Introduction

Enterococcus faecalis, a Gram-positive bacterium found in humans, animals, and various environments, is primarily a commensal microorganism but can act as an opportunistic pathogen causing various healthcare-associated and life-threatening diseases [1,2,3]. It is responsible for 80–90% of enterococcal infections, including life-threatening diseases, and is a leading cause of nosocomial infections worldwide [1, 4, 5]. Hospital-acquired infections are a global threat due to the rise of drug-resistant E. faecalis strains, which are resistant to most antimicrobial agents, including vancomycin [1, 2, 5,6,7]. This poses challenges for healthcare systems and requires new targeted therapies. Multidrug-resistant (MDR) E. faecalis strains can transfer resistant genes to other pathogens, further complicating treatment and increasing the risk to patients and healthcare professionals [5, 8, 9]. Understanding the global status of antimicrobial resistance (AMR) in E. faecalis isolates is crucial for effective infection control and treatment strategies. The rise of AMR is influenced by factors like antibiotic misuse, genetic factors, and the persistence of resistant strains in healthcare settings [10, 11]. E. faecalis has intrinsic resistance mechanisms, such as the absence of antibiotic targets, low-affinity targets, impermeability to certain antibiotics, presence of efflux pumps, and lack of uptake mechanisms for various antimicrobials [12, 13].

Intrinsic resistance in E. faecalis is typically encoded in the chromosome and not easily transferable between bacteria. MDR in E. faecalis can arise from the acquisition of resistance genes through mobile genetic elements like transposons, integrons, and plasmids, as well as chromosomal mutations and antibiotic-modifying enzymes [1, 11, 14,15,16]. Resistance genes can be transferred horizontally between closely related bacteria. The ability of E. faecalis to form biofilms enhances its resistance to antibiotics, posing challenges in treatment [2, 17].

E. faecalis exhibits resistance to vancomycin and beta-lactam antibiotics through various mechanisms [18,19,20,21]. Vancomycin resistance is primarily due to the acquisition of vancomycin-resistant genes (vanA, vanB, vanC, vanD, vanE, vanG, vanL, and vanM), which alter the peptidoglycan synthesis pathway [18,19,20,21]. Beta-lactam resistance results from producing beta-lactamases, such as penicillin-binding proteins (PBPs) that inactivate the antibiotics [22, 23]. Additionally, mutations in regulatory genes (e.g., pbp4, pbp5) contribute to beta-lactam resistance by modifying antibiotic targets [22, 23].

AMR in E. faecalis infections leads to increased morbidity, mortality, and healthcare costs. Limited treatment options for resistant strains highlight the need for alternative therapeutic strategies and the development of new antimicrobial agents [24, 25]. A comprehensive understanding of the global prevalence and trends of antimicrobial resistance in E. faecalis is essential to effectively address this challenge [1, 11, 14,15,16].

To address this challenge effectively, a comprehensive understanding of the global prevalence and trends of AMR in E. faecalis is crucial. We reviewed global E. faecalis resistance patterns, identifying high resistance rates to multiple antibiotics. Our findings guide clinical practice, policies, and research to combat multidrug-resistant strains and improve patient outcomes.

Methods

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines are followed in the reporting of this review [26].

Search strategy and study selection

We conducted a thorough and methodical exploration of various databases, including PubMed, Scopus, and Embase, until November 30, 2022. Our search approach involved the use of specific keywords such as Enterococci, Enterococcus faecalis, E. faecalis, antimicrobial resistance, antibiotic resistance, clinical samples, and human samples, with a focus on the Title/Abstract/Keywords fields. We did not impose any limitations on our database search. The study investigators were responsible for designing and executing the search strategy. Additionally, we meticulously scrutinized the reference lists of all relevant studies to identify any other noteworthy publications. To ensure data accuracy, we combined the records obtained from the database search and eliminated any duplicated entries using EndNote X8 (Thomson Reuters, New York, NY, USA). To verify the search results, one team researcher randomly assessed them and confirmed that no pertinent studies had been overlooked.

Eligibility criteria

The meta-analysis incorporated articles that fulfilled specific inclusion criteria. These criteria encompassed studies that examined antibiotic resistance in E. faecalis isolates derived from human sources. Furthermore, the articles had to undergo peer review and be published in the English language within the timeframe of 2000–2022. Additionally, the studies were required to specify the total number of E. faecalis clinical isolates and provide information on the antibiotic resistance rate observed in these isolates. Conversely, certain exclusion criteria were applied. These criteria encompassed studies that contained duplicate data or were overlapping articles. Non-clinical isolates and reports on antibiotic resistance of Enterococcus spp other than E. faecalis were also excluded. Moreover, reviews, cohort studies, pharmacokinetic studies, and conference abstracts were not considered. Lastly, articles that did not clearly present or report antibiotic resistance rates were also excluded from the meta-analysis.

