Prevalence and distribution of Carbapenem resistance In this study, 3421 Enterobacterales isolates were analyzed, with 1128 (32.97%) showing carbapenem resistance, indicating a significant public health concern. Among these, 908 (47.74%) inpatient isolates and 220 (14.48%) outpatient isolates exhibited resistance. Several factors contribute to higher inpatient resistance, including healthcare exposure, antibiotic selection pressure, transmission dynamics, healthcare-associated infections, and colonization. Urgent infection control measures are needed to address the alarming presence of carbapenem-resistant Enterobacterales in both hospital and community settings4,12. Further research and surveillance are essential for a comprehensive understanding of carbapenem resistance dynamics and effective control strategies.
Antimicrobial Resistance Profile of CRE Isolates: This study reveals a concerning antimicrobial resistance profile among Carbapenem-resistant Enterobacterales (CRE) isolates, with significant implications for clinical management:
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Resistance to Third-Generation Cephalosporins: All 213 CRE isolates exhibited complete resistance to third-generation cephalosporins, limiting treatment options and emphasizing the urgency of alternative therapies.
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Resistance to BL-BLI Combinations: Nearly all isolates (99.4%) were resistant to Beta-lactam Beta-lactamase inhibitor (BL-BLI) combinations, including Piperacillin-Tazobactam and Cefoperazone-Sulbactam, posing challenges for empirical therapy selection.
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Complete Resistance to Aztreonam: Aztreonam, often considered a last resort, showed 100% resistance among CRE isolates, further limiting treatment choices.
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Resistance to Other Antibiotics: CRE isolates displayed resistance to fluoroquinolones, aminoglycosides, Cotrimoxazole, and Nitrofurantoin, reducing the arsenal of effective antibiotics.
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Colistin Resistance: Although low, resistance to Colistin was observed in one isolate, raising concerns about its status as a last-resort option.
These findings underscore the critical need for alternative treatment strategies, antibiotic development, and stringent infection control practices to combat CRE infections effectively. Clinicians must remain vigilant in treatment decisions, considering the high resistance levels of CRE to commonly used antibiotics.
Global Prevalence of Carbapenem-resistant Enterobacterale (CRE) The prevalence of Carbapenem-resistant Enterobacterale (CRE) in this study, at 32.97%, aligns with findings from surveillance studies conducted in different regions as shown in Table 5. These variations in CRE prevalence underscore the impact of antibiotic use practices and the temporal dynamics of antimicrobial resistance. The high prevalence observed in some studies highlights the urgent need for effective control measures and judicious antibiotic use to mitigate the spread of CRE in healthcare settings.
High Prevalence of Carbapenem-Resistant Enterobacterales (CRE) in India Previous research (Table 5) in different regions of India reported varying rates ranging from 7.87%7 to 37.9%,12. These studies collectively demonstrate an increasing trend of carbapenem resistance among Enterobacterales in India over time.
This concerning trend in the prevalence of Carbapenem-resistant Enterobacterales (CRE) can be attributed to a confluence of factors. Firstly, the widespread use of Carbapenems within hospital settings exerts substantial selective pressure, creating a favorable environment for the emergence and dissemination of resistant strains, including CRE. Additionally, the overuse and misuse of antibiotics in clinical practice, characterised by inappropriate prescription practices, incomplete treatment regimens, and antibiotic mismanagement, play a pivotal role in driving resistance development, fostering conditions conducive to the rise of CRE. Furthermore, suboptimal infection prevention and control measures within healthcare facilities contribute significantly to CRE transmission. Insufficient hand hygiene protocols, lapses in sterilization procedures, and overcrowding within healthcare settings collectively promote the dissemination of these resilient strains among patients. Lastly, the use of antibiotics in agricultural practices, particularly in livestock farming for growth promotion and disease prevention, further amplifies the selection and dissemination of antibiotic-resistant bacteria. These resistant strains can infiltrate the human food chain, posing substantial risks to public health.
The study conducted a convenient sampling of 213 isolates to characterise Carbapenem-resistant Enterobacterales (CRE). The modified Carbapenem Inhibition Method (mCIM) was employed to detect the Carbapenemase enzyme (CP-CRE), with 95.31% of the isolates testing positive, confirming Carbapenemase presence. mCIM’s high sensitivity and specificity make it a recommended method, noted for its simplicity, cost-effectiveness, and adaptability to various laboratories. Another method, CIM, also demonstrated favorable sensitivity, specificity, and cost-effectiveness. The improved mCIM exhibited 100% sensitivity and specificity for CPE detection, surpassing conventional methods like MHT, CNP, and CIM. CNP, with its specificity and speed, can be valuable in urgent cases. Among CP-CRE isolates, 98.02% were Metallo-beta lactamase (Class B) positive using the eCIM test, confirming this carbapenemase’s presence.
