Polymicrobial bloodstream infections a risk factor for mortality in neonates at the national hospital, Tanzania: A case-control study

Joel Manyahi; Agricola Joachim; Frank Msafiri; Mary Migiro; Anthon Mwingwa; Mabula Kasubi; Helga Naburi; Mtebe Venance Majigo

doi:10.1371/journal.pone.0302076

Peer Review History

Original SubmissionSeptember 13, 2023
23 Oct 2023 Decision Letter - Iddya Karunasagar, Editor PONE-D-23-28734Polymicrobial bloodstream infections a risk factor for mortality at the national hospital, Tanzania: A case-control studyPLOS ONE Dear Dr. Manyahi, 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 address all points raised by the reviewers and comments made directly on the manuscript. ============================== Please submit your revised manuscript by Dec 07 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. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file. Please include the following items when submitting your revised manuscript: A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. 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We will update your Data Availability statement to reflect the information you provide in your cover letter. 3. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide. Additional Editor Comments: Both reviewers have raised a number of points in data analysis and presentation that needs improvement. Please address all comments point by point. [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: Partly Reviewer #2: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: No ****** 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: No Reviewer #2: No ****** 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 evidence for poly-microbial BSI is not very clear just isolation of two or more bacteria from blood culture does not substantiate the the poly-microbial BSI. Line 164 and 165 Acinetobacter and CONS, Pseudomonas and S.aureus in these combinations CONS and S.aureus could be skin contaminants in which case BSI is mono-microbial only. Therefore selection criteria of poly-microbial BSI cases to be clearly defined in which clinical conditions or comorbidities poly-microbial BSI is a possibility only such case to be selected. Line 166 and 167 Acinetobacter 15% (15/150) calculation error. While mentioning the antibiotic resistance consider the antibiotics used for blood stream infections not clindmycin, cotrimoxazole and chloramphenicol for S.aureus. Which are the disease comorbidities were considered for statistical analysis because these disease comorbidities will play very significant role in hospital mortality and 30 day mortality in patients with BSI besides the antimicrobial resistance. Reviewer #2: The paper made an interesting reading, dealing with polymicrobial infections Vs Monomicrbial Infections , the microbiological and clinical impact of these with respect to 30 day mortality and the extended hospital stay etc. Comments for the same are attached , the authors are advised to kindly refer to the same and address all the points mentioned ****** 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. Attachments Attachment Submitted filename: reviewof Plos one artice.docx https://doi.org/10.1371/journal.pone.0302076.r001
Revision 1
8 Dec 2023 Author Response Reviewer #1: The evidence for polymicrobial BSI is not very clear just isolation of two or more bacteria from blood culture does not substantiate the polymicrobial BSI. Comment: Line 164 and 165 Acinetobacter and CONS, Pseudomonas and S.aureus in these combinations CONS and S.aureus could be skin contaminants in which case BSI is mono-microbial only. Therefore, selection criteria of polymicrobial BSI cases to be clearly defined in which clinical conditions or comorbidities polymicrobial BSI is a possibility only such case to be selected. Response: Thank you for the comment. Our laboratory SoP for a blood culture states very clearly when to consider CoNS, and other possible skin contaminants as true pathogens, and we strictly adhered to the laboratory SoP in defining pathogens. S. aureus in blood culture is always considered a pathogen in our interpretation of the blood culture positive Comment: Line 166 and 167 Acinetobacter 15% (15/150) calculation error. Response: We appreciate for the comment, we have addressed calculation error Comment: While mentioning the antibiotic resistance consider the antibiotics used for blood stream infections not clindamycin, cotrimoxazole and chloramphenicol for S. aureus. Response: We appreciate for the comment. However, our results show the susceptibility pattern based on laboratory testing and not based treatment of S. aureus blood stream infections. In reporting AST results to clinician, our laboratory considers both bacteria and site of infections. Comment: Which are the disease comorbidities were considered for statistical analysis because these disease comorbidities will play very significant role in hospital mortality and 30-day mortality in patients with BSI besides the antimicrobial resistance. Response: Unfortunately, clinical conditions were so diverse, and a breakdown presentation was difficulties. Therefore, in our analysis we categorized either presence of comorbidity or