Carbapenem-resistant Enterobacterales/Enterobacteriaceae (CRE) in Indonesia: protocol for systematic review and meta-analysis

Ika N. Kadariswantiningsih; Maulana A. Empitu; Bulat Idrisov; Derren David Christian Homenta Rampengan; Roy Novri Ramadhan

doi:10.12688/f1000research.157380.1

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Study Protocol

Carbapenem-resistant Enterobacterales/Enterobacteriaceae (CRE) in Indonesia: protocol for systematic review and meta-analysis

[version 1; peer review: 2 approved with reservations]

Ika N. Kadariswantiningsih ^1,2, Maulana A. Empitu^3,4, Bulat Idrisov⁵, Derren David Christian Homenta Rampengan⁶, Roy Novri Ramadhan³

Ika N. Kadariswantiningsih ^1,2, Maulana A. Empitu^3,4, [...] Bulat Idrisov⁵, Derren David Christian Homenta Rampengan⁶, Roy Novri Ramadhan³

PUBLISHED 17 Oct 2024

Author details Author details

¹ Department of Medical Microbiology, Faculty of Medicine, Airlangga University, Surabaya, East Java, Indonesia
² Clinical Microbiology Residency Program, Dr. Soetomo Regional Hospital/ Faculty of Medicine, Airlangga University, Surabaya, East Java, Indonesia
³ Faculty of Medicine, Airlangga University, Surabaya, East Java, Indonesia
⁴ Faculty of Health, Medicine and Natural Sciences (FIKKIA), Airlangga University, Banyuwangi, East Java, Indonesia
⁵ Health Services Research Department of Health Systems and Population Health, University of Washington, Seattle, Washington, USA
⁶ Faculty of Medicine, Universitas Sam Ratulangi, Manado, North Sulawesi, Indonesia

Ika N. Kadariswantiningsih
Roles: Conceptualization, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Software, Supervision, Validation, Visualization, Writing – Original Draft Preparation

Maulana A. Empitu
Roles: Conceptualization, Data Curation, Formal Analysis, Investigation, Methodology, Project Administration, Resources, Supervision, Validation, Visualization, Writing – Original Draft Preparation

Bulat Idrisov
Roles: Conceptualization, Methodology, Supervision, Writing – Original Draft Preparation

Derren David Christian Homenta Rampengan
Roles: Formal Analysis, Investigation, Methodology, Software, Writing – Original Draft Preparation

Roy Novri Ramadhan
Roles: Data Curation, Formal Analysis, Investigation, Methodology, Visualization, Writing – Original Draft Preparation

OPEN PEER REVIEW

REVIEWER STATUS

Abstract

Background

Carbapenem-resistant Enterobacterales (CRE) pose a significant global health threat, with increasing prevalence worldwide, including in Indonesia. Despite the public health impact, comprehensive data on the burden of CRE in Indonesia remains fragmented. This protocol outlines a systematic review and meta-analysis aiming to estimate the prevalence of CRE in Indonesia, summarize trends over time, and identify key resistance mechanisms.

Methods

We will conduct a systematic search across multiple electronic databases, including PubMed, Scopus, and local Indonesian databases, for studies reporting the prevalence of CRE in Indonesia from 2008 to 2024. Eligibility criteria include observational studies (cross-sectional, cohort, and case-control) and surveillance reports. Data extraction will focus on CRE prevalence, bacterial species, sample types, resistance mechanisms, and study settings (hospital vs. community). Quality assessment of studies will be performed using the Newcastle-Ottawa Scale (NOS). Meta-analysis will be conducted using a random-effects model to estimate pooled prevalence, and subgroup analysis will explore variations by geographical region, period, and healthcare setting.

Discussion

This systematic review and meta-analysis will provide the first comprehensive overview of CRE prevalence in Indonesia, contributing to an improved understanding of the national burden and resistance patterns. The findings will guide public health policies and inform antimicrobial stewardship efforts in Indonesia.

Registration

PROSPERO CRD42024580177

Keywords

Carbapenem-resistant Enterobacterales, CRE, antimicrobial resistance, prevalence, Indonesia, infectious disease

Corresponding author: Ika N. Kadariswantiningsih

Competing interests: No competing interests were disclosed.

Grant information: The author(s) declared that no grants were involved in supporting this work.

Copyright: © 2024 Kadariswantiningsih IN et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

How to cite: Kadariswantiningsih IN, Empitu MA, Idrisov B et al. Carbapenem-resistant Enterobacterales/Enterobacteriaceae (CRE) in Indonesia: protocol for systematic review and meta-analysis [version 1; peer review: 2 approved with reservations]. F1000Research 2024, 13:1244 (https://doi.org/10.12688/f1000research.157380.1) First published: 17 Oct 2024, 13:1244 (https://doi.org/10.12688/f1000research.157380.1) Latest published: 10 Mar 2025, 13:1244 (https://doi.org/10.12688/f1000research.157380.2)

Introduction

The emergence of carbapenem-resistant Enterobacterales (CRE) is a global health challenge, with Southeast Asia experiencing particularly high prevalence rates of these multidrug-resistant organisms. The widespread dissemination of carbapenemase-producing Enterobacteriaceae (CPE) has been well documented, driven by both clonal expansion and horizontal gene transfer.^1,2 Within Southeast Asia, including Indonesia, carbapenem resistance rates are among the highest globally, with some healthcare settings reporting resistance rates exceeding 30%.^3,4 This trend underscores the urgency of implementing targeted interventions to curtail the spread of CRE.

Carbapenem resistance in Enterobacterales is mediated through complex mechanisms. The primary mechanism is the production of various carbapenemases such as Klebsiella pneumoniae carbapenemase (KPC), New Delhi metallo-β-lactamase (NDM), and oxacillinase-48 (OXA-48).^5,6 These enzymes degrade carbapenems, rendering them ineffective against infections once treatable with these last-resort antibiotics. Furthermore, resistance is compounded by additional factors such as efflux pumps and modifications to porin channels, further complicating therapeutic options.^7,8 A comprehensive understanding of these mechanisms is essential to developing effective surveillance and intervention strategies for CRE control in Indonesia.

In Indonesia, studies suggest that the prevalence of CRE varies across different regions. The variation is influenced by factors like antibiotic usage patterns, healthcare practices, and the presence of specific resistance genes.^9,10 This systematic review and meta-analysis will critically assess the prevalence and mechanisms of CRE resistance in Indonesia, contributing to the global effort to combat this escalating health crisis. The findings aim to inform healthcare policy and improve the management of CRE infections both within Indonesia and on a broader scale.

Protocol

Review question

This review seeks to answer the following question: What is the prevalence, antimicrobial resistance patterns, and clinical outcomes of Carbapenem-resistant Enterobacterales/Enterobacteriaceae (CRE) infections in Indonesia?

Study design and protocol registration

This systematic review and meta-analysis are designed to estimate the pooled prevalence of Carbapenem-resistant Enterobacterales (CRE) in Indonesia from 2004 to 2024, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) guidelines.¹¹ The PRISMA-P Checklist is detailed in the Extended data. The review will systematically identify and analyze published studies to provide a comprehensive assessment of CRE prevalence, trends, and resistance mechanisms across different settings in Indonesia. The review protocol has been registered in the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD42024580177.

Data source and search strategy

An exhaustive database search was conducted to gather all pertinent articles on Carbapenem-resistant Enterobacterales (CRE) in Indonesia, covering the period from January 1, 2004, to the start of this study. Publications in both English and Indonesian were sought in databases including PubMed, Google Scholar, Scopus, and Southeast Asian Index Medicus between January 1, 2004 and the start of this study, 2024. Additionally, a manual search using Google was performed to screen the references of identified articles, ensuring comprehensiveness and the inclusion of potentially missed studies.

The search strategy was developed using the CoCoPop (Condition, Context, Population) framework to structure the search questions and terms. The search terms included: (“Carbapenem-resistant Enterobacterales”), (CRE), (“prevalence”), and (“Indonesia”). These terms were combined using Boolean operators “OR” and “AND” to optimize and refine the search, ensuring the retrieval of all relevant articles. The search strategy is detailed in Appendix 1 (Extended data), and the flowchart of this systematic review is depicted in Appendix 2 (Extended data).

Eligibility criteria

This review includes studies involving patients or clinical isolates from all age groups (neonates, children, adults) that have been tested for Carbapenem-resistant Enterobacterales (CRE) in both community-acquired and hospital-acquired (nosocomial) infections. Only studies conducted in Indonesia will be included to ensure accurate representation of local epidemiology and CRE burden. The eligible study designs include observational studies (cohort, cross-sectional, case-control) and clinical trials that report on the prevalence, resistance patterns, clinical outcomes, or any measure of disease burden related to CRE. Both published and grey literature (e.g., theses, dissertations, conference proceedings) in English and Indonesian will be considered. Studies must report specific outcomes, such as prevalence rates, antimicrobial resistance profiles, morbidity, mortality, or length of hospital stay associated with CRE infections.

