Carbapenem resistant Enterobacteriaceae in the livestock, humans and environmental samples around the globe: A systematic review and meta-analysis

doi:10.21203/rs.3.rs-3754969/v1

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Carbapenem resistant Enterobacteriaceae in the livestock, humans and environmental samples around the globe: A systematic review and meta-analysis

https://doi.org/10.21203/rs.3.rs-3754969/v1

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published 14 Jul, 2024

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Introduction and objectives:

Carbapenem-resistant Enterobacteriaceae (CRE) have diminished treatment options causing serious morbidities and mortalities. This systematic review and meta-analysis assessed the prevalence and associated factors of Enterobacteriaceae infections in clinical, livestock and environmental settings globally.

Data sources:

The population intervention comparison and outcome (PICO) strategy was used to enroll studies using the Preferred Reporting System for Systematic Review and Meta-analysis (PRISMA) to include only cross-sectional studies. Search engines included journal author name estimator (JANE), PubMed, Google scholar, African Journals Online (AJOL), World cat, Green version, CrossRef and snow balling of retrieved articles. The Newcastle-Ottawa Scale (NOS) was used to assess the quality of studies.

Results

Sixteen articles from 2013 to 2023 in Africa, Asia, Europe and South America were studied. The pooled prevalence of CRE was 43.06% (95% CI, 21.57 to 66.03). Klebsiella pneumoniae (49.40%), Escherichia coli (26.42%), and Enterobacter cloacae (14.24%) were predominat. Klebsiella pneumoniae had the highest resistance with the blaKPC-2 in addition to blaNDM, blaOXA-48, blaIM and blaVIM. The blaKPC-2 genes occurence were associated with environmental (p. Value < 0.0001) and South American studies (p. Value < 0.0001), but there was no difference in the trends over time (p. Value = 0.745).

Conclusion

This study highlights the high rates of CRE infections, particularly within Klebsiella pneumoniae, especially the blaKPC production. Monitoring and surveillance programs, research and infection control measures should consider be strengthened. Additionally, further studies are needed to explore the mechanisms driving the predominance of specific bacterial species and the distribution of resistance genes within this bacterial family.

Biological sciences/Microbiology

Biological sciences/Molecular biology

Enterobacteriaceae

Carbapenem-resistance

Resistance genes

Enterobacteriaceae are a large and diverse group of gram-negative bacteria that are found in the environment and in the gut of animals, birds and humans. They can cause a variety of infections, including urinary tract infections, pneumonia, and sepsis. In recent years, there has been an increasing prevalence of Enterobacteriaceae that are resistant to several antibiotics (Jin et al., 2017).

Carbapenem-resistant Enterobacteriaceae (CRE) are a group of Gram-negative bacteria that have become resistant to carbapenems, which are a class of antibiotics that are last-line treatments for many serious infections. The CRE can be found in a variety of settings, including hospitals, nursing homes and several other health care facilities (Jin et al., 2017). However, they are also increasingly being found in the environment (Montezzi et al., 2015, Su et al., 2023, Piedra-Carrasco et al., 2017) and among people who have or not been recently hospitalized and livestock (Makharita et al., 2020, Nabti et al., 2022, Cizmeci et al., 2017, Jie Feng, 2021)(Chabou et al., 2018, Abdallah et al., 2015). The emergence of CRE in these various settings, has raised concerns about the widespread dissemination of these multidrug-resistant pathogens.

The potential for resistance gene transfer (through transformation, transduction and conjugation) for CRE is common. Therefore, there is a need for collective efforts globally to control AMR including CRE. The One Health concept, which emphasizes the interconnectedness of human, animal, and environmental health, is crucial for tackling the global issue of CRE prevalence. Collaborative efforts across these domains are essential for comprehensive control measures. Understanding the genetic constitution of the CRE would serve the primary role of unlocking this burden.

Aim of the study

The aim of this systematic review and meta-analysis was to assess the prevalence and associated factors of Enterobacteriaceae infections in clinical, livestock and environmental settings globally.

Selection

The population intervention comparison and outcome (PICO) strategy was used to make selection of the studies. Only cross-sectional studies that employed the molecular assays to assess CRE during data collection were included in the review. They should have been published in English. For clinical studies, those that included stool specimens were excluded in the review. Comparative groups were clinical, environmental and livestock with prevalence as the measure of outcome.

