Molecular epidemiology of antimicrobial resistance in central africa: A systematic review
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Background. In Central Africa, it is difficult to tackle antibiotic resistance, because of a lack of data and information on bacterial resistance, due to the low number of studies carried out in the field. To fill this gap, we carried out a systematic review of the various studies, and devised a molecular epidemiology of antimicrobial resistance from humans, animals and the environmental samples.
Method. A systematic search of all publications from 2005 to 2020 on bacterial resistance in Central Africa (Gabon, Cameroon, Democratic Republic of Congo, Central African Republic, Chad, Republic of Congo, Equatorial Guinea, São Tomé and Príncipe, Angola) was performed on Pubmed, Google scholar and African Journals Online (AJOL). All circulating resistance genes, prevalence and genetic carriers of these resistances were collected. The study area was limited to the nine countries of Central Africa.
Results. A total of 517 studies were identified through a literature search, and 60 studies carried out in eight countries were included. Among all articles included, 43 articles were from humans. Our study revealed not only the circulation of beta-lactamase and carbapenemase genes, but also several other types of resistance genes. To finish, we noticed that some studies reported mobile genetic elements such as integrons, transposons, and plasmids.
Conclusion. The scarcity of data poses difficulties in the implementation of effective strategies against antibiotic resistance, which requires a health policy in a ‘One Health’ approach.
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All suggestions and considerations have been fulfilled. Therefore, this manuscript is accepted for publication. Congratulations!
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In this revised version of the manuscript, Dikoumba et al. have applied all the comments and suggestions previously proposed. The text, as a whole, reads more fluid and clearer, and some inconsistencies have been fixed. Please find below some additional suggestions and minor amendments to apply. • Reviewer 1, comment 2: it would be interesting to add your response to this comment explicitly in the manuscript as a limitation. • Reviewer 1, comment 9: I suggest to change “gene-carrying molecular elements” for “genetic elements”, which comprises better chromosomal elements on one hand and mobile genetic elements on the other hand. • As this is a review manuscript, the Methods and Results sections do not contain the usual methods and results. I would suggest to rename the “Methods” section to “Bibliographical methods” or …
In this revised version of the manuscript, Dikoumba et al. have applied all the comments and suggestions previously proposed. The text, as a whole, reads more fluid and clearer, and some inconsistencies have been fixed. Please find below some additional suggestions and minor amendments to apply. • Reviewer 1, comment 2: it would be interesting to add your response to this comment explicitly in the manuscript as a limitation. • Reviewer 1, comment 9: I suggest to change “gene-carrying molecular elements” for “genetic elements”, which comprises better chromosomal elements on one hand and mobile genetic elements on the other hand. • As this is a review manuscript, the Methods and Results sections do not contain the usual methods and results. I would suggest to rename the “Methods” section to “Bibliographical methods” or something similar that conveys that there are no experimental methods. In the case of the “Results” section, I would suggest to remove this heading and use the sub-headings as main headings. This is because there are no actual results obtained from this study (it is a literature review), but this will a structure to the manuscript. • L54: change “human” to “humans” • L94: correct the difference between vertical and horizontal transfer. Vertical transfer is a genetic inheritance after an event of cell division (it is a bit more specific than transferring material between two cells of the same species). On the other hand, horizontal transfer is a genetic acquisition, by different means, from non-sibling cells or the environment. Please adapt these definitions as required citing the appropriate sources. • L105, L108: species names must be italicised, as well as gene names when appropriate according to the conventions. Please correct this throughout the manuscript. • L105 and throughout the manuscript: antibiotic names do not need a first letter in uppercase • L124: Replace “dealing with” by “related to”. • L125-126: “In order to ensure…avoid excluding certain studies”. This sentence seems a bit unclear and repetitive. Please rephrase and ideally clarify which studies you wanted to avoid excluding. • L134: replace “concern” by “concerns”. • L135: replace “whose” by “including”. • L138, L140: square kilometres need to be written with a superindex 2. • L159: Tables must be fully named as Table 1, Table 2 and Table 3 (also in L319). At this point, it would be helpful to explicitly mention they refer to studies un humans, animals and the environment, respectively. • L185: replace “most” by “highest” • L193: replace “lactamases” by “lactamase” • L194: replace “OXA-48, OXA-181” by “OXA-48 and OXA-181”; replace “oxacillinases” by “oxacillinase” • L198: replace “found” by “find”; replace “timeframe” by “timeframe of this study”; replace “carbapenemases” by “carbapenemase coding genes” • L200 and throughout the text: the terminology for naming bla genes is bla followed by the specific name (for example CTX-M or OXA) in subindex. Please correct throughout the text. • L201: replace “Tn 4651 and Tn 4652” by “Tn4651 and Tn4652” • L202-206: Please clarify the terminology for plasmids. “Other types of plasmids” means that the previously mentioned mobile genetic elements are plasmids, and they are not. “Non-typeable plasmid” is not a type of plasmid. Differentiating incompatibility groups as it is