<xhtml:span xmlns:xhtml="http://www.w3.org/1999/xhtml" xml:lang="en">Genotypic study of isolated resistance to isoniazid in the Mycobacterium tuberculosis&#160;complex in&#160; a Moroccan hospital </xhtml:span>

  1. Amine Amri
  2. Elmostafa BENAISSA
  3. Yassine BENLAHLOU
  4. Fatna BSAIBIS
  5. Adil MALEB
  6. Mariama CHADLI
  7. Mostafa ELOUENASS

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Abstract

Introduction: Despite the introduction 40 years ago of effective and low-cost treatment for tuberculosis, morbidity and mortality from this disease remain substantial worldwide. The World Health Organization (WHO) estimates that 10.6 million people contracted tuberculosis, with 1.3 million deaths in 2022. The increasing number of multidrug-resistant strains of Mycobacterium tuberculosis raises concerns Materials and Methods : This is a retrospective study conducted at the Bacteriology Department of Mohammed V Military Instruction Hospital over a period of 3 years. Data were collected via the laboratory information system. Clinical samples underwent treatment using both conventional bacteriological methods and molecular techniques. The study of resistance to major anti-tuberculosis drugs was performed using the reverse hybridization technique, specifically the HAIN method (GenoType® MTBDRplus by Hain Lifescience). Statistical analysis of the data was carried out using Excel software        Results :     The study involved 464 patients treated for pulmonary and extrapulmonary tuberculosis, including both new cases and those previously treated with positive cultures. The mean age of the patients was 42.2 years, with a range from 8 to 88 years. There was a predominance of males at 74%, with a sex ratio of 2.8. Pulmonary sputum samples accounted for 84.8% of the cases, whereas extrapulmonary samples representedonly15.2% , the positivity rates for direct examination and culture across all samples were74%and100%,respectively.Isoniazid resistance had a prevalence of 9% (43/464). Genetic mutations observed indicated that 63% of the clinical isolates resistant to INH had mutations in the KATG gene, while 37% had mutations in the inhA gene Conclusion : The increasing prevalence of Mycobacterium tuberculosis complex strains resistant to one or more first-line anti-tuberculosis drugs necessitates regular epidemiological surveillance to limit the spread of these strains in the general population

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  1. Access Microbiology

    Comments to Author

    Amri et al submit a report on a retrospective study of the prevalence of isoniazid resistance in Mycobacterium tuberculosis complex isolates from the Mohammed V Military Instruction Hospital. The paper is for the most part well written but could include some further expanding of results and clarification. I have the following comments: 1. The abstract should mention why the authors undertook this study (IE data on resistance in Morocco is lacking). 2. The introduction in its current form could be expanded. I am left wanting more information. a. Is there a reason younger individuals are more prone to TB in Morocco? b. How widespread is drug resistance/multi drug resistance in Morocco? c. What have the other studies on INH resistance found? And potentially what are their limitations? (IE short time period examined, only focus on pulmonary and not extrapulmonary, etc) d. Is Morocco using the BCG vaccine and how widespread are HIV/TB co-infections in Morocco? 3. Materials and methods: Explain the types of statistical analysis that were performed. 4. A Table incorporating patient data (age, sex, type of TB, known drugs treated with) and sample collection site for each patient to supplement the text and Figure 1 would be informational to readers and easier to follow than just the text. 5. If males make up 74% of patients, it is not surprising that more men had INH resistant TB than women (It would be surprising if women had more INH resistant TB, potentially signaling something specific to gender or sex. I would like to see of the 74% men how many had INH resistance and of the 26% women how many had INH resistance? 6. Figure 2: Define "S" and "R" as susceptible and resistance. 7. Figure 3: Denote gene names correctly: inhA should be italicized, katG should be lowercase "K" and italicized. If talking about the protein: denote as InhA and KatG. Please note that gene names should be italicized with the first letter lowercase in all instances found in the paper. 8. Lines 187-189: The reference cited makes no mention of MDP1 or dormant bacteria. This makes me question if other references are correct. Additionally, I can't find any reference cited that mentions MDP1 conferring INH resistance. There is a paper I found (doi: https://doi.org/10.1074/jbc.M111.333385) referencing MDP1 as a katG regulator in BCG but it is unclear how translatable this would be to clinical isolates, as MDP1 appears essential and the phenotype described was due to conditional knockdown and not altered function. a. Dormancy and persister cells are a unique phenomenon that likely renders cells tolerant due to suppressed or altered metabolic states. The authors even use a robust review citing this information later in the discussion (citation #12). 9. Lines 192-196: Make sure to differentiate that the katG mutation prevalence referred here is from a global study (as based on earlier, S315 mutations are 60-70% in Morocco) and cite this information. 10. What is the MIC of katG mutations to compare to inhA? 11. The second half of the discussion is a nice summary of katG and inhA INH resistance mutations and alternative routes to resistance, but I fail to see the how this information ties into the current study unless the authors did work identifying if isolates had any efflux gene mutations as well. Is this a limitation of the study? It might be worth mentioning that phenotypically resistant isolates may be katG/inhA mutation negative due to alternative routes?