Data search

The Preferred Reporting System for Systematic Review and Meta-analysis (PRISMA) standards was used to guide the process that includes literature search and data extraction, data cleaning, data analysis and interpreting result a seen in figure 1. The primary studies that investigated epidemiology, transmission dynamics of molecular analysis of carbapenem resistant Enterobacteriaceae in community and health care settings were adopted for the systematic review. Search engines included journal author name estimator (JANE), PubMed, Google scholar, African Journals Online (AJOL), World cat, Green version, CrossRef, and snow balling using retrieved articles. We included data from articles published between January, 2010 to December 2022.

Search terms were (“Carbapenem Resistant Enterobacteriaceae”), (“Hospital Carbapenem Resistant Enterobacteriaceae”), (“Community Carbapenem Resistant Enterobacteriaceae”), (“Carbapenem Resistant Enterobacteriaceae in livestock”), (“Environment Carbapenem Resistant Enterobacteriaceae”) and, from the articles databases. The (“Phylogeny relationship of Carbapenem Resistant Enterobacteriaceae”) and (“Nucleotide homology comparison of Carbapenem Resistant Enterobacteriaceae”) search term shall be used to extract data from the DNA databases. Snow balling shall be done after text review of references for related articles. Search articles were organized in Endnote from which the duplicates were removed.

Screening

A thorough screening of the articles was performed starting with title and abstract and then full text reading. This was performed by two reviewers (Ms. Barbra Tuhamize and Assoc Prof. Joel Bazira) from 1^st August to 21^stOctober 2023. The two also performed quality appraisal of the recruited articles as cross-sectional in nature to avoid bias using the Cochrane risk of bias assessment tool. Any disagreement between the two reviewers were settled by a consensus during the weekly evaluation meetings that sat every Wednesday of the week.

Assessment of data quality

The Newcastle-Ottawa Scale (NOS) was used to assess the quality of studies that passed the text reviews. Studies with a NOS of three or less were dropped from the meta-analysis.

The meta-analysis (Quantitative data synthesis)

The effect size for each study was checked and later the combined estimate of effect size generated. The random effects model was considered to include heterogeneity. The forest plot was drawn to check the heterogeneity. The funnel plot and the Egger’s and Beggs tests were used to assess the publication bias. Sensitivity analysis was performed by removing one article at ago and check result variation.

Subgroup analysis was later performed for the highly predominant blaKPC gene amongst the different sample sources, continent and trends over time. The distribution of the blaKPC gene among the sample sources and the different continents was performed using the metanalysis of pooled prevalence using the chi square test at 95% CI and trends over time from 2013 to 2023 using linear regression at 95% CI.

Systematic review

The search and systematic review yielded 16 studies from 2013 to 2023 in Africa, Asia, Europe and South America (Table 1) using the PRISMA standards guide (Fig. 1)

These 16 studies that were included in the study, were caried out from African, Asia, Europe and South America using samples from environmental, livestock and clinical specimens (Makharita et al., 2020, Ribeiro et al., 2013, Nabti et al., 2022, Cizmeci et al., 2017, Li et al., 2018, Chabou et al., 2018, Jin et al., 2017, Montezzi et al., 2015, Solgi et al., 2017, Sonnevend et al., 2015, Okoche et al., 2015, Su et al., 2023, Jie Feng, 2021, Abdallah et al., 2015, Piedra-Carrasco et al., 2017). Several Enterobacteriaceae were reported to carry resistance genes as shown in Table 1 below.