Data extraction

Each included study provided the following information: the first author’s name, publication year, continent, WHO regions, country, number of E. faecalis clinical isolates, number of antibiotic resistance rate in E. faecalis isolates, infection source (bloodstream, gastrointestinal tract, urinary tract, mixed), and antimicrobial susceptibility testing (MIC-based methods and disk diffusion agar). Two independent examiners collected the data, and another researcher verified its accuracy.

Quality assessment

Two reviewers independently evaluated the quality of the studies included in the analysis. They employed a modified version of the Newcastle–Ottawa assessment scale, which was adapted for cross-sectional studies [27]. Each study was assigned a score ranging from 0 to 8 points, with a score of 6 or higher indicating high quality, while a score of 5 or lower indicated low quality. In cases where there was a disagreement between the two reviewers, a third reviewer was consulted to resolve the discrepancy.

Statistical analysis

The meta-analysis included studies that provided raw data on antibiotic resistance in clinical isolates of E. faecalis. The analysis was conducted using the meta-prop [28] command in the R statistical software, considering prevalence statistics based on antibiotic, region (continents/countries), year, infection source, and antimicrobial susceptibility testing (AST). The results of the meta-analysis consisted of a prevalence statistic accompanied by 95% confidence intervals, which were calculated using weighted prevalence statistics from all the studies within the specified sub-group. Meta-regression models were employed to examine any changes in antibiotic resistance over time. To assess publication bias, Egger and Begg tests were utilized. All statistical interpretations were reported with a 95% confidence interval (CI). The statistical package R 3.6.0, developed by the R Foundation for Statistical Computing in Vienna, Austria, was used for all the statistical analyses [29].

Study outcomes

The primary focus of this study was to determine the prevalence of antibiotic resistance in clinical isolates of E. faecalis, using the guidelines provided by the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST). To further analyse the data, subgroup analyses were conducted based on the following factors: (1) year of publication (2000–2013, 2014–2022), (2) geographical location (continent/country), (3) source of infection, and (4) antimicrobial susceptibility testing (AST).

Results

Systematic literature search

The initial search yielded a total of 4580 records. After an initial screening of the title and abstract, 4430 articles were deemed irrelevant or duplicates and were subsequently excluded. The full texts of the remaining 150 articles were thoroughly reviewed (Fig. 1). Among these 150 articles, 79 were excluded for the same reasons mentioned earlier. Ultimately, 74 studies [30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96,97,98,99,100,101,102,103] published between 2000 and 2022 (Supplementary Table) were included in the analysis. The screening and selection process was visually summarized in the PRISMA flow chart (Fig. 1).

Fig. 1
figure 1

PRIMA flowchart of included studies

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Characteristics of included studies

Data on antibiotic resistance were collected from 28 countries spanning 5 continents, including Poland, Egypt, Iran, Sweden, Turkey, China, US, Brazil, Uganda, India, Cuba, South Korea, Hungary, Kuwait, Italy, Israel, Australia, Germany, Taiwan, Lebanon, Romania, Hong Kong, Czechia, Algeria, Indonesia, Nigeria, Pakistan, and Japan. The forest plot in Fig. 2 presented the proportion of resistance isolates to selected antibiotics, with subgroup analyses by time, area, source of samples, and AST shown in the Supplementary File. The Supplementary File also included meta-regression results for changes in antibiotic resistance over time. Figure 3 displayed changes in resistance proportions based on time, continent, WHO regions, AST, and source of samples for the selected antibiotics, while Fig. 4 showed changes in resistance proportions based on countries. The summary of resistance rate trends and the results of publication bias tests using Egger and Begg tests were presented in the Supplementary File.

