Improved penicillin susceptibility of Streptococcus pneumoniae and increased penicillin consumption in Japan, 2013–18

Shinya Tsuzuki; Takayuki Akiyama; Nobuaki Matsunaga; Koji Yahara; Keigo Shibayama; Motoyuki Sugai; Norio Ohmagari

doi:10.1371/journal.pone.0240655

Peer Review History

Original SubmissionJuly 26, 2020
21 Aug 2020 Decision Letter - Shampa Anupurba, Editor PONE-D-20-23245 Improved penicillin susceptibility of Streptococcus pneumoniae and increased penicillin consumption in Japan, 2013–18 PLOS ONE Dear Dr. Tsuzuki, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please submit your revised manuscript by Oct 05 2020 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. 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Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: [The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.] 3.We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. In your revised cover letter, please address the following prompts: a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). 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If your ethics statement is written in any section besides the Methods, please move it to the Methods section and delete it from any other section. Please also ensure that your ethics statement is included in your manuscript, as the ethics section of your online submission will not be published alongside your manuscript. [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: The authors have carried out an important data analysis to reflect on the Penicillin susceptibility of Streptococcus pneumoniae and to show its relationship with consumption . They have collated data from JANIS , collected from 2000 healthcare setups. Appropriate statistical tools have been applied to show the changing outcomes . The diagrammatic representations would of the useful if appropriate legends as and explanatory statements had been placed for the table. Few queries that and be addressed by the authors : Whether the changes across the years were significantly different for Penicillin? Why did the antibiotic consumption come down across the spectrum? Was any regulatory mechanism influence the decrease? It is interesting to note that as consumption went up the resistance came down, contrary to existing belief. This calls for further look at genetic mechanism and factors influencing Reviewer #2: The manuscript conveys an important message that, used appropriately, penicillin consumption may not be necessarily associated with increased resistance of Streptococcus pneumoniae to penicillin, by analyzing penicillin consumption data with penicillin susceptibility data over 5 years. They also addressed the relative suitability of various MIC breakpoints for such surveillance. It is well written. The figures have an orientation problem, particularly for the text, are difficult to interpret and needs attention. Though the study has been based on MIC, it only presents categorical interpretation (susceptible or resistant) of Streptococcus pneumoniae and doesn't mention the actual MICs of the isolates anywhere. A scatter diagram showing the exact MICs of isolates over time is desirable and will enhance understanding. ****** 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: Reba Kanungo Reviewer #2: Yes:** Dr Pallab Ray 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.0240655.r001
Revision 1
21 Sep 2020 Author Response 18th September 2020 Shampa Anupurba, Academic Editor, PLOS ONE Dear Dr Anupurba, Thank you very much for the comments regarding the manuscript we submitted, entitled “Improved penicillin susceptibility of Streptococcus pneumoniae and increased penicillin consumption in Japan, 2013–18” (ONE-D-20-23245), and for the opportunity to revise the paper. The reviewers’ and your feedback were great help in highlighting ways to improve our manuscript. Attached you will find a revised version of the manuscript with track changes, a cleaned version of the revision. Following this letter are reviewers’ comments with our responses in blue italics. We believe that the paper improved significantly, and we hope that you agree. Once again, thank you for the helpful feedback. Sincerely, Shinya Tsuzuki, MD, MSc AMR Clinical Reference Center, National Center for Global Health and Medicine stsuzuki@hosp.ncgm.go.jp ONE-D-20-23245 Improved penicillin susceptibility of Streptococcus pneumoniae and increased penicillin consumption in Japan, 2013–18 PLOS ONE Journal Requirements: When submitting your revision, we need you to address these additional requirements. 2.Thank you for stating the following in the Funding Section of your manuscript: [This study was funded by a grant 256 from the Ministry of Health, Labour and Welfare (Grant number H29 shinkougyousei shitei 005) and Research Program on Emerging and Re-emerging Infectious Diseases from the Japan Agency for Medical Research and Development (AMED) under grant number JP19fk0108061.] We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form. Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows: [The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.] We removed this sentence. Our study was supported by a grant from the Ministry of Health, Labour and Welfare (Grant number 20HA2003, changed from the previous one) and Research Program on Emerging and Re-emerging Infectious Diseases from the Japan Agency for Medical Research and Development (AMED) under grant number JP19fk0108061.]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No author received a salary from the funders. 3.We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. In your revised cover letter, please address the following prompts: a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. We will update your Data Availability statement on your behalf to reflect the information you provide. Thank you for your suggestion. We uploaded the data we used in the present study. 