PONE-D-21-14320

Risk factors for treatment failure in women with uncomplicated lower urinary tract infection

PLOS ONE

Dear Dr. Martischang,

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PLOS ONE

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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: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: Yes

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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

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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

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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 article has been well written and provides evidence for risk factors for clinical and microbiological failure of treatment in a relatively large population of women with lower UTI. However, you conclude that based on the result that postmenopausal age is a risk factor for treatment failure, this risk factor should be considered when considering delayed antibiotic therapy. I do not understand how you came to this part of the conclusion. In delayed antibiotic therapy you do not treat and you rely on spontaneous recovery within a week. In my opinion the risk in delayed therapy is that spontaneous recovery does not happen or that an upper UTI infection develops. Can you elaborate on your conclusion concerning delayed therapy?

Your study included hospitalized and ambulatory adult women with lower UTI symptoms. I expect delayed therapy to be applied only to ambulatory adult women. Do you know whether your conclusions also apply to ambulatory women only?

An ethical statement is missing.

It took me a lot of time to understand figure 1, comparing it with the numbers you mention in the Abstract and in Methods. I think it would help if you put all the main groups in the left column and the groups with clinical and microbiological failure on the right, together with the numbers of controls. In Figure 1 it seems like the 340 women with microbiologically confirmed UTI is divided into a group with clinical failure (126 and 214 controls?), a group with micromiological failure (102 with 220 controls) and women with E-coli related UTI (70 with 134 controls?) and 136 women with non-E.coli related UTI.

For the women with E.coli related UTI you only show the women with clinical failure (70 and 134 controls?) but you do not show the women with microbiological failure (71 and 128 controls?).

In the Abstract,section Methods you mention that controls were those who did not expoerience clin of microbiol failure. In lines 105 and 106 you mention that only women adhering to the RCT's protocol were included. I noticed that cases plus controls not always add up to the total number of women in a main group. In the Result section, I would expect a mention of how many cases or controls were missing because of this.

Line 195: 4 should be in line with the other numbers below 10.

Reviewer #2: This study assessed risk factors for clinical and microbiological failure in women with lower UTI via a case-control study nested within a randomized clinical trial. Postmenopausal age was an independent risk factor for clinical and microbiological treatment failure in women with lower UTI; diabetes was not associated with failure. The authors’ assessment of microbiological failure provides an understudied insight that would be of interest to a general urology and primary care audience.

Abstract and Introduction:

-Given that the authors are from Switzerland, it would be useful for them to identify (either in the abstract of Introduction) whether their cohort – and thus their recommendations – should apply to only a Switzerland demographic, or whether their research could extend outside (or not).

-Similarly, there is some evidence to suggest that women’s menopausal status may also impact of doctor’s choice of therapy and effects of that therapy. The authors do comment on this (and include age as a variable in their analyses), but a more thorough description of this would be useful in describing the demographic, as well as treatment failure (particularly as it relates to age).

Methods:

-The authors state that “only women adhering to the RCT’s protocol were included to avoid the problems of missing data/outcomes and non-adherence” – how many patients were excluded due to this? And was missing data quantified in any way? That is, did most of these patients with missing data have 1-2 missing data points vs. most of their data points missing? And did the demographics of excluded patients differ from those who were included?

-It’s unclear based on the author’s current description why a cutoff of 52 years was chosen and this could use further explanation, particularly given that it is critical to the main results and interpretation.

-What statistical analysis software was used?

Results:

-Although age was entered based on the 52.5 cutoff, it might be worth classifying women as pre-menopausal or post-menopausal and including that as a variable in the models, if that data was collected by the authors.

-Table 2 is quite helpful, but it would be useful to see the full models (all variables entered).

Discussion:

-The authors note that recruitment site (and variation among centres) impact clinical outcomes. Why was this the case? Additional explanation is needed for results to be interpretable.

-Given that the finding that diabetes was strongly associated with microbiological failure, more discussion should be included. Was this predicted/hypothesized? If yes, why or why not?

-When discussing limitations, the authors note that strength of their study was that it was multi-centre; however, these centres clearly varied (given recruitment site impacted outcomes). Why might that be more of a limitation? – the authors might want to discuss this a bit more.

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Reviewer #1: No

Reviewer #2: No

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Risk factors for treatment failure in women with uncomplicated lower urinary tract infection

PONE-D-21-14320R1

Dear Dr. Martischang,

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.

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Kind regards,

Justyna Gołębiewska

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

Reviewer #2: All comments have been addressed

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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: (No Response)

Reviewer #2: Yes

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3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: (No Response)

Reviewer #2: Yes

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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: (No Response)

Reviewer #2: Yes

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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: (No Response)

Reviewer #2: Yes

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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: (No Response)

Reviewer #2: The authors did a great job address reviewer comments and feedback. With these revisions, I recommend the manuscript be accepted for publication.

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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: No

Reviewer #2: No