done here can be understood as if the previously mentioned plasmids do not have any incompatibility. This needs to be fixed. • L212: remove “)” after fosA • L213: replace “chloramphenicole” by “chloramphenicol” • L239: replace “carbapenemases” by “carbapenemase coding genes”; “EPC” would be “CPE” here? • L269: remove “with” after “corroborate” • L276: replace “using” by “use” • L279: replace “in the manuscript” by “in this review” • L287: replace “West” by “Western countries”. If this refers to Europe and the USA I would suggest to mention them explicitly • L304: replace “in the review” by “in the reviewed literature” • L318: although efflux pumps are a means of resistance, it seems out of place in this list. Please clarify or remove. • L324: as “Staphylococcus aureus” has been previously mentioned in the manuscript, there is no need to clarify the abbreviation S. aureus in brackets. • L329-330 and L335-336: These two references to “One Health” would read better as only one reference at the end of the paragraph. • L341: replace “genes types” by “gene types” • L342: replace “no interest” by “not enough attention” Please provide a revised version of the manuscript as well as a point-by-point response to these comments within 2 weeks.
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I would like to thank the authors for providing a revised version of the manuscript. Some changes proposed by the reviewers have been applied. However, the most important suggestions and concerns brought up by the reviewers are still unclear or completely unaddressed. There are many statements that are too vague and do not get to transmit the information. The writing still needs a major revision, as it is very hard to read many parts of the manuscript. Some examples are: • The literature database with the articles that passed each filter has not been made available. • The term “non-beta-lactamase genes” is not appropriate to group every other antibiotic resistance mechanism different from beta-lactamases, as the rest of antibiotic resistance genes the authors refer to can be completely unrelated from a functional and …
I would like to thank the authors for providing a revised version of the manuscript. Some changes proposed by the reviewers have been applied. However, the most important suggestions and concerns brought up by the reviewers are still unclear or completely unaddressed. There are many statements that are too vague and do not get to transmit the information. The writing still needs a major revision, as it is very hard to read many parts of the manuscript. Some examples are: • The literature database with the articles that passed each filter has not been made available. • The term “non-beta-lactamase genes” is not appropriate to group every other antibiotic resistance mechanism different from beta-lactamases, as the rest of antibiotic resistance genes the authors refer to can be completely unrelated from a functional and epidemiologic point of view. • Figure 2 has lost the format in the revised manuscript • L51-52: number should be expressed either in digits or in words. Please homogenise. • L56: chromosomes are not mobile genetic elements. • L154-155, L300: Tables are not correctly cited and it cannot be known what each table refers to here. • L159-160: eligibility criteria and the reasons to filter out articles are still not clear. • L199: “plasmid groups of incompatibility” is not a correct term as it does not refer to a mobile genetic element, which be a plasmid. The incompatibility groups refer to a co-existence of plasmids in the cell and their replication according to compatible replication mechanisms. • L274: “In this study…” Do you mean in the manuscript? The prevalence data you are handling are extracted from other studies, it is not produced by this work. • L275-281: It is mentioned here that ESBL prevalence in Central Africa is 3-100%, and continue to say that is it similar to that of East Africa (42%) and China (46%), and significantly lower than those of Germany and USA (10-15%, 4-12%, respectively). This does not make sense. • L284: “resistance genes with damaging effects on human health”. The resistance genes do not cause a disease themselves. • L286-288: this is an example of a vague statement. There is a mention to changes in therapeutic recommendations due to AMR, but it does not exemplify those changes. • L300-302: Another example of a vague sentence. “…” is inappropriate when listing these genes because the reader cannot figure out what follows in the list. Equally, finishing the sentence with “…and many others” does not help the reader to understand which genes the authors mean. Even if they are collected in the tables, their explanation in the text needs to improve. Specific examples (not the only ones) of lines/sentences that need grammar correction or that are difficult to understand are: L88, L227-228, L254-256, L256-259, L261, L262-264, L270-271, L314-315. There are also examples of specific reviewer suggestions that have not been accomplished in all instances throughout the manuscript or not accomplished at all. Examples are: Reviewer 1 • Comment 2, comment 5 and comment 9 not changed. • Specific comment 1 only changed once out of 7 total references to the terminology that was suggested to change. • Specific comment 5: African Journal Online only corrected once in the manuscript. • Specific comment 10: this explanation is hard to reconcile with the fact that the authors give a prevalence range for “non-beta-lactamase genes” in L276. Reviewer 2 • Comment 3 has not been applied to L83 and L252 • Comment 5: The definition of the Ambler’s classification has been completely removed from the manuscript. However, its categories are still mentioned (L190, L192) without contextualising what that classification refers to. Please provide a revised version of the manuscript, addressing all these changes and applying the suggestions to the entirety of the manuscript, as well as improving the grammar and the readability. Provide also a point-by-point response to these specific comments.