Table 1

General characteristics of Characteristics of studies included in the review.
SN	First Author	Publication year	Country	Continent	Sample source	Sample type	Sample size	Organism		Individual genes
SN	First Author	Publication year	Country	Continent	Sample source	Sample type	Sample size	Organism	Genes per bacteria	blaNDM-1	blaNDM-5	blaIMP-4	blaKPC-2	blaOXA-48	blaVIM
1	Makharita R. Rabab et al, 2022	2022	Egypt	Africa	Human	Urine	37	Klebsiella pneumoniae (18)	blaKPC-2 (9) & blaGES (9)				9
								Escherichia coli	blaKPC-2 (1) & blaGES (1)				1
								Enterobacter aerogenes (2)	0
								Proteus mirabilis (1)	0
2	Vanessa Bley Ribeiro et al, 2013	2013	Brazil	South America	Human	Urine	345	Klebsiella pneumoniae (93)	blaKPC-2 (5)				5
								Klebsiella oxytoca (1)	0
								Enterobacter aerogenes (31)	0
								Enterobacter cloacae (193)	blaKPC-2 (6)				6
								Escherichia coli (18)	0
								Proteus mirabilis (1)	0
								Serratia marcescens (8)	blaKPC-2 (3)				3
3	Larbi Zakaria Nabti et al, 2021	2021	Algeria	North Africa	Human	Urine	123	Klebsiella pneumoniae (52)	blaOXA-48 (4)					4
								Escherichia coli (24)	blaOXA-48 (1)					1
								Enterobacter cloacae (19)	blaNDM-1 (1)	1
								Proteus mirabilis (11)	0
								Proteus vulgaris (1)	0
								Serratia marcescens (4)	0
								Citrobacter freundii (4)	0
								Citrobacter braakii (2)	0
								Providencia rettgeri (1)	0
4	Zeynep Cizmeci et al, 2017	2017	Turkey	Europe	Human	Urine	76	Klebsiella pneumoniae (69)	blaNDM-1 (15), blaOXA-48 (50) & blaVIM (2)	15				50	2
								Enterobacter cloacae (4)	blaNDM-1 (3) & blaVIM (1)	3					1
								Enterobacter aerogenes (4)	blaOXA-48 (2)					2
								Escherichia coli (1)	blaOXA-48 (1)					1
5	Yi Li et al, 2018	2018	China	Asia	Human	Urine	302	Escherichia coli (34)	blaNDM-5 (18) & blaKPC-2 (4)		18		4
								Klebsiella pneumoniae (268)	blaNDM-5 (12), blaIMP-4 (4) & blaKPC-2 (237)		12	4	237
6	Eman Hamza et al, 2016	2016	Egypt	Africa	Bird	faecal	100	Klebsiella pneumoniae (35)	blaNDM-5 (15), blaKPC-2 (11) & blaOXA-48 (11)		15		11	11
7	Longyang Jin et al, 2017	2016	China	Asia	Environment	Sewage	37	Klebsiella pneumoniae (11)	blaKPC-2 (4)				4
								Escherichia coli (10)
								Enterobacter cloacae (13)	blaNDM-1 (1) & blaKPC-2 (5)	1			5
								Citrobacter freundii (3)	blaNDM-1 (2)	2
8	Lara Feital Montezzi et al, 2015	2015	Brazil	South America	Environment	recreational water	18	kluyvera (2)	blaKPC-2 (2)				2
								Enterobacter cloacae (8)	blaKPC-2 (8)				8
								Citrobacter freundii (1)	blaKPC-2 (1)				1
								Klebsiella pneumoniae (1)
9	Solgi et al, 2017	2017	Iran	Asia			95	Escherichia coli (43)				13
								Enterobacter cloacae (12
10	Sonnevend A et al, 2015	2015	Saudi Arabia	Asia	Human	Urine	265	Klebsiella pneumoniae (145)		85				50	6
								Klebsiella oxytoca (2)	2
								Escherichia coli (28)		9				9	1
								Enterobacter cloacae (17)		2				8	5
								Serratia marcescens (1)
								Citrobacter freundii (3)
								Citrobacter koseri (1)
								Providencia stuartii (1)
								Morganella morganii (2)
11	Okoche et al, 2015	2015	Uganda	Africa	Human	Urine	192	Klebsiella pneumoniae (78)		4		5	3	7	16
								Klebsiella oxytoca (4)	4					1
								Escherichia coli (84)				6	4	8	1
								Enterobacter cloacae (9)		1			1	2	1
								Proteus mirabilis (6)			1		1
								Proteus vulgaris (3)
								Citrobacter freundii (8)							1
12	Su Yaxin et al, 2023	2023	China	Asia	Bird	environmental	707	Klebsiella oxytoca (50)	50	5				3
								Escherichia coli (168)		6				3
								Proteus mirabilis (33)						1
13	Basem M. Alraddadi et al, 2022	2022	Saudi Arabia	Asia	Human	Urine	189	Klebsiella pneumoniae (165)	blaNDM-1 (20), blaKPC-2 (1) & blaOXA-48 (10)	20			1	10
14	Jie Feng et al, 2021	2021	China	Asia	Animal	meat	760	Escherichia coli (24)		4				5
								Klebsiella pneumoniae (9)		3			5
								Escherichia coli (43)		39
								Enterobacter cloacae (1)
15	Abdalla H et al, 2015	2015	Egypt	Africa	Bird	meat	112	Klebsiella pneumoniae (44)	blaNDM-1 (11)	11
								Klebsiella oxytoca (2)	blaNDM-1 (1)	1
								Escherichia coli (38)
								Enterobacter aerogenes (4)
								Enterobacter cloacae (17)
								Citrobacter freundii (1)
16	Piedra-Carrasco et al, 2017	2017	Spain	Europe	Environment	water	224	Klebsiella pneumoniae (1)	blaKPC-2 (1)				1
								Klebsiella oxytoca (1)	blaKPC-2 (1)				1
								Escherichia coli (3)	blaKPC-2 (3)				3
								Enterobacter cloacae (2)	blaKPC-2 (2) & blaVIM (2)				2		2
								Raoultella ornithinolytica (1)	blaVIM (1)						1

