Dear Dr. Mariana,

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.

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We look forward to receiving your revised manuscript.

Kind regards,

Saki Raheem, PhD

Academic Editor

PLOS ONE

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[Universitas Indonesia   http://dx.doi.org/10.13039/501100006378    NKB_292   Prof Purwanty Ascobat]. 

Please state what role the funders took in the study.  If the funders had no role, please state: "The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."

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[This study was funded by the Directorate of Research and Development, Universitas Indonesia, under Hibah PUTI 2024 (Grant No NKB_292).]

We note that you have provided funding information that is not currently declared in your Funding Statement. However, funding information should not appear in the Acknowledgments section or other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.

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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?

Reviewer #1: Yes

Reviewer #2: Partly

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

Reviewer #1: Yes

Reviewer #2: No

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3. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: No

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4. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: No

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Reviewer #1: This study addresses an important public health issue in a high TB-burden setting by evaluating pharmacokinetic/pharmacodynamic (PK/PD) parameters, specifically the Cmax/MIC ratio of bedaquiline and levofloxacin, and their association with early sputum conversion in MDR-TB patients.

The research is relevant and executed within clinical contexts reflective of Indonesian practice.

However, several aspects require critical clarifications.

The number of evaluable patients for bedaquiline (n = 32) and levofloxacin (n = 48) Cmax measurements is relatively small and unbalanced between conversion and non-conversion groups, especially for bedaquiline (only 4 non-converters).

While the authors report a significant difference in bedaquiline Cmax/MIC between conversion and non-conversion groups, the small number of non-converters (n = 4) undermines confidence in the statistical validity of this finding. The assumption of normality for parametric tests (e.g., t-test) with such small group sizes is questionable.

The lack of significance in levofloxacin Cmax/MIC differences is presented without adequate discussion.

Reviewer #2: The authors looked at the extent to which the peak dosage at 1 month of 2 antibiotics given for multidrug-resistant tuberculosis (levofloxacinand bedaquiline) was associated with microbiological success (sputum negativation at 4 months).

This is a relevant objective, and the data are interesting.

However, we are hampered by the absence of an essential piece of data: the minimum inhibitory concentrations for the 2 antibiotics according to the outcome (sputum conversion or not). MIC are described in general, but not per outcome.

The authors observe that the ratio between the maximal concentration and the MIC does indeed differ according to microbiological success, However, the variable most strongly associated with this success may be the MIC rather than the ratio Cmax/MIC.

The fact that the ratio peak/MIC is not different according to the microbiological sucess for levofloxacin is maybe due to the facts that 1) MIC for levofloxacin are for all but 2 cases under the breakpoint (1 mg/L), and 2) the concentration are not different according to outcome (11.4 vs 11.0 mg/L).

Meanwhile, for bedaquiline, most of the strains are above the "clinical breakpoint" (see https://www.who.int/publications/i/item/WHO-CDS-TB-2018.5). Therefore, when the authors report the important difference in Cmaw according to the outcome, it would be far more clear if they also provide MIC. For example, a figure showing in the X axis the Cmax and in the Y axis the MIC, each case represented by a point, and with different point shape or color according to the outcome, may add clarity.

Moreover, the authors perform a peak concentration for levofloxacin as if it was a legitimate parameter for an antibiotic which they describe as dose-dependent, but, for fluoroquinolones, the parameter most often reported as relevant is the ratio between the air under the curve (AUC) and the MIC, and measuring AUC requires more than just one point.

In addition, the author report that 58 patients are analysed; meanwhile, they have data for Cmax and MIC for only 48 patients for levofloxacin, and 32 for bedaquiline. Why announce 58 in the abstract?

In the same line, it is not appropriate to perform statistical tests with numbers so small (ex: non-conversion group: only 4 Cmax values for bedaquiline).

At last, multiple sentences should be reviewed, being structured in a strange way or lacking verb.

