Tricuspid Valve Endocarditis Due to Methicillin-Resistant Staphylococcus aureus in a Previously Healthy Young Patient without a Drug Abuse History: A Case Report and a Review of the Literature

Round 1

Reviewer 1 Report

In this case report authors from Croatia report about an seemingly immunocompetent patient who developed tricuspid valve MRSA endocarditis in the absence of traditionally recognized risk factors. The case is interesting in my opinion, well described and would be useful for readers of this journal.

1. I wanted to bring authors' attention to recently published case regarding MRSA pericarditis ( https://pubmed.ncbi.nlm.nih.gov/35912380/) where patient was immunocompetent and also did not have major risk factors for MRSA infection. Similar to your patient the infection was community acquired. Please compare and contrast findings in your case with other published cases in the literature on this topic, and compare MRSA endocarditis with MRSA pericarditis ( risks, presentation, outcome). This will enrich educational value of this report. In the case above, similar to your case, the patient was a smoker and this association should be further explored.

2. The table with literature review from PubMed is excellent and I would just suggest adding smoking habits as it appears to be a possible risk factor. 

3. Lines 258-263- discussion regarding HIV seems irrelevant since your patient did not have HIV. 

4. Following 6 weeks of antibiotics therapy, did you obtain surveillance blood culture to assure the bacteremia has cleared while patients was off of antibiotics?

5. Ceftaroline is another option for MRSA endocarditis and this should be mentioned

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499876/

https://pubmed.ncbi.nlm.nih.gov/22797874/

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Author Response

Dear colleague,

I greatly appreciate the time and attention you dedicated to thoroughly reviewing the manuscript. Your suggestions for improvement have been carefully considered and discussed by the authors and we hope that the changes in the previous manuscript will contribute to the quality of our work.

1. We appreciate the reviewer's suggestion to include a comparison with the paper presenting MRSA pericarditis (https://pubmed.ncbi.nlm.nih.gov/35912380/)  in our case report. While both cases involve the same causative agent risk factors, the clinical presentation, etiology and diagnostic procedures of these two entities are significantly different, warranting separate discussions. Firstly, endocarditis is commonly associated with underlying structural heart disease, intravenous drug use, prosthetic heart valves, and invasive medical procedures, among others. On the other hand, pericarditis often occurs as the spreading of infection “per continuitatem”, usually from lung or cardiac abscess or via hematogenous spreading from another body site. Moreover, the clinical presentation and diagnosis of endocarditis and pericarditis exhibit notable distinctions. The clinical presentation of pericarditis was markedly different from the patient presented. Pericarditis is characterized by sharp, stabbing chest pain that worsens with movement and is relieved by sitting forward. A pericardial friction rub is often detected upon auscultation, and electrocardiogram (ECG) changes, such as widespread ST-segment elevation and PR-segment depression, are commonly observed. None of these symptoms were presented in our patient.  Also, multiple blood culture sets are typically positive in IE but not for pericarditis as pericarditis does not involve bloodstream invasion. Considering these notable differences in risk factors, clinical presentation, and diagnosis between endocarditis and pericarditis, we believe that a direct comparison of the two entities would be more appropriate in a separate discussion rather than within the context of our MRSA endocarditis case report. However, we acknowledge the importance of pericarditis in the broader context of infectious cardiac conditions and will include a brief mention of pericarditis and its association with MRSA with reference, in the discussion section, to provide a comprehensive overview of cardiac infections caused by this pathogen.
2. In the available literature, it is not stated that smoking is a primary risk factor for the development of right-sided endocarditis. As smoking can contribute to the development of atherosclerotic disease, it can cause changes in the heart valves and secondarily contribute to an increased risk of endocarditis. Unfortunately, in most of the cases shown in the table, smoking was not mentioned and could not be classified as a risk factor.
3. HIV can significantly contribute to the risk of developing infective endocarditis. Since during the first submission we received a suggestion from the Section Managing Editor to further elaborate on this topic, we have included a short discussion about HIV in our text.
4. Based on the most recent recommendations for patient follow-up (referencing UpToDate, Wang et al., Overview of the management of infective endocarditis in adults with infective endocarditis), it is no longer necessary to obtain a blood culture once the six-week therapy has been completed. Throughout the treatment period, daily blood cultures were obtained until the blood was microbiologically sterilized, which was achieved after adjusting the vancomycin dosage and reaching an adequate concentration of vancomycin in the bloodstream.
5. We have included your suggestion about Ceftaroline in the discussion and provided literature citations.

Reviewer 2 Report

Thank you for the opportunity to review this excellent manuscript which combines an individual case study presentation and a relevant review of the literature on a not often encountered problem.  We hope that this problem will not become more prevalent, but must remain vigilant for its assessment and aware of its possibility.  As I first read the manuscript, I made a note that the authors may want to consider reversing the order of terms in the title after the colon:  "A review of the literature and case study," because the literature review was surely the most compelling of the two.  However, as I read further, the case study was as interesting and compelling as the review of the literature.  My only reasoning for suggesting a reordering of the terms in the title is to follow the order of presentation in the article - both components are well presented.  

