A retrospective review on antibiotic use in acute watery diarrhea in children in a tertiary care hospital of Karachi, Pakistan

Sonia Qureshi; Shahzadi Resham; Mariam Hashmi; Abdullah B. Naveed; Zoya Haq; Syed Asad Ali

doi:10.1371/journal.pone.0253712

Peer Review History

Original SubmissionFebruary 11, 2021
9 Mar 2021 Decision Letter - Robert Jeenchen Chen, Editor PONE-D-21-04700 Association between antibiotic use and length of hospital stay among children presented with acute watery diarrhea in a tertiary care hospital, Karachi- A Cross-sectional Study PLOS ONE Dear Dr. Qureshi, 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 revise accordingly. Please submit your revised manuscript by Apr 23 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. 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Reviewer #1: Partly Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 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 ****** 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: No ****** 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 present retrospective study aimed to study the association between antibiotic use and length of hospital stay among children with acute watery diarrhea in a Pakistani tertiary care hospital. This is an important topic with important clinical implications. However, the study has some serious limitations, particularly in the methodology. • The authors should provide more details on the methods of medical records review. What is the system for medical recording in this hospital? Is it electronic or paper based? Is “acute watery diarrhea” an agreed diagnostic term or has a specific code to be recorded? Who reviewed the records (a single person? Two?)? Was there a double check or revision? ….etc • Authors should provide the indications of hospital admission for cases included in this study, what were the guidelines for antibiotics prescription in acute watery diarrhea in this hospital (39.4% of children with acute watery diarrhea who have no dysentery, no chronic illness, and no immunocompromised status received antibiotics), what were the guidelines for giving intravenous fluids (as need for intravenous rehydration after 24 hours of hospital admission was one of the study outcomes, and what were the discharge criteria (as length of hospital stay is the primary outcome). Is it possible that children who received the antibiotics stayed for a longer time in the hospital in order to complete a certain course of antibiotics? • Authors should provide methods for assessment of the severity of dehydration, • The authors conclude that antibiotic use was associated with a prolonged hospital stay in children with acute watery diarrhea. They report that the expected length of hospital stay for the antibiotic group was 0.22 hours higher than the group that did not receive antibiotics. However, even if this finding is statistically significant, I am concerned about the clinical importance with this small effect size (0.22 hours). • In the discussion, authors should explain the possible reasons/mechanisms for their findings, such as the association of antibiotic use and increased length of hospital stay and the association between male gender and longer hospital of stay. • The authors incorrectly use “cross-sectional study” instead of “retrospective study” in the title and methods. Reviewer #2: Thank you for allowing me to review this important manuscript which is concerned with one of the most important diseases in children less than 5 years of age which represents a considerable cause of childhood mortality The Language needs to be more polished and correction of some grammatical errors is essential ****** 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: Yes:** Elsayed Abdelkreem Reviewer #2: 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/. 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Revision 1
6 May 2021 Author Response Comments Responses Reviewer#1: 1. The authors should provide more details on the methods of medical records review. What is the system for medical recording in this hospital? Is it electronic or paper based? Is “acute watery diarrhea” an agreed diagnostic term or has a specific code to be recorded? Who reviewed the records (a single person? Two?)? Was there a double check or revision? …. etc Response:The system of recording at the hospital is paper-based and a digital record is also maintained for diagnosis from which data is extracted by using ICD codes. We pulled out medical record numbers of all children admitted with acute gastroenteritis during the defined time period and those fulfilling the pre-defined clinical definition were enrolled. 2. Authors should provide the indications of hospital admission for cases included in this study, what were the guidelines for antibiotics prescription in acute watery diarrhea in this hospital (39.4% of children with acute watery diarrhea who have no dysentery, no chronic illness, and no immunocompromised status received antibiotics), what were the guidelines for giving intravenous fluids (as need for intravenous rehydration after 24 hours of hospital admission was one of the study outcomes, and what were the discharge criteria (as length of hospital stay is the primary outcome). Is it possible that children who received the antibiotics stayed for a longer time in the hospital in order to complete a certain course of antibiotics? Response: There is no local guideline. We usually follow the standard guidelines but decision to prescribe antibiotics depends upon the severity of underlying illness and at the physician’s discretion. Similarly IV rehydration is provided if child has severe loses or doesn’t tolerate orally. 3. Authors should provide methods for assessment of the severity of dehydration, Response: The clinical assessment for severity of illness is based on skin turgor, eagerness to drink, sunken eyes and irritability as defined by WHO IMCI (Integrated Management of Childhood Illness) chart. We follow these four criteria for dehydration severity grading in our hospital. As it is a retrospective review, we collected documented information from medical record file of each patient at the time of presentation. 