Multi-center prospective population pharmacokinetic study and the performance of web-based individual dose optimization application of intravenous vancomycin for adults in Hong Kong: A study protocol

Ka Ho Matthew Hui; Chung Yan Grace Lui; Ka Lun Alan Wu; Jason Chen; Yin Ting Cheung; Tai Ning Teddy Lam

doi:10.1371/journal.pone.0267894

Peer Review History

Original SubmissionAugust 15, 2021
5 Jan 2022 Decision Letter - Steven Eric Wolf, Editor PONE-D-21-24164 Multi-center prospective population pharmacokinetic study and the performance of web-based individual dose optimization application of intravenous vancomycin for adults in Hong Kong: A study protocol PLOS ONE Dear Dr. Lam, 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. This is an interesting approach that has merit, but the reviewers include several suggestions for improvement. In particular, please minimize the use of acronyms which often serve only to irritate the reader - we have more than enough 'electron space' to simply spell most of these out save those in the common vernacular (e.g. ICU, KDIGO, etc.). I look forward to seeing the revision which I will send back to the same referees for decision. Please submit your revised manuscript by Feb 11 2022 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, Steven Eric Wolf, MD 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 your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability. Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized. Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access. We will update your Data Availability statement to reflect the information you provide in your cover letter. 3. Your abstract cannot contain citations. Please only include citations in the body text of the manuscript, and ensure that they remain in ascending numerical order on first mention. 4. 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. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions? The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field. Reviewer #1: Yes Reviewer #2: Partly Reviewer #3: Yes ******** 2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses? The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory. Reviewer #1: Partly Reviewer #2: Partly Reviewer #3: Yes ****** 3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable? Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible. Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes ****** 4. Have the authors described where all data underlying the findings will be made available when the study is complete? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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 Reviewer #3: Yes ****** 5. Is the manuscript presented in an intelligible fashion and written in standard English? PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here. Reviewer #1: Yes Reviewer #2: Yes Reviewer #3: Yes ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics. You may also provide optional suggestions and comments to authors that they might find helpful in planning their study. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: This is an interesting PK study that primarily describes a carefully planned PK analysis. The statistician is clearly an expert in NONMEM7. Although I am a statistical reviewer, I am more concerned that the paper is primarily written about the statistical procedures rather than the design of the study itself. Some of the omissions that I see are: --multi-center studies should describe how each center's personnel will be trained on the protocol so that patient procedures are homogeneous --A lot of data will be collected, and this is well-described, but its relation to the study objectives is less clearly described. --There is no sample size justification. Why 300? Why 50? --Bayesian methods seem appropriate. Yet you are using t-tests and standard survival estimators for the comparison. --More on historical controls. How can we be certain that the historical controls are comparable? --Far too many acronyms throughout the paper. I know PK people like acronyms, but it is overwhelming for the reader to keep track. --Details such as in lines 208-212 would be better shown in a figure or flow chart. --Remove the software used in the abstract. NONMEM is not a statistical procedure, it is a software designed to do certain modeling. It is better to say the statistical modeling technique rather than refer to the software. --A sweeping conclusion that related all these NONMEM C_s analyses to clinical practice. Reviewer #2: The introduction needs to clarify the other recommendations and guidelines being used to guide the new study. Recommend addressing that reference method or “gold standard” for calculating MIC is called broth microdilution (BMD) and how that incorporates to the study. Target range should be AUC:MIC ratio of 400-600. Reviewer #3: Multi-center prospective pharmacokinetic study and the performance of web-based individual dose optimization application of intravenous vancomycin for adults in Hong Kong: A study protocol I commend the authors on this ambitious study to develop an algorithm for area under the curve based individual vancomycin dosing. Line 111: Please define “HA” Line 137: explain methods for a priori sample sizes Table 1 Constant Data: Consider