Exclusion criteria include studies conducted outside of Indonesia or those that do not provide relevant data to the Indonesian context. Review articles, meta-analyses, systematic reviews, editorials, and opinion pieces are excluded. Additionally, studies focusing on non-human subjects, including veterinary medicine, agriculture (e.g., livestock, aquaculture), or environmental sampling (e.g., water, soil) are excluded unless directly related to human health outcomes. Studies that fail to report specific data on CRE are also excluded, as well as case reports and case series due to potential bias and challenges in generalizing findings from individual cases or small samples.

Data extraction

A structured data extraction approach will be employed for this systematic review and meta-analysis. Initially, two authors will independently screen studies based on their titles and abstracts. Subsequently, full-text articles will be thoroughly reviewed using the predetermined inclusion and exclusion criteria to identify relevant data. A predefined data extraction sheet will be used to systematically record all relevant details from selected studies. Key information to be extracted includes authors, publication year, title, study name, the year the study was conducted, study site (city, province, region), study design, study setting (hospital, community), population (age group), sampling site, comorbidities, CRE detection method, total sample/total isolates, CRE prevalence, upper-lower confidence intervals (CI), CRE prevalence from specific pathogens (e.g., Escherichia coli and Klebsiella pneumoniae), and clinical outcomes other than prevalence (e.g., mortality, survival). Data extraction will be conducted by two authors, and a third author will cross-verify the retrieved data during the analysis phase to ensure accuracy and consistency.

Quality assessment

The quality of the included studies will be assessed by two authors using a modified version of the Newcastle-Ottawa Scale (NOS) for observational studies. Studies receiving 0-3 stars will be considered poor quality, those with 4-5 stars acceptable, and those with 6-9 stars high quality. In cases of disagreement between the reviewers, consensus will be reached through discussion.

Outcome variables

The primary outcome of this systematic review and meta-analysis is to determine the pooled prevalence of CRE in Indonesia. Secondary outcomes include the pooled prevalence of CRE by region, the prevalence in adults versus children, and the prevalence in hospital versus community settings. The review will also examine the prevalence of the most common CRE pathogens.

Statistical analysis

A random effects model will be applied to estimate the pooled prevalence and antimicrobial resistance patterns of CRE. Subgroup and meta-regression analyses will be conducted to explore potential sources of heterogeneity. Heterogeneity between studies will be quantified using Cochran’s Q test and I² statistics, with a p-value of <0.05 indicating significant heterogeneity. The Der Simonian-Laird random effects model will account for this variability. Meta-Essentials, a tool compatible with Microsoft Excel, will be used for analysis. Subgroup analyses will focus on region, age group, hospital versus community settings, and specific pathogens. Results will be presented in tabular form and forest plots, and publication bias will be assessed using funnel plot symmetry.

Dissemination

Upon completion, the systematic review will be sent for publication in a peer-reviewed journal.

Study status

This study has not been started yet.

Discussion

This systematic review and meta-analysis aim to provide a comprehensive overview of Carbapenem-resistant Enterobacterales (CRE) in Indonesia. The findings are expected to shed light on the growing prevalence of CRE, particularly in hospital settings, which mirrors global trends in antimicrobial resistance. This study’s results will be pivotal for shaping infection control policies and antimicrobial stewardship programs within Indonesia’s healthcare system, highlighting the need for enhanced surveillance and targeted interventions.

Regional variations in CRE prevalence are likely to emerge, influenced by disparities in healthcare infrastructure, antimicrobial usage, and infection control practices. These variations may underscore the need for localized strategies in regions with a higher burden of CRE. Additionally, the study will assess the prevalence across different population groups and between hospital and community settings, which could reveal the spread of CRE beyond healthcare facilities, complicating containment efforts and necessitating broader public health interventions.

While this review offers critical insights, it may face challenges such as heterogeneity in study designs, diagnostic methods, and the potential for publication bias. Subgroup and meta-regression analyses will be employed to address these limitations, but caution is warranted when interpreting the pooled data. Nevertheless, this analysis will provide crucial information for guiding national policies on antimicrobial resistance and informing future research and interventions to mitigate the threat posed by CRE in Indonesia.

Ethical considerations

This systematic review is based on the analysis of published articles (secondary data) and does not require approval by an ethics committee.

Data availability

Underlying data

No data are associated with this article.

Extended data

Figshare: Extended dataset for: “Carbapenem-resistant Enterobacterales/Enterobacteriaceae (CRE) in Indonesia: protocol for systematic review and meta-analysis.”, https://doi.org/10.6084/m9.figshare.27134661.v5.¹²

This project contains the following extended data:

1. Appendix 1. Search strategy for Pubmed
2. Appendix 2. PRISMA Flowchart
3. PRISMA-P checklist

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

Reporting guidelines

Figshare: PRISMA-P checklist for ‘Carbapenem-resistant Enterobacterales/Enterobacteriaceae (CRE) in Indonesia: protocol for systematic review and meta-analysis’, https://doi.org/10.6084/m9.figshare.27134661.v5.¹²

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

References

1. Logan LK, Weinstein RA: The Epidemiology of Carbapenem-Resistant Enterobacteriaceae: The Impact and Evolution of a Global Menace. J. Infect. Dis. 2017; 215(suppl_1): S28–S36. PubMed Abstract | Publisher Full Text | Free Full Text
2. Duin D v, Doi Y: The Global Epidemiology of Carbapenemase-Producing Enterobacteriaceae. Virulence. 2016; 8(4): 460–469.
3. Hsu LY, Apisarnthanarak A, Khan E, et al.: Carbapenem-Resistant Acinetobacter Baumannii and Enterobacteriaceae in South and Southeast Asia. Clin. Microbiol. Rev. 2017; 30(1): 1–22. PubMed Abstract | Publisher Full Text | Free Full Text
4. Potter RF, D’Souza AW, Dantas G: The Rapid Spread of Carbapenem-Resistant Enterobacteriaceae. Drug Resist. Updat. 2016; 29: 30–46. PubMed Abstract | Publisher Full Text | Free Full Text
5. Mekonnen Y: Fecal Carriage of Carbapenem Resistant Enterobacterales and Associated Factors Among Admitted Patients in Saint Paul’s Hospital Millennium Medical College, Addis Ababa, Ethiopia. Infect. Drug Resist. 2023; 16: 6345–6355. PubMed Abstract | Publisher Full Text | Free Full Text
6. Iovleva A, Doi Y: Carbapenem-Resistant Enterobacteriaceae. Clin. Lab. Med. 2017; 37(2): 303–315. PubMed Abstract | Publisher Full Text | Free Full Text
7. Jaggi N, Chatterjee N, Singh V, et al.: Carbapenem Resistance in Escherichia Coli and Klebsiella Pneumoniae Among Indian and International Patients in North India. Acta Microbiol. Immunol. Hung. 2019; 66(3): 367–376. PubMed Abstract | Publisher Full Text
8. Paveenkittiporn W, Lyman M, Biedron C, et al.: Molecular Epidemiology of Carbapenem-Resistant Enterobacterales in Thailand, 2016–2018. Antimicrob Resist. Infect. Control. 2021; 10(1). Publisher Full Text
9. Musa AY: Detection of Carbapenem Resistance Among Enterobacteriaceae Pathogens Isolated From Clinical Samples in Shendi Locality. Middle East Res. J. Microbiol. Biotechnol. 2023; 3(02): 43–47. Publisher Full Text
10. Ali SY, Malik T: Detection of Carbapenem Resistant Klebsiella Species Isolated From Clinical Samples. Pure Appl. Biol. 2020; 9(2). Publisher Full Text
11. Sarkis-Onofre R, Catalá-López F, Aromataris E, et al.: How to properly use the PRISMA Statement. Syst. Rev. 2021; 10: 1–3.
12. Kadariswantiningsih IN, Empitu MA: Extended Dataset for “Carbapenem-resistant Enterobacterales/Enterobacteriaceae (CRE) in Indonesia: protocol for systematic review and meta-analysis”. Dataset. figshare. 2024. Publisher Full Text

Comments on this article Comments (0)

Version 2

VERSION 2 PUBLISHED 17 Oct 2024

Author details Author details

Bulat Idrisov
Roles: Conceptualization, Methodology, Supervision, Writing – Original Draft Preparation

Derren David Christian Homenta Rampengan
Roles: Formal Analysis, Investigation, Methodology, Software, Writing – Original Draft Preparation

Roy Novri Ramadhan
Roles: Data Curation, Formal Analysis, Investigation, Methodology, Visualization, Writing – Original Draft Preparation

Competing interests

No competing interests were disclosed.

