Multistep antimicrobial stewardship intervention on antibiotic prescriptions and treatment duration in children with pneumonia

Sara Rossin; Elisa Barbieri; Anna Cantarutti; Francesco Martinolli; Carlo Giaquinto; Liviana Da Dalt; Daniele Doná

doi:10.1371/journal.pone.0257993

Peer Review History

Original SubmissionJanuary 31, 2021
19 Mar 2021 Decision Letter - Iddya Karunasagar, Editor PONE-D-21-03385 Multistep antimicrobial stewardship intervention on antibiotic prescriptions and treatment duration in children with pneumonia PLOS ONE Dear Dr. Rossin, Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. Please revise considering reviewer comments point by point. Please submit your revised manuscript by May 03 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. 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Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. Additional Editor Comments: Reviewers have suggested a number of minor improvements in the manuscript. Please revise addressing these comments. [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 manuscript titled " Multi step antimicrobial stewardship intervention on antibiotic prescriptions and treatment duration in children with pneumonia The paper does look well into the problem and is well written. The following observations are in order that may require addressal 1. Materials and Methods ( ( Study population and Case definition) : There is no reference for the criteria that define CAP . 2. Data sources and outcomes : The line " The CP suggestedamoxicillin of ..... guidelines . There is no reference for standard guidelines used 3. Table 1: Percentages have been calculated for denominator s less than 20 ( ideally 30) and this may lead to spuriously higher percentages 4. Table - 2 : There are two categories mentioned against Beta lactams inhibitors , One is Co-amoxiclav . The second category of Beta lactams inhibitors does not state which inhibitors were used . This is not explained in the text as well and the same holds good for 4 5. If we compare the Table -1 and 3 , there is a category that alludes to those children who have not completed the immunisation plan. However the discussion section does not talk about the impact that this may have had on the development of CAP or the requirement of hospitalisation and the final outcome ( the LOT, LOS AND DOT ) in patients who either were sent home from the PED or were admitted to the hospital for CAP. . This needs some discussion 6. Table 2 & 4 The authors have not specified the generation of cephalosporins used for treating children with CAP in both the categories. This is important as it does have an impact on the management of CAP Vs HAP 7. Discussion : The second paragraph describes the mechanism of PRP as the reason for first line therapy empiric , and calls for Co- amoxiclav as the second choice. A S. pneumomiae isolate that develops penicillin resistance may not be well managed even with Amoxycillin clavulanic acid. Reviewer #2: Dear Authors The paper gives a clear picture of the impact of clinical pathway and AMS on treatment duration on a paediatric hospital. It is a good study that has been well described by the authors. I request the authors to explain the following 1. What were the cost implications of the use of procalcitonin in your set up? Especially in out-patient settings. What was the turnaround time for results in the out patient settings that influenced the decision of antimicrobial prescribing behavior? 2. In the methodology, each phase of the study was 6 months (October to April). But in 2019, the phase was split due to the new intervention being introduced. However, if we look at the out patient numbers in each year, there was a dip in 2015-2016 (88 vs an average of 148 patients) and during the time period of October 2019 to April 2020 ( though split as 2 phases), the total number that visited the OPD was 177( 43+134). Could the authors explain the increase or the decrease during these years? What was the incidence of Influenza those years? 3. What were the beta lactam, beta lactamase combinations or macrolides or glycopeptides or fluoroquinolones used? 4. The authors explain that the increase in the use broad spectrum antibiotics in the pre-2nd intervention stage is due to a reduced sample size. Could that also be the reason for the days of therapy and the length of therapy being increased in this period. ****** 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. https://doi.org/10.1371/journal.pone.0257993.r001
Revision 1
16 Jun 2021 Author Response Dear Editors, Dear Reviewers, We would like to thank you for the helpful comments and suggestions. We have included a translation of the CP since we believe some comments arose because CP figures were in Italian. We are resubmitting our manuscript after addressing point-by-point all the comments. Sincerely, Sara Rossin, on behalf of all the Authors Reviewer 1 The manuscript titled " Multi step antimicrobial stewardship intervention on antibiotic prescriptions and treatment duration in children with pneumonia. The paper does look well into the problem and is well written. The following observations are in order that may require addressal. 1. Materials and Methods ( Study population and Case definition) : There is no reference for the criteria that define CAP. We thank the reviewer for this comment. We have added the following reference used to define CAP criteria in the appropriate section. Bradley JS, Byington CL, Shah SS, Alverson B, Carter ER, Harrison C, et al. Pediatric Infectious Diseases Society and the Infectious Diseases Society of America: The Management of Community- Acquired Pneumonia in Infants and Children Older Than 3 Months of Age: Clinical Practice Guidelines by the Pediatric Infectious Diseases Society of America. Clin Infect Dis 2011; 53(7): e25–76 https://doi. org/10.1093/cid/cir531 PMID: 21880587 2. Data sources and outcomes : The line " The CP suggested amoxicillin of ..... guidelines . There is no reference for standard guidelines used. We thank the reviewer for this comment. We have added the following reference used to define the treatment for CAP in the CP. The 2019-CP the referred guidelines were the same as the 2015-CP since no update on the antibiotic treatment was published. Bradley JS, Byington CL, Shah SS, Alverson B, Carter ER, Harrison C, et al. Pediatric Infectious Diseases Society and the Infectious Diseases Society of America: The Management of Community- Acquired Pneumonia in Infants and Children Older Than 3 Months of Age: Clinical Practice Guidelines by the Pediatric Infectious Diseases Society of America. Clin Infect Dis 2011; 53(7): e25–76 https://doi. org/10.1093/cid/cir531 PMID: 21880587 3. Table 1: Percentages have been calculated for denominators less than 20 ( ideally 30) and this may lead to spuriously higher percentages Thank you for this comment, we agree with the reviewer. For this reason, we reported in the first line of table 1 the numbers of patients used as a denominator for each period. The limited number of patients in some periods was reported as a limitation in the discussion section. 