staging acute kidney injury at baseline and throughout the treatment protocol (ie RIFLE, AKIN, or KDIGO). This can easily be calculated with proposed laboratory values to be collected and can further stratify patients adding greater depth and applicability to the web-based model. Also, include source of infection Dynamic Data Items: Include renal based outcome (ie time to development of AKI, Time to ESRD, time to change in AKI stage, etc.) Line 127: For patients with a new IDCP, please explain how this new IDCP will be treated during the data analysis. Will this be a unique dataset? Define the timeframe between cessation of vancomycin and a new IDCP. Line 189: Define dosing interval. Line 227: 168 hours is between 28 and 42 half-lives of vancomycin. This seems excessive. Consider reducing this time frame or explain why this time frame is chosen. Line 290: Define TTT, TTA, TTN ****** 7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose “no”, your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review?** For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No Reviewer #3: 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.0267894.r001
Revision 1
15 Mar 2022 Author Response Dear Editor, All authors and I would like to thank the editorial staff and reviewers for handling our manuscript. Please see the following point-to-point responses to the editors’ and reviewers’ comments. Editors’ and reviewers’ comments are quoted in smaller grey font with tight line spacing, while our responses are in blue. 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 Thank you for the information. We have reformatted our manuscript accordingly. 2. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability. Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized. Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access. We will update your Data Availability statement to reflect the information you provide in your cover letter. The protocol does not report any result. We have specified so in the Data Availability section. 3. Your abstract cannot contain citations. Please only include citations in the body text of the manuscript, and ensure that they remain in ascending numerical order on first mention. Our abstract does not contain any citation. 4. 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. We have added the caption for our Supporting Information files at the end of our manuscript and updated any in-text citations accordingly. Reviewer #1: This is an interesting PK study that primarily describes a carefully planned PK analysis. The statistician is clearly an expert in NONMEM7. Although I am a statistical reviewer, I am more concerned that the paper is primarily written about the statistical procedures rather than the design of the study itself. Thank you for your time reviewing our manuscript and your valuable comments. We understand that our current manuscript is lacking certain details regarding study design. Please see our responses below. Some of the omissions that I see are: --multi-center studies should describe how each center's personnel will be trained on the protocol so that patient procedures are homogeneous We will explain the protocol thoroughly to the site coordinators, answer all questions they have before study commencement, and closely monitor the recruitment of and study procedures done on the first subject at each center. The section “Compliance to ethical standard, registration, and approval” has been supplemented. --A lot of data will be collected, and this is well-described, but its relation to the study objectives is less clearly described. Thank you for your reminder. We have supplemented the “Structural and parameter models” and “Covariate model” sections to explain how the data help characterize the concentration-time profiles of IV vancomycin, considering potential covariate effects. --There is no sample size justification. Why 300? Why 50? Unlike hypothesis testing, where the minimum sample size required can be approximated based on the expected effect size and the power needed, in a popPK modeling study where the major covariates are also known a priori, there is no established way to calculate the minimum sample size. The sample sizes of previously published popPK models vary significantly, for e.g., 16 and 36 in Hui K. H. et al (2019) DOI: 10.1002/jcph.1349, 326 in Francis J. et al (2019) DOI: 10.1128/AAC.01964-18, and 1,151 subjects in Stringer F. et al (2013) DOI: 10.1177/0091270012447121. We notice that most popPK reports had sample sizes that range from 50 to 300. Therefore, we aim at the higher end of the range by defining a sample size of 300 and hope for more accurate estimates while avoiding further increasing the study burden. Similarly, there is no established way to calculate the minimum sample size for external validation. Our decision to include 50 subjects for external validation was based on the observation that most popPK studies adopt a sample size for external validation that is about 15-30% of the sample size for model estimation. (300 * 17% = 50) --Bayesian methods seem appropriate. Yet you are using t-tests and standard survival estimators for the comparison. Bayesian methods are being applied to estimate the individual PK and thus optimal doses. However, successfully verifying the