Table 5 highlights geographical variations in metallo-carbapenemase distribution. These prevalence variations can be attributed to differences in study populations, geographic locations, and detection methods. In this study, phenyl boronic acid and cloxacillin were used as inhibitors for Class A and Class C carbapenemases, revealing that 30.04% of CREs expressed Class A carbapenemase and 4.4% expressed Class C carbapenemase. In contrast, other studies reported lower rates for Class A and Class C carbapenemases.
Class D (OXA-48-like) carbapenemase was detected in only 1.47% of isolates using Temocillin discs, but the presence of blaOXA48 gene suggests potential underreporting. This may be attributed to the limited specificity (43.9%) of Temocillin for OXA-48-like carbapenemases, as demonstrated in a study by Koroska et al.27 To enhance OXA-48 detection, EUCAST recommends a Temocillin inhibition zone < 11 mm, serving as a marker for certain carbapenemases, particularly OXA-48. Combining tests may offer confirmation when other tests yield negative results.
In this study, Class B carbapenemase predominated, observed in 70% of E. coli and 55% of Klebsiella pneumoniae isolates. Co-expression of Class B and Class A carbapenemases occurred in 23% of E. coli and 36.2% of Klebsiella pneumoniae isolates, with other phenotypes also identified.
The findings regarding Carbapenem-resistant Enterobacterales (CRE) in this study raise concerns. Treating CRE infections is challenging due to limited and expensive treatment options, imposing financial burdens on patients. Screening patients for CRE presence upon admission presents feasibility and cost-related challenges. Additionally, patients with CRE colonization or infection require isolation facilities to prevent the spread of drug-resistant pathogens to non-infected individuals, posing a challenge for healthcare facilities. In light of these circumstances, it becomes crucial to curb the rise of CRE by developing and implementing an antimicrobial policy based on local antibiograms and ensuring adherence to infection control practices.
Effective interventions, such as patient contact isolation, cohorting colonized patients, promoting hand hygiene, surface decontamination, routine rectal surveillance for CRE screening, and implementing antibiotic stewardship programs, have been documented to reduce resistance rates. Simulation models have also shown that without interventions to restrict CRE transmission, it may become endemic, emphasizing the need for local and regional interventions to slow its spread. While these interventions may seem costly, the cost-effectiveness is far greater than dealing with endemic CRE once it takes hold. Despite having infection prevention and control protocols in place at our institution, the high prevalence of CRE suggests inadequate implementation of these protocols.
The study’s recommendations encompass several crucial aspects of managing Carbapenem-Resistant Enterobacterales (CRE) infections in resource-limited settings. First, standardising phenotypic tests for CRE class identification is proposed as a practical and cost-effective approach to guide therapy and enhance infection control. Additionally, the study introduces an algorithm tailored for resource-constrained laboratories to ensure prompt and accurate CRE class diagnosis (Fig. 3). Given the predominance of Class B carbapenemase (blaNDM), suggested empirical therapies include Cefiderocol or a combination of Ceftazidime-avibactam with Aztreonam. Recognizing limited treatment options, the study emphasizes the urgent need for research and development of new antibiotics. Stringent infection control measures, such as hand hygiene, equipment disinfection, patient isolation, and CRE colonization surveillance, are vital in healthcare settings. Improved diagnostic capabilities, ongoing surveillance, and monitoring of CRE prevalence and resistance patterns are crucial for understanding resistance dynamics and shaping effective antimicrobial stewardship policies. These recommendations have broad applicability in addressing CRE challenges not only in India but also in other resource-limited regions facing similar issues, serving as valuable guidance for healthcare practices and antimicrobial resistance control.
Flowchart showing proposed diagnostic algorithm for the Identification of Carbapenem- Resistant Enterobacterales.
Although this study focused on phenotypic characterisation, a subset of isolates underwent molecular testing to validate findings. In this unpublished dataset, PCR-based genotyping of 98 mCIM-positive CRE isolates revealed blaNDM in 63.27%, blaOXA-48 in 61.22%, followed by blaIMP (10.20%), blaKPC (5.10%), and blaVIM (3.06%). The predominant species were E. coli (61.22%) and K. pneumoniae (33.67%), mirroring the phenotypic distribution. These results reinforce the phenotypic classification and highlight the local dominance of metallo-β-lactamase producers.