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In this manuscript, Dikoumba et al. present a systematic review about antimicrobial resistance molecular epidemiology in Central Africa. This work is timely and appropriate, given the lack of comprehensive information about antimicrobial resistance in this region. However, several concerns have emerged after the review process. Please, address the reviewers’ suggestions and comments thoroughly, especially those concerning: • Reframing the study to focus on beta-lactamases only (this would entail a change in the title accordingly) or give a comprehensive view of the rest of antibiotic resistance mechanisms mentioned to fulfil the scope of the manuscript. • Making available the literature database used for this study. Ideally, the publications that did not pass the different suitability filters should be provided as well, putting …
In this manuscript, Dikoumba et al. present a systematic review about antimicrobial resistance molecular epidemiology in Central Africa. This work is timely and appropriate, given the lack of comprehensive information about antimicrobial resistance in this region. However, several concerns have emerged after the review process. Please, address the reviewers’ suggestions and comments thoroughly, especially those concerning: • Reframing the study to focus on beta-lactamases only (this would entail a change in the title accordingly) or give a comprehensive view of the rest of antibiotic resistance mechanisms mentioned to fulfil the scope of the manuscript. • Making available the literature database used for this study. Ideally, the publications that did not pass the different suitability filters should be provided as well, putting the emphasis on the ones that passed the filters and support this work. Please, provide a revised manuscript containing all suggestions and a point-by-point response to the reviewers’ comments within 1 month.
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Comments to Author
Dear Authors Thank you for the opportunity to review this paper. Please see my suggested revisions below: 1. Review the paper throughout for efficient use of proper grammar and sentence structure prior to publication. 2. In the Methods section (page 2 line 44) list the included list of countries for readers ease of access and interest. It is relevant and crucial to list the origin of the discussed data even in the abstract of the script. 3. Line 64: Consider revising the sentence as " limited data, rather than "few". 4. Line 66: I suggest not describing the "Antimicrobial Resistance" as a "disease", avoid using the emerging global disease term and replace the disease with "threat". 5. Line 74: The sentence that mentions Ambler classification is out of place in the text. Consider revising or moving …
Comments to Author
Dear Authors Thank you for the opportunity to review this paper. Please see my suggested revisions below: 1. Review the paper throughout for efficient use of proper grammar and sentence structure prior to publication. 2. In the Methods section (page 2 line 44) list the included list of countries for readers ease of access and interest. It is relevant and crucial to list the origin of the discussed data even in the abstract of the script. 3. Line 64: Consider revising the sentence as " limited data, rather than "few". 4. Line 66: I suggest not describing the "Antimicrobial Resistance" as a "disease", avoid using the emerging global disease term and replace the disease with "threat". 5. Line 74: The sentence that mentions Ambler classification is out of place in the text. Consider revising or moving to more relevant section of the abstract. 6. Line 95: Consider removing this sentence (Furthermore, resistant bacteria and resistance genes can be shared between humans, animals and the environment.), does not add any value since this is already mentioned in the sentence starting in line 87. 7. Line 101: "In Central Africa, antimicrobial resistance is increasing to worrisome proportions. " You must elaborate this statement with clinical and/or epi data added to the section. In fact, consider revising the sections line 101 through 104 by adding available clinical data even if it is p[ersonal communications. 8. Line 135: Doer these studies were peer reviewed, if yes how many? 9. Section 4. Discussions", Line 243: "Antimicrobial Resistance presents an increasing public and animals health across the world... " incomplete sentence, revise and clarify intended statement. 10. Line 257: " Our literature review identified a number of data sources for the epidemiology of antimicrobial resistance in central Africa. Thus, we found especially 517 articles whose only 60 were eligible." Consider removing, this information has been repeated multiple times, focus on the relevancy of collected information from these studies and conclusion being made. 11. Line 264: Consider removing the sentence regarding plasmid transmission, general statement without value. 