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what does this mean? ). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #2: No

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Dear Dr. Mariana,

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 submit your revised manuscript by Oct 30 2025 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.

• 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 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,

Saki Raheem, PhD

Academic Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

Reviewer #2: (No Response)

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2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #1: Yes

Reviewer #2: Yes

**********

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

Reviewer #1: Yes

Reviewer #2: No

**********

4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #1: Yes

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #1: Yes

Reviewer #2: No

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Reviewer #1: The number of samples were increased in supplement section in all conditions. Also, 3. the lack of significance in levofloxacin Cmax/MIC differences is now presented in discussion. Thus, all concerns are well addressed in the revised version.

Reviewer #2: The authors have addressed most of the comments from the reviewers.

This is important, as the data reported deserve publication.

There is still some issues with some points:

for the abstract:

- "58 patients completed the analysis at four months of treatment.": again, no. Your article title is on antibiotic concentration, so you cannot say that 58 patients completed the study if 10 of them did not. The sentence that corrects this figure just after is a point, but you should straightforward say 48, not 58.

- "There was a statistically significant difference between the Cmax/MIC ratio of bedaquiline in the sputum conversion and non-conversion groups (9.10 vs. 1.65; p < 0.001).": again, you cannot do a statistical analysis with 3 or 4 patients in one of the group.

for the text:

- "The MIC values for bedaquiline and levofloxacin, based on clinical outcome (sputum conversion or non-conversion), did not show significant differences (see S3 Table).": I is a good thing that the authors added this data. However, this is a major data, it should not be in a supplementary table, but as a part of the main table describing the particularities of the patients included.

- "In this study, MIC bedaquiline 0.25 mg/L was 21 (41.2%) Mtb isolates,": this fragment sentence makes no sense, a word or a mathematical sign is lacking.

- "Meanwhile, MIC alone could not be compared with the clinical outcome (sputum conversion)": this sentence is not clear. What would one want to compare a MIC with non-MIC data? Maybe the authors want to say " Groups made according to MIC alone could not be compared with the clinical outcome (sputum conversion)"; but if it is what they had in mind, I do not understand why - it is basic practice to see whether people infected with a bacterial strain with high MIC have or not an outcome different from people infected wiht a bacterial strain with lower MIC.

- "MIC distribution of bedaquiline for Mtb was presented in this study, which showed high pharmacodynamic variability.": it is a bit confusing to say so, as pharmacodynamic also result from PK. Moreover, there is not "pharmacodynamic variability"; conversely, pharmacodynamic analyses lead to variable conclusions according to PK and to MIC

- "According to the MIC of levofloxacin, most of the MICs of levofloxacin against Mtb in this study were 0.25 mg/L (68.6%)": the sentence makes no sense; maybe the authors want to say "Regarding the MIC of levofloxacin, most (68.6%) of the Mtb strains in this study were under the value of 0.25 mg/L" (or "were equal to 0.25 mg/L").

for the new figure 3: remove the lines of "correlation": the idea was not to see a correlation (this would be completely nonsense in this case), but to better visualise the data. (Moreover, it is not possible to draw a correlation line with 3 dots...)

**********

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

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[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

The Peak Plasma Concentration (Cmax)/Minimum Inhibitory Concentration (MIC) of Bedaquiline and Levofloxacin with Special Attention to the Sputum Conversion in the Treatment of Multidrug-Resistant Tuberculosis in Indonesia

PONE-D-25-28090R2

Dear Dr. Mariana,

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,

Saki Raheem, PhD

Academic Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions??>

Reviewer #2: (No Response)

**********

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

Reviewer #2: (No Response)

**********

4. Have the authors made all data underlying the findings in their manuscript fully available??>

The PLOS Data policy

Reviewer #2: (No Response)

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English??>

Reviewer #2: (No Response)

**********

Reviewer #2: (No Response)

**********

what does this mean? ). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy

Reviewer #2: Yes:  Olivier Epaulard

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