not. Reviewer #2: The paper made an interesting reading, dealing with polymicrobial infections Vs Monomicrobial Infections , the microbiological and clinical impact of these with respect to 30 day mortality and the extended hospital stay etc. Comments for the same are attached , the authors are advised to kindly refer to the same and address all the points mentioned The paper deals with the differences (Both Microbiological yield and clinical outcomes) in patients with Polymicrobial and Monomicrobial Bacteremia Infections; The Following observations are in order and must be addressed before the manuscript can be taken forward Comment: The title of the paper does not reveal that the major component of the study is in children, adolescents, neonates, infants or adults. However, the Table No 4 & 5 refer to clinical outcomes in neonates only. Response: Thank you for the comment. We agree that the title does not mention the major components of the participants. Our study aimed at creating awareness of the negative effects of polymicrobial bloodstreams on patient care for both laboratory personnel and clinicians. Being a lab-based retrospective, we therefore enrolled all patients with polymicrobial bloodstreams matching their counterparts by age, date of admission, and admitting wards. However, because we had a significant number of participants who were neonates, we decided to perform a sub-analysis for neonates only, as appears in Tables 4 and 5. On the other hand, we have done sub-analysis in none neonates, Therefore, we have modified the title to show the component affected. Comment: Moreover, the Table – 1 which deals with age and sex distribution does not give a breakdown of the age groups and refers to a median age alone. Response: Thank you for the comment. Our study design was a case control, which was matched by age; therefore, we found most participants were populated in the same age category. However, we have added age breakdown in table1 Comment: The discussion section refers to certain observations which have been compared with other studies and these deal with outcomes in neonates only. Response: We appreciate for the comment, we have improved our citation and omitted references which do not match with our study population Comment: In the section “Materials and Methods “ “study setting and design ‘ the authors have stated that results are obtained in age groups from 1-86 years and of these 50 patients were selected and 150 controls. What was the age distribution taken into consideration when this selection was made. The clinical outcomes may be different in different age groups with polymicrobial bacteremia. Response: We appreciate for the good comment, in this study we included all age groups from 0-86. Understanding the age have influence on the clinical outcome, first we adjusted for age in multivariable analysis. Then we did stratification analysis for neonate only and non-neonate. Having this analysis, we are assured we have controlled the age a possible confounder influencing our outcome of interest. Comment: The authors have stated a definition for Polymicrobial infections in the section “Definition of terms”. However, the term polymicrobial need not be restricted to 2 organisms as there are instances of blood stream infections caused by more than 2 organisms, including a yeast. How has the selection for polymicrobial infections data been made. Moreover the Results section talks of common organisms as Nos/ 100 which means that the authors have considered only 2 organisms per blood culture in a patient (total no of patients being 50). Response: Thank you for this observation. We completely agree polymicrobial infections can be caused by two or more bacteria. Unfortunate, during the review of the laboratory data, we did not come to an instance of having more than two pathogens. Furthermore, we had one case of polymicrobial bloodstream infections involving bacteria and candida species. Comment: The clinical outcomes for blood stream infections in conditions such as Perforation peritonitis, Carcinoma colon etc may depend on the nos of organisms causing the Polymicrobial Infection. Has this been taken into account. There is no mention anywhere in the manuscript and yeasts do not form part of the study. Response: In our analysis we considered co-morbidities as one of the confounders, which could influence our outcome of interest, and in multivariable analysis we controlled for comorbidities, however, we found this did not influence our outcome. Furthermore, we did not document any case with perforation or peritonitis, but there was only one case of polymicrobial infections in patient with rectal carcinoma. In table 2, we have mentioned yeast being part of the study. Comment: The authors have stated that Viridans streptococcus and Corynebacteria have been disregarded as contaminants. However, these organisms may assume huge clinical significance in certain clinical situations such as immunocompromise and malignancies in patients with BSI’s. The authors have not provided a break up of clinical conditions in the 50 cases and 150controls which in itself may skew the clinical outcome data of patients. Response: Thank you for the comment. Our laboratory