A meta-analysis was conducted among the 16 articles. The pooled prevalence of CRE was 43.06% (95% confidence interval [CI], 21.57 to 66.03) using a random effect model, catering for heterogeneity (Fig. 2). Bias was assessed using the funnel plot indicated in Fig. 3 below.

The predominant bacteria species were, Klebsiella pneumoniae (49.40%), Escherichia coli (26.42%), and Enterobacter cloacae (14.24%). Other bacteria species included Klebsiella oxytoca (2.99%), Proteus mirabilis (2.55%), Enterobacter aerogenes (1.95%), Proteus vulgaris (0.19%), Kluyvera (0.19%), Morganella morganii (0.19%), Citrobacter freundii (0.99%), Serratia marcescens (0.65%), Citrobacter braakii (0.19%), and Citrobacter koseri (0.05%), Providencia rettgeri (0.05%), Providencia stuartii (0.05%), Raoultella ornithinolytica (0.05%) were the least isolated (Table 2).

High prevalence of CRE was exhibited among Klebsiella pneumoniae isolates. The gene occurrence was higher for the blaKPC-2, followed by blaNDM, blaOXA-48, blaIMP, blaVIM, and the least was blaGES, no resistance was reported by Citrobacter braakii, Klebsiella oxytoca, Proteus mirabilis, Proteus vulgaris, and Providencia rettgeri (Table 3). Organisms carried resistance genes from one to as many as seven per bacteria.

Table 3

CRE gene distribution for the different Enterobacteriaceae
Organism	Number of bacteria	Genes carried						Total genes
Organism	Number of bacteria	blaKPC-2	blaOXA-48	blaNDM-5	blaVIM	blaNDM-1	blaIMP-4	Total genes
Klebsiella pneumoniae	989	582	313	106	58	16	7	1082
Escherichia coli	529	5	2	18				25
Enterobacter cloacae	285	14			1	4		19
Others	119	6	2	0	0	1	0	10
Total		607	317	124	59	21	7	1136

The blaKPC-2 gene was dominant, carried more among Klebsiella pneumoniae (582/989; 59%), followed by Kluyvera spp (2/4; 50%), Serratia marcescens (3/13; 23%) and lowly carried by Enterobacter cloacae (14/285; 5%), Citrobacter freundii (1/20; 5%) and Escherichia coli (5/529; 1%) (Fig. 4)

The highly prevalent blaKPC gene’s occurrence was evaluated amongst the sample sources (Table 4), continents (Table 5) and trends over time from 2013 to 2023 (Fig. 5). Environmental samples recorded the highest prevalence of the blaKPC gene compared the humans (p. Value < 0.0001) and livestock (p. Value < 0.0001). Amongst the continents, South American studies produced the highest as compared to Asia (p. Value < 0.0001), Africa (p. Value < 0.0001) and Europe (p. Value < 0.0001). There was no significant difference in the trends of occurrence of the blaKPC gene over time (p. Value = 0.745).

Table 4

The occurrence of blaKPC gene among the sample sources for bacteria
Continent	Number of records	Analysis of the prevalence		Analysis of heterogeinity	p. het	Model
Continent	Number of records	pooled pevalence (95%CI)	p value	I2(95% CI)	p. het	Model
Environmental	3	24.786(1.627 to 62.751) ref		95.63%(90.45 to 98.00)	< 0.0001	random
Human	9	7.63(0.155 to 31.797)	< 0.0001	99.40(99.26 to 99.51)	< 0.0001	random
Livestock	4	1.335(0.0330 to 4.488)	< 0.0001	92.25%(83.36 to 96.39)	< 0.0001	random