prior distribution to be used in the Bayesian estimation process does not imply that using the developed interface to guide dosing will improve the overall clinical outcome. Therefore, t-tests and Cox regression are proposed to compare the clinical outcomes of the two treatment approaches: with vs without the developed Bayesian application. These are statistical tests commonly used to test for treatment effects in conventional clinical studies. --More on historical controls. How can we be certain that the historical controls are comparable? We will verify the comparability through baseline characteristics comparison and, if necessary, propensity score matching. We have supplemented this under the sub-section “Statistical analyses for outcomes” in the Material and methods section. --Far too many acronyms throughout the paper. I know PK people like acronyms, but it is overwhelming for the reader to keep track. We apologize for using too many acronyms. We have removed most acronyms for technical terms (such as Cs,ss,trough) and those used sparingly in the updated manuscript. --Details such as in lines 208-212 would be better shown in a figure or flow chart. Thank you for your recommendation. We think it is a great idea to trim the passage to improve readability. We have added a figure to explain the ideal and alternative sampling schedules with respect to the dosing schedule. --Remove the software used in the abstract. NONMEM is not a statistical procedure, it is a software designed to do certain modeling. It is better to say the statistical modeling technique rather than refer to the software. We have removed NONMEM from the abstract and replaced it with non-linear mixed-effect modeling techniques. --A sweeping conclusion that related all these NONMEM C_s analyses to clinical practice. We have added a conclusive sentence at the end of the sub-section “PopPK model estimation and validation” in the Materials and methods section. Thank you for the recommendation. Reviewer #2: The introduction needs to clarify the other recommendations and guidelines being used to guide the new study. Thank you for your time reviewing our manuscript. We have further explained (1) the choice of a popPK model as the prior distribution for Bayesian estimation as a recommendation of the guideline. Recommend addressing that reference method or “gold standard” for calculating MIC is called broth microdilution (BMD) and how that incorporates to the study. Target range should be AUC:MIC ratio of 400-600. We have included an explanation in the footnote of Table 1 about the methods used to measure MIC. Reviewer #3: Multi-center prospective pharmacokinetic study and the performance of web-based individual dose optimization application of intravenous vancomycin for adults in Hong Kong: A study protocol I commend the authors on this ambitious study to develop an algorithm for area under the curve based individual vancomycin dosing. Thank you very much for your support of our work. Please see our responses to your valuable comments below. Line 111: Please define “HA” HA refers to Hospital Authority, the statutory body governing public hospitals in Hong Kong. The definition has been supplemented at its first appearance in the main text. Line 137: explain methods for a priori sample sizes Unlike hypothesis testing, where the minimum sample size required can be approximated based on the expected effect size and the power needed, in a popPK modeling study where the major covariates are also known a priori, there is no established way to calculate the minimum sample size. The sample sizes of previously published popPK models vary significantly, for e.g., 16 and 36 in Hui K. H. et al (2019) DOI: 10.1002/jcph.1349, 326 in Francis J. et al (2019) DOI: 10.1128/AAC.01964-18, and 1,151 subjects in Stringer F. et al (2013) DOI: 10.1177/0091270012447121. We notice that most popPK reports had sample sizes that range from 50 to 300. Therefore, we aim at the higher end of the range by defining a sample size of 300 and hope for more accurate estimates while avoiding further increasing the study burden. Similarly, there is no established way to calculate the minimum sample size for external validation. Our decision to include 50 subjects for external validation was based on the observation that most popPK studies adopt a sample size for external validation that is about 15-30% of the sample size for model estimation. (300 * 17% = 50) Table 1 Constant Data: Consider staging acute kidney injury at baseline and throughout the treatment protocol (ie RIFLE, AKIN, or KDIGO). This can easily be calculated with proposed laboratory values to be collected and can further stratify patients adding greater depth and applicability to the web-based model. Also, include source of infection Dynamic Data Items: Include renal based outcome (ie time to development of AKI, Time to ESRD, time to change in AKI stage, etc.) We agree that adding AKI staging enables deeper analyses, such as the dose relationship of AKI. We have added a statement about conversion to AKI stages at the end of the sub-section “Data exclusion and management” and a description of corresponding statistical analyses in the sub-section “Statistical analyses for outcomes” under the Materials and methods section. Besides, we have added the