Reduction strategies for inpatient oral third-generation cephalosporins at a cancer center: An interrupted time-series analysis

Naoya Itoh; Takanori Kawabata; Nana Akazawa; Daichi Kawamura; Hiromi Murakami; Yuichi Ishibana; Eiichi N. Kodama; Norio Ohmagari

doi:10.1371/journal.pone.0281518

Peer Review History

Original SubmissionSeptember 28, 2022
19 Dec 2022 Decision Letter - Iddya Karunasagar, Editor PONE-D-22-26924Reduction strategies for inpatient oral third-generation cephalosporins at a cancer center: an interrupted time-series analysisPLOS ONE Dear Dr. Itoh, 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. ==============================The language needs improvement. ============================== Please submit your revised manuscript by Feb 02 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. 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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: Dear authors, This is a good study about AMS outcomes especially in a setting where antimicrobial agents are often used out of fear to prevent and treat infections. It would be useful to reduce the number of times the phases of the study are repeated in the result section. ****** 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: Aruna Poojary ******** [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.0281518.r001
Revision 1
4 Jan 2023 Author Response Our point-by-point responses to the comments and suggestions by Reviewer 1 are listed below. We thank the reviewer for reviewing our manuscript and for the insightful comment that has helped us to significantly improve our manuscript. Although not an issue pointed out by the reviewer, we found an error in the description of the monthly DOT for macrolides in Phases 3 to 4 and revised the relevant passages, but it did not affect the main subject. Please note that our changes in the manuscript are highlighted in yellow. Comment: It would be useful to reduce the number of times the phases of the study are repeated in the result section. Response: We thank the reviewer for this comment. We removed statistically insignificant findings from the "results section" that duplicated those in the "figure legends" section as follows (Results, Page 10-20). There were no significant changes in trends and levels from Phases 2 to 3 or from Phases 3 to 4. (Page 10, Lines: 229–230) Each dot refers to the third-generation cephalosporins (3GCs) per 100 patients each month, and the slope is based on the linear regression in the four phases: Phase 1 (pre-intervention period from April 1, 2017, to May 31, 2019); Phase 2 (review of clinical pathways from June 1, 2019, to March 31, 2020); Phase 3 (establishing an infectious disease (ID) consultation service and implementing the antimicrobial stewardship program (ASP) from April 1, 2020, to June 30, 2021); Phase 4 (educational lecture and pop-up displays for oral antimicrobials from July 1, 2021, to March 31, 2022). (Fig 1, Page 11, Lines: 233–239) There were no significant changes in trends and levels for cephalexin from Phases 1 to 2 or from Phases 2 to 3. The trend in the monthly DOT of cephalexin did not change from Phases 3 to 4, but the level increased (coefficients: 0.42; 95% CI: 0.03 to 0.81, p = 0.04; Fig. 2). (Page 11, Lines: 243–246) There were no significant changes in the trend and level of the monthly DOT of amoxicillin and amoxicillin-clavulanate from Phases 1 to 2 (Fig. 3). The trend in the monthly DOT of amoxicillin and amoxicillin-clavulanate increased from Phases 2 to 3 (coefficients: 0.26; 95% CI: 0.07 to 0.45, p = 0.01) and decreased from Phases 3 to 4 (coefficients: -0.67; 95% CI: -0.89 to -0.45, p < 0.001), while the level did not change. (Page 11, Lines: 247–251) The trend and level of the monthly DOT of sulfamethoxazole-trimethoprim did not change significantly from Phases 1 to 2 or Phases 2 to 3 (Fig. 4). However, the trend in the monthly DOT of sulfamethoxazole-trimethoprim increased from Phases 3 to 4 (coefficients: 0.26; coefficient: 0.38; 95% CI: 0.07 to 0.70, p = 0.02), while the level did not change. (Page 11, Lines: 252–255) Each dot refers to cefalexin per 100 patients in each month, and the slope is based on the linear regression in the four phases: Phase 1 (pre-intervention period from April 1, 2017, to May 31, 2019); Phase 2 (review of clinical pathways from June 1, 2019, to March 31, 2020); Phase 3 (establishing an ID consultation service and implementing the ASP from April 1, 2020, to June 30, 2021); and Phase 4 (educational lecture and pop-up displays for oral antimicrobials from July 1, 2021, to March 31, 2022). (Fig 2, Page 12, Lines: 258–263) Each dot refers to the amoxicillin and