 submit your revised manuscript by Dec 18 2023 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: https://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,

Kwame Kumi Asare, Ph.D

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

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 #4: (No Response)

**********

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 #4: Yes

**********

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

Reviewer #4: No

**********

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 #4: 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 #4: 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 #4: The authors did not address one of my previous comments regarding the use of mixed models. The authors should perform a model with prescribers as random effects because in the study there are repeated measurements within prescribers, though it is true that in the study there are no repeated measurements within patients and the study is no longitudinal. However it is also true that in the study prescribers characteristics are included in the model (this is correct) but patients followed by the same prescriber are correlated and this should be accounted for in the adjusted model. Maybe the results would not change so much and the conclusions will remain the same. Anyway the authors should perform this analysis. The rest of the manuscript sounds good and once performed this analysis and correct the methods and results accordingly, the manuscript would be suitable for publication (unless other issues would not come out after this analysis).

**********

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 #4: No

**********

[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.

Antibiotic prescription patterns in patients with suspected Urinary Tract Infections in Ecuador

PONE-D-23-12797R4

Dear Dr. Jimbo,

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,

Kwame Kumi Asare, Ph.D

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 #4: All comments have been addressed

**********

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 #4: Yes

**********

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

Reviewer #4: 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 #4: 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 #4: 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 #4: I have no other comments. The authors addressed all my previous comments. The manuscript could be accepted.

**********

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 #4: No

**********