12. Line 270: Consider removing the sentence regarding One Health, already use as a closing statement for this section. 13. Line 278: "Indeed, the diseases caused by these drug-resistant bacteria are lethal, due most often to the absence of effective treatments." Strong statement without supporting data, either revise as "Could be" or add relevant data to support the claim from the referred publication. 14. Line 282: Again, concept of plasmid transmission is repeated multiple times in numerous sections within the paper, review throughout the paper and remove repetitions of this statement: "In all the three cases it was usually carried by plasmids, which made its spread easier and therefore increased the prevalence rate of ESBL-PE in humans, animals and the environment, leading to the spread of multidrug-resistant pathogens responsible for human and animal infectious diseases [24]." 15. Discussions section overall need to be strengthen with the available data from these 60 papers for the importance of the strong AMR threat in Central Africa region.
Please rate the quality of the presentation and structure of the manuscript
Satisfactory
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
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Comments to Author
First and foremost, I would like to commend the authors on the efforts spent in producing this manuscript. This study attempts to shed some light on the AMR picture in central Africa. Upon reviewing this manuscript, I have some comments and questions to be addressed: General comments: 1- If you are looking to analyze the molecular epidemiology of AMR genes, why are concentrating mainly on ESBLs? Most of the genes responsible for the resistances mentioned in L64-71 should be analyzed, especially that these are highly prevalent forms of resistances in Africa, not obscure or indolent. I suggest you could either alter the aim of the study to only concentrate on ESBLs or expand the analysis and tables to include other types of resistances that are highly prevalent and equally serious from infection …
Comments to Author
First and foremost, I would like to commend the authors on the efforts spent in producing this manuscript. This study attempts to shed some light on the AMR picture in central Africa. Upon reviewing this manuscript, I have some comments and questions to be addressed: General comments: 1- If you are looking to analyze the molecular epidemiology of AMR genes, why are concentrating mainly on ESBLs? Most of the genes responsible for the resistances mentioned in L64-71 should be analyzed, especially that these are highly prevalent forms of resistances in Africa, not obscure or indolent. I suggest you could either alter the aim of the study to only concentrate on ESBLs or expand the analysis and tables to include other types of resistances that are highly prevalent and equally serious from infection control standpoint. (You should not refer to them as other resistance genes). 2- L245-247: Please rethink this statement, there may be a dearth in reports to support your particular aim, but annual epidemiological reporting from most of parts of Africa is common practice. 3- L116: Could you provide the reasoning behind choosing this timeframe, if it was to cover 15 years, why not make it (2007-2022) to be a more recent investigation. 4- The discussion part of the manuscript lacks comparisons with other regions in and out of Africa. It is important to compare the rates in this review with other rates recorded in other regions and discuss the proposed causes of increase or decrease in certain AMR genes. 5- L314-318: Please expand on your recommendations to better implement One Health policies in central Africa. Specific Comments: 1- L39: "…to fight against antibiotic resistance" rethink the expression. 2- L53-54: Please clarify this sentence. 3- L111: Methodology misspelled. 4- L112: Please modify the citation. e.g. by Moher et al (ref no.). 5- L114: African journal online should be capitalized and maybe add the abbreviation AJOL. 6- L114: "focused on the collection of research…". 7- L121: do you mean Sub-Saharan Region; this misspell is recurring throughout the manuscript. 8- L124-130: Please use references. 9- L173: "genetic supports" do you mean mobile genetic elements? if yes please change accordingly. 10- L205: To be more informative, I would suggest analyzing each resistance separately. 11- L254: "The aim of establishing these strategies…" 12- L273: 'and' misspelled.
Please rate the quality of the presentation and structure of the manuscript
Good
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
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