4. Your ethics statement must appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please move it to the Methods section and delete it from any other section. Please also ensure that your ethics statement is included in your manuscript, as the ethics section of your online submission will not be published alongside your manuscript. Ethical approval is stated in “Data Source” subsection in “Materials and Methods” section. Reviewer #1: The authors have carried out an important data analysis to reflect on the Penicillin susceptibility of Streptococcus pneumoniae and to show its relationship with consumption. They have collated data from JANIS, collected from 2000 healthcare setups. Appropriate statistical tools have been applied to show the changing outcomes. The diagrammatic representations would of the useful if appropriate legends as and explanatory statements had been placed for the table. Thank you very much for your comment. We updated Figure 3 and 5 as an explanatory diagram for the contents of Table 1 and 2. We also made Figure 4 according to another reviewer’s suggestion, then original Figure 3, 4, and 5 were renamed as Figure 6, 7, and 8. In addition, we modified the title and the legend of Table 3 to help readers’ understanding. We added the duration of the study (2013-2018) to the original title and a footnote about MICs used (isolates whose MICs ≤0.06 mg/L were classified as “susceptible”, i.e. we used “Meinigitis MIC” in Table 3). Few queries that and be addressed by the authors: Whether the changes across the years were significantly different for Penicillin? Thank you for your question. When we conducted a linear regression analysis after decomposing seasonality influence, sales data of penicillins showed significant increase trend (p < 0.001). In contrast, total sales of antibiotics and cephalosporin showed decrease trend (p < 0.001). Why did the antibiotic consumption come down across the spectrum? Thank you for giving us an opportunity to explain this issue. These questions stated above can be explained by not only National Action Plan of our country (reference [11] and please also refer to our “Introduction” section) but also other countermeasures before publication of National Action Plan. Abuse of unnecessary antibiotics has been an important health issue in Japan, then various interventions have been implemented in Japanese healthcare system. For example, Ministry of Health, Labour and Welfare Japan became to provide incentives to healthcare facilities which implemented infection control team and other interventions in 2012. Although publication of National Action Plan was 2016, such interventions were considered to have influence on antimicrobial consumption across the spectrum at national level. As for penicillin consumption, it can be considered as a result of promoting appropriate antibiotic use because the use of cephalosporin and other classes of antibiotic consumption in Japan was higher than that in other countries. When we reduced inappropriate cephalosporin and other classes of antibiotic consumption, a part of it should be replaced by penicillin. These explanations are also added in “Discussion” section in the revised manuscript. Was any regulatory mechanism influence the decrease? As explained in our answer to the previous question, our National Action Plan might be considered as one of important regulatory factor. In addition, we have implemented several interventions before publication of National Action Plan such as incentive provision for appropriate antibiotic use. It is interesting to note that as consumption went up the resistance came down, contrary to existing belief. This calls for further look at genetic mechanism and factors influencing We appreciate your insightful comment. As stated in “Discussion” section, it is one of limitations that we did not include factors other than antibiotics sales data. Then we explicitly discussed in the main text that we did not take genetic mechanisms into consideration, and further research about mechanisms between penicillin susceptibility and its consumption will be a future challenge. One of reasonable hypotheses is that, deeply related to our previous answer, reduction in other classes of antibiotics had positively influenced on penicillin susceptibility of S. pneumoniae. Especially, since cephalosporins are another class of beta-lactams, then consumption reduction in this class might do good to penicillin susceptibility. It is possible that even in case the increase of penicillin consumption negatively influences the susceptibility of S. pneumoniae, its influence might be cancelled by positive influence of consumption reduction of other classes. We also explained this hypothesis in “Discussion” section in the revised manuscript. Reviewer #2: The manuscript conveys an important message that, used appropriately, penicillin consumption may not be necessarily associated with increased resistance of Streptococcus pneumoniae to penicillin, by analyzing penicillin consumption data with penicillin susceptibility data over 5 years. They also addressed the relative suitability of various MIC breakpoints for such surveillance. It is well written. The figures have an orientation problem, particularly for the text, are difficult to interpret and needs attention. Though the study has been based on MIC, it only presents categorical interpretation (susceptible or resistant) of Streptococcus pneumoniae and doesn't mention the actual MICs of the isolates anywhere. A scatter diagram showing the exact MICs of isolates over time is desirable and will enhance understanding. Thank you very much for your constructive suggestion. We made a new cumulative bar chart as you can see the actual distribution of MICs of the isolates (Figure 4). We did not make a scatter diagram but a cumulative bar chart, because MICs take discrete values (e.g. 0.06, 0.12, 0.25, and so forth) then if we try to “scatter” them, they do not seem as a scattered plot. We believe that the bar chart makes it clear that the proportion of isolates whose MICs are ≤0.06 mg/L (“Susceptible”) has been increased gradually and isolates whose MICs are higher than 2 mg/L has not changed drastically, and it will help readers’ understanding. We also updated Figure 3 and 5 according to another reviewer’s suggestion, they explained the contents of Table 1 and 2 diagrammatically. Consequently, original Figure 3, 4, and 5 were renamed as Figure 6, 7, and 8. https://doi.org/10.1371/journal.pone.0240655.r002
1 Oct 2020 Decision Letter - Shampa Anupurba, Editor Improved penicillin susceptibility of Streptococcus pneumoniae and increased penicillin consumption in Japan, 2013–18 PONE-D-20-23245R1 Dear Dr. Tsuzuki, 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, Shampa Anupurba, MD Academic Editor PLOS ONE 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: The authors have explained and clarified the reviewers comments satisfactorily. The manuscript can now be accpted for publication. Reviewer #2: The reviewer's comments have been adequately addressed to satisfaction and the manuscript is acceptable for publication. ****** 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: Yes: Reba Kanungo Reviewer #2: Yes:** Dr Pallab Ray https://doi.org/10.1371/journal.pone.0240655.r003
Formally Accepted
9 Oct 2020 Acceptance Letter - Shampa Anupurba, Editor PONE-D-20-23245R1 Improved penicillin susceptibility of Streptococcus pneumoniae and increased penicillin consumption in Japan, 2013–18 Dear Dr. Tsuzuki: 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. Shampa Anupurba Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0240655.r004

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