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

Introduction

Carbapenems are among the most critical classes of β-lactam antibiotics, often considered the last line of defense against multidrug-resistant (MDR) Gram-negative bacterial infections. These broad-spectrum antibiotics, including imipenem, meropenem, doripenem, and ertapenem, exhibit potent activity against a wide range of bacterial pathogens.^1,2 Carbapenems are also reserved for treating severe, life-threatening infections such as hospital-acquired pneumonia, complicated urinary tract infections, and infections in immunocompromised patients.^1,2 The efficacy of carbapenems stems from their ability to resist hydrolysis by most β-lactamases, including extended-spectrum β-lactamases (ESBLs), making them the preferred treatment option when first-line antibiotics fail.^1,2

However, the emergence of carbapenem-resistant Enterobacterales (CRE) has severely compromised the effectiveness of these life-saving antibiotics. Southeast Asia experiences particularly high prevalence rates of CRE. The widespread dissemination of carbapenemase-producing Enterobacteriaceae (CPE) has been well documented, driven by both clonal expansion and horizontal gene transfer.^3,4 Within Southeast Asia, including Indonesia, carbapenem resistance rates are among the highest globally, with some healthcare settings reporting resistance rates exceeding 30%.^5,6 The presence of CRE in a patient often indicates treatment failure, as these bacteria exhibit resistance to nearly all β-lactam antibiotics, including penicillins, cephalosporins, and carbapenems.⁷ Consequently, infection with CRE is associated with higher morbidity and mortality rates, as alternative treatment options are limited.⁷ 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).^8,9 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.^10,11 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 of prevalence is influenced by factors like antibiotic usage patterns, healthcare practices, and the presence of specific resistance genes.^12,13 A research has identified a significant presence of the New Delhi metallo-β-lactamase-1 (NDM-1) enzyme among carbapenem-resistant Gram-negative bacilli in Indonesia, suggesting its widespread dissemination. In a study focusing on urinary tract infections, 81.8% of carbapenemase-producing isolates were NDM-1 producers, predominantly found in Enterobacteriaceae and Acinetobacter species.¹⁴ Comparative data from Asian countries reveal that Indonesia has one of the highest imipenem resistance rates among Enterobacterales, estimated at 5.8%, with varieties across its different regions.¹⁵ This rate surpasses those reported in neighboring countries such as Vietnam (3.0%) and the Philippines (3.7%), underscoring the critical need for targeted antimicrobial stewardship and infection control measures within Indonesian healthcare settings.¹⁵

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

Discussion

This systematic review and meta-analysis aim to provide a comprehensive overview of CRE in Indonesia, a nation confronting a significant public health challenge due to the high prevalence of antimicrobial-resistant organisms.^14,19 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.

One of the most concerning carbapenem resistance mechanisms in Indonesia is NDM-1, an enzyme that hydrolyzes nearly all β-lactam antibiotics, including carbapenems, rendering them ineffective. First identified in Klebsiella pneumoniae and Escherichia coli isolates from a patient in Sweden in 2008, NDM-1 has since spread globally, with a high prevalence in South and Southeast Asia, including Indonesia.^20,21 A study focusing on urinary tract infections identified 116 carbapenem-resistant Gram-negative bacilli among 1,082 isolates, with Klebsiella pneumoniae and Providencia rettgeri among the notable pathogens.¹² The dominant resistance mechanism identified was the production of NDM-1, accounting for 81.8% of carbapenemase-producing isolates.¹⁴ Another study analyzing bloodstream infections in Indonesian intensive care units found that 31% of patients harbored CRE, with NDM-1 being the most commonly detected carbapenemase gene.²² The dissemination of NDM-1-producing CRE in nosocomial infections raises serious concerns about the effectiveness of existing antimicrobial therapies, as these strains are often resistant to multiple antibiotic classes, including aminoglycosides and fluoroquinolones.²²

The spread of NDM-1 is particularly concerning because of its association with mobile genetic elements such as plasmids and transposons, which facilitate horizontal gene transfer between bacterial species.²³ This means that once an NDM-1-producing strain enters a healthcare facility, it can rapidly disseminate within the hospital environment, infecting immunocompromised patients and those undergoing invasive procedures such as mechanical ventilation or catheterization.^23,24 Several hospital outbreaks of NDM-1-producing CRE have been reported in Indonesia, particularly in neonatal and intensive care units, where infection control measures may be less effective due to resource constraints.^12,22

Regional variations in CRE prevalence are likely to emerge, influenced by disparities in healthcare infrastructure, antimicrobial usage, and infection control practices. Urban tertiary-care hospitals often report higher burdens of these resistant organisms compared to smaller healthcare facilities, suggesting that resource availability and patient demographics play critical roles in their dissemination. For instance, a study evaluating the Xpert Carba-R assay in an Indonesian intensive care unit found a 31% colonization rate of carbapenem-resistant organisms among patients, with the NDM gene being the most frequently detected carbapenemase gene.²⁵ These variations may underscore the need for localized strategies in regions with a higher burden of CRE. Additionally, this 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. The analysis and interpretation will be conducted independently by the authors, ensuring that no external influence affects the findings.

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.