Grant information

The author(s) declared that no grants were involved in supporting this work.

Article Versions (2)

version 2

Revised

Published: 10 Mar 2025, 13:1244

https://doi.org/10.12688/f1000research.157380.2

version 1

Published: 17 Oct 2024, 13:1244

https://doi.org/10.12688/f1000research.157380.1

© 2024 Kadariswantiningsih IN et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Kadariswantiningsih IN, Empitu MA, Idrisov B et al. Carbapenem-resistant Enterobacterales/Enterobacteriaceae (CRE) in Indonesia: protocol for systematic review and meta-analysis [version 1; peer review: 2 approved with reservations]. F1000Research 2024, 13:1244 (https://doi.org/10.12688/f1000research.157380.1)

NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.

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Open Peer Review

Version 1

VERSION 1

PUBLISHED 17 Oct 2024

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Reviewer Report 26 Feb 2025

Ingrid Maribel Leon Moreno, Department of Veterinary Pathobiology, Texas A&M University (Ringgold ID: 14736), College Station, Texas, USA

Harvey Morgan Scott, Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA

Approved with Reservations

https://doi.org/10.5256/f1000research.172818.r365246

Explain why the treatment with the carbapenem family is so very important for human health. It likely seems self-evident to many, but if the cited prevalence data of ~30% are correct, does finding a CRE in a patient indicate treatment failure, or other outcomes (surveillance for quarantine of patients, etc).
Please indicate briefly that carbapenemase enzymes also break down other ‘lower-order'beta-lactam antibiotics such as third and fourth generation cephalosporins so impact is on almost all beta-lactams used for Enterobacterales and not just carbapenems.
Should the NOS scale have a cited reference?

Data source and search strategy

The search coverage in the body of the manuscript was from January 1, 2004 to 2024. Note that the abstract says only from 2008. There is an inconsistency. Was something discovered regarding the available papers from the first 4 years to render them less useful and therefore excluded? Some genes had yet to be discovered/characterized (e.g., NDM-1 in 2008). Is this the reason? If so please explain.
Abbreviations should be explained when mentioned for the first time, for example, MDR and XDR
Smaller Indonesian islands (e.g., Nussa Tenggara Islands and Maluku Islands) were not included in the search for geographical locations in Indonesia. Exclusion criteria should likewise be mentioned and likely impacts on search (i.e., will search under ‘Indonesia’ capture these?).
What is the impact of not including the specific search strategy of antimicrobial resistance via the carbapenemase genes, since that is included in the scope of interest. For instance: NDM, KPC, etc. Will the other search terms ensure papers focused on the genetic elements be captured?

Statistical analysis

Please explain how the random effects model will be used to estimate the pooled prevalence and the antimicrobial resistance patterns of CRE?
Is the Meta-Essentials tool, the Excel compatible software used to do the analysis capable of conducting the random effects model above? A quick looks at the software website at Erasmus University does not make this clear.

Funding statement
Please check if the below are required for published protocols. These are common for publishing results, but it is not clear to me if these aspects of disclosure are needed at this stage.

It is important to explain who the sponsors and funders of the study are.
In the protocol, it should be clear the involvement and potential influence of any party.
In the protocol, it should outline the roles and responsibilities of the contributors in study design, data analysis and interpretation, writing, and dissemination of results.

Is the rationale for, and objectives of, the study clearly described?

Yes
Is the study design appropriate for the research question?

Yes
Are sufficient details of the methods provided to allow replication by others?

Partly
Are the datasets clearly presented in a useable and accessible format?

Not applicable

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Epidemiology, Antimicrobial Resistance Research, Foodborne Pathogens, Microbiology

We confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however we have significant reservations, as outlined above.

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Author Response 10 Mar 2025

IKA NINDYA, Department of Medical Microbiology, Faculty of Medicine, Airlangga University, Surabaya, Indonesia

10 Mar 2025

Author Response

The manuscript by Kadariswantiningsih and co-authors represents a protocol for the systematic review and meta-analysis of Carbapenem-resistant Enterobacterales/ Enterobacteriaceae (CRE) regarding the prevalence of CRE in Indonesia and via various ... Continue reading The manuscript by Kadariswantiningsih and co-authors represents a protocol for the systematic review and meta-analysis of Carbapenem-resistant Enterobacterales/ Enterobacteriaceae (CRE) regarding the prevalence of CRE in Indonesia and via various subgroups and characteristics. The protocol offers valuable insights, though it requires some minor improvements as outlined in the specific examples below.

Response: Thank you for your encouraging and positive comments. Your suggestion helps us to improved the protocol and manuscript.

Comments and edits:
INTRODUCTION

1. Explain why the treatment with the carbapenem family is so very important for human health. It likely seems self-evident to many, but if the cited prevalence data of ~30% are correct, does finding a CRE in a patient indicate treatment failure, or other outcomes (surveillance for quarantine of patients, etc).
Response: We have revised the introduction and add the explanation about this in paragraph 1.

2. Please indicate briefly that carbapenemase enzymes also break down other ‘lower-order'beta-lactam antibiotics such as third and fourth generation cephalosporins so impact is on almost all beta-lactams used for Enterobacterales and not just carbapenems.
Response: We have revised the introduction and add the explanation about this in paragraph 2.

3. Should the NOS scale have a cited reference?
Response: We have added a reference about NOS.

DATA SOURCE AND SEARCH STRATEGY

1. The search coverage in the body of the manuscript was from January 1, 2004 to 2024. Note that the abstract says only from 2008. There is an inconsistency. Was something discovered regarding the available papers from the first 4 years to render them less useful and therefore excluded? Some genes had yet to be discovered/characterized (e.g., NDM-1 in 2008). Is this the reason? If so please explain.
Response: We apologize for the mistake. We have changed the abstract text to 2004 instead of 2008. We want to capture the trends within the last 20 years.

2. Abbreviations should be explained when mentioned for the first time, for example, MDR and XDR
Response: In the revised manuscript, we have explained those abbreviations when when mentioned for the first time.

3. Smaller Indonesian islands (e.g., Nussa Tenggara Islands and Maluku Islands) were not included in the search for geographical locations in Indonesia. Exclusion criteria should likewise be mentioned and likely impacts on search (i.e., will search under ‘Indonesia’ capture these?).
Response: We have revised the search strategy to include other smaller islands such as Bali, Nusa Tenggara, Timor and Maluku. The exclusion criteria are mentioned in the “Eligibility Criteria” section and will be used during the screening of title, abstract and full-text.

4. What is the impact of not including the specific search strategy of antimicrobial resistance via the carbapenemase genes, since that is included in the scope of interest. For instance: NDM, KPC, etc. Will the other search terms ensure papers focused on the genetic elements be captured?Response: Thank you for the suggestion. Wee include the following keywords to the new search strategy:
("Carbapenem resistance"[MeSH] OR "Antimicrobial resistance"[MeSH] OR "Multidrug-resistant organisms"[MeSH] OR "MDR"[Title/Abstract] OR "XDR"[Title/Abstract] OR "Carbapenemase" OR "Carbapenem resistance" OR "Carbapenem-resistant" OR "Beta-lactamase" OR "β-lactamase" OR ("bla_KPC" OR "bla_NDM" OR "bla_OXA-48" OR "bla_OXA-181" OR "bla_OXA-232" OR "bla_OXA-58" OR "bla_OXA-244" OR "bla_IMP" OR "bla_VIM" OR "bla_GES" OR "bla_SME" OR "bla_KHM" OR "bla_DIM" OR "bla_AIM" OR "bla_FIM" OR "bla_SPM" OR "bla_BIC" OR "bla_IMI" OR "bla_CGB" OR "bla_CCR")

STATISTICAL ANALYSIS
1. Please explain how the random effects model will be used to estimate the pooled prevalence and the antimicrobial resistance patterns of CRE?
Response: We have added these explanation in the revised manuscript, “Statistical Analysis” section:
“A random effects model will be applied to estimate the pooled prevalence and antimicrobial resistance patterns of CRE. Prevalence and resistance rates will be extracted as proportions and transformed using logit transformation to stabilize variance. The pooled estimates will be calculated using inverse variance weighting, incorporating both the within-study variance and between-study variance (τ²), which will be estimated using the DerSimonian-Laird method.”

2. Is the Meta-Essentials tool, the Excel compatible software used to do the analysis capable of conducting the random effects model above? A quick looks at the software website at Erasmus University does not make this clear.
Response: Thank you for your concern. The tool is capable of conducting the random effect model as validated here: Suurmond, R., van Rhee, H., & Hak, T. (2017). Introduction, comparison, and validation of Meta‐Essentials: a free and simple tool for meta‐analysis. Research synthesis methods, 8(4), 537-553.

FUNDING STATEMENT
Please check if the below are required for published protocols. These are common for publishing results, but it is not clear to me if these aspects of disclosure are needed at this stage.