Fig. 2
figure 2

Forrest plots of included antibiotics

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Fig. 3
figure 3

Subgroup analysis results based on (A) continent, (B) WHO regions, (C) AST classification, and (D) over time

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Fig. 4
figure 4

Subgroup analysis of antibiotic resistance proportion in various countries

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Subgroup analysis

Overview of antibiotic resistance prevalence

Proportion of vancomycin resistance through 30 reports, with 1533 resistant isolates among 11912 investigated isolates was 4.3% (95% CI 0.022, 0.082), and heterogeneity between report was significant (I2 = 98.01%, p = 0.001). Proportion of gentamicin resistance through 41 reports, with 4775 resistant isolates among 9198 investigated isolates was 49.7% (95% CI 0.421, 0.574), and heterogeneity between report was significant (I2 = 97.03%, p = 0.001). Proportion of amoxicillin-clavulanic acid resistance through 4 reports, with 39 resistant isolates among 132 investigated isolates was 29.4% (95% CI 0.158, 0.482), and heterogeneity between report was not significant (I2 = 0.00%, p = 0.662). Proportion of ampicillin resistance through 56 reports, with 1703 resistant isolates among 12065 investigated isolates was 9.5% (95% CI 0.058, 0.151), and heterogeneity between report was significant (I2 = 97.30%, p = 0.001). Proportion of chloramphenicol resistance through 24 reports, with 494 resistant isolates among 3483 investigated isolates was 18.4% (95% CI 0.126, 0.261), and heterogeneity between report was significant (I2 = 92.12%, p = 0.001). Proportion of ciprofloxacin resistance through 45 reports, with 2505 resistant isolates among 5647 investigated isolates was 44.2% (95% CI 0.364, 0.523), and heterogeneity between report was significant (I2 = 94.82%, p = 0.001). Proportion of daptomycin resistance through 6 reports, with 2 resistant isolates among 1103 investigated isolates was 0.7% (95% CI 0.002, 0.021), and heterogeneity between report was not significant (I2 = 21.18%, p = 0.274). Proportion of doxycycline resistance through 7 reports, with 186 resistant isolates among 404 investigated isolates was 31.4% (95% CI 0.126, 0.593), and heterogeneity between report was significant (I2 = 93.96%, p = 0.001). Proportion of erythromycin resistance through 31 reports, with 3348 resistant isolates among 5591 investigated isolates was 60.3% (95% CI 0.523, 0.677), and heterogeneity between report was significant (I2 = 96.23%, p = 0.001). Proportion of fosfomycin resistance through 9 reports, with 53 resistant isolates among 888 investigated isolates was 6.5% (95% CI 0.02, 0.187), and heterogeneity between report was significant (I2 = 91.65%, p = 0.001). Proportion of imipenem resistance through 11 reports, with 96 resistant isolates among 3578 investigated isolates was 2.6% (95% CI 0.008, 0.081), and heterogeneity between report was significant (I2 = 94.58%, p = 0.001). Proportion of levofloxacin resistance through 21 reports, with 2361 resistant isolates among 4981 investigated isolates was 36.7% (95% CI 0.283, 0.46), and heterogeneity between report was significant (I2 = 95.28%, p = 0.001). Proportion of linezolid resistance through 32 reports, with 1074 resistant isolates among 9601 investigated isolates was 1.3% (95% CI 0.004, 0.043), and heterogeneity between report was significant (I2 = 77.24%, p = 0.001). Proportion of minocycline resistance through 3 reports, with 150 resistant isolates among 1273 investigated isolates was 44.9% (95% CI 0.051, 0.925), and heterogeneity between report was significant (I2 = 88.10%, p = 0.001). Proportion of moxifloxacin resistance through 3 reports, with 100 resistant isolates among 281 investigated isolates was 26.4% (95% CI 0.046, 0.725), and heterogeneity between report was significant (I2 = 79.79%, p = 0.007). Proportion of nitrofurantoin resistance through 20 reports, with 718 resistant isolates among 3932 investigated isolates was 6.2% (95% CI 0.027, 0.138), and heterogeneity between report was significant (I2 = 96.61%, p = 0.001). Proportion of norfloxacin resistance through 4 reports, with 24 resistant isolates among 124 investigated isolates was 31.3% (95% CI 0.062, 0.759), and heterogeneity between report was significant (I2 = 90.47%, p = 0.001). Proportion of penicillin resistance through 24 reports, with 1532 resistant isolates among 4245 investigated isolates was 33.6% (0.2, 0.506), and heterogeneity between report was significant (I2 = 97.44%, p = 0.001). Proportion of quinupristin-dalfopristin resistance through 13 reports, with 1609 resistant isolates among 3025 investigated isolates was 34.3% (95% CI 0.137, 0.632), and heterogeneity between report was significant (I2 = 98.49%, p = 0.001). Proportion of rifampicin resistance through 10 reports, with 988 resistant isolates among 1664 investigated isolates was 61.3% (95% CI 0.442, 0.759), and heterogeneity between report was significant (I2 = 95.66%, p = 0.001). Proportion of streptomycin resistance through 22 reports, with 2864 resistant isolates among 5430 investigated isolates was 48.2% (95% CI 0.391, 0.573), and heterogeneity between report was significant (I2 = 96.46%, p = 0.001). Proportion of teicoplanin resistance through 35 reports, with 1493 resistant isolates among 9966 investigated isolates was 5.3% (95% CI 0.027, 0.099), and heterogeneity between report was significant (I2 = 96.98%, p = 0.001). Proportion of tetracycline resistance through 27 reports, with 3085 resistant isolates among 4659 investigated isolates was 66.6% (0.568, 0.751), and heterogeneity between report was significant (I2 = 95.70%, p = 0.001). Proportion of tigecycline resistance through 11 reports, with 18 resistant isolates among 3691 investigated isolates was 0.7% (95% CI 0.005, 0.011), and heterogeneity between report was not significant (I2 = 0.00%, p = 0.533). Proportion of cotrimoxazole resistance through 12 reports, with 826 resistant isolates among 1827 investigated isolates was 49.7% (95% CI 0.33, 0.665), and heterogeneity between report was significant (I2 = 96.44%, p = 0.001).