SoP for a blood culture states very clearly when to consider CoNS, Viridans Streptococcus, Corynebacterium as true pathogens, and we strictly followed the lab SoP regarding these as pathogenic. Unfortunately, clinical conditions were diverse, and a breakdown presentation in a table would be difficult for a reader. Comment: The description of Results section under “Antimicrobial Susceptibility Pattern” does not match the data outlined in Table -3. Response: Thank you for observation, we have edited on the total number of MDR bacteria Comment: There is no reference to certain Resistance mechanisms such as Carbapenem resistant Enterobacterales (CRE), Amp C enzymes MLSBi/c detection in S. aureus. All of these do impact treatment outcomes. How have these been factored in the selection of 50 cases and 150 controls in the study as these would most certainly affect the final analyses Response: Thank you for the valid comment. In the selection of cases and controls, we did not consider if patients had resistant strains or not because our study hypothesized that polymicrobial bloodstream infections were associated with poor treatment outcomes, and we designed this study as a case control to answer our research question. We had thought of controlling for MDR or resistant strains, but the analysis could have been different and not for a case-control study, maybe cross-sectional. Comment: The section on Discussion gives vague references to 30-day mortality and extended hospital stay etc without actual figures and how these may compare with similar data brought out in other studies. There are equal references to other studies in neonates without actually discussing the distribution of cases among neonates in the present study. Response: Thank you for the comments, we have improved our reference to include reference from similar study group. Comment: Based on the data presented and discussed the authors may have to modify the conclusion section as no definite conclusions emerge out of the discussion cited. Response: Thank you, we have rephrased our conclusion. Attachments Attachment Submitted filename: Response to reviewerd.docx https://doi.org/10.1371/journal.pone.0302076.r002
28 Feb 2024 Decision Letter - Iddya Karunasagar, Editor PONE-D-23-28734R1Polymicrobial bloodstream infections a risk factor for mortality in neonates at the national hospital, Tanzania: A case-control studyPLOS ONE Dear Dr. Manyahi, 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 address all comments of the reviewer and please indicate the changes in your response.============================== Please submit your revised manuscript by Apr 13 2024 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. 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). You should upload this letter as a separate file labeled 'Response to Reviewers'. A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'. An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter. If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols. We look forward to receiving your revised manuscript. Kind regards, Iddya Karunasagar Academic Editor PLOS ONE Additional Editor Comments: Manuscript still needs improvement as per reviewer comments. [Note: HTML markup is below. Please do not edit.] Reviewers' comments: Reviewer's Responses to Questions Comments to the Author 1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation. Reviewer #3: (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 #3: Partly ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #3: 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 #3: 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 #3: 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 #3: The authors need to mark ALL the sentences in the manuscript where they have responded to the reviewer's comments. This has not been done. There are still some grammatical errors that need correction. ****** 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 #3: 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. Attachments Attachment Submitted filename: PONE-D-23-28734_R1.pdf https://doi.org/10.1371/journal.pone.0302076.r003
Revision 2
5 Mar 2024 Author Response Reviewer #3: The authors need to mark ALL the sentences in the manuscript where they have responded to the reviewer's comments. This has not been done. There are still some grammatical errors that need correction. Response: Thank you for the comments to improve our manuscript. We have added yellow highlights in areas we have made changes in a Revised Manuscript with Track Changes. Furthermore, we have addressed some of the grammatical errors as suggested. In addition, below are authors response from the previous reviewers Response to review Review of the paper titled Polymicrobial Blood stream Infections; a risk factor for mortality at the National Hospital Tanzania; A case control study Reviewer #1: The evidence for polymicrobial BSI is not very clear just isolation of two or more bacteria from blood culture does not substantiate the polymicrobial BSI. Comment: Line 164 and 165 Acinetobacter and CONS, Pseudomonas and S.aureus in these combinations CONS and S.aureus could be skin contaminants in which case BSI is mono-microbial