4. The authors conclude that antibiotic use was associated with a prolonged hospital stay in children with acute watery diarrhea. They report that the expected length of hospital stay for the antibiotic group was 0.22 hours higher than the group that did not receive antibiotics. However, even if this finding is statistically significant, I am concerned about the clinical importance with this small effect size (0.22 hours). Response:Thank you for highlighting this point. We understand this limitation. This may be because of small sample size. 5. In the discussion, authors should explain the possible reasons/mechanisms for their findings, such as the association of antibiotic use and increased length of hospital stay and the association between male gender and longer hospital of stay. This is really an important point which we missed in our manuscript to discuss. Response: Our findings indicated that antibiotic use was associated with a longer hospital stay. This may be because more children (7.3%) in the antibiotic group presented with severe dehydration compared to the non-antibiotic group (1.9%). Similarly 74/116 (63.7%) of male patients had signs of dehydration on presentation compared to females 35/59, (59.3%) or because in developing countries where illiteracy rate is high, families are more prone to insist on prolonged admission of their male heirs as compared to females. This can be a major contributing factor in the difference in results, especially when viewed as a component of gender inequality. We have added the reasoning in the modified version of the manuscript (Line no: 215-216, 225-231, 234-241) 6. The authors incorrectly use “cross-sectional study” instead of “retrospective study” in the title and methods. Response: This query has been addressed in the updated manuscript and the title has been edited. Reviewer#2: 1. The Language needs to be more polished, and correction of some grammatical errors is essential Response: This query has been addressed by an in-depth analysis of the paper and corrections in the updated manuscript. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0253712.r002
9 May 2021 Decision Letter - Robert Jeenchen Chen, Editor PONE-D-21-04700R1 Association between antibiotic use and length of hospital stay among children presented with acute watery diarrhea in a tertiary care hospital, Karachi- A Cross-sectional Study PLOS ONE Dear Dr. Qureshi, 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 revise accordingly. Please submit your revised manuscript by Jun 23 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, Robert Jeenchen Chen, MD, MPH 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 #3: (No Response) 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 #3: No Reviewer #4: No ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #3: No 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 #3: Yes 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 #3: Yes Reviewer #4: No ****** 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 #3: General comment: The study aimed to investigate the association between length of hospitalization and antibiotic use in children with acute watery diarrhea. They found a 0.22-hour difference in length of stay. After revision, the overall quality increased. However, the major limitations were limited clinical significance and limited information because of retrospective setting. Major comments: 1. P6, L112: Is it a cross-section study or retrospective study? 2. The indication for antibiotic use or admission should be provided to make the result or conclusion more convincing. Or this could be the major limitation in your study. 3. The association between antibiotics use and prolonged hospitalization was not explained well in the discussion. In different settings, antibiotic choices, different background, all variables will change. In limited information from limited cases, the association was not strong enough to make the conclusion. Try to find more variables, such as categories of antibiotics, pathogens, might be helpful. 4. I have the same question about the clinical significance of “0.22 hour” longer in hospitalization as previous reviewer stated. It has minimal drive for clinician to change their daily practice. Minor comments: 1. Virus should not be italic or uppercase compared with bacteria. Ex: Diarrhea caused by “rotavirus” and “Campylobacter jejuni” Reviewer #4: General comments: The authors retrospectively reviewed the effects of antibiotics on the length of hospital stay in 175 children with acute watery diarrhea in a single hospital. They found that the expected length of hospital stays for children who received antibiotic therapy was 0.22 hours higher than that of children who did not. The conclude that antibiotic use was associated with a prolonged hospital stay in children with acute watery diarrhea compared to children who did not receive antibiotics. General concerns: 1. Methods: The diagnosis criteria of acute watery diarrhea were not defined. The authors described only exclusion criteria. The authors did stool culture (Table 1. Stool culture positive rate). Please describe the inclusion criteria and the antibiotics category and duration. 2. Antibiotic therapy is not necessary for acute diarrhea in children because rehydration is the crucial treatment and symptoms resolve without specific therapy. Please describe the indication for antibiotics in this manuscript. 3. Methods, page 112: The phrase “A cross-sectional study was conducted at the department of Pediatric---” was not corrected in the revised manuscript. 4. Figure 1: Please describe the number of the enrolled participants in each group. ****** 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 #3: No 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. https://doi.org/10.1371/journal.pone.0253712.r003
Revision 2
