Peer Review History
Original SubmissionJuly 16, 2020 |
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PONE-D-20-22107 Impact of initial vancomycin pharmacokinetic/pharmacodynamic parameters on the clinical and microbiological outcomes of Methicillin-resistant Staphylococcus aureusbacteremia in children PLOS ONE Dear Dr. Lee, 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. As you can see, both reviewers were positive about your study and made many constructive comments and recommendations. Please revise your manuscript by addressing their comments and suggestions. Please submit your revised manuscript by December 7, 2020. 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:
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 We look forward to receiving your revised manuscript. Kind regards, Taeok Bae 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 2. Thank you for providing the following ethics information in the methods section of your manuscript “This study was approved by the Institutional Review Board of Asan Medical Center with a waiver of informed consent due to the study being retrospective and using de-identified data collection and analysis (IRB No. 2019-1638)”. Please also provide this information in the ethics statement on the online submission form 3.Thank you for stating the following financial disclosure: [The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.]. At this time, please address the following queries:
Please include your amended statements within your cover letter; we will change the online submission form on your behalf. [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: 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: 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: Thank you for the opportunity to your manuscript. Line 48-49 - Reword to "Vancomycin is an important treatment option...", as saying it's "an important treatment of choice" implies there are multiple choices. Line 52 - Vancomycin is concentration dependent, not independent. Line 55 - This is true when MIC is 1 or less than 1 Line 61 - Ctrough is correlated if MIC is 1 or less but otherwise it is correlated. Trough of 15-20 will achieve AUC/MIC > 400 for S. aureus > 90% of the time if MIC is 1 or less. The problem is the "MIC creep" in which AUC/MIC > 400 is more difficult to achieve. I suggest reviewing Pai et al. Advanced Drug Delivery Reviews. 2014;77:55-57 and Alsutan et al. Peditr Infect Dis J. 2018;37:880-885. Line 106 - Why did you not define renal toxicity as also a need to adjust the vancomycin dose based on SCr? Or even a clinical definition of AKI? Would have been more useful to capture a more inclusive definition/data. Line 125 - Did you calculate power? It is unclear to me which outcome is your primary outcome. Line 176 - The phenomenon of "MIC creep" could have skewed your data. There is now a higher proportion of "susceptible" S. aureus isolates that have an MIC of 2 versus 0.5 or 1 and increased clinical failure. Line 179 - You mention the creep here; how are you defining it? 213 - Make sure you have %s in the parentheses where appropriate throughout the entire chart. Line 222 - Why did those whose vancomycin MIC was 1 or less have more persistent bacteremia? What confounders were at play? Dose differences? Line 226 - This is an important finding. I would recommend also stratifying by > 80 mg/kg, as doses this high would warrant a switch to a different antibiotic. I would also stratify AUC > 400 attainment by < 60, 60-80, and > 80 mg/kg/day. Line 273 - You reference a study showing AUC/MIC > 300 can be used as a marker of clinical efficacy, but the standard is > 400. A value of 300-400 would be subtherapeutic and even though you found an initial AUC/MIC > 300 is superior to < 300, you did not (as far as I can tell) address the role of the MIC. What is important is correlating AUC with MIC, dose, trough, and bacteremia clearance. Line 293 - Why would you have to draw and peak and trough 2 hours apart for this method? Line 297 - You mention there was no difference between MC Line 300 - You state there is no MIC creep; how are you defining this? 60% of patients with MIC 2 had persistent bacteremia. I would say that the fact that initial AUC > 400 was only achieved 33% of time could be due to MIC creep. It is a privilege to review this manuscript. Thank you. Reviewer #2: Yoo and colleagues have evaluated vancomycin PK/PD parameters in the treatment of pediatric MRSA bacteremia with regards to clinical and microbiological outcomes. In a retrospective single center cohort study over 8 years, they found that there was a weak relationship between trough concentration and AUC/MIC, and that initial AUC/MIC <300 was associated with persistent MRSA bacteremia at 48-72 hours. Despite the long study period, there were only 73 children in the final analysis and even fewer children who experienced the outcomes of interest. Given the dearth in PK/PD and clinical outcome data in pediatric S. aureus bacteremia, the authors are to be commended for their research, and show that the published AUC/MIC target of 400 for adults is also reasonable for children. Comments: Lines 72-73: The authors proposed to study Ctrough and AUC/MIC for optimal dosing to achieve favorable clinical and microbiological outcomes. However this really is a study of initial Ctrough or AUC/MIC, rather than a study of PK/PD parameters over time during a treatment course. It maybe that subsequent Ctrough or AUC/MIC are also important in outcomes, but this has not been evaluated. This should be highlighted in the introduction and in the discussion. Line 96: Vancomycin MIC was performed using MicroScan. The establishment of AUC/MIC targets were established using BMD, and there are known method-based differences that lead to differences in MIC results. Was there any consideration for performing BMD? Lines 108-109: The definition of renal toxicity included … “the need to replace vancomycin with an alternate antibiotic because of serum creatinine elevation”. Although no patients experienced renal toxicity, the latter definition is very vague. How much serum creatinine elevation was required to meet this definition? Did it differ between treating clinicians? This may underestimate the true incidence of renal toxicity. Line 114: One of the clinical