item “source of infection” in Table 1. Similarly, we have included renal outcomes in terms of AKI staging in Table 1 and the sub-section “Statistical analyses for outcomes”. Line 127: For patients with a new IDCP, please explain how this new IDCP will be treated during the data analysis. Will this be a unique dataset? Define the timeframe between cessation of vancomycin and a new IDCP. The primary purpose of defining the IDCP is to ensure the necessary rich Cs sampling near the start of vancomycin treatment. The new IDCP will still belong to the same subject in the dataset. There will be no wash-out period between consecutive IDCPs – once a new IDCP is indicated to start due to vancomycin re-initiation, the remaining vancomycin estimated to be in the subject’s body from the doses in the previous IDCP will be carried over for the estimation of Cs in the subsequent IDCP(s). A sentence has been added to the end of the first paragraph of the sub-section ”Data exclusion and management” under the Materials and methods section. Line 189: Define dosing interval. Dosing interval has been defined later in the same paragraph. We apologize for putting the definitions after usage, thus causing confusion. We have moved the definition to the start of the paragraph. Line 227: 168 hours is between 28 and 42 half-lives of vancomycin. This seems excessive. Consider reducing this time frame or explain why this time frame is chosen. Thank you for pointing this out. The intention of introducing this time frame is to remove any Cs whose prediction might be inaccurate due to missing dosing records. (E.g. it is reasonable to suspect that there are missing dosing records when vancomycin remains detectable in a subject with normal renal function 1 week after the last dose.) It is true that 168 hours is typically 28 to 42 half-lives of vancomycin. However, this ratio is much reduced in subjects with profound renal impairment. Therefore, we would like to take a 7-day period as an approximated average. Besides, we will keep an eye on any significant underestimation for Cs recorded after a suspiciously long period after the last dose in case any missing dosing records are not being picked up by the above 7-day method. Line 290: Define TTT, TTA, TTN To reduce the use of acronyms, as suggested by other reviewers, we have removed the acronyms TTT (time to therapeutic target attainment), TTA (time to afebrile), and TTN (time to normal white blood cell count) from the text. Attachments Attachment Submitted filename: Responses_to_reviewers_v1.1.docx https://doi.org/10.1371/journal.pone.0267894.r002
19 Apr 2022 Decision Letter - Steven Eric Wolf, Editor Multi-center prospective population pharmacokinetic study and the performance of web-based individual dose optimization application of intravenous vancomycin for adults in Hong Kong: A study protocol PONE-D-21-24164R1 Dear Dr. Lam, 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, Steven Eric Wolf, MD Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions? The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field. Reviewer #1: Yes ******** 2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses? The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory. Reviewer #1: Yes ****** 3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable? Descriptions of methods and materials in the protocol should be reported in sufficient detail for another researcher to reproduce all experiments and analyses. The protocol should describe the appropriate controls, sample size calculations, and replication needed to ensure that the data are robust and reproducible. Reviewer #1: Yes ****** 4. Have the authors described where all data underlying the findings will be made available when the study is complete? The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. 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 ****** 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 ****** 6. Review Comments to the Author Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics. You may also provide optional suggestions and comments to authors that they might find helpful in planning their study. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: ****** 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 https://doi.org/10.1371/journal.pone.0267894.r003
Formally Accepted
25 Apr 2022 Acceptance Letter - Steven Eric Wolf, Editor PONE-D-21-24164R1 Multi-center prospective population pharmacokinetic study and the performance of web-based individual dose optimization application of intravenous vancomycin for adults in Hong Kong: A study protocol Dear Dr. Lam: 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. Steven Eric Wolf Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0267894.r004

Open letter on the publication of peer review reports

PLOS recognizes the benefits of transparency in the peer review process. Therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. Reviewers remain anonymous, unless they choose to reveal their names.

We encourage other journals to join us in this initiative. We hope that our action inspires the community, including researchers, research funders, and research institutions, to recognize the benefits of published peer review reports for all parts of the research system.

Learn more at ASAPbio .