12 May 2021 Author Response Comments Responses Reviewer#3: 1. P6, L112: Is it a cross-section study or retrospective study? Response: We are very sorry that we forgot to do this change in the study manuscript.We have done the corrections in the revised manuscript (P5, L103). Sorry for the inconvenience. 2. The indication for antibiotic use or admission should be provided to make the result or conclusion more convincing. Or this could be the major limitation in your study Response: There is no local hospital guideline. We usually follow the standard guideline. The common practice in our institute to prescribe antibiotics depends upon the severity of underlying illness and at the physician’s discretion. This is the basis of conducting this study to increase the awareness of our physicians that all should stick and follow the standard guidelines and if diverting from the pathway there must be some rationale of starting the antibiotics as in acute watery diarrhea there is no role of antibiotics. Similarly most common reasons for admission in our hospital are unable to tolerate feed, dehydration and parental anxiety. As this is the retrospective review this information is difficult to collect. This study helps us in developing a local hospital guideline and improving the knowledge of our HCWS so that everyone follow that standard pathway and in this way we can able to control the unnecessary use of antibiotics in our setting and in settings where such practice follows by disseminating the results of our study. 3. The association between antibiotics use and prolonged hospitalization was not explained well in the discussion. In different settings, antibiotic choices, different background, all variables will change. In limited information from limited cases, the association was not strong enough to make the conclusion. Try to find more variables, such as categories of antibiotics, pathogens, might be helpful. Response: We have mentioned the categories of antibiotics prescribed in our manuscript. Very few stool cultures came out to be positive. The description of which is given in the write-up. We know that the yield of stool culture to detect a bug is very low particularly in the setting where self-medication and overuse of antibiotics are common practice in the community. We agree with you that this association is not strong enough to make conclusion. To answer this question we need more large scale studies which we recommended in our conclusion. This study will help in developing the background/rationale to design large scale multicenter studies/trials. We have also mentioned/modified our recommendation in the abstract and in main text (P3, L51-52, P19, L276-277)). We hope we have responded your query appropriately. 4. I have the same question about the clinical significance of “0.22 hour” longer in hospitalization as previous reviewer stated. It has minimal drive for clinician to change their daily practice Thank you for highlighting this point. Response: We have elaborated this point in comment 3. We understand this limitation. Therefore we recommend larger studies in our conclusion. 5. Virus should not be italic or uppercase compared with bacteria. Ex: Diarrhea caused by “rotavirus” and “Campylobacter jejuni” Response: Thank you for picking this up. We have made corrections as suggested (P4, L82). Reviewer#4: 1. Methods: The diagnosis criteria of acute watery diarrhea were not defined. The authors described only exclusion criteria. The authors did stool culture (Table 1. Stool culture positive rate). Please describe the inclusion criteria and the antibiotics category and duration Response: Inclusion criteria is elaborated in methods section (P5, L106-108). Antibiotics categories and median duration of antibiotics are mentioned in the text of result section (P6, L146-149). Details of positive stool cultures are mentioned in the text of result section (P8, L155-159). 2. Antibiotic therapy is not necessary for acute diarrhea in children because rehydration is the crucial treatment and symptoms resolve without specific therapy. Please describe the indication for antibiotics in this manuscript. Response: Same as response 2 mentioned in reviewer 3 comments. 3. Methods, page 112: The phrase “A cross-sectional study was conducted at the department of Pediatric---” was not corrected in the revised manuscript. Response: Thankyou so much for highlighting this. We have corrected it in the revised manuscript (P5, L103). 4. Figure 1: Please describe the number of the enrolled participants in each group. Response: We have added this information in the Figure. Kindly refer to the revised version. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0253712.r004
17 May 2021 Decision Letter - Robert Jeenchen Chen, Editor PONE-D-21-04700R2 Association between antibiotic use and length of hospital stay among children presented with acute watery diarrhea in a tertiary care hospital, Karachi- Retrospective Study PLOS ONE Dear Dr. Qureshi, 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 revise the Title to make it concise whereas informative. Please submit your revised manuscript by Jul 01 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, Robert Jeenchen Chen, MD, MPH 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 #3: All comments have been addressed 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 #3: Yes Reviewer #4: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #3: Yes 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 #3: Yes 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 #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 #3: The authors tried hard to response all the issues I mentioned. Although some limitations and clinical questions exist, I expect to see more new results in the future. I have no more comment about the manuscript. Reviewer #4: The authors have addressed the concerns. ****** 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 #3: No Reviewer #4: Yes:** Chung-Ming Chen [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. https://doi.org/10.1371/journal.pone.0253712.r005
Revision 3
19 May 2021 Author Response 1. Please revise the Title to make it concise whereas informative Response: We have revised the title as suggested. Kindly refer to the revised manuscript. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0253712.r006
