Dear Dr. Alvis Guzman,

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Academic Editor

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?

Reviewer #1: Partly

Reviewer #2: Yes

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

Reviewer #1: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: This is an interesting paper entitled: Evaluation of Streptococcus pneumoniae as a cause of acute otitis media in Colombia: a prospective study. I want to thank the authors for their efforts in researching pneumococci. Even when the paper is well-written and has some important information, in my scope, it looks like a mix of information in different sections. The manuscript has some major aspects that must be addressed before your work is ready for publication. Grammatically it is well-written and understandable. However, it lacks an organized structure; some sections are very long and lose a common thread. A major restructure, and a new version of the discussion is needed.

Structure:

Please number the lines of the document to make it easier to track sentences that need changes or improvements.

Authors Contribution: use the author’s initials for each section

Introduction:

The introduction looks very long and should be reorganized, with a maximum structure of 3 or 4 paragraphs. In some parts, authors seem to be throwing out ideas for discussion about the subject matter, but they are not argued and remain as free sentences. The number of paragraphs of less than 10 lines hinders the reader from jumping to ideas. Provide more information about MEF and its used in previous studies

The initial sentence in paragraph 4 should be modified. Also, reference number 4 does not support the sentence; there are many different pathways related to the development of SPN AOM. SPN colonization is considered a prerequisite, but there is some controversial data in this regard.

Paragraph 5 does not include meningitis as a complication; relevant data about SPN AOM igniting invasive pneumococcal disease is available. this paragraph is weak; it lacks data on vaccination, vaccination coverage, and circulating serotypes. Colombian literature on these topics has been written by authors such as Severiche et al. and Serrano et al.

Paragraph 6 mentioned several studies, but the references do not match. You should revise the metanalysis in this regard. There is so much information in children rather than in adults. The section that refers to the SPN capsular switch needs more data and support.

Paragraph 7, please include the rates of effective vaccination in Colombia with the previous two vaccines. To provide background information to the reader about which vaccine provided “protection” while the study was being performed.

Paragraph 8: Please provide the numbers for the decrease in incidence.

Methods

Please provide clear information about the type of study. Is this a monocentric study? (provide a line saying so )

What kind of guidelines were followed to perform a study on children? Please provide some lines in the first paragraph of methods standing the Helsinki declaration, the informed consent process, and the approval of an ethical committee. Consider moving the ethical considerations section after the first paragraph as this is a study performed in children.

As tympanocentesis is an invasive procedure with several risks, I would like the authors to provide supplemental information a copy of the informed consent.

It is important to include in figure 1 the number of patients screened

How did the authors avoid reporting a false SPN such as Streptococcus pseudonemoniae, which usually shows alpha hemolysis halo and sensitivity to optokine?

how was the value of patients to be included estimated?

Results

There is a typo in the first paragraph of results (after ... April 2023…)

Only 6 SPN cases among 61 patients were recruited. What was the etiology for the other 55 ?

There are several typos repeatedly in the results “(Error! Reference source not found.)”

I suggest that the authors review the reporting structure of the results, use simple numerators and denominators when referring to percentages to make it easier to read, e.g. : XX/XX (XX%)

Discussion

It is ambitious to say that this single-center study of 62 patients describes the effect of vaccination in children suffering from otitis when 1 in 4 children who consult for this possible diagnosis. Likewise, it is estimated that 40% of the consultations are for AOM in children, and this cut-off seems small and even more so when it is mentioned that the hospital where it was carried out is the one that provides the most care to patients from both the private and public sectors.

The discussion must be reorganized and reformulated. The aspects to be discussed should be contrasted with external or internal data previously found before the PCV-10 vaccine introduction.

The strengths of the study should be focused on supporting the results by using high-quality techniques, standard procedures, and double-checked test were performed, not in the team training.

Best wishes , look forward to see a new version of your work !

Reviewer #2: I find this article very interesting, as it contributes to the understanding of the epidemiology of pneumococcus as a cause of acute otitis media in Colombia.

In the introduction, the sentence: “In Latin America, the incidence of AOM ranges from 4.25% to 6.78% [2]. In a 2016 study published in a Caribbean city in Colombia, the incidence of AOM was found to be 29.4% per 1,000 children [3]. This poses a challenge for public health and health economics”

It is recommended that the values be presented in the same units to facilitate comparison, either as percentages or as rates per 1,000 children. Review the text "29.4% per 1,000 children," as the "%" sign is unnecessary.