Table 5

Comparison of the blaKPC gene occurrence among the continents
Continent	Number of records	Analysis of the prevalence		Analysis of heterogeinity	p. het	Model
Continent	Number of records	pooled prevalence (95%CI)	p value	I²(95% CI)	p. het	Model
South America	2	26.416 (1.725 to 87.626) ref		97.05% (92.32 to 98.86)	< 0.0001	random
Asia	7	8.39 (0.263 to 35.570)	< 0.0001	99.62% (99.53 to 99.69)	< 0.0001	random
Africa	5	5.363 (0.693 to 14.041)	< 0.0001	92.03% (84.38 to 95.93)	< 0.0001	random
Europe	2	1.649 (0.00359 to 6.194)	< 0.0001	72.72% (0.00 to 93.86)	0.0555	random

The findings of this systematic review and meta-analysis provide critical insights into the prevalence and characteristics of Enterobacteriaceae infections, as well as the distribution of carbapenemase resistance genes within this bacterial family. These bacteria can cause a wide range of infections, including urinary tract infections, surgical site infections, pneumonia, bloodstream infections, and diarrhea (Klein and Hultgren, 2020, Kłos and Wójkowska-Mach, 2019, Darlene and Anne, 2014). Enterobacteriaceae infections can be particularly serious in young children, the elderly, and people with weakened immune systems (Kłos and Wójkowska-Mach, 2019). The results from this systematic review and meta-analysis have important implications for public health to curb AMR.

Prevalence of Enterobacteriaceae Infections:

This systematic review and meta-analysis were unique that they pooled studies that researched on several sample sources including humans (urine samples), livestock (faeces and cloaca) and in the environment.

The findings of this meta-analysis, based on a comprehensive review of 16 articles, provide important insights into the global prevalence of Carbapenem-resistant Enterobacteriaceae infections. The pooled prevalence of CRE infections was estimated at 43.06%, (95% CI 21.57–66.03%). Notably, a random effect model was employed to account for the observed heterogeneity among the studies. This finding is consistent with the increasing reports of CRE infections from various parts of the world, reflecting the growing challenge of antibiotic resistance in clinical and non-clinical settings (Kelly et al., 2017). The observed pooled prevalence of 43.06% underscores the alarming global prevalence of CRE infections, suggesting that this issue is more widespread than previously thought.

The wide 95% confidence interval (21.57–66.03%) reflects the substantial variability in CRE prevalence across different regions and populations. The heterogeneity observed in the meta-analysis may be attributed to several factors, including variations in healthcare practices, antibiotic use, and infection control measures among different countries and healthcare settings (van Loon et al., 2018). This heterogeneity highlights the need for a multifaceted approach to address CRE, as a one-size-fits-all strategy may not be sufficient.

It is essential to contextualize the implications of this prevalence estimate in the broader landscape of antimicrobial resistance. CRE is particularly concerning due to their resistance to carbapenem antibiotics, which are often considered the last line of defence against severe infections caused by Gram-negative bacteria (Darlene and Anne, 2014). The high prevalence of CRE signifies a critical need for effective interventions to curb the spread of resistant strains and preserve the efficacy of existing antibiotics. Like Kelly et al., (2017) (Kelly et al., 2017) suggested, this is one area prime to support especially through the one health approach if AMR must be tamed .

In addition to the overall prevalence estimate, the findings of this meta-analysis provide a foundation for understanding the scope of the CRE problem across various populations and regions. This information is instrumental in guiding public health policies, infection control strategies, and antimicrobial stewardship programs aimed at mitigating the impact of CRE.

To address the challenges posed by CRE, we concur with (Woodford et al., 2013) that acomprehensive approach is warranted, including the judicious use of antibiotics, stringent infection control measures in healthcare facilities, and active surveillance to detect and contain CRE outbreaks. Furthermore, international collaboration is essential to share best practices and prevent the further dissemination of CRE strains.

It is important to note that the limitations of this meta-analysis include potential publication bias and variations in data reporting and methodology among the included studies. Future research should continue to monitor CRE prevalence and investigate the genetic mechanisms underlying carbapenem resistance to develop targeted interventions.

Predominant Bacterial Species:

The identification of predominant bacterial species within the Enterobacteriaceae family is essential for understanding the epidemiology of these infections. Klebsiella pneumoniae emerged as the most prevalent species, accounting for 49.40% of isolates. Escherichia coli and Enterobacter cloacae followed as the next most frequently isolated species, with prevalence rates of 26.42% and 14.24%, respectively.