1. It is important to explain who the sponsors and funders of the study are.
Response: In the Grant information section and Funding Section, we mentioned “The author(s) declared that no grants were involved in supporting this work.” (https://f1000research.com/articles/13-1244/v1)

2. In the protocol, it should be clear the involvement and potential influence of any party.Response: We have added this sentence to the “Ethical consideration” statement: “The analysis and interpretation will be conducted independently by the authors, ensuring that no external influence affects the findings.” In the “Competing interests”, we write: “No competing interests were disclosed.”

3. In the protocol, it should outline the roles and responsibilities of the contributors in study design, data analysis and interpretation, writing, and dissemination of results.
Response: We added the following section:
Author Contribution Statement:
The roles and responsibilities of the contributors in this study will be as follows: INK will conceptualize the study, design the methodology, supervise the research process, and contribute to data analysis, interpretation, and manuscript drafting; MAE and RNR will participate in data collection, statistical analysis, and interpretation of findings; BI will provide expertise in systematic review methodology and meta-analysis, ensuring adherence to best practices; DDCHR will assist in literature screening, data extraction, and manuscript writing. All authors will review and approve the final manuscript and contribute to the dissemination of results.
The manuscript by Kadariswantiningsih and co-authors represents a protocol for the systematic review and meta-analysis of Carbapenem-resistant Enterobacterales/ Enterobacteriaceae (CRE) regarding the prevalence of CRE in Indonesia and via various subgroups and characteristics. The protocol offers valuable insights, though it requires some minor improvements as outlined in the specific examples below.

Response: Thank you for your encouraging and positive comments. Your suggestion helps us to improved the protocol and manuscript.

Comments and edits:
INTRODUCTION

1. Explain why the treatment with the carbapenem family is so very important for human health. It likely seems self-evident to many, but if the cited prevalence data of ~30% are correct, does finding a CRE in a patient indicate treatment failure, or other outcomes (surveillance for quarantine of patients, etc).
Response: We have revised the introduction and add the explanation about this in paragraph 1.

2. Please indicate briefly that carbapenemase enzymes also break down other ‘lower-order'beta-lactam antibiotics such as third and fourth generation cephalosporins so impact is on almost all beta-lactams used for Enterobacterales and not just carbapenems.
Response: We have revised the introduction and add the explanation about this in paragraph 2.

3. Should the NOS scale have a cited reference?
Response: We have added a reference about NOS.

DATA SOURCE AND SEARCH STRATEGY

1. The search coverage in the body of the manuscript was from January 1, 2004 to 2024. Note that the abstract says only from 2008. There is an inconsistency. Was something discovered regarding the available papers from the first 4 years to render them less useful and therefore excluded? Some genes had yet to be discovered/characterized (e.g., NDM-1 in 2008). Is this the reason? If so please explain.
Response: We apologize for the mistake. We have changed the abstract text to 2004 instead of 2008. We want to capture the trends within the last 20 years.

2. Abbreviations should be explained when mentioned for the first time, for example, MDR and XDR
Response: In the revised manuscript, we have explained those abbreviations when when mentioned for the first time.

3. Smaller Indonesian islands (e.g., Nussa Tenggara Islands and Maluku Islands) were not included in the search for geographical locations in Indonesia. Exclusion criteria should likewise be mentioned and likely impacts on search (i.e., will search under ‘Indonesia’ capture these?).
Response: We have revised the search strategy to include other smaller islands such as Bali, Nusa Tenggara, Timor and Maluku. The exclusion criteria are mentioned in the “Eligibility Criteria” section and will be used during the screening of title, abstract and full-text.

4. What is the impact of not including the specific search strategy of antimicrobial resistance via the carbapenemase genes, since that is included in the scope of interest. For instance: NDM, KPC, etc. Will the other search terms ensure papers focused on the genetic elements be captured?Response: Thank you for the suggestion. Wee include the following keywords to the new search strategy:
("Carbapenem resistance"[MeSH] OR "Antimicrobial resistance"[MeSH] OR "Multidrug-resistant organisms"[MeSH] OR "MDR"[Title/Abstract] OR "XDR"[Title/Abstract] OR "Carbapenemase" OR "Carbapenem resistance" OR "Carbapenem-resistant" OR "Beta-lactamase" OR "β-lactamase" OR ("bla_KPC" OR "bla_NDM" OR "bla_OXA-48" OR "bla_OXA-181" OR "bla_OXA-232" OR "bla_OXA-58" OR "bla_OXA-244" OR "bla_IMP" OR "bla_VIM" OR "bla_GES" OR "bla_SME" OR "bla_KHM" OR "bla_DIM" OR "bla_AIM" OR "bla_FIM" OR "bla_SPM" OR "bla_BIC" OR "bla_IMI" OR "bla_CGB" OR "bla_CCR")

STATISTICAL ANALYSIS
1. Please explain how the random effects model will be used to estimate the pooled prevalence and the antimicrobial resistance patterns of CRE?
Response: We have added these explanation in the revised manuscript, “Statistical Analysis” section:
“A random effects model will be applied to estimate the pooled prevalence and antimicrobial resistance patterns of CRE. Prevalence and resistance rates will be extracted as proportions and transformed using logit transformation to stabilize variance. The pooled estimates will be calculated using inverse variance weighting, incorporating both the within-study variance and between-study variance (τ²), which will be estimated using the DerSimonian-Laird method.”

2. Is the Meta-Essentials tool, the Excel compatible software used to do the analysis capable of conducting the random effects model above? A quick looks at the software website at Erasmus University does not make this clear.
Response: Thank you for your concern. The tool is capable of conducting the random effect model as validated here: Suurmond, R., van Rhee, H., & Hak, T. (2017). Introduction, comparison, and validation of Meta‐Essentials: a free and simple tool for meta‐analysis. Research synthesis methods, 8(4), 537-553.

FUNDING STATEMENT
Please check if the below are required for published protocols. These are common for publishing results, but it is not clear to me if these aspects of disclosure are needed at this stage.

1. It is important to explain who the sponsors and funders of the study are.
Response: In the Grant information section and Funding Section, we mentioned “The author(s) declared that no grants were involved in supporting this work.” (https://f1000research.com/articles/13-1244/v1)

2. In the protocol, it should be clear the involvement and potential influence of any party.Response: We have added this sentence to the “Ethical consideration” statement: “The analysis and interpretation will be conducted independently by the authors, ensuring that no external influence affects the findings.” In the “Competing interests”, we write: “No competing interests were disclosed.”

3. In the protocol, it should outline the roles and responsibilities of the contributors in study design, data analysis and interpretation, writing, and dissemination of results.
Response: We added the following section:
Author Contribution Statement:
The roles and responsibilities of the contributors in this study will be as follows: INK will conceptualize the study, design the methodology, supervise the research process, and contribute to data analysis, interpretation, and manuscript drafting; MAE and RNR will participate in data collection, statistical analysis, and interpretation of findings; BI will provide expertise in systematic review methodology and meta-analysis, ensuring adherence to best practices; DDCHR will assist in literature screening, data extraction, and manuscript writing. All authors will review and approve the final manuscript and contribute to the dissemination of results.
Competing Interests: No competing interests were disclosed. Close
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COMMENTS ON THIS REPORT

Author Response 10 Mar 2025

IKA NINDYA, Department of Medical Microbiology, Faculty of Medicine, Airlangga University, Surabaya, Indonesia

10 Mar 2025

Author Response

The manuscript by Kadariswantiningsih and co-authors represents a protocol for the systematic review and meta-analysis of Carbapenem-resistant Enterobacterales/ Enterobacteriaceae (CRE) regarding the prevalence of CRE in Indonesia and via various ... Continue reading The manuscript by Kadariswantiningsih and co-authors represents a protocol for the systematic review and meta-analysis of Carbapenem-resistant Enterobacterales/ Enterobacteriaceae (CRE) regarding the prevalence of CRE in Indonesia and via various subgroups and characteristics. The protocol offers valuable insights, though it requires some minor improvements as outlined in the specific examples below.

Response: Thank you for your encouraging and positive comments. Your suggestion helps us to improved the protocol and manuscript.

Comments and edits:
INTRODUCTION

1. Explain why the treatment with the carbapenem family is so very important for human health. It likely seems self-evident to many, but if the cited prevalence data of ~30% are correct, does finding a CRE in a patient indicate treatment failure, or other outcomes (surveillance for quarantine of patients, etc).
Response: We have revised the introduction and add the explanation about this in paragraph 1.

2. Please indicate briefly that carbapenemase enzymes also break down other ‘lower-order'beta-lactam antibiotics such as third and fourth generation cephalosporins so impact is on almost all beta-lactams used for Enterobacterales and not just carbapenems.
Response: We have revised the introduction and add the explanation about this in paragraph 2.