amoxicillin-clavulanate per 100 patients each month, and the slope is based on the linear regression in the four phases: Phase 1 (pre-intervention period from April 1, 2017, to May 31, 2019); Phase 2 (review of clinical pathways from June 1, 2019, to March 31, 2020); Phase 3 (establishing an ID consultation service and implementing the ASP from April 1, 2020, to June 30, 2021); and Phase 4 (educational lecture and pop-up displays for oral antimicrobials from July 1, 2021, to March 31, 2022). (Fig 3, Page 12, Lines: 266–272) Each dot refers to the sulfamethoxazole-trimethoprim per 100 patients each month, and the slope is based on the linear regression in the four phases: Phase 1 (pre-intervention period from April 1, 2017, to May 31, 2019); Phase 2 (review of clinical pathways from June 1, 2019, to March 31, 2020); Phase 3 (establishing an ID consultation service and implementing the ASP from April 1, 2020, to June 30, 2021); and Phase 4 (educational lecture and pop-up displays for oral antimicrobials from July 1, 2021, to March 31, 2022). (Fig 4, Page 12, Lines: 275–281) The trend and level of the monthly DOT of all three quinolones (moxifloxacin, ciprofloxacin, and levofloxacin) did not change significantly during the study period (Fig. 5). (Page 13, Lines: 284–285) The trend in the monthly DOT of the three macrolides (erythromycin, azithromycin, and clarithromycin) decreased from Phases 1 to 2 (coefficients: -0.13; 95% CI: -0.22 to -0.04, p < 0.01), but the level did not change (Fig. 6). The trend in the monthly DOT of macrolides did not change from Phases 2 to 3 or from Phases 3 to 4, but the level decreased (coefficient: -0.96; 95% CI: -1.62 to -0.30, p < 0.01) and increased (coefficients: 0.92; 95% CI: 0.28 to 1.57, p < 0.01), respectively. (Page 13, Lines: 286–291) Each dot refers to the quinolones per 100 patients in each month, and the slope is based on the linear regression in the four phases: Phase 1 (pre-intervention period from April 1, 2017, to May 31, 2019); Phase 2 (review of clinical pathways from June 1, 2019, to March 31, 2020); Phase 3 (establishing an ID consultation service and implementing the ASP from April 1, 2020, to June 30, 2021); and Phase 4 (educational lecture and pop-up displays for oral antimicrobials from July 1, 2021, to March 31, 2022). (Fig 5, Page 13, Lines: 294–299) Each dot refers to the macrolides per 100 patients each month, and the slope is based on the linear regression in the four phases: Phase 1 (pre-intervention period from April 1, 2017, to May 31, 2019); Phase 2 (review of clinical pathways from June 1, 2019, to March 31, 2020); Phase 3 (establishing an ID consultation service and implementing the ASP from April 1, 2020, to June 30, 2021); and Phase 4 (educational lecture and pop-up displays for oral antimicrobials from July 1, 2021, to March 31, 2022). (Fig 6, Pages 13–14, Lines: 302–307) The trend and level of the monthly incidence of ESBL-producing Enterobacteriaceae, PRSP, resistant H. influenzae and CDI did not change significantly during the study period (Figs. 7–10). The trend in the monthly incidence of methicillin-resistant Staphylococcus aureus (MRSA) increased during the study period (coefficients: 0.05; 95% CI: 0.04 to 0.07, p < 0.001), but the level did not change (Fig. 11). (Page 14, Lines: 311–315) Each dot refers to ESBL-producing Enterobacteriaceae per 1000 patients in each month; the slope is based on linear regression in the four phases: Phase 1 (pre-intervention period from April 1, 2017, to May 31, 2019); Phase 2 (review of clinical pathways from June 1, 2019, to March 31, 2020); Phase 3 (establishing an infectious disease (ID) consultation service and implementing the antimicrobial stewardship program from April 1, 2020, to June 30, 2021); and Phase 4 (educational lecture and pop-up displays for oral antimicrobials from July 1, 2021, to March 31, 2022). (Fig 7, Page 14, Lines: 319–325) Each dot refers to the PRSP per 1000 patients in each month; the slope is based on linear regression in the four phases: Phase 1 (pre-intervention period from April 1, 2017, to May 31, 2019); Phase 2 (review of clinical pathways from June 1, 2019, to March 31, 2020); Phase 3 (establishing an infectious disease (ID) consultation service and implementing the antimicrobial stewardship program from April 1, 2020, to June 30, 2021); and Phase 4 (educational lecture and pop-up displays for oral antimicrobials from July 1, 2021, to March 31, 2022). (Fig 8, Pages 14–15, Lines: 329–335) Each dot refers to resistant H. influenzae per 1000 patients each month; the slope is based on linear regression in the four phases: Phase 1 (pre-intervention period from April 1, 2017, to