Laboratory-based versus population-based surveillance of antimicrobial resistance to inform empirical treatment for suspected urinary tract infection in Indonesia

Adhi Kristianto Sugianli; Franciscus Ginting; R. Lia Kusumawati; Ida Parwati; Menno D. de Jong; Frank van Leth; Constance Schultsz

doi:10.1371/journal.pone.0230489

Peer Review History

Original SubmissionJuly 12, 2019
12 Nov 2019 Decision Letter - Iratxe Puebla, Editor PONE-D-19-19644 Laboratory-based versus population-based surveillance of antimicrobial resistance to inform empirical treatment for suspected urinary tract infection in Indonesia PLOS ONE Dear Prof. Schultsz, 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 manuscript has been assessed by two reviewers; their comments are available below. The reviewers find the work of relevance but have raised some comments that need attention in a revision. The reviewers recommend that the relationship to the study reported in your earlier publication in J Antimicrob Chemother. 2017;72: 1469–77 is described in greater detail and in particular, that you clarify any overlap in sample populations between the two studies. The reviewers recommend that the analysis of additional pathogens is included, or if that is not possible, that this is clearly acknowledged as a limitation. Could you please revise the manuscript to carefully address the concerns raised by the reviewers? We would appreciate receiving your revised manuscript by Dec 26 2019 11:59PM. When you are 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. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. To enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'. Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out. We look forward to receiving your revised manuscript. Kind regards, Iratxe Puebla Senior Managing Editor, PLOS ONE Journal Requirements: 1. When submitting your revision, we need you to address these additional requirements. 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 http://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf [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: Overview: The study assessed the difference in antibiotic resistance between laboratory based surveillance and population based surveillance in uropathogens in Indonesia. They focused the microbiology work on Escherichia coli and Klebsiella pneumoniae as these are the main burden of UTIs. The population based surveillance involved collection through a cross sectional survey from people with symptoms corresponding to UTI attending clinics and hospitals as outpatients. Data was collected between the 1st of April 2014 and the 31st of May 2015. Some of the main results were that there was a higher prevalence of resistance to Piperacillin-tazobactam (63.1%) and ceftriaxone (85.2%) in the laboratory based surveillance strains compared to the population based surveillance at 41.3% and 74.2% respectively. Overall comments: This is a very relevant study which addresses many questions being raised at the moment to understand the bias of results reported in hospital microbiology laboratories. A community based study such as this will help to solve many questions on bias for antibiotic resistance. Specific queries: • Although I note this study was previously published and referenced in the current publication [1], I believe there needs to be more description about the study subjects. In particular I would like to understand how the researchers were able to determine the patients who were in patients in the population based study. Particularly as the major difference between the laboratory and population based studies occurred in the outpatients when the population based inpatients were removed. Further explanation about this is necessary in the text. • Please further explain the following sentence in your discussion: “A reduction in resistance was observed when only clinically relevant culture results were reported in the laboratory”, what does this mean? • It would be useful to have a map of the area depicting where the hospital is based and where the population based work took place • What is the age and gender distribution of your patients? Could there be a difference in your results due to either of these variables? • The major difference seems to be between outpatient samples and whether the results are derived from the laboratory or the population based work, although numbers of strains are low in these groups for Klebsiella pneumoniae at 33 and 40 strains respectively). I would like to see more discussion on your thoughts as to why this is the case. • Is there a difference in prescribing of antibiotics in those patients who are included in the population based study compared to the laboratory results, might this impact on the results that you have reported? Reference 1. Sugianli, A.K., et al., Antimicrobial resistance in uropathogens and appropriateness of empirical treatment: a population-based surveillance study in Indonesia. J Antimicrob Chemother, 2017. 72(5): p. 1469-1477. Reviewer #2: The authors have assessed laboratory-based surveillance versus population-based surveillance for studying the prevalence of antimicrobial resistance in UTI in Indonesia. The data presented is sound and the methodology as well as the analysis are supporting the outcome of this paper. I have a few minor suggestions that may improve the paper further: MINOR: - In the background, the authors address the bias in the selection process that may occur in laboratory based surveillance. I would suggest adding some clarification on the reasoning behind this bias. - Is the population-based surveillance data presented in this manuscript exactly as the same data that was previously published in J Antimicrob Chemother. 2017;72: 1469–77? If so, I would suggest including a clarification to further highlight this point. I also would like to encourage the authors to visit the permission requirements of JAC to make sure that the reuse of the published data is in alignment with the journal's policy. This can be found in https://academic.oup.com/jac/pages/General_Instructions#Permissions MAJOR: - The authors have clearly addressed the possible bias that may occur from laboratory-based surveillance, alongside the selection bias on E. coli and K. pneumoniae to represent uropathogens, as suggested by GLASS. When conducting this study, the authors have decided to apply to same bias and only select for E. coli and K. pneumoniae in the population based study. Is it possible to include the analysis of the other pathogens isolated in the results? If not possible, I think it would be important to address this limitation and highlight the need to test the value of population-based surveillance on a wider range of uropathogens. ****** 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: Catrin E Moore Reviewer #2: Yes: Hosam Zowawi [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 to be viewed.] 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 us at figures@plos.org. Please note that Supporting Information files do not need this step. https://doi.org/10.1371/journal.pone.0230489.r001