I think the addition of discussion of ceftaroline or ceftaroline fosamid (CPT-f) is warranted for the literature review.  CPT-f as a monotherapy is not approved for a blood stream infection and may be why it is not considered initially in IE patients without any other known IE disease risks.  This patient was initially suspected to have community-acquired pneumonia, then a positive blood culture before IE was suspected.  When Vancomycin was added, and IE diagnosed, the patient recovered.  Incidentally, CPT-f and daptomycin can also be effective in combination, when needed.

I do not agree with smoking supported as an independent risk factor in the literature for IE.  As the second reviewer pointed out, smoking seems to be associated with those who already have other known highly associated and supported risk factors for IE, such as valvular heart disease and/or IV drug use.  I think smoking is a secondary risk factor, or a moderating variable, for having a risk factor such as valvular heart disease and/or IV drug use.  Whether it is a risk factor in a person without these risk factors as applies to this case study is unknown.  https://pubmed.ncbi.nlm.nih.gov/35924572/

Author Response

2. review

I would like to express my sincere gratitude for your valuable input and constructive feedback during the peer review process of our manuscript. We think that your comments and suggestions will contribute to improving the quality and comprehensiveness of our work. In particular, we appreciate your comment regarding the discussion of Ceftaroline. Your suggestion to include specific recommendations and references related to Ceftaroline has been carefully considered and integrated into the revised version of the manuscript. We have included a dedicated section highlighting the potential role of Ceftaroline and Ceftaroline-Daptomycin combination in the treatment of MRSA right-sided infective endocarditis. Furthermore, we have supplemented the discussion with relevant references that support our statements and provide additional context to the readers.

Reviewer 3 Report

In the article idr-2369566 entitled Tricuspid valve endocarditis due to methicillin-resistant Staphylococcus aureus in a previously healthy young patient without a drug abuse history, Dr. Andrijašević and colleagues reports a case of an 18-year-old young healthy male patient who diagnosed as methicillin-resistant Staphylococcus aureus (MRSA) tricuspid valve endocarditis. The patient had no histories for drug abuse or compromised backgrounds. The authors concluded that clinicians should take care that even such healthy patients could suffer from MRSA endocarditis.

Although the topic of this manuscript is interesting, there should be some important points to be reconsidered. Critiques are described below.

1)   It might be rare that young healthy individuals who have no risks including drug abuse suffer from community-associated MRSA (CA-MRSA) infective endocarditis (IE). However, the authors focused too much at the assessment for drug abuse to fully consider other risk factors. Millar et al. reported in her review that a large proportion of cases of CA-MRSA IE have a documented history of some form of skin lesion, including furunculosis, cellulitis and/or iv drug abuse, and that all cases reported to date have been associated with native valves, predominately the tricuspid valve. (PMID: 17962214) As is reported in the current case, vegetations formed at tricuspid valves are common for CA-MRSA IE. It should be more careful to be considered whether the young patient had other factors for such severe infection. In addition, not only Dalman et al. (as the authors referenced as #39) but Millar et al. also had pointed that transmission (person-to-person via shared facilities including sports equipment) could be one of the factors for CA-MRSA.

2)   How about the vital signs on admission? Blood pressure, heart rate and SpO2 are at least willing to be shown.

3)   Although the results of laboratory blood test are described in the text, it is preferred to be shown in a table. In addition, there are no assessments for diabetes, cardiac biomarkers and immuno-deficiency in the laboratory test.

4)   How did the authors assess the initial findings in the chest X-ray? Did the patient suffer from not only IE but pneumoniae? How was the result of sputum culture test? In addition, what caused the bilateral pleural effusion on the second day?

5)   In usual cases, tricuspid valves are more easily scanned by transthoracic echocardiography (TTE) than by transesophageal echocardiography (TEE). The reviewer wonders why no vegetations were observed in the first TTE, despite the vegetation size on TEE was as large as 3*11 mm. Significant tricuspid regurgitation must be also observed in the TTE, and the sonographer would have taken attention at tricuspid valves. Vega et al. reported that routine TEE might not be required to identify IE for patients with low risks of CA-MRSA. (PMID: 26676855) How do the authors consider their findings?

Author Response

3. review

I greatly appreciate the time and attention you dedicated to thoroughly reviewing the manuscript. Your suggestions for improvement have been carefully considered and incorporated into the manuscript, with the belief that it will enhance the overall content and strengthen the arguments presented. Your expertise in the field has provided valuable insights that have contributed to the scholarly merit of the work.