only. Therefore, selection criteria of polymicrobial BSI cases to be clearly defined in which clinical conditions or comorbidities polymicrobial BSI is a possibility only such case to be selected. Response: Thank you for the comment. Our laboratory SoP for a blood culture states very clearly when to consider CoNS, and other possible skin contaminants as true pathogens, and we strictly adhered to the laboratory SoP in defining pathogens. S. aureus in blood culture is always considered a pathogen in our interpretation of the blood culture positive Comment: Line 166 and 167 Acinetobacter 15% (15/150) calculation error. Response: We appreciate for the comment, we have addressed calculation error Comment: While mentioning the antibiotic resistance consider the antibiotics used for blood stream infections not clindamycin, cotrimoxazole and chloramphenicol for S. aureus. Response: We appreciate for the comment. However, our results show the susceptibility pattern based on laboratory testing and not based treatment of S. aureus blood stream infections. In reporting AST results to clinician, our laboratory considers both bacteria and site of infections. Comment: Which are the disease comorbidities were considered for statistical analysis because these disease comorbidities will play very significant role in hospital mortality and 30-day mortality in patients with BSI besides the antimicrobial resistance. Response: Unfortunately, clinical conditions were so diverse, and a breakdown presentation was difficulties. Therefore, in our analysis we categorized either presence of comorbidity or not. Reviewer #2: The paper made an interesting reading, dealing with polymicrobial infections Vs Monomicrobial Infections , the microbiological and clinical impact of these with respect to 30 day mortality and the extended hospital stay etc. Comments for the same are attached , the authors are advised to kindly refer to the same and address all the points mentioned The paper deals with the differences (Both Microbiological yield and clinical outcomes) in patients with Polymicrobial and Monomicrobial Bacteremia Infections; The Following observations are in order and must be addressed before the manuscript can be taken forward Comment: The title of the paper does not reveal that the major component of the study is in children, adolescents, neonates, infants or adults. However, the Table No 4 & 5 refer to clinical outcomes in neonates only. Response: Thank you for the comment. We agree that the title does not mention the major components of the participants. Our study aimed at creating awareness of the negative effects of polymicrobial bloodstreams on patient care for both laboratory personnel and clinicians. Being a lab-based retrospective, we therefore enrolled all patients with polymicrobial bloodstreams matching their counterparts by age, date of admission, and admitting wards. However, because we had a significant number of participants who were neonates, we decided to perform a sub-analysis for neonates only, as appears in Tables 4 and 5. On the other hand, we have done sub-analysis in none neonates, Therefore, we have modified the title to show the component affected. Comment: Moreover, the Table – 1 which deals with age and sex distribution does not give a breakdown of the age groups and refers to a median age alone. Response: Thank you for the comment. Our study design was a case control, which was matched by age; therefore, we found most participants were populated in the same age category. However, we have added age breakdown in table1 Comment: The discussion section refers to certain observations which have been compared with other studies and these deal with outcomes in neonates only. Response: We appreciate for the comment, we have improved our citation and omitted references which do not match with our study population Comment: In the section “Materials and Methods “ “study setting and design ‘ the authors have stated that results are obtained in age groups from 1-86 years and of these 50 patients were selected and 150 controls. What was the age distribution taken into consideration when this selection was made. The clinical outcomes may be different in different age groups with polymicrobial bacteremia. Response: We appreciate for the good comment, in this study we included all age groups from 0-86. Understanding the age have influence on the clinical outcome, first we adjusted for age in multivariable analysis. Then we did stratification analysis for neonate only and non-neonate. Having this analysis, we are assured we have controlled the age a possible confounder influencing our outcome of interest. Comment: The authors have stated a definition for Polymicrobial infections in the section “Definition of terms”. However, the term polymicrobial need not be restricted to 2 organisms as there are instances of blood stream infections caused by more than 2 organisms, including a yeast. How has the selection for polymicrobial infections data been made. Moreover the Results section talks of common organisms as Nos/ 100 which means that the authors have considered only 2 organisms per blood culture in a patient (total no of patients being 50). Response: Thank you for this observation. We