May 31, 2019); Phase 2 (review of clinical pathways from June 1, 2019, to March 31, 2020); Phase 3 (establishing an infectious disease consultation service and implementing the antimicrobial stewardship program from April 1, 2020, to June 30, 2021); and Phase 4 (educational lecture and pop-up displays for oral antimicrobials from July 1, 2021, to March 31, 2022). (Fig 9, Page 15, Lines: 339–345) Each dot refers to the CDI per 1000 patients each month, and the slope is based on linear regression in the four phases: Phase 1 (pre-intervention period from April 1, 2017, to May 31, 2019); Phase 2 (review of clinical pathways from June 1, 2019, to March 31, 2020); Phase 3 (establishing an infectious disease (ID) consultation service and implementing the antimicrobial stewardship program from April 1, 2020, to June 30, 2021); and Phase 4 (educational lecture and pop-up displays for oral antimicrobials from July 1, 2021, to March 31, 2022). (Fig 10, Pages 15–16, Lines: 349–355) Each dot refers to MRSA per 1000 patients each month, and the slope is based on linear regression in the four phases: Phase 1 (pre-intervention period from April 1, 2017, to May 31, 2019); Phase 2 (review of clinical pathways from June 1, 2019, to March 31, 2020); Phase 3 (establishing an infectious disease (ID) consultation service and implementing the antimicrobial stewardship program from April 1, 2020, to June 30, 2021); and Phase 4 (educational lecture and pop-up displays for oral antimicrobials from July 1, 2021, to March 31, 2022). (Fig 11, Page 16, Lines: 359–365) The actual (Phase 1 to 2: p < 0.001; Phase 2 to 3: p < 0.01, Phase 3 to 4: p < 0.001) and adjusted 3GC purchase costs (Phase 1 to 2: p < 0.001; Phase 2 to 3: p < 0.01, Phase 3 to 4: p < 0.01) per patient-days significantly decreased during the study period. (Page 16, Lines: 369–371) There was no significant change in the trend of in-hospital mortality, length of hospital stay, or their level (Figs. 12 and 13). (Page 17, Lines: 392–393) Each dot refers to the in-hospital mortality each month, and the slope is based on the linear regression in the four phases: Phase 1 (pre-intervention period from April 1, 2017, to May 31, 2019); Phase 2 (review of clinical pathways from June 1, 2019, to March 31, 2020); Phase 3 (establishing an infectious disease (ID) consultation service and implementing the antimicrobial stewardship program from April 1, 2020, to June 30, 2021); and Phase 4 (educational lecture and pop-up displays for oral antimicrobials from July 1, 2021, to March 31, 2022). (Fig 12, Page 18, Lines: 396–402) Each dot refers to the length of hospital stay each month, and the slope is based on linear regression in the four phases: Phase 1 (pre-intervention period from April 1, 2017, to May 31, 2019); Phase 2 (review of clinical pathways from June 1, 2019, to March 31, 2020); Phase 3 (establishing an infectious disease (ID) consultation service and implementing the antimicrobial stewardship program from April 1, 2020, to June 30, 2021); and Phase 4 (educational lecture and pop-up displays for oral antimicrobials from July 1, 2021, to March 31, 2022). (Fig 13, Page 18, Lines: 405–411) https://doi.org/10.1371/journal.pone.0281518.r002
25 Jan 2023 Decision Letter - Iddya Karunasagar, Editor Reduction strategies for inpatient oral third-generation cephalosporins at a cancer center: an interrupted time-series analysis PONE-D-22-26924R1 Dear Dr. Itoh, 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, Iddya Karunasagar Academic Editor PLOS ONE Additional Editor Comments (optional): All reviewer comments have been addressed satisfactorily 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 ******** 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 ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: 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 ****** 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. 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: Dear Authors, Thank you for addressing the previous comments to this manuscript. It addresses a very important topic on antimicrobial stewardship . Best wishes ****** 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: Aruna Poojary ******** https://doi.org/10.1371/journal.pone.0281518.r003
Formally Accepted
31 Jan 2023 Acceptance Letter - Iddya Karunasagar, Editor PONE-D-22-26924R1 Reduction strategies for inpatient oral third-generation cephalosporins at a cancer center: an interrupted time-series analysis Dear Dr. Itoh: 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. Iddya Karunasagar Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0281518.r004

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