Subgroup analysis based on year group

The subgroup analysis provided valuable insights into the trends of antibiotic resistance across different year groups. It identified significant disparities in the prevalence rates of resistance to three antibiotics ciprofloxacin, penicillin, and rifampicin. For ciprofloxacin, a notable decrease in resistance was observed from the 2000–2013 year group, which had a prevalence rate of 54.3%, to the 2014–2022 year group, where the rate dropped to 35.2%. This decline suggests a possible change in the susceptibility patterns of the targeted bacterial strains during this period. Similarly, penicillin resistance also exhibited a downward trend when comparing the 2000–2013 year group to the 2014–2022 year group. The resistance rate fell from 54.2 to 16.1%, indicating a substantial decrease in the prevalence of penicillin-resistant strains. In the case of rifampicin, the analysis revealed a significant drop in resistance between the same two year groups. The resistance rate decreased from a high of 73% in 2000–2013 to 36.2% in 2014–2022, demonstrating an appreciable change in susceptibility patterns over time.

To analyze the trends for changes in the rate of antibiotics resistance in different years, we performed a meta-regression analysis for changes in the proportions of antibiotics resistance over time (Supplementary File). According to the meta-regression, the chloramphenicol, fosfomycin, imipenem, linezolid, minocycline, norfloxacin, quinupristin-dalfopristin, and tetracycline resistance rate increased over time; although, was not statistically significant.

Subgroup analysis based on country

The subgroup analysis conducted on antibiotic resistance rates across various countries revealed significant disparities in the prevalence of resistance to different antibiotics. Among the countries studied, Australia consistently demonstrated the lowest rates of resistance, while Taiwan consistently exhibited the highest rates. In terms of specific antibiotics, Australia exhibited the lowest rates for erythromycin (31.5%), penicillin (0.4%), teicoplanin (0.1%), ampicillin (0.1%), and vancomycin (0.1%). Sweden also reported minimal resistance to chloramphenicol (0.4%) and gentamicin (5.1%). Poland, Turkey, and Taiwan each displayed low resistance levels to ciprofloxacin (0.9%), rifampicin (5.1%), and tetracycline (12.8%), respectively. In contrast, South Korea experienced the highest resistance rates for erythromycin (91.2%), gentamicin (91.8%), and rifampicin (96.4%). Taiwan had the highest resistance rates for penicillin (95%), teicoplanin (81%), ciprofloxacin (83%), and vancomycin (99%). Algeria demonstrated the highest resistance to tetracycline at 92.5%. Additionally, India and Italy showed the highest resistance rates to ampicillin (74.1%) and chloramphenicol (72.9%), respectively.

Subgroup analysis based on WHO regional offices

The subgroup analysis identified significant differences in antibiotic resistance rates among various WHO regional offices. The Region of the Americas had the lowest ampicillin resistance rate at 0.4%, while the South-East Asia Region had the highest ampicillin resistance at 77.3%. The Eastern Mediterranean Region had the lowest erythromycin resistance rate at 46%, with the South-East Asia Region having the highest at 79%. For gentamicin, the Eastern Mediterranean Region/Islamic Republic of Iran region had the lowest resistance rate at 29.5%, while the South-East Asian Region had the highest at 85.5%. The lowest levofloxacin resistance rate was in the Eastern Mediterranean Region/Islamic Republic of Iran region at 10.3%, and the European Region had the highest at 96%. Penicillin resistance was lowest in the European Region at 1.4% and highest in the South-East Asia Region at 97.5%. Rifampicin resistance was lowest in the European Region at 38.9% and highest in the Western Pacific Region at 91.8%. Teicoplanin resistance was lowest in the African Region at 0.6% and highest in the Western Pacific Region at 34.6%.