Revision 1
9 Jan 2020 Author Response Reviewer #1: Overview: The study assessed the difference in antibiotic resistance between laboratory based surveillance and population based surveillance in uropathogens in Indonesia. They focused the microbiology work on Escherichia coli and Klebsiella pneumoniae as these are the main burden of UTIs. The population based surveillance involved collection through a cross sectional survey from people with symptoms corresponding to UTI attending clinics and hospitals as outpatients. Data was collected between the 1st of April 2014 and the 31st of May 2015. Some of the main results were that there was a higher prevalence of resistance to Piperacillin-tazobactam (63.1%) and ceftriaxone (85.2%) in the laboratory based surveillance strains compared to the population based surveillance at 41.3% and 74.2% respectively. Overall comments: This is a very relevant study which addresses many questions being raised at the moment to understand the bias of results reported in hospital microbiology laboratories. A community based study such as this will help to solve many questions on bias for antibiotic resistance. We thank the reviewer for the positive comments. Specific queries: • Although I note this study was previously published and referenced in the current publication [1], I believe there needs to be more description about the study subjects. In particular I would like to understand how the researchers were able to determine the patients who were in patients in the population based study. Particularly as the major difference between the laboratory and population based studies occurred in the outpatients when the population based inpatients were removed. Further explanation about this is necessary in the text. We have described the inclusion of inpatients in the Methods section: “Population-based AMR surveillance data were collected in a cross-sectional survey of AMR in E. coli and K. pneumoniae isolated from urine samples from patients suspected of a UTI, carried out from 1 April 2014 until 31 May 2015, as described previously. In brief, consecutive patients attending four public and private outpatient clinics of urology and obstetrics/gynaecology, or who were admitted to the internal medicine-, surgery-, obstetrics/gynaecology-, or neurology wards, were actively screened for the presence of symptoms of UTI, according to CDC definitions.” In other words, the population of inpatients included in the population-based study consisted of those who were admitted to the internal medicine-, surgery-, obstetrics/gynaecology-, or neurology wards at the time of sampling and had symptoms of UTI. Admitted patients were screened on a daily basis for these symptoms. We have added more details regarding the inclusion procedure of inpatients to the Methods section. • Please further explain the following sentence in your discussion: “A reduction in resistance was observed when only clinically relevant culture results were reported in the laboratory”, what does this mean? We are not clear which sentence the reviewer is referring to. The sentence the reviewer is quoting is not in our manuscript. • It would be useful to have a map of the area depicting where the hospital is based and where the population based work took place All study sites are in the city of Medan. The Adam Malik hospital is a tertiary referral hospital which services the city of Medan as well as the provinces North Sumatera, Aceh, West Sumatera and Riau on the island of Sumatra. We have provided this information which we believe is more helpful than a city map of Medan. • What is the age and gender distribution of your patients? Could there be a difference in your results due to either of these variables? Data on gender and age distribution were not available for the laboratory-based surveillance. However, out of 860 samples, 36 (4%) were from paediatric departments. Only adult patients (≥ 18 years) were included in the population-based surveillance. Taken together, the difference in gross age distribution (paediatric vs adult) is unlikely to explain the differences between laboratory-based and population-based surveillance. We have added this information to the Discussion. • The major difference seems to be between outpatient samples and whether the results are derived from the laboratory or the population based work, although numbers of strains are low in these groups for Klebsiella pneumoniae at 33 and 40 strains respectively). I would like to see more discussion on your thoughts as to why this is the case. As indicated in the Discussion, the major difference in AMR estimates between the two surveillance approaches is explained by the fact that in laboratory-based surveillance prevalence estimates for outpatients are markedly higher than estimates in the population-based surveillance. We have elaborated on the potential causes of this difference in the Discussion and consider sampling bias in the laboratory-based surveillance (clinician’s decision to submit a sample to the laboratory vs systematic inclusion), laboratory practice (definition of a positive culture), as well as differences in age distribution (see comment above). We focused our analysis on E. coli and K. pneumoniae since these are the most common pathogens in UTI and since these are the priority pathogens for surveillance as recommended by WHO-GLASS. We analysed these two pathogens together and did not perform a separate analysis for the K. pneumoniae isolates since this is compatible with clinical practice where during prescription of empirical therapy the causative pathogen