    Please rate the manuscript for methodological rigour

    Good

    Please rate the quality of the presentation and structure of the manuscript

    Satisfactory

    To what extent are the conclusions supported by the data?

    Partially support

    Do you have any concerns of possible image manipulation, plagiarism or any other unethical practices?

    No

    Is there a potential financial or other conflict of interest between yourself and the author(s)?

    No

    If this manuscript involves human and/or animal work, have the subjects been treated in an ethical manner and the authors complied with the appropriate guidelines?

    Yes

  2. Access Microbiology

    The reviewers have highlighted major concerns with the work presented. Please ensure that you address each of their comments and make corresponding changes to the manuscript and figures. In addition to the reviewer comments, several other points need to be addressed for this manuscript to be considered fit for publication: - The ethical approval for this study is unclear. While the use of patient samples may mean that direct consent is not necessary, IRB/institutional approval is still required to provide assurance that ethical guidelines were followed throughout the study. An IRB protocol or signed approval form would be sufficient, along with an updated statement in the text. - The included figures are low-quality and lack accompanying legends. Please ensure that all figures are generated in a high-quality format and have legends describing what they show - There is a concerning lack of references used in the manuscript, particularly in the introduction. Please be sure that factual statements have relevant sources cited in the text.

  3. Access Microbiology

    Comments to Author

    This manuscript, "Genotypic study of isolated resistance to isoniazid in the Mycobacterium tuberculosis complex in a Moroccan hospital," is a study that provides important insights into the genetic basis of isoniazid resistance in Morocco, a topic of significant public health importance. Below are my comments and suggestions to enhance the quality and impact of your manuscript. Major Comments: - While the manuscript identifies the prevalence of katG and inhA mutations, it does not sufficiently explore the clinical implications of these findings. Please expand on how these mutations may influence treatment strategies or guide local tuberculosis (TB) control programs. Consider discussing the potential role of alternative therapeutic options, such as ethionamide, especially in cases with inhA mutations. Consider elaborating on how these mutations affect isoniazid activation and efficacy, referencing broader literature on the topic. - The study mentions global and national resistance trends but lacks a detailed comparison with similar studies from other countries in the region. Adding such comparisons could provide better contextualization of your findings. - The manuscript primarily relies on basic descriptive statistics. Incorporating advanced statistical tools, such as significance testing or confidence intervals for prevalence rates, would strengthen the reliability of your conclusions. Specifically, address whether the sample size (464 patients) is representative of the TB population in Morocco and whether any sampling biases could have influenced the results. - Provide additional details about the quality control measures implemented during molecular testing, beyond the use of H37Rv as a reference strain. Also, clarify how the GenoType MTBDRplus assay results were validated, if applicable. - The figures are poorly executed and unrepresentative. Use a professional tool for producing publication-quality figures. Also, include additional details in the figure legends to make them standalone and more informative. - The manuscript does not provide clear future research directions or practical recommendations. Including these could enhance the utility of your findings for both researchers and public health practitioners.

    Please rate the manuscript for methodological rigour

    Satisfactory

    Please rate the quality of the presentation and structure of the manuscript

    Poor

    To what extent are the conclusions supported by the data?

    Partially support

    Do you have any concerns of possible image manipulation, plagiarism or any other unethical practices?

    No

    Is there a potential financial or other conflict of interest between yourself and the author(s)?

    No

    If this manuscript involves human and/or animal work, have the subjects been treated in an ethical manner and the authors complied with the appropriate guidelines?

    No: no specific ethical approval number is mentioned, there are no apparent ethical violations

  4. Version published to 10.1099/acmi.0.000928.v1 on Access Microbiology