Subgroup analysis based on AST methods

The subgroup analysis revealed a statistically significant disparity in the prevalence of antibiotic resistance, including that of ciprofloxacin, gentamicin, penicillin, quinupristin-dalfopristin, among various AST classification. For the antibiotic ciprofloxacin, the AST classification with the lowest rate of resistance was Multiple Standards, exhibiting a prevalence rate of 8.9%, while conversely, the AST classification with the highest resistance rate was observed in CLSI, with a prevalence rate reaching 46.9%. For the antibiotic gentamicin, the AST classification with the lowest rate of resistance was EUCAST, exhibiting a prevalence rate of 11.8%, while conversely, the AST classification with the highest resistance rate was observed in Unknown, with a prevalence rate reaching 53.7%. For the antibiotic penicillin, the AST classification with the lowest rate of resistance was Multiple Standards, exhibiting a prevalence rate of 0.4%, while conversely, the AST classification with the highest resistance rate was observed in CLSI, with a prevalence rate reaching 38.9%. For the antibiotic quinupristin dalfopristin, the AST classification with the lowest rate of resistance was CLSI, exhibiting a prevalence rate of 25.1%.

Discussion

Initially considered a benign member of the gut microbiota in both humans and animals, E. faecalis has emerged as an opportunistic pathogen and ranks among the most prevalent bacteria in nosocomial-acquired infections worldwide, trailing only Escherichia coli and Staphylococcus. Numerous global studies have highlighted the predominance of E. faecalis in a broad spectrum of life-threatening infections, especially among hospitalized patients [1]. The ability of E. faecalis to cause widespread and difficult-to-treat diseases is due to its resistance to various antimicrobial substances, which has now become one of the most significant global public health threats. This bacterium has extensive inherent and acquired resistance to different types of antibiotics [104]. Several risk factors, including immunosuppression, comorbid diseases, prolonged hospital stays, heightened occupancy rates particularly patients hospitalized in intensive care units, insufficient exposure to antibiotics or disinfectants, and irrational/extensive antibiotic usage, are associated with the development of resistance among E. faecalis strains [1, 5]. Significantly, Higher morbidity and mortality rates, extended length of hospital stay, higher treatment costs, and the spread of resistance determinants to other infectious agents are the consequences of infections caused by resistant pathogens including E. faecalis [5, 105, 106].

To our knowledge, our study represents the first systematic review and meta-analysis research to comprehensively assess the pooled prevalence of AMR profile of E. faecalis around the World. In the present study, the prevalence of resistance of E. faecalis strains to 25 different antibiotics has been evaluated from 2000 to 2022 in the world.

The most studies have been conducted on vancomycin, followed by ampicillin, and the least studies are related to minocycline, moxifloxacin and norfloxacin antibiotics. Considering that E. faecalis is one of the most common causes of MDR hospital infections, it is necessary to study and monitor their antimicrobial resistance to prevent and control the spread of resistant strains [107].

The findings of our study indicate that the highest resistance was observed against tetracycline, with a prevalence rate of 66.6%. The high proportion of tetracycline resistance among clinical strains of E. faecalis considered as a serious public health warning. Subsequently, the high frequency of resistance in E. faecalis strains was associated with rifampicin, erythromycin, gentamicin, trimethoprim-sulfamethaxazole (cotrimoxazole), streptomycin, minocycline and ciprofloxacin with rates of 61.3, 60.3, 49.7, 49.7, 48.2, 44.9, and 44.2% respectively. Correspondingly, numerous studies have revealed significant resistance of Enterococcus faecium strains to tetracycline and erythromycin, which indicates that they are not recommended for the treatment of infections caused by this bacterium. Both antibiotics possess a broad-spectrum effect against various pathogens, potentially contributing to the development of resistance in enterococci during the treatment of other infections [6, 108,109,110]. These findings underline the importance of enhanced monitoring of the prescription and use of these antimicrobial agents in the treatment of enterococci infections.