The predominance of K. pneumoniae would be explained by their isolation from clinical studies abundantly, whose (the clinical samples) sample sizes were higher than those from the environment and livestock. This distribution of predominant species suggests that certain Enterobacteriaceae members may possess specific virulence factors or resistance mechanisms that contribute to their prevalence. Some known highly virulent bacteria including Salmonella and Shigella were not reported, but this is explained by them being enteric (by transmission) and very rarely or occassionary cause urinary tract infections (MayoClinic, 2020).

The abundance of Enterobacteriaceae in environmental sources is an indicator of their animal and human fecal sources (Davies and Davies, 2010), and the cross distribution of carbapenem resistance genes worries AMR control program and the One health approach (Montezzi et al., 2015; de Araujo et al., 2016; Paschoal et al., 2017). Moreover, Kluyvera, a less human pathogen (reference) was found to carry blaKPC genes (that is predominantly isolated from clinical specimens). This highlights a need to study comprehensively several other environmental sources such as indoor air and surface areas from public places including schools, hotels, office spaces and day care centers among others.

Further research is warranted to elucidate the factors driving the predominance of these species and to develop targeted interventions for their control.

Carbapenemase Resistance Genes:

One of the most concerning aspects of Enterobacteriaceae infections is the emergence and spread of carbapenem-resistant strains (CRE). Our analysis identified Klebsiella pneumoniae as a major contributor to CRE prevalence, with a notably high occurrence of carbapenemase resistance genes within this species.

Among the carbapenemase resistance genes, blaKPC-2 exhibited the highest occurrence, followed by blaNDM, blaOXA-48, blaIMP, and blaVIM being the least prevalent. The diversity of carbapenemase genes highlights the complexity of antimicrobial resistance within the Enterobacteriaceae family. In environmental and sewage sources, several authors have reported about the abundance of the CRE and their potential to dissemination (Szekeres et al., 2017, Li et al., 2020, Haller et al., 2018, Jie Feng, 2021, Gong et al., 2018). Therefore, the presence of these genes underscores the urgent need for stringent infection control measures and the judicious use of antibiotics to prevent further dissemination of CRE (Li et al., 2020).

It is worth noting that certain bacterial species, including Proteus mirabilis (51) and Klebsiella oxytoca (60) never carried any resistance genes. These species could serve as valuable models for studying resistance mechanisms and potentially inform strategies for combating CRE. However, a similar observation cannot be made for Raoultella ornithinolytica, Proteus vulgaris, Citrobacter braakii, Citrobacter koseri, Providencia rettgeri, Providencia stuartii and Morganella morganii for not expressing any resistance genes because their frequencies were too low to generate any statistical inference.

The blaKPC dominance:

The findings of this systematic review and meta-analysis reveal crucial insights into the prevalence and distribution of the blaKPC-2 gene among different bacterial species in diverse settings, shedding light on the genetic determinants of Carbapenem-resistant Enterobacteriaceae (CRE).

The dominance of the blaKPC-2 gene, particularly in Klebsiella pneumoniae, is a significant and concerning finding. Klebsiella pneumoniae is a well-known nosocomial pathogen responsible for a wide range of infections, and its association with the blaKPC-2 gene indicates the potential for challenging therapeutic outcomes (CDC, 2010). The high prevalence of this gene among Klebsiella pneumoniae (59%) is similar to what (Su et al., 2021) reported in China. This underscores the importance of this species as a key contributor to the CRE problem, especially in healthcare settings where carbapenems are frequently used.

Furthermore, the detection of the blaKPC-2 gene in other species like Kluyvera spp, Serratia marcescens, Enterobacter cloacae, Citrobacter freundii, and Escherichia coli highlights the diversity of bacterial species capable of carrying this resistance gene. While these species might not be as common as Klebsiella pneumoniae in clinical infections, their capacity to harbor blaKPC-2 is a critical concern. In particular, the presence of this gene in Kluyvera spp and Serratia marcescens (which are commonly found in the environment) is noteworthy, given the potential for these species to act as reservoirs for resistance genes and share them with more clinically relevant pathogens.

The variation in the prevalence of the blaKPC-2 gene across different bacterial species suggests that the distribution of carbapenem resistance determinants is not uniform and may be influenced by species-specific factors and selective pressures. For example, Enterobacter cloacae and Escherichia coli exhibit lower prevalences (5% and 1%, respectively) of the blaKPC-2 gene, indicating that other resistance mechanisms may be more prevalent in these species or that their association with CRE may be mediated by different resistance genes encoded by plasmids or bacteriophages (Liu et al., 2021). These variations are consistent with previous studies that have reported differential resistance gene carriage among different Enterobacteriaceae species (Partridge, 2015).