4. Table - 2 : There are two categories mentioned against Beta lactams inhibitors , One is Co-amoxiclav . The second category of Beta lactams inhibitors does not state which inhibitors were used . This is not explained in the text as well and the same holds good for 4. We thank the reviewer for the comment. We have specified in Table 2, Table 4, and the manuscript the different molecules for each antibiotic category. 5. If we compare Table -1 and 3 , there is a category that alludes to those children who have not completed the immunisation plan. However the discussion section does not talk about the impact that this may have had on the development of CAP or the requirement of hospitalisation and the final outcome ( the LOT, LOS AND DOT ) in patients who either were sent home from the PED or were admitted to the hospital for CAP. This needs some discussion. We thank the reviewer for the suggestion. Children not vaccinated received broad-spectrum antibiotics in line with our CPs and the guidelines reported in the references. The population of children that were not fully vaccinated did not differ in the various periods. Moreover, the decision algorithm for hospitalization is not based on the immunization status but age (> or < 6 months) and the signs and symptoms. We think it could not be helpful to compare outcomes in outpatients with patients hospitalized for pneumonia since the CP is different. 6. Table 2 & 4 The authors have not specified the generation of cephalosporins used for treating children with CAP in both the categories. This is important as it does have an impact on the management of CAP Vs HA. We thank the reviewer for the comment. We acknowledge that different types of antibiotics are used in the management of HAP and CAP. The CP has been explicitly designed for community-acquired LRTI. Hence we did not include HAP episodes in the study. Furthermore, we have now specified in the text the class and the type of cephalosporines suggested by the CP and prescribed (III generation). 7. Discussion : The second paragraph describes the mechanism of PRP as the reason for first line therapy empiric , and calls for Co- amoxiclav as the second choice. A S. pneumomiae isolate that develops penicillin resistance may not be well managed even with Amoxycillin clavulanic acid. Thank you for this comment. In our Region, the rate of penicillin-resistant S . pneumoniae isolates in children is low compared to other Regions in Italy or other European countries. We agree with the reviewer that a penicillin-resistant S. pneumoniae is not well managed with co-amoxiclav, and we specified it in the discussion section. In our CP, the use of co-amoxiclav is recommended in not fully immunized patients (to cover H. Influenzae). While in the case of penicillin/amoxicillin treatment failure, ceftriaxone is the drug of choice. Reviewer #2: Dear Authors The paper gives a clear picture of the impact of clinical pathway and AMS on treatment duration on a paediatric hospital. It is a good study that has been well described by the authors. I request the authors to explain the following 1. What were the cost implications of the use of procalcitonin in your set up? Especially in out-patient settings. What was the turnaround time for results in the outpatient settings that influenced the decision of antimicrobial prescribing behavior? We thank the reviewer for the comment. The economic impact was not the study's goal, but it is the aim of another study currently underway. The turnaround time of PCT exams is the same as other tests usually performed in the ER. For this reason, this test could change prescribing behavior of physicians helping them distinguish possible bacterial infections in the same amount of time. 2. In the methodology, each phase of the study was 6 months (October to April). But in 2019, the phase was split due to the new intervention being introduced. However, if we look at the out patient numbers in each year, there was a dip in 2015-2016 (88 vs an average of 148 patients) and during the time period of October 2019 to April 2020 ( though split as 2 phases), the total number that visited the OPD was 177( 43+134). Could the authors explain the increase or the decrease during these years? What was the incidence of Influenza those years? Thank you for the comment. During the study period, the proportion of LRTI pediatric emergency department visits on overall PED visits was constant, with a peak between December and January of each study period (see Figure 1 below). PED Visits related to flu were higher between 2015-2020 compared to 2014-15, while monthly total PED visits were stable across all study periods. (see Figure 2 below). Please note that the data presented in the Figures below represent overall PED visits, and no exclusion was performed based on our study exclusion criteria. A possible explanation for the different sizes in outpatient numbers in 2015-2016 might be linked to the differences in eligibility criteria for CP use. In particular, the CP does not apply to children visited in the PED already taking an antibiotic treatment prescribed previously by their primary care pediatrician. We would like to highlight that all episodes with a descriptive diagnosis were independently assessed by two pediatricians (SR and FM). Any disagreement was resolved by discussion with a third infectious disease pediatrician (DD) as stated in the Methods part – Study population and case definition. Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0257993.r002
16 Sep 2021 Decision Letter - Iddya Karunasagar, Editor Multistep antimicrobial stewardship intervention on antibiotic prescriptions and treatment duration in children with pneumonia PONE-D-21-03385R1 Dear Dr. Rossin, 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 comments have been addressed. 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 #2: (No Response) ******** 2. Is the manuscript technically sound, and do the data support the conclusions? The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #2: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? 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 #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 #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 #2: Given the aims and objectives of the study the authors have sufficiently addressed all queries. The manuscript may be accepted ****** 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 #2: Yes:** Anusha Rohit https://doi.org/10.1371/journal.pone.0257993.r003
Formally Accepted
24 Sep 2021 Acceptance Letter - Iddya Karunasagar, Editor PONE-D-21-03385R1 Multistep antimicrobial stewardship intervention on antibiotic prescriptions and treatment duration in children with pneumonia Dear Dr. Rossin: 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.0257993.r004

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