The lowest frequency of antibiotic resistance in E. faecalis clinical strains is related to daptomycin and tigecycline with a prevalence of 0.7%. These findings suggest that daptomycin and tigecycline are the most effective drugs for treating E. faecalis infections. Consistent with our discoveries, other systematic review studies focusing on Enterococcus faecium strains demonstrate a considerable sensitivity of these strains to daptomycin and tigecycline, underscoring their viability as appropriate treatment choices for combating resistant infections attributed to this strain [5, 6]. Our study also revealed that linezolid, imipenem, vancomycin, teicoplanin, nitrofurantoin, fosfomycin, and ampicillin displayed significantly the lowest resistance rates at 1.3, 2.6, 4.3, 5.3, 6.2, 6.5, and 9.5%, respectively. Although the considerable low level of resistance of E. faecalis strains to these antibiotics has made them appropriate options for the treatment of clinical infections, their recent increase in resistance rate necessitates improved executive management to prevent the overgrowth and dissemination of resistant bacteria [1, 6, 107, 111, 112]. This underscores the need for a more vigilant approach to their use in clinical settings to effectively address the challenge of resistance.

The healthcare systems have faced significant challenges due to the COVID-19 pandemic, resulting in constrained roles of infectious diseases services, irrational and excessive utilization of disinfectants and antimicrobial agents, and a rise in the incidence of infections caused by MDR microorganisms [113]. Numerous studies conducted globally have demonstrated an augmentation in the resistance of gram-negative and gram-positive bacteria, including enterococci, to a range of antibiotics during the COVID-19 period in comparison to pre-pandemic times [113,114,115,116,117,118]. Our study reveals notable alterations in the resistance rates of E. faecalis strains to certain antibiotics when comparing the pre- and post-Covid-19 pandemic periods. Specifically, the prevalence of resistance to ampicillin and penicillin during the period spanning 2000–2019 (prior to the Covid-19 pandemic) was significantly higher than the period of 2020–2022 (post the Covid-19 pandemic). On the other hand, the resistance of E. faecalis to amoxicillin-clavulanic acid, chloramphenicol, fosfomycin, imipenem, minocycline, moxifloxacin, norfloxacin, quinupristin/dalfopristin, and tetracycline has displayed a relatively increased level in the period 2020–2022 compared to 2000–2019. Although the difference in the outcomes of these antibiotics between the pre- and post-Covid-19 pandemic periods does not exhibit statistical significance, it elucidates the importance of escalating resistance during the covid-19 pandemic [117, 119, 120]. The irrational and excessive utilization/prescription of antibiotics, self-antibiotics medication and non-prescription drug sales, empirical administration of antimicrobials, physician prescribed antibacterials for in-patients admitted for the viral infection, and antibiotics prescribed by general practitioners have been identified as the main risk factors contributing to the elevated levels of antibiotic resistance during the COVID-19 pandemic, particularly in underdeveloped or developing countries [115, 117, 119, 120]. Consequently, it is essential to enforce antibiotic resistance surveillance and adhere strictly to antibiotic prescriptions in accordance with antimicrobial stewardship programs (ASP) and the guidelines outlined by the WHO. This approach is crucial not only for bolstering resistant-infections prevention or control but also for ensuring robust and consistent AMR surveillance as an integral component of the COVID-19 pandemic response and recovery [114].

It is noteworthy that the trend of drug resistance rate of E. faecalis strains has demonstrated significant changes over the years (from 2000 to 2022) with regard to certain antibiotics. The trend of resistance rate to ciprofloxacin, penicillin, and rifampicin have shown a significant decrease during this period. Meanwhile, the resistance trends for doxycycline, erythromycin, moxifloxacin, ampicillin, levofloxacin, and vancomycin have displayed a non-significant decrease over time. The downward trend of resistance rate to these antibiotics in the world may be attributed to effective management and monitoring policies governing the rational prescription and consumption of antibiotics, alongside the implementation of appropriate strategies to curb the spread of resistant strains in developed countries [121, 122]. Conversely, the trend of resistance rate to minocycline, fosfomycin, norfloxacin, quinupristin/dalfopristin, chloramphenicol, tetracycline, nitrofurantoin, and teicoplanin have shown a non-significant increase over the same period. The comparative analysis conducted in this study reveals that resistance levels to specific antibiotics were notably elevated in certain countries when compared globally. Taiwan exhibited significantly higher resistance to vancomycin, penicillin, teicoplanin, and ciprofloxacin. South Korea showed meaningfully increased resistance to gentamicin, erythromycin, and rifampicin. India and Italy had significantly higher resistance to ampicillin and chloramphenicol, respectively. Algeria demonstrated significantly higher resistance level to tetracycline in comparison to other countries. Conversely, Australia had significantly lower resistance levels to erythromycin, penicillin, teicoplanin, ampicillin, and vancomycin. Sweden exhibited significant decreased resistance rates to chloramphenicol and gentamicin. Turkey showed a significant lower resistance to rifampicin, while Poland had a lower resistance to ciprofloxacin in comparison to other countries. These findings highlight the disparities in antibiotic resistance patterns across different regions. Our data clearly demonstrates that clinical E. faecalis strains in Asian countries exhibit significantly higher levels of antibiotic resistance compared to strains from other global regions. The considerable increase in resistance observed in Asia, especially in developing countries, underscores the absence of effective AMR national action plans and strict monitoring programs aimed at mitigating antibiotic resistance [122, 123]. In contrast, the considerable decrease in the prevalence of drug-resistant strains in Australia and subsequently in Sweden highlights the pivotal role of well-implemented healthcare policies and strategies in preventing the emergence and dissemination of AMR within these countries.