3. Should the NOS scale have a cited reference?
Response: We have added a reference about NOS.

DATA SOURCE AND SEARCH STRATEGY

1. The search coverage in the body of the manuscript was from January 1, 2004 to 2024. Note that the abstract says only from 2008. There is an inconsistency. Was something discovered regarding the available papers from the first 4 years to render them less useful and therefore excluded? Some genes had yet to be discovered/characterized (e.g., NDM-1 in 2008). Is this the reason? If so please explain.
Response: We apologize for the mistake. We have changed the abstract text to 2004 instead of 2008. We want to capture the trends within the last 20 years.

2. Abbreviations should be explained when mentioned for the first time, for example, MDR and XDR
Response: In the revised manuscript, we have explained those abbreviations when when mentioned for the first time.

3. Smaller Indonesian islands (e.g., Nussa Tenggara Islands and Maluku Islands) were not included in the search for geographical locations in Indonesia. Exclusion criteria should likewise be mentioned and likely impacts on search (i.e., will search under ‘Indonesia’ capture these?).
Response: We have revised the search strategy to include other smaller islands such as Bali, Nusa Tenggara, Timor and Maluku. The exclusion criteria are mentioned in the “Eligibility Criteria” section and will be used during the screening of title, abstract and full-text.

4. What is the impact of not including the specific search strategy of antimicrobial resistance via the carbapenemase genes, since that is included in the scope of interest. For instance: NDM, KPC, etc. Will the other search terms ensure papers focused on the genetic elements be captured?Response: Thank you for the suggestion. Wee include the following keywords to the new search strategy:
("Carbapenem resistance"[MeSH] OR "Antimicrobial resistance"[MeSH] OR "Multidrug-resistant organisms"[MeSH] OR "MDR"[Title/Abstract] OR "XDR"[Title/Abstract] OR "Carbapenemase" OR "Carbapenem resistance" OR "Carbapenem-resistant" OR "Beta-lactamase" OR "β-lactamase" OR ("bla_KPC" OR "bla_NDM" OR "bla_OXA-48" OR "bla_OXA-181" OR "bla_OXA-232" OR "bla_OXA-58" OR "bla_OXA-244" OR "bla_IMP" OR "bla_VIM" OR "bla_GES" OR "bla_SME" OR "bla_KHM" OR "bla_DIM" OR "bla_AIM" OR "bla_FIM" OR "bla_SPM" OR "bla_BIC" OR "bla_IMI" OR "bla_CGB" OR "bla_CCR")

STATISTICAL ANALYSIS
1. Please explain how the random effects model will be used to estimate the pooled prevalence and the antimicrobial resistance patterns of CRE?
Response: We have added these explanation in the revised manuscript, “Statistical Analysis” section:
“A random effects model will be applied to estimate the pooled prevalence and antimicrobial resistance patterns of CRE. Prevalence and resistance rates will be extracted as proportions and transformed using logit transformation to stabilize variance. The pooled estimates will be calculated using inverse variance weighting, incorporating both the within-study variance and between-study variance (τ²), which will be estimated using the DerSimonian-Laird method.”

2. Is the Meta-Essentials tool, the Excel compatible software used to do the analysis capable of conducting the random effects model above? A quick looks at the software website at Erasmus University does not make this clear.
Response: Thank you for your concern. The tool is capable of conducting the random effect model as validated here: Suurmond, R., van Rhee, H., & Hak, T. (2017). Introduction, comparison, and validation of Meta‐Essentials: a free and simple tool for meta‐analysis. Research synthesis methods, 8(4), 537-553.

FUNDING STATEMENT
Please check if the below are required for published protocols. These are common for publishing results, but it is not clear to me if these aspects of disclosure are needed at this stage.

1. It is important to explain who the sponsors and funders of the study are.
Response: In the Grant information section and Funding Section, we mentioned “The author(s) declared that no grants were involved in supporting this work.” (https://f1000research.com/articles/13-1244/v1)

2. In the protocol, it should be clear the involvement and potential influence of any party.Response: We have added this sentence to the “Ethical consideration” statement: “The analysis and interpretation will be conducted independently by the authors, ensuring that no external influence affects the findings.” In the “Competing interests”, we write: “No competing interests were disclosed.”

3. In the protocol, it should outline the roles and responsibilities of the contributors in study design, data analysis and interpretation, writing, and dissemination of results.
Response: We added the following section:
Author Contribution Statement:
The roles and responsibilities of the contributors in this study will be as follows: INK will conceptualize the study, design the methodology, supervise the research process, and contribute to data analysis, interpretation, and manuscript drafting; MAE and RNR will participate in data collection, statistical analysis, and interpretation of findings; BI will provide expertise in systematic review methodology and meta-analysis, ensuring adherence to best practices; DDCHR will assist in literature screening, data extraction, and manuscript writing. All authors will review and approve the final manuscript and contribute to the dissemination of results.
The manuscript by Kadariswantiningsih and co-authors represents a protocol for the systematic review and meta-analysis of Carbapenem-resistant Enterobacterales/ Enterobacteriaceae (CRE) regarding the prevalence of CRE in Indonesia and via various subgroups and characteristics. The protocol offers valuable insights, though it requires some minor improvements as outlined in the specific examples below.

Response: Thank you for your encouraging and positive comments. Your suggestion helps us to improved the protocol and manuscript.

Comments and edits:
INTRODUCTION

1. Explain why the treatment with the carbapenem family is so very important for human health. It likely seems self-evident to many, but if the cited prevalence data of ~30% are correct, does finding a CRE in a patient indicate treatment failure, or other outcomes (surveillance for quarantine of patients, etc).
Response: We have revised the introduction and add the explanation about this in paragraph 1.

2. Please indicate briefly that carbapenemase enzymes also break down other ‘lower-order'beta-lactam antibiotics such as third and fourth generation cephalosporins so impact is on almost all beta-lactams used for Enterobacterales and not just carbapenems.
Response: We have revised the introduction and add the explanation about this in paragraph 2.

3. Should the NOS scale have a cited reference?
Response: We have added a reference about NOS.

DATA SOURCE AND SEARCH STRATEGY

1. The search coverage in the body of the manuscript was from January 1, 2004 to 2024. Note that the abstract says only from 2008. There is an inconsistency. Was something discovered regarding the available papers from the first 4 years to render them less useful and therefore excluded? Some genes had yet to be discovered/characterized (e.g., NDM-1 in 2008). Is this the reason? If so please explain.
Response: We apologize for the mistake. We have changed the abstract text to 2004 instead of 2008. We want to capture the trends within the last 20 years.

2. Abbreviations should be explained when mentioned for the first time, for example, MDR and XDR
Response: In the revised manuscript, we have explained those abbreviations when when mentioned for the first time.

3. Smaller Indonesian islands (e.g., Nussa Tenggara Islands and Maluku Islands) were not included in the search for geographical locations in Indonesia. Exclusion criteria should likewise be mentioned and likely impacts on search (i.e., will search under ‘Indonesia’ capture these?).
Response: We have revised the search strategy to include other smaller islands such as Bali, Nusa Tenggara, Timor and Maluku. The exclusion criteria are mentioned in the “Eligibility Criteria” section and will be used during the screening of title, abstract and full-text.

4. What is the impact of not including the specific search strategy of antimicrobial resistance via the carbapenemase genes, since that is included in the scope of interest. For instance: NDM, KPC, etc. Will the other search terms ensure papers focused on the genetic elements be captured?Response: Thank you for the suggestion. Wee include the following keywords to the new search strategy:
("Carbapenem resistance"[MeSH] OR "Antimicrobial resistance"[MeSH] OR "Multidrug-resistant organisms"[MeSH] OR "MDR"[Title/Abstract] OR "XDR"[Title/Abstract] OR "Carbapenemase" OR "Carbapenem resistance" OR "Carbapenem-resistant" OR "Beta-lactamase" OR "β-lactamase" OR ("bla_KPC" OR "bla_NDM" OR "bla_OXA-48" OR "bla_OXA-181" OR "bla_OXA-232" OR "bla_OXA-58" OR "bla_OXA-244" OR "bla_IMP" OR "bla_VIM" OR "bla_GES" OR "bla_SME" OR "bla_KHM" OR "bla_DIM" OR "bla_AIM" OR "bla_FIM" OR "bla_SPM" OR "bla_BIC" OR "bla_IMI" OR "bla_CGB" OR "bla_CCR")

STATISTICAL ANALYSIS
1. Please explain how the random effects model will be used to estimate the pooled prevalence and the antimicrobial resistance patterns of CRE?
Response: We have added these explanation in the revised manuscript, “Statistical Analysis” section:
“A random effects model will be applied to estimate the pooled prevalence and antimicrobial resistance patterns of CRE. Prevalence and resistance rates will be extracted as proportions and transformed using logit transformation to stabilize variance. The pooled estimates will be calculated using inverse variance weighting, incorporating both the within-study variance and between-study variance (τ²), which will be estimated using the DerSimonian-Laird method.”