In the introduction, review the sentence: “during the early introduction of PCV-7/PCV-13 (2003-2005), and in the late period after the introduction of PCV-7/PCV-13 (2006-2009)”.

PCV13 was not available during those time periods.

In the introduction, review the sentence: “In Colombia, the PCV-7 vaccine (Prevnar®) was introduced in the Expanded Program on Immunization (EPI) in Bogotá D.C. in 2009 with a '2+1' schedule at 2, 4, and 12 months of age. It was implemented throughout the country during 2010 and 2011”.

Other studies report different dates for the implementation of PCV7 in Colombia: “In Colombia, vaccination against pneumococcus began in 2006 with PCV7, initially targeting children under 2 years of age at high risk of IPD. Since 2008, the vaccine was administered universally initially in Bogotá, and since 2009 it was extended to the departments of Colombia with the highest mortality from acute respiratory infection. In the 2010–2011 period, given the withdrawal of PCV7 from the market, PCV13 was administered in Bogotá and in the higher risk departments”. Ref: Camacho-Moreno G, Leal AL, Patiño-Niño J et al. Serotype distribution, clinical characteristics, andantimicrobial resistance of pediatric invasive pneumococcal disease in Colombia during

PCV10 mass vaccination (2017–2022). Front. Med 2024, 11:1380125.doi: 10.3389/fmed.2024.1380125.

The implementation dates of PCV10 and PCV13 are the same as those reported in other studies from Colombia.

In results: A total of 61 patients were included in the study. How many cases of otitis media occurred in the hospital during the study period? What proportion of patients who presented with AOM were included in the study?

Figure 1 indicates that 82 patients were candidates; I recommend including this information in the main text.

In results delete the phrases: “Error! Reference source not found.Error! Reference source not found”

I recommend describing in the results the type of pneumococcal vaccine received by the 5 patients who were vaccinated. The phrase: “Of the six cases with S. pneumoniae isolation, five had received PCV-10 given that they were born before April 30, 2022” in the discussion should be moved to the results section.

It is also recommended to describe, in the results section, the vaccines used in patients who experienced non-pneumococcal otitis.

How many patients had negative cultures? In table 2 "55 AOM patients, microorganism other than S. pneumoniae," suggesting that all cultures were positive and in Figure 3, the culture results are described, and it indicates that all cases had microbiological isolation, 18 had microbiome of the external auditory canal. However, the discussion states, "In 37% of the cultures, there was no bacterial growth, a finding similar to our study." Review this phrase.

In results the phrase: “Regarding resistance patterns, Figure indicates that all pneumococcal serotypes isolated showed some degree of antimicrobial resistance” Add the corresponding figure number.

Table 3. Clarify whether the beta-lactam resistance is to penicillin and/or ceftriaxone. If resistant to penicillin or ceftriaxone, it is advisable to report the MIC.

In the discussion section the phrase: “who received PCV-10 previously In addition” Add a period after previously.

In the discussion section the phrase: “The findings of AOM-causing pneumococcal serotypes not included in PCV-10 (19, 10F and 35)” The serotype is 19ª

In the discussion section the phrase: “Our study found that the samples exhibited a resistance pattern consistent with what has been described in the literature. This included resistance to macrolides, clindamycin, TMP/SMX, and aminoglycosides” Pneumococcus is intrinsically resistant to aminoglycosides.

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Reviewer #1: No

Reviewer #2: Yes:  German Camacho-Moreno

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Dear Dr. Alvis Guzman,

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 May 23 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 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,

Luis Felipe Reyes, M.D., Ph.D., MSc.

Academic Editor

PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

**********

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: N/A

Reviewer #2: Yes

**********

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

**********

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

Reviewer #1: Yes

Reviewer #2: Yes

**********

Reviewer #1: I want to thank the authors for their effort and dedication. They have responded to the suggestions made in the previous revision, and their manuscript is now a better version.

Despite the improvement of this manuscript, some suggestions persist, and I quote below:

1. In line 52, a reference is missing to support this sentence.

2. The study by Sierra Lopez and Zapata should also be included in the introduction to give specific context to the entity in question.