Global findings reveal that the greatest number of studies pertaining to the prevalence of antibiotic resistance in E. faecalis strains has been conducted in Asia, surpassing research conducted in other continents. Subsequently, Europe represents a higher number of studies in comparison to other continents, while the continent of Oceania has the least studies in this domain. The prevalence of resistance to ciprofloxacin and norfloxacin among E. faecalis strains in Asia is significantly higher than in other continents. Africa has also shown a statistically significant increase in resistance to ampicillin and penicillin relative to other continents. Conversely, Oceania has experienced a significant decrease in resistance to gentamicin, ampicillin, ciprofloxacin, and penicillin. Europe and the Americas follow, with notably lower resistance to chloramphenicol and norfloxacin, respectively. Based on our findings, it is evident that Asian and African countries are significantly impacted by the escalating of AMR in clinical strains. Economically, the scarcity and elevated cost of broad-spectrum antibiotics in these continents have likely resulted in heightened usage of narrow-spectrum antibiotics, consequently contributing to an increase in resistance against them [6]. In general, the proportions of antibiotic resistance in the studied pathogens were lower in high-income countries compared to low- and lower-middle-income nations. This observation aligns with data from the Global Burden of Disease study 2019, indicating that the burden of infections caused by antibiotic-resistant bacteria is notably higher in areas with limited resources, such as African countries, in contrast to high-income regions such as Europe and North America [7]. In underdeveloped or developing countries, several factors contribute to the emergence of MDR microorganisms. These include limited access to effective antibiotics, unregulated administration and production of antibacterials, and abbreviated antibiotic treatment due to financial constraints [115, 123]. Additionally, the complexities underlying AMR in developing countries may be attributed to healthcare professionals’ practices, patient behaviors regarding antimicrobial use, and the incomplete antibiotic supply chain. These factors encompass inadequate hygiene practices, suboptimal prescribing practices, insufficient patient education, constrained diagnostic facilities, unauthorized antimicrobial sales, the absence of comprehensive ASP, and non-medical use of antimicrobials [124, 125].

The subgroup analysis based on WHO regional offices indicates a significantly elevated resistance of clinical E. faecalis strains to ampicillin, gentamicin, erythromycin, and penicillin within the South-East Asia region. In contrast, the Americas, Eastern Mediterranean/Islamic Republic of Iran, Eastern Mediterranean, and European regions exhibit significantly lower resistance to these antibiotics, respectively. Our study indicates a significantly higher frequency of resistance to rifampicin and teicoplanin in the Western Pacific region compared with other regions. Conversely, the European and African regions show significantly lower resistance to rifampicin and teicoplanin, respectively. The Eastern Mediterranean/Islamic Republic of Iran region demonstrates a significantly lower resistance rate to levofloxacin compared with other regions. Given that South-East Asian countries are substantial importers of poultry and livestock, the excessive use of antibiotics in these products contributes to the spread of MDR enterococci, which can be transmitted to humans through consumption of these products. This, in turn, leads to increased antibiotic resistance in these countries [6, 126]. Moreover, inappropriate consumption/prescription of antibiotics by patients/physicians, as well as in industries, are likely the primary factors lead to the enhancement of antibiotic-resistance in developing countries such as South-East Asian countries. In contrast, access to antibiotics is restricted in other regions [123, 125].