1. We are grateful for the recommendation to supplement the text with a description of the additional risk factor concerning skin lesions. In the description of the patient's status, we added that the patient's skin was intact, without any changes in the form of neurodermatitis, furuncles, or carbuncles that could be associated with a bacterial infection. In the discussion, we added a section on skin lesions as a risk factor, with an accompanying reference (Millar et al.), and commented on the intactness of the skin. We also added a suggested reference in the discussion considering risk factors for the spread of CA-MRSA infections among athletes (Millar et al.).
2. We have added information about blood pressure, heart rate, and peripheral blood oxygen saturation to the Case presentation section of the text.
3. A table has been included in the manuscript, containing lab data, as well as data on glucose blood levels, cardiac biomarkers, and flow cytometry results. Additionally, in order to avoid redundancy, values within the reference range listed in the table have been omitted from the main text. Instead, the text now focuses on discussing values that deviated from the reference interval, with appropriate comments provided.
4. In the Discussion section, a comment related to your proposal was added, which reads: Given the morphology of the radiological findings, it was challenging to definitively discern whether the changes originated from pneumonic infiltration or were a consequence of the early phase of cardiac decompensation associated with endocarditis.
5. According to your comment, we have added in the discussion section part: Prolonged MRSA bacteremia without additional risk factors may not necessarily have a strong statistical association with the diagnosis of IE (Vega et al). However, patients who have MRSA bacteremia along with other clinical prediction criteria, including prolonged duration of bacteremia, are at a higher risk for IE and should undergo a clinical evaluation, such as a TEE (Vega et al, Habib). Following the 2015 ESC Guidelines for the management of infective endocarditis, despite a negative result from a TTE, we decided to conduct a TEE examination. This TEE revealed lesions on the tricuspid valve with significant tricuspid regurgitation. Furthermore, if additional risk factors like intravenous drug use, intravascular prosthetic material, skin lesions, or previous medical treatment were present, the leading diagnosis would likely be established more promptly, potentially before subsequent positive blood cultures occur

Round 2

Reviewer 1 Report

The authors have responded to my questions/concerns. In my opinion the paper is suitable for publication in this journal

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Author Response

1 peer review

We would like to express our gratitude for your time, effort, and expertise throughout the peer review process. Your valuable contributions have played a vital role in shaping the final version of the manuscript, and we are grateful for the opportunity to benefit from your insightful guidance.

Thank you for your continued support and invaluable input.

Reviewer 3 Report

The reviewer thanks the authors to thoroughly revise the article along with the previous comments. Although the writings come up to be improved, there still be some concerns related to the previous comments (#3 and #5). Remaining critiques are described as following.

1)   The reviewer thanks the authors to tabulate the results for blood test as pointed. However, there are still no assessments for diabetes and cardiac biomarkers which should be preferred to be added. If they have no data, it also should be acknowledged.

2)   The reviewer recognizes the importance of TEE for diagnosing IE along with the guideline. However, it seems strange that the vegetation on tricuspid valves (as large as 3*11 mm) had not been detected at all by TTE in spite of the significant tricuspid regurgitation which should make the sonographer to attend searching vegetations. In other words, why do the authors think TTE could not scan the vegetation? In common cases, tricuspid valves are familiar to be observed by TTE rather than TEE, which is different from the cases for aortic and mitral valves.

Author Response

We highly appreciate the time and effort you dedicated to carefully assessing the content of the manuscript. Your expertise and attention to detail have been instrumental in enhancing its overall scientific rigor and coherence. Your specific recommendations regarding cardiac biomarkers, diabetes mellitus, and TEE, have been especially helpful in refining the arguments and strengthening the conclusions.

We are pleased to inform you that I have incorporated your valuable comments into the revised version of the manuscript. Each of your suggestions has been duly addressed, and we believe that the changes made have significantly strengthened the manuscript. Your expertise has played a crucial role in shaping the final version, and we hope that the manuscript is now even more robust and compelling as a result of your input.

1. We have added a comment related to diabetes that reads (Discussion, page 10): Based on the blood glucose value falling within the established reference interval, both the glucose load test and the assessment of HbA1c levels were deemed unnecessary, leading to the conclusion that diabetes was not a potential risk factor given the normal blood sugar levels. Also, we have added a comment related to cardiac biomarkers (Case presentation, page 6): D-dimers showed elevated levels, whereas the values of creatinine kinase and troponin fell within the reference interval. Pro-bmp was not performed.
2. We changed the part of the text related to TTE and TEE and commented on why vegetation on the tricuspid valve was not visualized. That part of the manuscript now looks like this (Case presentation, page 7): Upon establishing the diagnosis of probable endocarditis, transthoracic echocardiography (TEE) was initially performed. However, the examination did not yield successful results due to inadequate visualization of the tricuspid valve caused by a poor acoustic window subcostally and parasternally. Consequently, a decision was made to proceed with transesophageal ultrasonography, which revealed the presence of a 3 x 11 mm floating vegetation on the anterior leaflet of the tricuspid valve, accompanied by significant tricuspid regurgitation (3+).

Thank you once again for your valuable contribution, and I look forward to your continued support as we move forward with the publication process.