completely agree polymicrobial infections can be caused by two or more bacteria. Unfortunate, during the review of the laboratory data, we did not come to an instance of having more than two pathogens. Furthermore, we had one case of polymicrobial bloodstream infections involving bacteria and candida species. Comment: The clinical outcomes for blood stream infections in conditions such as Perforation peritonitis, Carcinoma colon etc may depend on the nos of organisms causing the Polymicrobial Infection. Has this been taken into account. There is no mention anywhere in the manuscript and yeasts do not form part of the study. Response: In our analysis we considered co-morbidities as one of the confounders, which could influence our outcome of interest, and in multivariable analysis we controlled for comorbidities, however, we found this did not influence our outcome. Furthermore, we did not document any case with perforation or peritonitis, but there was only one case of polymicrobial infections in patient with rectal carcinoma. In table 2, we have mentioned yeast being part of the study. Comment: The authors have stated that Viridans streptococcus and Corynebacteria have been disregarded as contaminants. However, these organisms may assume huge clinical significance in certain clinical situations such as immunocompromise and malignancies in patients with BSI’s. The authors have not provided a break up of clinical conditions in the 50 cases and 150controls which in itself may skew the clinical outcome data of patients. Response: Thank you for the comment. Our laboratory SoP for a blood culture states very clearly when to consider CoNS, Viridans Streptococcus, Corynebacterium as true pathogens, and we strictly followed the lab SoP regarding these as pathogenic. Unfortunately, clinical conditions were diverse, and a breakdown presentation in a table would be difficult for a reader. Comment: The description of Results section under “Antimicrobial Susceptibility Pattern” does not match the data outlined in Table -3. Response: Thank you for observation, we have edited on the total number of MDR bacteria Comment: There is no reference to certain Resistance mechanisms such as Carbapenem resistant Enterobacterales (CRE), Amp C enzymes MLSBi/c detection in S. aureus. All of these do impact treatment outcomes. How have these been factored in the selection of 50 cases and 150 controls in the study as these would most certainly affect the final analyses Response: Thank you for the valid comment. In the selection of cases and controls, we did not consider if patients had resistant strains or not because our study hypothesized that polymicrobial bloodstream infections were associated with poor treatment outcomes, and we designed this study as a case control to answer our research question. We had thought of controlling for MDR or resistant strains, but the analysis could have been different and not for a case-control study, maybe cross-sectional. Comment: The section on Discussion gives vague references to 30-day mortality and extended hospital stay etc without actual figures and how these may compare with similar data brought out in other studies. There are equal references to other studies in neonates without actually discussing the distribution of cases among neonates in the present study. Response: Thank you for the comments, we have improved our reference to include reference from similar study group. Comment: Based on the data presented and discussed the authors may have to modify the conclusion section as no definite conclusions emerge out of the discussion cited. Response: Thank you, we have rephrased our conclusion. Attachments Attachment Submitted filename: Response to reviewers comment.docx https://doi.org/10.1371/journal.pone.0302076.r004
27 Mar 2024 Decision Letter - Iddya Karunasagar, Editor Polymicrobial bloodstream infections a risk factor for mortality in neonates at the national hospital, Tanzania: A case-control study PONE-D-23-28734R2 Dear Dr. Manyahi, 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 will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, 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 #3: 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 #3: Yes ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #3: 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 #3: 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 #3: 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 #3: The authors have addressed the comments and suggestions made by the reviewers adequately and satisfactorily. This manuscript does not appear to be a dual publication, as declared by the authors, and adheres to ethical principles in a laboratory-based study. ****** 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 #3: No ******** https://doi.org/10.1371/journal.pone.0302076.r005
Formally Accepted
5 Apr 2024 Acceptance Letter - Iddya Karunasagar, Editor PONE-D-23-28734R2 PLOS ONE Dear Dr. Manyahi, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps. Lastly, 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 customercare@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.0302076.r006

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