Enterococci infections are experiencing a rapid escalation in hospitals globally, primarily attributable to their ability to survive under harsh conditions for long periods and remarkable adaptability to environmental conditions. This capability positions enterococci as a crucial reservoir for the transmission and spread of drug resistance determinants [5]. Furthermore, the emergence and spreading of AMR-E. faecalis are influenced by other factors, encompassing environmental, societal, and economic effects, alongside local and regional idiosyncrasies [127,128,129]. Addressing AMR-E. faecalis requires a comprehensive approach that integrates multiple strategies for prevention, control, and treatment. We suggest the implementation of the following measures to curtail the further escalation of AMR among E. faecalis, particularly in countries with a high prevalence of resistance. First, establish a national AMR policy is imperative to comprehensively comprehend the emergence, spread, and aspects influencing antibiotic resistance. Second, stringent management policies should be enforced to prevent the transmission of resistant infections within hospital environments. Third, measures should be taken to prohibit antibiotic self-medication and deter irrational and unconventional antibiotic consumption/prescription practices. Fourth, efforts are needed to educate healthcare professionals and patients about the appropriate use of antimicrobials, alongside training healthcare workers for the nosocomial infections control methods. Fifth, the development of rapid point-of-care infectious agent detection should be employed to support the accurate use of antimicrobial drugs. Sixth, regular surveillance programs are essential to ascertain the precise prevalence of antibiotic resistance. Strengthening surveillance and monitoring systems is essential for tracking resistance patterns, detecting new resistant strains early, and enabling timely interventions. Seventh, implement strict infection control and prevention strategies, including hygiene practices, hand hygiene, and environmental cleaning protocols, to prevent the spread of resistant strains. As well, regular enforcing ASP in healthcare settings is vital to guide appropriate treatment strategies and minimize resistance development in clinical isolates. Lastly, there is a need to foster the expansion of new antimicrobial agents. Encouraging research and development efforts contributes to the development of new antibiotics, diagnostic tools, and alternative therapies, ultimately enhancing the fight against AMR-E. faecalis isolates. Integrating these strategies into clinical practice and healthcare policies is essential in mitigating the challenges posed by resistant strains of E. faecalis and improving patient outcomes. A coordinated global response involving healthcare providers, researchers, policymakers, and the pharmaceutical industry is necessary to achieving the goals effectively and defeat this pressing global health threat.

The heterogeneous results in this study can be attributed to varying resistance patterns based on the geographical area under study, studied population, source and size of the samples, and variations in bacterial identification and AST methodologies.

The main strength of our study is that, for the first time, we have comprehensively investigated the prevalence of antibiotic resistance in E. faecalis strains isolated from clinical samples all over the world during 22 years. Furthermore, we conducted comparative analyses between different points, examining the resistance trend over the time and comparing its fluctuations in long-term time periods, including in the periods before and after the COVID-19 pandemic. Nonetheless, it should be noted that there are several limitations to our study. First, only published full-text research articles were evaluated in our study. Second, only the studies on clinical strains of E. faecalis were assessed and other studies on environmental samples were excluded. Third, the lack of differentiation of clinical samples, which ultimately did not conclude the prevalence of E. faecalis in various infections. Forth, microbiological diagnostics is not routinely performed for typical infections, such as uncomplicated UTIs in outpatient care, consequently AMR patterns may not be sufficiently reflected in the dataset. Fifth, the lack of unit definition of resistance in the analysis of the literature that was used. In 2019, EUCAST redefined susceptibility testing categories as: susceptible (S), susceptible increased exposure (I), and resistant (R). EUCAST changes in category (I) may have led to changes in pooled resistance ratios compared to pre-2019 data. Sixth, considering that this is a global systematic review study, we might have missed some relevant studies. Finally, the lack of information on resistance mechanisms and associated genetic factors restricts our understanding of the primary drivers of resistance.

Conclusions

Our study highlights the alarming global prevalence of antibiotic resistance in E. faecalis, particularly affecting developing countries. This urgent issue calls for comprehensive strategies to address antibiotic resistance. Understanding regional resistance patterns is crucial for informing research, guiding antimicrobial stewardship programs, and curbing the spread of resistant strains. Daptomycin and tigecycline show potential as treatment options due to lower resistance rates, but careful management is needed to prevent drug-resistant strains. Learning from successful preventive strategies in low-resistance regions like Europe and Australia can help combat resistance. A multipronged approach involving surveillance, research, and stewardship programs is vital to preserve existing antibiotics' efficacy and protect public health.