The identification and prevalence of specific carbapenemase genes, such as the blaKPC-2 gene, within CRE are critical for understanding the dynamics of resistance gene dissemination across different reservoirs, including environmental samples, humans, and livestock. This systematic review and meta-analysis have revealed noteworthy findings regarding the dominance and prevalence of the blaKPC-2 gene in these diverse reservoirs.

Understanding the diversity of species carrying the blaKPC-2 gene is crucial for the development of effective infection control and antimicrobial stewardship strategies. Also, to focusing on well-known CRE pathogens like Klebsiella pneumoniae, efforts should also target species with lower prevalence but potential for gene dissemination. Additionally, monitoring and surveillance programs should consider the presence of the blaKPC-2 gene in environmental samples, as these reservoirs can contribute to the spread of resistance determinants among both clinical and non-clinical settings.

The findings of this study emphasize the importance of continued research into the genetic determinants of CRE and the factors influencing their distribution among different bacterial species. By understanding the prevalence of resistance genes like blaKPC-2, we can better address the evolving threat of CRE and develop strategies to mitigate its impact on public health.

The study by (Su et al., 2023) only reported blaNMD and blaOXA but not blaIMP, blaKPC, blaVIM and blaGES similar to. This was different from other studies that reported at least one of these genes with dominance of blaKPC.

Attributes to blaKPC occurrence:

The ecological niche of the blaKPC gene:

In this research, a higher prevalence of the blaKPC gene in environmental samples was obtained compared to both humans and livestock. This result suggests that environmental sources, such as water, soil, or wastewater, may serve as a reservoir for CRE carrying the blaKPC gene especially in community transmission. Several factors could contribute to this higher prevalence in environmental though none of the studies assessed these factors. The environment can act as a bridge for CRE transmission between humans, animals, and the surrounding ecosystem (Jin et al., 2017). The contamination of the environment with CRE from human or livestock sources can establish a cycle of transmission.

Understanding the higher prevalence of the blaKPC gene in environmental samples emphasizes the need for improved environmental surveillance and management to reduce the dissemination of carbapenem resistance. It is essential to consider the complex interplay between human activities, the environment, and antimicrobial resistance.

These findings underscore the importance of adopting a "One Health" approach, which recognizes the interconnectedness of human, animal, and environmental health. Efforts should be made to monitor and mitigate CRE in all these domains to effectively combat the global spread of antibiotic resistance.

The systematic review and meta-analysis of CRE prevalence and genetic determinants, particularly the blaKPC-2 gene, have yielded intriguing insights into the distribution of carbapenem resistance across continents. The findings not only highlight the dominance of the blaKPC-2 gene but also reveal significant variations in its prevalence among different continents.

Variation in Prevalence among Continents:

The marked differences in blaKPC gene prevalence among continents are of substantial concern and indicate significant geographical disparities in CRE distribution:

The highest prevalence of the blaKPC gene in South American studies, as compared to Asia, Africa, and Europe, points to a particularly critical situation in this region. South America has witnessed increasing challenges in healthcare-associated infections and antimicrobial resistance, which may be contributing to the high prevalence of CRE

Asia came second to South America and this is similar to recent reports. Asia has been a significant focus of CRE research due to its large population and diverse healthcare systems. Various studies have highlighted the presence of blaKPC-carrying CRE in the region, indicating the multifaceted nature of the issue.

The comparatively lower prevalence of the blaKPC gene in Africa may be influenced by variations in healthcare infrastructure, antimicrobial use, and epidemiological factors. However, CRE has been a growing concern in parts of Africa, and its prevalence is expected to evolve.

Europe's comparatively lower prevalence suggests a more controlled situation, likely due to stringent infection control measures and antibiotic stewardship programs in place. However, localized outbreaks and variations within European countries are also evident.

Consistent Trends in blaKPC Gene Occurrence Over Time:

The systematic review and meta-analysis findings, highlighting the dominance of the blaKPC-2 gene, and the consistent trends in the occurrence of the blaKPC gene over a ten-year period (2013–2023), provide valuable insights into the dynamics of carbapenem resistance in CRE. These findings indicates the persistence and resilience of this carbapenemase gene within the global CRE landscape.