24 May 2021 Decision Letter - Robert Jeenchen Chen, Editor PONE-D-21-04700R3 A retrospective review on antibiotic use in acute watery diarrhea in children in a tertiary care hospital, Karachi. PLOS ONE Dear Dr. Qureshi, 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 revise accordingly and also the Title. Readers have no idea of the location name. Please revise the Title to make it concise and informative. Please submit your revised manuscript by Jul 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, Robert Jeenchen Chen, MD, MPH 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 #3: All comments have been addressed 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 #3: Yes Reviewer #4: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #3: Yes 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 #3: Yes 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 #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 #3: The author have adequately addressed all the issues I mentioned. I have no further comment on this manuscript. Reviewer #4: The authors have addressed the concerns. I have no further comments. The authors have addressed the concerns. I have no further comments. ****** 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 #3: No Reviewer #4: Yes:** Chung-Ming Chen [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. https://doi.org/10.1371/journal.pone.0253712.r007
Revision 4
25 May 2021 Author Response 1. Readers have no idea of the location name. Please revise the Title to make it concise and informative. Response: We have added the location in title in the revised file. Kindly refer to the revised manuscript. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0253712.r008
1 Jun 2021 Decision Letter - Robert Jeenchen Chen, Editor PONE-D-21-04700R4 A retrospective review on antibiotic use in acute watery diarrhea in children in a tertiary care hospital of Karachi, Pakistan. PLOS ONE Dear Dr. Qureshi, 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 revise accordingly Please submit your revised manuscript by Jul 16 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, Robert Jeenchen Chen, MD, MPH 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 #3: All comments have been addressed Reviewer #4: All comments have been addressed Reviewer #5: (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 #3: Yes Reviewer #4: Yes Reviewer #5: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #3: Yes Reviewer #4: Yes Reviewer #5: 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 #3: Yes Reviewer #4: Yes Reviewer #5: 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 #3: Yes Reviewer #4: Yes Reviewer #5: 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 #3: The author have addressed all the issues I mentioned. I have no further comment to this manuscript. Reviewer #4: The authors have addressed all the raised concerns. The authors have addressed all the raised concerns. Reviewer #5: It is professionally written paper on one of important public health issue of developing countries. I suggest excluding table 3 and table 4 as both intravenous fluid and diarrheal episodes are not primary objectives of the report. Table 2 is sufficient to present association of clinical manifestations with hospital stay. ****** 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 #3: No Reviewer #4: Yes: Chung-Ming Chen Reviewer #5: Yes:** Prof Sajid Soofi [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. https://doi.org/10.1371/journal.pone.0253712.r009
Revision 5
2 Jun 2021 Author Response Reviewer 5: 1. It is professionally written paper on one of important public health issue of developing countries. I suggest excluding table 3 and table 4 as both intravenous fluid and diarrheal episodes are not primary objectives of the report. Table 2 is sufficient to present association of clinical manifestations with hospital stay Response: Thank you for your suggestion. We agree that table 3 and 4 are covering our secondary objectives. We request you to kindly keep it in the manuscript as they were our secondary objectives (Refer to highlighted part on page 5 of revised manuscript). These tables provide additional findings related to antibiotic use in acute watery diarrhea and number of diarrheal episodes and need of IV rehydration. They are adding further strength to our paper. If still reviewer wants to remove these tables we will remove them. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0253712.r010
11 Jun 2021 Decision Letter - Robert Jeenchen Chen, Editor A retrospective review on antibiotic use in acute watery diarrhea in children in a tertiary care hospital of Karachi, Pakistan. PONE-D-21-04700R5 Dear Dr. Qureshi, 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, Robert Jeenchen Chen, MD, MPH 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 #3: All comments have been addressed 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 #3: Yes Reviewer #4: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #3: Yes 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 #3: Yes 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 #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 #3: The author have addressed all the issues I mentioned. I have no further comment to this manuscript. Reviewer #4: The authors have fully addressed the reviewers concerns. The authors have fully addressed the reviewers concerns. ****** 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 #3: No Reviewer #4: Yes:** Chung-Ming Chen https://doi.org/10.1371/journal.pone.0253712.r011
Formally Accepted
6 Jul 2021 Acceptance Letter - Robert Jeenchen Chen, Editor PONE-D-21-04700R5 A retrospective review on antibiotic use in acute watery diarrhea in children in a tertiary care hospital of Karachi, Pakistan. Dear Dr. Qureshi: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. 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. If we can help with anything else, please email us at plosone@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Robert Jeenchen Chen Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0253712.r012

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