2. Is the Meta-Essentials tool, the Excel compatible software used to do the analysis capable of conducting the random effects model above? A quick looks at the software website at Erasmus University does not make this clear.
Response: Thank you for your concern. The tool is capable of conducting the random effect model as validated here: Suurmond, R., van Rhee, H., & Hak, T. (2017). Introduction, comparison, and validation of Meta‐Essentials: a free and simple tool for meta‐analysis. Research synthesis methods, 8(4), 537-553.

FUNDING STATEMENT
Please check if the below are required for published protocols. These are common for publishing results, but it is not clear to me if these aspects of disclosure are needed at this stage.

1. It is important to explain who the sponsors and funders of the study are.
Response: In the Grant information section and Funding Section, we mentioned “The author(s) declared that no grants were involved in supporting this work.” (https://f1000research.com/articles/13-1244/v1)

2. In the protocol, it should be clear the involvement and potential influence of any party.Response: We have added this sentence to the “Ethical consideration” statement: “The analysis and interpretation will be conducted independently by the authors, ensuring that no external influence affects the findings.” In the “Competing interests”, we write: “No competing interests were disclosed.”

3. In the protocol, it should outline the roles and responsibilities of the contributors in study design, data analysis and interpretation, writing, and dissemination of results.
Response: We added the following section:
Author Contribution Statement:
The roles and responsibilities of the contributors in this study will be as follows: INK will conceptualize the study, design the methodology, supervise the research process, and contribute to data analysis, interpretation, and manuscript drafting; MAE and RNR will participate in data collection, statistical analysis, and interpretation of findings; BI will provide expertise in systematic review methodology and meta-analysis, ensuring adherence to best practices; DDCHR will assist in literature screening, data extraction, and manuscript writing. All authors will review and approve the final manuscript and contribute to the dissemination of results.
Competing Interests: No competing interests were disclosed. Close
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Reviewer Report 28 Jan 2025

Oznur Caliskan-Aydogan, Michigan State University, East Lansing, Michigan, USA

Approved with Reservations

https://doi.org/10.5256/f1000research.172818.r354977

General Comments
Methods and protocol of this manuscript is detailly documented well. However, Introduction and discussion should be extended. Conclusion and future perspectives should be included. The details and data about the mentioned reviewed papers for this manuscript have not been summarized. This manuscript need to be improved and enriched with the more literature resources and their findings.

Specific comments
Carbapenem-resistant Enterobacterales have been used by CDC since 2022, please update all Enterobacteriaceae to Enterobacterales.

CRE abbrevetion is already defined in the introduction. In each section CRE is defined several times.

In the abstract, it is mentioned resources used from 2008 to 2024. However, it is mentioned in protocol as 2004 to 2024. Please correct it.

Is the rationale for, and objectives of, the study clearly described?

Yes
Is the study design appropriate for the research question?

Yes
Are sufficient details of the methods provided to allow replication by others?

Yes
Are the datasets clearly presented in a useable and accessible format?

Partly

Competing Interests: No competing interests were disclosed.

Reviewer Expertise: Microbiology and nanotechnology

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.

CITE

Report a concern

Author Response 10 Mar 2025

IKA NINDYA, Department of Medical Microbiology, Faculty of Medicine, Airlangga University, Surabaya, Indonesia

10 Mar 2025

Author Response

General Comments
Methods and protocol of this manuscript is detailly documented well. However, Introduction and discussion should be extended. Conclusion and future perspectives should be included. The details and data ... Continue reading General Comments
Methods and protocol of this manuscript is detailly documented well. However, Introduction and discussion should be extended. Conclusion and future perspectives should be included. The details and data about the papers mentioned and reviewed for this manuscript have not been summarized. This manuscript need to be improved and enriched with the more literature resources and their findings.
Response: Thank you for your encouraging and positive comments. We add some elaboration to the previous findings and literature.

We have revised the introduction section and added an explanation about why carbapenems are important antibiotics and what the impacts of CRE are. We also add the previous finding about the significant presence of the New Delhi metallo-β-lactamase-1 (NDM-1) enzyme in Indonesia and how the prevalence rate of imipenem resistance differs from that of other countries in the same regions.

We have expanded the discussion to highlight the significant role of NDM-1 as a dominant carbapenem resistance mechanism in Indonesia, emphasizing its widespread prevalence in both urinary tract and bloodstream infections. We further elaborated on the impact of mobile genetic elements in facilitating the rapid dissemination of NDM-1-producing CRE within hospital environments, particularly affecting immunocompromised patients and those undergoing invasive procedures, with documented outbreaks in neonatal and intensive care units. Additionally, we addressed regional variations in CRE prevalence, linking higher burdens to differences in healthcare infrastructure, antimicrobial stewardship, and infection control practices while also underscoring the potential for CRE spread beyond hospital settings, necessitating broader public health interventions.

Specific comments
1. Carbapenem-resistant Enterobacterales have been used by CDC since 2022, please update all Enterobacteriaceae to Enterobacterales.
Response: We have updated all Enterobacteriaceae to Enterobacterales.

2. CRE abbrevetion is already defined in the introduction. In each section CRE is defined several times.
Response: Thank you. We have corrected all the redundant CRE descriptions.

3. In the abstract, it is mentioned resources used from 2008 to 2024. However, it is mentioned in protocol as 2004 to 2024. Please correct it.
Response: Thank you. The text in the abstract has been revised to 2004 to 2024 instead of 2008 to 2024.
General Comments
Methods and protocol of this manuscript is detailly documented well. However, Introduction and discussion should be extended. Conclusion and future perspectives should be included. The details and data about the papers mentioned and reviewed for this manuscript have not been summarized. This manuscript need to be improved and enriched with the more literature resources and their findings.
Response: Thank you for your encouraging and positive comments. We add some elaboration to the previous findings and literature.

We have revised the introduction section and added an explanation about why carbapenems are important antibiotics and what the impacts of CRE are. We also add the previous finding about the significant presence of the New Delhi metallo-β-lactamase-1 (NDM-1) enzyme in Indonesia and how the prevalence rate of imipenem resistance differs from that of other countries in the same regions.

We have expanded the discussion to highlight the significant role of NDM-1 as a dominant carbapenem resistance mechanism in Indonesia, emphasizing its widespread prevalence in both urinary tract and bloodstream infections. We further elaborated on the impact of mobile genetic elements in facilitating the rapid dissemination of NDM-1-producing CRE within hospital environments, particularly affecting immunocompromised patients and those undergoing invasive procedures, with documented outbreaks in neonatal and intensive care units. Additionally, we addressed regional variations in CRE prevalence, linking higher burdens to differences in healthcare infrastructure, antimicrobial stewardship, and infection control practices while also underscoring the potential for CRE spread beyond hospital settings, necessitating broader public health interventions.

Specific comments
1. Carbapenem-resistant Enterobacterales have been used by CDC since 2022, please update all Enterobacteriaceae to Enterobacterales.
Response: We have updated all Enterobacteriaceae to Enterobacterales.

2. CRE abbrevetion is already defined in the introduction. In each section CRE is defined several times.
Response: Thank you. We have corrected all the redundant CRE descriptions.

3. In the abstract, it is mentioned resources used from 2008 to 2024. However, it is mentioned in protocol as 2004 to 2024. Please correct it.
Response: Thank you. The text in the abstract has been revised to 2004 to 2024 instead of 2008 to 2024.
Competing Interests: No competing interests were disclosed. Close
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COMMENTS ON THIS REPORT

Author Response 10 Mar 2025

IKA NINDYA, Department of Medical Microbiology, Faculty of Medicine, Airlangga University, Surabaya, Indonesia

10 Mar 2025

Author Response

General Comments
Methods and protocol of this manuscript is detailly documented well. However, Introduction and discussion should be extended. Conclusion and future perspectives should be included. The details and data ... Continue reading General Comments
Methods and protocol of this manuscript is detailly documented well. However, Introduction and discussion should be extended. Conclusion and future perspectives should be included. The details and data about the papers mentioned and reviewed for this manuscript have not been summarized. This manuscript need to be improved and enriched with the more literature resources and their findings.
Response: Thank you for your encouraging and positive comments. We add some elaboration to the previous findings and literature.

We have revised the introduction section and added an explanation about why carbapenems are important antibiotics and what the impacts of CRE are. We also add the previous finding about the significant presence of the New Delhi metallo-β-lactamase-1 (NDM-1) enzyme in Indonesia and how the prevalence rate of imipenem resistance differs from that of other countries in the same regions.