It is important to note that while the overall trends in the occurrence of the blaKPC gene appear stable, there may be localized variations and fluctuations within different regions, healthcare facilities, and ecological niches. These nuances could be influenced by factors such as local infection control practices, antibiotic use patterns, and the introduction of new CRE strains (Kelly et al., 2017, Tilahun et al., 2021). The observed stability in the occurrence of the blaKPC gene from 2013 to 2023 reflects the ongoing challenges posed by carbapenem resistance. These results emphasize the importance of continued vigilance, surveillance, and the development of strategies to combat CRE and its associated carbapenemase genes.

Limitations:

While this systematic review and meta-analysis provide valuable insights, some limitations should be acknowledged. Firstly, there may be heterogeneity among the included studies, which could impact the generalizability of the results. Secondly, the analysis is based on existing literature up to the cutoff date and may not capture more recent developments in the field. Thirdly, the risk factors to CRE were not presented for all the studies that qualified to the meta-analysis which makes it difficult to establish control measures. Finally, publication bias could affect the prevalence estimates, as studies with significant findings are more likely to be published.

Implications for public health

The findings of this study have important implications for public health. The high prevalence of Enterobacteriaceae infections, especially in hospitals, highlights the need for infection prevention and control measures. These measures should include hand hygiene, proper cleaning and disinfection of surfaces, and the use of antibiotics only when necessary.

The increasing prevalence of Carbapenem-resistant Enterobacteriaceae is a serious threat to public health. These bacteria can be difficult to treat, and they can cause serious infections that can lead to death. It is important to continue research on new antibiotics and other treatments for Enterobacteriaceae infections.

There is need to improve article scrutiny during review to allow better information generation that could potentially lead to control of the MDR bacteria isolates.

In conclusion, this systematic review and meta-analysis highlight the substantial prevalence (43.06% (95% CI: 21.57 to 66.03)) of Enterobacteriaceae infections, the variability in prevalence based on the source of isolation, and the concerning emergence of carbapenem-resistant strains, particularly within Klebsiella pneumoniae, particularly the blaKPC production. monitoring and surveillance programs should consider the presence of the blaKPC-2 gene in environmental samples, as these reservoirs can contribute to the spread of resistance determinants among both clinical and non-clinical settings. These findings emphasize the importance of ongoing research, surveillance, and infection control measures to address the public health challenges posed by Enterobacteriaceae infections and antimicrobial resistance. Additionally, further studies are needed to explore the mechanisms driving the predominance of specific bacterial species and the distribution of resistance genes within this bacterial family.

Recommendations

The following recommendations are made based on the findings of this systematic review:

Implement comprehensive infection prevention and control measures in healthcare settings to reduce the transmission of Enterobacteriaceae.
Promote the judicious use of antibiotics in humans and livestock to slow the development of antibiotic resistance.
Conduct regular surveillance of Enterobacteriaceae infections and antibiotic resistance patterns to inform public health interventions.
Develop new strategies for the prevention and treatment of Enterobacteriaceae infections, including new antibiotics and vaccines.

Ethics approval and consent to participate: This is a systematic review and meta-analysis. We reviewed published studies and only those that had received ethics approval during data collection.

Consent for publication: We have referenced all articles reviewed.

Availability of data and material: Data is available with journal author name estimator (JANE), PubMed, Google scholar, African Journals Online (AJOL), World cat, Green version and CrossRef.

Competing interests: There are no competing interests.

Funding: The study was not funded.

Authors contribution: Both authors contributed equally in data extraction, review, analysis and discussion.

Acknowledgements: The department of microbiology faculty of medicine, Mbarara University of Science and Technology. Authors of the primary articles including; Solgi et al, 2017, Rabab R Makharita et al, 2022, Vanessa Bley Ribeiro et al, 2013, Larbi Zakaria Nabti et al, 2021, Zeynep Cizmeci et al, 2017, Yi Li et al, 2018, Eman Hamza et al, 2016, Sonnevend A et al, 2015, Longyang Jin et al, 2017, Lara Feital Montezzi et al, 2015, Okoche et al, 2015, Su Yaxin et al, 2023, Basem M et al. Alraddadi, 2022, Jie Feng et al, 2021, Abdalla H et al, 2015 and N Piedra-Carrasco et al, 2017.

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Table 2 is available in the Supplementary Files section.

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Carbapenem resistant Enterobacteriaceae in the livestock, humans and environmental samples around the globe: A systematic review and meta-analysis

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Consistent Trends in blaKPC Gene Occurrence Over Time:

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