3. It is important to review the lines referring to the introduction of the vaccines; the flow of information varies from global to local contexts repeatedly and can confuse the reader. I suggest introducing the complete global context and ending with the local context. lines 76-77

4. Line 83 has no reference

5. I understand that for safe handling of sensitive data, the hospital information cannot be accessed; however, in the methodology, they mention that case definitions were made, and then, based on this, inclusion and exclusion criteria were applied. I have two doubts about this: 1. The definition of case 2 includes unspecific symptoms of systemic infection that, in the age of the selected population, encompasses a broad spectrum of entities. It is also unclear whether the definition should include all symptoms or just one. Thus, is why it would be important to show how many cases were defined as case definition 1 o r case definition 2 and then which ones met the inclusion criteria. to modify the figure 1. In case you do not have or can not show the suggested data, explain better the screening and recruitment method. Were all patients who met a case definition (1 or 2) assessed to evaluate inclusion and exclusion criteria, and then it was defined that they entered the study?

6. Regarding MEF sample collection, no references are cited to support the procedure used in this study. Is the sampling protocol proprietary? Was it adapted? I request the authors to provide further information in this regard.

7. Since the authors' results suggest existing differences in the groups' characteristics, it would be worthwhile to analyze the difference through the appropriate statistical tests and add the p-value of this result to Table 1. This would evidence the differences.

8. There appears to be a difference in median age between patients with PNS and those with other causes, which should be discussed further. Could this be related to the increase in transient SPN colonization of the nasopharynx in school children?

9. In the discussion, when referring to the vaccine recommendation, other types of vaccines, such as PCV10-SII (PNEUMOSIL) that protect against SPN serotypes 1, 5, 6A, 6B, 7F, 9V, 14, 19A, 19F, and 23F are not discussed. PCV-15 and PCV-20 are not mentioned either. Likewise, this recommendation does not make sense because the phenomenon of capsular replacement in other countries has already shown that once the vaccine is changed, the circulating serotypes begin to change in the following 5-10 years. Colombia started vaccination with PCV-13 3 years ago after many countries included PCV-15 in their programs. The discussion about the recommendation for the next vaccine should revolve around vaccines after PCV-13. Suggested references PMID (38336559, 39591182, 39153492)

10. Although one of their important findings is that serotype 19a was found in a higher proportion, they do not discuss how, in Colombia, this circulating serotype is also the major cause of IPD PMID (34641809,32964223).

11. There are paragraphs in the discussion that merely mention facts but do not contradict or support the researchers' findings and do not contribute to the scope referred to in the objective. Examples of these are found in lines 344-347, 357-367, and 386-389.

12. I kindly suggest refining the information in the discussion to make the reader understand in a more adequate way the importance of the findings and how this study is the basis for further research on pneumococcal diseases different from IPD, as well as how the impact of the vaccination that has been applied to the Colombian context is reflected in its results and could be modified with the introduction of other vaccines.

I consider the findings of this group of researchers very valuable. I believe this study could be the cornerstone for implementing a program of active surveillance and tracking of causes of acute otitis media. I hope my suggestions can be incorporated into an improved version of their wonderful work.

Reviewer #2: (No Response)

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Reviewer #1: No

Reviewer #2: Yes:  German Camacho Moreno

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Evaluation of Streptococcus pneumoniae as a cause of acute otitis media in Colombia: a prospective study

PONE-D-24-41495R2

Dear Dr. Alvis Guzman,

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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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,

Luis Felipe Reyes, M.D., Ph.D., MSc.

Academic Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

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

Reviewer #1: Yes

Reviewer #3: Yes

**********

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

Reviewer #1: Yes

Reviewer #3: Yes

**********

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

The PLOS Data policy

Reviewer #1: Yes

Reviewer #3: Yes

**********

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

Reviewer #1: Yes

Reviewer #3: Yes

**********

Reviewer #1: Thank you for addressing all the comments so thoroughly. I believe the manuscript is now in much better shape and is clearly grounded in the significance of the findings. In my opinion, this is a strong manuscript, and I recommend it for publication.

Reviewer #3: The authors have addressed all the comments raised adequately. The language is grammatically correct and conveys the meaning to the reader.

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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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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 #3: No

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