We have expanded the discussion to highlight the significant role of NDM-1 as a dominant carbapenem resistance mechanism in Indonesia, emphasizing its widespread prevalence in both urinary tract and bloodstream infections. We further elaborated on the impact of mobile genetic elements in facilitating the rapid dissemination of NDM-1-producing CRE within hospital environments, particularly affecting immunocompromised patients and those undergoing invasive procedures, with documented outbreaks in neonatal and intensive care units. Additionally, we addressed regional variations in CRE prevalence, linking higher burdens to differences in healthcare infrastructure, antimicrobial stewardship, and infection control practices while also underscoring the potential for CRE spread beyond hospital settings, necessitating broader public health interventions.

Specific comments
1. Carbapenem-resistant Enterobacterales have been used by CDC since 2022, please update all Enterobacteriaceae to Enterobacterales.
Response: We have updated all Enterobacteriaceae to Enterobacterales.

2. CRE abbrevetion is already defined in the introduction. In each section CRE is defined several times.
Response: Thank you. We have corrected all the redundant CRE descriptions.

3. In the abstract, it is mentioned resources used from 2008 to 2024. However, it is mentioned in protocol as 2004 to 2024. Please correct it.
Response: Thank you. The text in the abstract has been revised to 2004 to 2024 instead of 2008 to 2024.
General Comments
Methods and protocol of this manuscript is detailly documented well. However, Introduction and discussion should be extended. Conclusion and future perspectives should be included. The details and data about the papers mentioned and reviewed for this manuscript have not been summarized. This manuscript need to be improved and enriched with the more literature resources and their findings.
Response: Thank you for your encouraging and positive comments. We add some elaboration to the previous findings and literature.

We have revised the introduction section and added an explanation about why carbapenems are important antibiotics and what the impacts of CRE are. We also add the previous finding about the significant presence of the New Delhi metallo-β-lactamase-1 (NDM-1) enzyme in Indonesia and how the prevalence rate of imipenem resistance differs from that of other countries in the same regions.

We have expanded the discussion to highlight the significant role of NDM-1 as a dominant carbapenem resistance mechanism in Indonesia, emphasizing its widespread prevalence in both urinary tract and bloodstream infections. We further elaborated on the impact of mobile genetic elements in facilitating the rapid dissemination of NDM-1-producing CRE within hospital environments, particularly affecting immunocompromised patients and those undergoing invasive procedures, with documented outbreaks in neonatal and intensive care units. Additionally, we addressed regional variations in CRE prevalence, linking higher burdens to differences in healthcare infrastructure, antimicrobial stewardship, and infection control practices while also underscoring the potential for CRE spread beyond hospital settings, necessitating broader public health interventions.

Specific comments
1. Carbapenem-resistant Enterobacterales have been used by CDC since 2022, please update all Enterobacteriaceae to Enterobacterales.
Response: We have updated all Enterobacteriaceae to Enterobacterales.

2. CRE abbrevetion is already defined in the introduction. In each section CRE is defined several times.
Response: Thank you. We have corrected all the redundant CRE descriptions.

3. In the abstract, it is mentioned resources used from 2008 to 2024. However, it is mentioned in protocol as 2004 to 2024. Please correct it.
Response: Thank you. The text in the abstract has been revised to 2004 to 2024 instead of 2008 to 2024.
Competing Interests: No competing interests were disclosed. Close
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Version 2

VERSION 2 PUBLISHED 17 Oct 2024

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Oznur Caliskan-Aydogan, Michigan State University, East Lansing, USA
Ingrid Maribel Leon Moreno, Texas A&M University (Ringgold ID: 14736), College Station, USA

Harvey Morgan Scott, Texas A&M University, College Station, USA

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08 Apr 2025 | for Version 2

Oznur Caliskan-Aydogan, Michigan State University, East Lansing, Michigan, USA

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Approved

no further comments

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Microbiology and nanotechnology

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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21 Mar 2025 | for Version 2

Ingrid Maribel Leon Moreno, Department of Veterinary Pathobiology, Texas A&M University (Ringgold ID: 14736), College Station, Texas, USA

Harvey Morgan Scott, Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA

5 Views Cite this report Responses(0)

Approved

General Comments:
The authors have successfully integrated most of the suggested changes, improving the clarity and structure of the research review protocol.
Specific Comments:

Clarification of XDR in PubMed Search Strategy:
The abbreviation XDR in the search strategy for PubMed table should be explicitly defined. Specifying it as "extensively drug-resistant (XDR)" in the search query or providing a clear definition in the methods section would enhance clarity and ensure consistency in search results.
Inconsistency in Search Strategy Table and Protocol Text:
The search strategy table includes only PubMed, whereas the protocol text under Data Source and Search Strategy mentions additional databases such as Google Scholar, Scopus, and Southeast Asian Index Medicus. The authors should ensure consistency by either updating the table to include all mentioned databases or revising the protocol text to reflect only the sources used.

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Epidemiology, Antimicrobial Resistance Research, Foodborne Pathogens, Microbiology

We confirm that we have read this submission and believe that we have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.

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21 Views

26 Feb 2025 | for Version 1

Ingrid Maribel Leon Moreno, Department of Veterinary Pathobiology, Texas A&M University (Ringgold ID: 14736), College Station, Texas, USA

Harvey Morgan Scott, Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA

21 Views Cite this report Responses(1)

Approved With Reservations

Explain why the treatment with the carbapenem family is so very important for human health. It likely seems self-evident to many, but if the cited prevalence data of ~30% are correct, does finding a CRE in a patient indicate treatment failure, or other outcomes (surveillance for quarantine of patients, etc).
Please indicate briefly that carbapenemase enzymes also break down other ‘lower-order'beta-lactam antibiotics such as third and fourth generation cephalosporins so impact is on almost all beta-lactams used for Enterobacterales and not just carbapenems.
Should the NOS scale have a cited reference?

Data source and search strategy

The search coverage in the body of the manuscript was from January 1, 2004 to 2024. Note that the abstract says only from 2008. There is an inconsistency. Was something discovered regarding the available papers from the first 4 years to render them less useful and therefore excluded? Some genes had yet to be discovered/characterized (e.g., NDM-1 in 2008). Is this the reason? If so please explain.
Abbreviations should be explained when mentioned for the first time, for example, MDR and XDR
Smaller Indonesian islands (e.g., Nussa Tenggara Islands and Maluku Islands) were not included in the search for geographical locations in Indonesia. Exclusion criteria should likewise be mentioned and likely impacts on search (i.e., will search under ‘Indonesia’ capture these?).
What is the impact of not including the specific search strategy of antimicrobial resistance via the carbapenemase genes, since that is included in the scope of interest. For instance: NDM, KPC, etc. Will the other search terms ensure papers focused on the genetic elements be captured?

Statistical analysis

Please explain how the random effects model will be used to estimate the pooled prevalence and the antimicrobial resistance patterns of CRE?
Is the Meta-Essentials tool, the Excel compatible software used to do the analysis capable of conducting the random effects model above? A quick looks at the software website at Erasmus University does not make this clear.

It is important to explain who the sponsors and funders of the study are.
In the protocol, it should be clear the involvement and potential influence of any party.
In the protocol, it should outline the roles and responsibilities of the contributors in study design, data analysis and interpretation, writing, and dissemination of results.

Is the rationale for, and objectives of, the study clearly described?

Yes
Is the study design appropriate for the research question?

Yes
Are sufficient details of the methods provided to allow replication by others?

Partly
Are the datasets clearly presented in a useable and accessible format?

Not applicable

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Epidemiology, Antimicrobial Resistance Research, Foodborne Pathogens, Microbiology

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Responses (1)

Author Response

10 Mar 2025

IKA NINDYA, Department of Medical Microbiology, Faculty of Medicine, Airlangga University, Surabaya, Indonesia

The manuscript by Kadariswantiningsih and co-authors represents a protocol for the systematic review and meta-analysis of Carbapenem-resistant Enterobacterales/ Enterobacteriaceae (CRE) regarding the prevalence of CRE in Indonesia and via various subgroups and characteristics. The protocol offers valuable insights, though it requires some minor improvements as outlined in the specific examples below.

Response: Thank you for your encouraging and positive comments. Your suggestion helps us to improved the protocol and manuscript.

Comments and edits:
INTRODUCTION

1. Explain why the treatment with the carbapenem family is so very important for human health. It likely seems self-evident to many, but if the cited prevalence data of ~30% are correct, does finding a CRE in a patient indicate treatment failure, or other outcomes (surveillance for quarantine of patients, etc).
Response: We have revised the introduction and add the explanation about this in paragraph 1.

2. Please indicate briefly that carbapenemase enzymes also break down other ‘lower-order'beta-lactam antibiotics such as third and fourth generation cephalosporins so impact is on almost all beta-lactams used for Enterobacterales and not just carbapenems.
Response: We have revised the introduction and add the explanation about this in paragraph 2.