outcomes was “recurrence of MRSA bacteremia”. The definition for this outcome does not appear until the footnote of Table 2. Suggest insert into the Methods section here. Lines 142-148, 164-170, 171-172: These paragraphs are simply repeating information that is found in Table 1. There is no need to repeat data in the text that are also found in the Table. Suggest re-work text/table so that there is no repetition of material. Lines 187-191: The authors have reported mean Ctrough and AUC/MIC values. Were these normally distributed? Looking at the mean and range distributions provided, I suspect the data are non-parametric, so median values might be better. Also, it is not clear that mean +/- SD are reported because SD has not been indicated in the text. Lines 271-280: The authors have referenced predominantly adult literature for PK/PD targets. The updated vancomycin consensus guideline has been released (Rybak Am J Health Syst Pharm 2020) and now includes pediatric sections. Suggest that this is included in discussion and references, rather than the superceded 2009 version. This updated guideline also recommends similar AUC/MIC targets to the adult population. Table 1: Please also include number of patients with 30-day mortality, not just percentage (to be consistent with formatting of the rest of the table). What was the rate of recurrent bacteremia? Table 2: Although it is not summarized elsewhere, the number of children with recurrent bacteremia was 14. From the denominator population of 62 children (presumably there were incomplete/missing data for the remaining 11 children), this is 23%. Additionally, there were 27 children with persistent bacteremia (37%). These are extraordinarily high rates of recurrent and persistent bacteremia. Do the authors have any explanation for these high rates? Table 3: Presentation of the adjusted multivariable model for persistent MRSAB and mortality should only include the final parsimonious model (ie. only variables with p<0.05). Note that the small numbers of children with these outcomes (27 for persistent SAB and 9 for mortality) makes multivariable analysis challenging due to the low event rate. This should be added to the discussion. Minor errors: Line 126: Fischer should be spelt Fisher Table 2: The numbers in each group of AUC/MIC category should also be presented (as has been done for Ctrough) The numbers in each group (persistent MRSAB, recurrent MRSAB, mortality) should be presented in the top columns. Figure 1: Both axes should have a unit of measurement presented. ********** 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: 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. |
Revision 1 |
PONE-D-20-22107R1 Impact of Initial Vancomycin Pharmacokinetic/Pharmacodynamic Parameters on the Clinical and Microbiological Outcomes of Methicillin-Resistant Staphylococcus aureus Bacteremia in Children PLOS ONE Dear Dr. Lee, 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. Since the raised points are mostly about formatting, your manuscript will proceed to the next step without further review if you address them sufficiently. Please submit your revised manuscript by Feb. 2, 2021. 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:
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 We look forward to receiving your revised manuscript. Kind regards, Taeok Bae 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 #1: All comments have been addressed 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: Thank you for addressing my comments. It is a pleasure to review your updated manuscript. 1. Abstract, line 32-33: Rephrase to make clear C trough was measured X times within the time period of Jan. 2010 to March 2018. 2. Abstract, line 36: Make clear that the 47.5% you are referring to is for mechanically ventilated patients (vs ICU admissions). Adding a comma after "intensive care unit stay" should help to clarify that. 3. Abstract, line 37 and 45: "mortality" used more commonly than "fatality" 4. Abstract, line 41, 44, 47: In general, I am noticing "hours" is abbreviated "hrs" or "hr". This should be consistent throughout; I would probably just keep the word spelled out as "hours" in your manuscript text. 5. Introduction, line 51: "major health concerns" is very broad/indirect. One of the major health concerns for what? Pediatrics? Hospitalized patients? 6. Introduction, line 56: cite 7. Introduction, line 58: You say "studies" but only give one citation 8. Discussion, page 20, line 4: "good relationship" should be changed to "positive correlation" or something else more objective. 9. Discussion, page 20, line 5: "good linear relationship" - same comment as above 10. Discussion, page 21, line 10: Please use quotations and define "MIC creep" when first introduced in your manuscript. 11. Discussion, page 21, line 11: Use >/= consistently vs switching to spelling out "greater than". Also, "MIC creep" is when MIC is > 1, not equal to or greater than 1, and still reported as susceptible. 12. Discussion, page 21, line 23-24: Rephrase; "could expose them to adverse effects such as nephrotoxicity or ototoxicity" or something similar that implies the potential only (and ototoxicity should be mentioned) Thank you for addressing my previous comments so thoroughly. I am grateful for the opportunity to review this manuscript again. Reviewer #2: I am satisfied that the authors have made revisions according to previous reviewer comments submitted. ********** 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 [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. |
Revision 2 |
Impact of Initial Vancomycin Pharmacokinetic/Pharmacodynamic Parameters on the Clinical and Microbiological Outcomes of Methicillin-Resistant Staphylococcus aureus Bacteremia in Children PONE-D-20-22107R2 Dear Dr. Lee, 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, Taeok Bae Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: |
Formally Accepted |
PONE-D-20-22107R2 Impact of Initial Vancomycin Pharmacokinetic/Pharmacodynamic Parameters on the Clinical and Microbiological Outcomes of Methicillin-Resistant Staphylococcus aureus Bacteremia in Children Dear Dr. Lee: 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. Taeok Bae Academic Editor PLOS ONE |
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