is unknown but likely to be E. coli and/or K. pneumoniae. We have modified the Discussion to include the latter consideration. • Is there a difference in prescribing of antibiotics in those patients who are included in the population based study compared to the laboratory results, might this impact on the results that you have reported? The primary objective of our study was to assess the difference in AMR prevalence estimates between laboratory-based and population-based surveillance. We did not specifically focus on the antibiotic pre-treatment or prescriptions. Indeed, differences in antibiotic pre-treatment may explain some of the bias which we observe in laboratory-based surveillance because patients for whom samples have been submitted may have been pre-treated more frequently. We have added this to the description of the bias in laboratory-based surveillance in the Discussion. Reviewer #2: The authors have assessed laboratory-based surveillance versus population-based surveillance for studying the prevalence of antimicrobial resistance in UTI in Indonesia. The data presented is sound and the methodology as well as the analysis are supporting the outcome of this paper. I have a few minor suggestions that may improve the paper further: We thank the reviewer for the positive comments. MINOR: - In the background, the authors address the bias in the selection process that may occur in laboratory based surveillance. I would suggest adding some clarification on the reasoning behind this bias. We added some examples of potential bias in laboratory-based surveillance to clarify. - Is the population-based surveillance data presented in this manuscript exactly as the same data that was previously published in J Antimicrob Chemother. 2017;72: 1469–77? If so, I would suggest including a clarification to further highlight this point. I also would like to encourage the authors to visit the permission requirements of JAC to make sure that the reuse of the published data is in alignment with the journal's policy. This can be found in https://academic.oup.com/jac/pages/General_Instructions#Permissions The data are not exactly the same; we used a limited data set, i.e. only one of two study areas from our previous study that matched with the laboratory-based surveillance data which we added to this study. We checked the JAC requirements. MAJOR: - The authors have clearly addressed the possible bias that may occur from laboratory-based surveillance, alongside the selection bias on E. coli and K. pneumoniae to represent uropathogens, as suggested by GLASS. When conducting this study, the authors have decided to apply to same bias and only select for E. coli and K. pneumoniae in the population based study. Is it possible to include the analysis of the other pathogens isolated in the results? If not possible, I think it would be important to address this limitation and highlight the need to test the value of population-based surveillance on a wider range of uropathogens. We focused our analysis on E. coli and K. pneumoniae since these are the most common pathogens in UTI and since these are the priority pathogens for surveillance as recommended by WHO-GLASS. We therefore do not consider our focus as a limitation of the study. We don’t have additional information for other pathogens isolated for the population-based surveillance. However, we agree that for inpatients in particular, surveillance of other pathogens may be helpful. We added this to the Discussion. Authors’ note added to the review: - We have corrected the denominators in S4-6 Tables and S2 Figure. These corrections do not affect the results. - We have added the URL at which the study data and associated code book can be accessed. https://doi.org/10.1371/journal.pone.0230489.r002
3 Mar 2020 Decision Letter - Davida S. Smyth, Editor Laboratory-based versus population-based surveillance of antimicrobial resistance to inform empirical treatment for suspected urinary tract infection in Indonesia PONE-D-19-19644R1 Dear Dr. Schultsz, We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements. Within one week, you will receive an e-mail containing information on the amendments required prior to publication. When all required modifications have been addressed, you will receive a formal acceptance letter and your manuscript will proceed to our production department and be scheduled for publication. Shortly after the formal acceptance letter is sent, an invoice for payment will follow. To ensure an efficient production and billing process, please log into Editorial Manager at https://www.editorialmanager.com/pone/, click the "Update My Information" link at the top of the page, and update your user information. 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 enable them to help maximize its impact. If they will be preparing press materials for this manuscript, you must inform our press team as soon as possible and 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. With kind regards, Davida S. Smyth, Ph.D. Academic Editor PLOS ONE Additional Editor Comments (optional): 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: The authors have addressed my comments adequately, I have no additional comments on the new manuscript. ****** 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: Dr Catrin Moore https://doi.org/10.1371/journal.pone.0230489.r003
Formally Accepted
13 Mar 2020 Acceptance Letter - Davida S. Smyth, Editor PONE-D-19-19644R1 Laboratory-based versus population-based surveillance of antimicrobial resistance to inform empirical treatment for suspected urinary tract infection in Indonesia Dear Dr. Schultsz: I am 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 notify them about your upcoming paper at this point, to enable them to help maximize its impact. If they will be preparing press materials for this manuscript, 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. For any other questions or concerns, please email plosone@plos.org. Thank you for submitting your work to PLOS ONE. With kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Davida S. Smyth Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0230489.r004

Open letter on the publication of peer review reports

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

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

Learn more at ASAPbio .