3. Should the NOS scale have a cited reference?
Response: We have added a reference about NOS.

DATA SOURCE AND SEARCH STRATEGY

1. The search coverage in the body of the manuscript was from January 1, 2004 to 2024. Note that the abstract says only from 2008. There is an inconsistency. Was something discovered regarding the available papers from the first 4 years to render them less useful and therefore excluded? Some genes had yet to be discovered/characterized (e.g., NDM-1 in 2008). Is this the reason? If so please explain.
Response: We apologize for the mistake. We have changed the abstract text to 2004 instead of 2008. We want to capture the trends within the last 20 years.

2. Abbreviations should be explained when mentioned for the first time, for example, MDR and XDR
Response: In the revised manuscript, we have explained those abbreviations when when mentioned for the first time.

3. Smaller Indonesian islands (e.g., Nussa Tenggara Islands and Maluku Islands) were not included in the search for geographical locations in Indonesia. Exclusion criteria should likewise be mentioned and likely impacts on search (i.e., will search under ‘Indonesia’ capture these?).
Response: We have revised the search strategy to include other smaller islands such as Bali, Nusa Tenggara, Timor and Maluku. The exclusion criteria are mentioned in the “Eligibility Criteria” section and will be used during the screening of title, abstract and full-text.

4. What is the impact of not including the specific search strategy of antimicrobial resistance via the carbapenemase genes, since that is included in the scope of interest. For instance: NDM, KPC, etc. Will the other search terms ensure papers focused on the genetic elements be captured?Response: Thank you for the suggestion. Wee include the following keywords to the new search strategy:
("Carbapenem resistance"[MeSH] OR "Antimicrobial resistance"[MeSH] OR "Multidrug-resistant organisms"[MeSH] OR "MDR"[Title/Abstract] OR "XDR"[Title/Abstract] OR "Carbapenemase" OR "Carbapenem resistance" OR "Carbapenem-resistant" OR "Beta-lactamase" OR "β-lactamase" OR ("bla_KPC" OR "bla_NDM" OR "bla_OXA-48" OR "bla_OXA-181" OR "bla_OXA-232" OR "bla_OXA-58" OR "bla_OXA-244" OR "bla_IMP" OR "bla_VIM" OR "bla_GES" OR "bla_SME" OR "bla_KHM" OR "bla_DIM" OR "bla_AIM" OR "bla_FIM" OR "bla_SPM" OR "bla_BIC" OR "bla_IMI" OR "bla_CGB" OR "bla_CCR")

STATISTICAL ANALYSIS
1. Please explain how the random effects model will be used to estimate the pooled prevalence and the antimicrobial resistance patterns of CRE?
Response: We have added these explanation in the revised manuscript, “Statistical Analysis” section:
“A random effects model will be applied to estimate the pooled prevalence and antimicrobial resistance patterns of CRE. Prevalence and resistance rates will be extracted as proportions and transformed using logit transformation to stabilize variance. The pooled estimates will be calculated using inverse variance weighting, incorporating both the within-study variance and between-study variance (τ²), which will be estimated using the DerSimonian-Laird method.”

2. Is the Meta-Essentials tool, the Excel compatible software used to do the analysis capable of conducting the random effects model above? A quick looks at the software website at Erasmus University does not make this clear.
Response: Thank you for your concern. The tool is capable of conducting the random effect model as validated here: Suurmond, R., van Rhee, H., & Hak, T. (2017). Introduction, comparison, and validation of Meta‐Essentials: a free and simple tool for meta‐analysis. Research synthesis methods, 8(4), 537-553.

FUNDING STATEMENT
Please check if the below are required for published protocols. These are common for publishing results, but it is not clear to me if these aspects of disclosure are needed at this stage.

1. It is important to explain who the sponsors and funders of the study are.
Response: In the Grant information section and Funding Section, we mentioned “The author(s) declared that no grants were involved in supporting this work.” (https://f1000research.com/articles/13-1244/v1)

2. In the protocol, it should be clear the involvement and potential influence of any party.Response: We have added this sentence to the “Ethical consideration” statement: “The analysis and interpretation will be conducted independently by the authors, ensuring that no external influence affects the findings.” In the “Competing interests”, we write: “No competing interests were disclosed.”

3. In the protocol, it should outline the roles and responsibilities of the contributors in study design, data analysis and interpretation, writing, and dissemination of results.
Response: We added the following section:
Author Contribution Statement:
The roles and responsibilities of the contributors in this study will be as follows: INK will conceptualize the study, design the methodology, supervise the research process, and contribute to data analysis, interpretation, and manuscript drafting; MAE and RNR will participate in data collection, statistical analysis, and interpretation of findings; BI will provide expertise in systematic review methodology and meta-analysis, ensuring adherence to best practices; DDCHR will assist in literature screening, data extraction, and manuscript writing. All authors will review and approve the final manuscript and contribute to the dissemination of results.

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Competing Interests

No competing interests were disclosed.

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Reviewer Report

16 Views

28 Jan 2025 | for Version 1

Oznur Caliskan-Aydogan, Michigan State University, East Lansing, Michigan, USA

16 Views Cite this report Responses(1)

Approved With Reservations

Is the rationale for, and objectives of, the study clearly described?

Yes
Is the study design appropriate for the research question?

Yes
Are sufficient details of the methods provided to allow replication by others?

Yes
Are the datasets clearly presented in a useable and accessible format?

Partly

Competing Interests

No competing interests were disclosed.

Reviewer Expertise

Microbiology and nanotechnology

Respond to this report

Responses (1)

Author Response

10 Mar 2025

IKA NINDYA, Department of Medical Microbiology, Faculty of Medicine, Airlangga University, Surabaya, Indonesia

General Comments
Methods and protocol of this manuscript is detailly documented well. However, Introduction and discussion should be extended. Conclusion and future perspectives should be included. The details and data about the papers mentioned and reviewed for this manuscript have not been summarized. This manuscript need to be improved and enriched with the more literature resources and their findings.
Response: Thank you for your encouraging and positive comments. We add some elaboration to the previous findings and literature.

We have revised the introduction section and added an explanation about why carbapenems are important antibiotics and what the impacts of CRE are. We also add the previous finding about the significant presence of the New Delhi metallo-β-lactamase-1 (NDM-1) enzyme in Indonesia and how the prevalence rate of imipenem resistance differs from that of other countries in the same regions.

We have expanded the discussion to highlight the significant role of NDM-1 as a dominant carbapenem resistance mechanism in Indonesia, emphasizing its widespread prevalence in both urinary tract and bloodstream infections. We further elaborated on the impact of mobile genetic elements in facilitating the rapid dissemination of NDM-1-producing CRE within hospital environments, particularly affecting immunocompromised patients and those undergoing invasive procedures, with documented outbreaks in neonatal and intensive care units. Additionally, we addressed regional variations in CRE prevalence, linking higher burdens to differences in healthcare infrastructure, antimicrobial stewardship, and infection control practices while also underscoring the potential for CRE spread beyond hospital settings, necessitating broader public health interventions.

Specific comments
1. Carbapenem-resistant Enterobacterales have been used by CDC since 2022, please update all Enterobacteriaceae to Enterobacterales.
Response: We have updated all Enterobacteriaceae to Enterobacterales.

2. CRE abbrevetion is already defined in the introduction. In each section CRE is defined several times.
Response: Thank you. We have corrected all the redundant CRE descriptions.

3. In the abstract, it is mentioned resources used from 2008 to 2024. However, it is mentioned in protocol as 2004 to 2024. Please correct it.
Response: Thank you. The text in the abstract has been revised to 2004 to 2024 instead of 2008 to 2024.

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Competing Interests

No competing interests were disclosed.

Alongside their report, reviewers assign a status to the article:

Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approved - fundamental flaws in the paper seriously undermine the findings and conclusions

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[8] 8. Paveenkittiporn W, Lyman M, Biedron C, et al.: Molecular Epidemiology of Carbapenem-Resistant Enterobacterales in Thailand, 2016–2018. Antimicrob Resist. Infect. Control. 2021; 10(1). Publisher Full Text

[9] 9. Musa AY: Detection of Carbapenem Resistance Among Enterobacteriaceae Pathogens Isolated From Clinical Samples in Shendi Locality. Middle East Res. J. Microbiol. Biotechnol. 2023; 3(02): 43–47. Publisher Full Text

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Carbapenem-resistant Enterobacterales/Enterobacteriaceae (CRE) in Indonesia: protocol for systematic review and meta-analysis

Abstract

Abstract

Background

Methods

Discussion

Registration

Keywords

Introduction

Protocol

Review question

Study design and protocol registration

Data source and search strategy

Eligibility criteria

Data extraction

Quality assessment

Outcome variables

Statistical analysis

Dissemination

Study status

Discussion

Ethical considerations

Data availability

Underlying data

Extended data

Reporting guidelines

References

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