Dear Dr Saito,

Thank you very much for submitting your manuscript "A prospective observational study of community-acquired bacterial bloodstream infections in Metro Manila, the Philippines" for consideration at PLOS Neglected Tropical Diseases. Your paper was reviewed by members of our editorial team and by one peer reviewer. While we typically will not proceed with a single peer reviewer, after many months we have not been able to get any additional reviewers and do not want to hold up this manuscript any longer. In light of the reviews (below this email), we would like to invite the resubmission of a significantly-revised version that takes into account the reviewers' comments.

We cannot make any decision about publication until we have seen the revised manuscript and your response to the reviewers' comments. Your revised manuscript is also likely to be sent to reviewers for further evaluation.

When you are ready to resubmit, please upload the following:

[1] A letter containing a detailed list of your responses to the review comments and a description of the changes you have made in the 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.

[2] Two versions of the revised manuscript: one with either highlights or tracked changes denoting where the text has been changed; the other a clean version (uploaded as the manuscript file).

Important additional instructions are given below your reviewer comments.

Please prepare and submit your revised manuscript within 60 days. If you anticipate any delay, please let us know the expected resubmission date by replying to this email. Please note that revised manuscripts received after the 60-day due date may require evaluation and peer review similar to newly submitted manuscripts.

Thank you again for your submission. We hope that our editorial process has been constructive so far, and we welcome your feedback at any time. Please don't hesitate to contact us if you have any questions or comments.

Sincerely,

Andrew S. Azman

Deputy Editor

PLOS Neglected Tropical Diseases

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Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: -Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

While this was mainly a descriptive study of patients with bloodstream infection, and the objectives are explained, there are no hypotheses clearly stated. Yet, statistical tests with p values etc are presented in the results, so hypothesis testing is implied. I think these should be more clearly articulated or it should be clarified that this was a purely descriptive study and no hypotheses are being examined. However, there are clearly some hypotheses being tested here - eg. whether BC positivity changes over time, by seasons, by clinical variables etc

-Is the study design appropriate to address the stated objectives?

Yes, the design is broadly appropriate. I think the choice of control group may need some further explanation. Why only dengue positive cases were chosen, for instance? Why this sample size for the control population, or was it just a convenience sample? It seems the point of the control group was to demonstrate that positive blood cultures are not being missed in patients with other febrile syndromes

(editor comment) Ln 116: What does “clinically suspected to have a bacterial bloodstream infection” mean exactly?

-Is the population clearly described and appropriate for the hypothesis being tested?

Yes

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

No formal sample size calculations are presented - and this ties back to the lack of clear hypotheses. While the sample size is probably reasonable for this kind of descriptive study, questions of power adequacy are hard to answer as it is not clear what precisely is being tested.

-Were correct statistical analysis used to support conclusions?

A few potential issues to note:

a) I am not sure that ORs to compare the year of admission (using 2015-6 as a baseline reference) and the rate of BC positivity is the best way to do this. I would have thought that a test for temporal trends might be more appropriate (although I am not a statistician so seeking advice on this would be recommended). I wonder whether it might be more informative to present these graphically in some way, which may also show seasonal variation as well as year-year trends?

b) there are mulitple ORs calculated for a number of clinical and demographic variables - was there any adjustment for multiplicity of testing? Is there not a risk that some associations will thrown up by chance alone?

c) It was a little unclear with the "initial" clinical diagnosis if several of these were made on the basis of the blood culture results (e.g. meningococcus, endocarditis), in which case comparing the likelihood of BC positivity seems confounded and not very informative (and again comparing ORs to pneumonia as a baseline condition seems like an unusual way to present things)?

-Are there concerns about ethical or regulatory requirements being met?

None

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Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: -Does the analysis presented match the analysis plan?

The presentation of multiple ORs in Table 1 is not really explained or justified in the statistical methods (see above)

-Are the results clearly and completely presented?

Otherwise OK - see above about presentation and analysis of the seasonal / time trends

They state that no MDR/XDR E coli strains were found, but at least one was meropenem resistant in Table 3 - are the authors sure there was no carbapenem-resistant E coli, which would normally be at least MDR if not XDR? Some further clarity here would be useful.

-Are the figures (Tables, Images) of sufficient quality for clarity?

Yes

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Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: -Are the conclusions supported by the data presented?

Overall yes

-Are the limitations of analysis clearly described?

I think it would be worth stating that Leptospira IgM positivity alone (or even seroconversion with confirmatory testing like MAT) can have false positives.

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

Yes - present useful data overall

-Is public health relevance addressed?

Yes and placed into context of other similar studies in the region

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Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: Few minor typos etc:

1, Table 5: check spelling of species as some errors e.g. "Acinetoaceter", "B. pseudomalle" "S pneumonia"

2. Author summary "Melioidosis" is a disease, not a pathogen - suggest "Burkholderia pseudomallei" is referring to the organism

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Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: Overall I think the study presents some useful data, and the authors should be commended on the amount of work it must have taken to collect the information. My main concerns relate to a clearer articulation of the hypothesis and presentation of the analysis, but publication would be worthwhile if these can be addressed.

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Reviewer #1: No

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Dear Dr Saito,

We are pleased to inform you that your manuscript 'A prospective observational study of community-acquired bacterial bloodstream infections in Metro Manila, the Philippines' has been provisionally accepted for publication in PLOS Neglected Tropical Diseases.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

Should you, your institution's press office or the journal office choose to press release your paper, you will automatically be opted out of early publication. We ask that you notify us now if you or your institution is planning to press release the article. All press must be co-ordinated with PLOS.

Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Neglected Tropical Diseases.

Best regards,

Andrew Azman

Deputy Editor

PLOS Neglected Tropical Diseases

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Reviewer's Responses to Questions

Key Review Criteria Required for Acceptance?

As you describe the new analyses required for acceptance, please consider the following:

Methods

-Are the objectives of the study clearly articulated with a clear testable hypothesis stated?

-Is the study design appropriate to address the stated objectives?

-Is the population clearly described and appropriate for the hypothesis being tested?

-Is the sample size sufficient to ensure adequate power to address the hypothesis being tested?

-Were correct statistical analysis used to support conclusions?

-Are there concerns about ethical or regulatory requirements being met?

Reviewer #1: yes

**********

Results

-Does the analysis presented match the analysis plan?

-Are the results clearly and completely presented?

-Are the figures (Tables, Images) of sufficient quality for clarity?

Reviewer #1: yes

**********

Conclusions

-Are the conclusions supported by the data presented?

-Are the limitations of analysis clearly described?

-Do the authors discuss how these data can be helpful to advance our understanding of the topic under study?

-Is public health relevance addressed?

Reviewer #1: yes

**********

Editorial and Data Presentation Modifications?

Use this section for editorial suggestions as well as relatively minor modifications of existing data that would enhance clarity. If the only modifications needed are minor and/or editorial, you may wish to recommend “Minor Revision” or “Accept”.

Reviewer #1: No additional comments

**********

Summary and General Comments

Use this section to provide overall comments, discuss strengths/weaknesses of the study, novelty, significance, general execution and scholarship. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. If requesting major revision, please articulate the new experiments that are needed.

Reviewer #1: Thank you for the responses to the earlier comments. I am satisfied with the revised manuscript and would recommend acceptance at this stage

**********

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