Antibiotic Resistance Trends Among Enterobacteriaceae in Saudi Arabia: A Systematic Review

Antibiotic resistance is a global public health concern that poses a significant threat to the effective treatment of bacterial infections. Enterobacteriaceae, a family of gram-negative bacteria, are associated with a wide range of infections, including urinary tract infections, bloodstream infections, and respiratory tract infections. This systematic review aimed to examine the antibiotic resistance trend among Enterobacteriaceae in Saudi Arabia in the period between 2003 and 2023. Five databases (PubMed, Medline, Ovid, Scopus, and Cochrane) were searched using the keywords “Resistance AND Enterobacteriaceae AND Saudi Arabia” in the title and abstract. All papers assessing the prevalence of resistance among Enterobacteriaceae in Saudi Arabia were included in the systematic review. Out of 97 papers that were extracted through the database search, 22 articles were considered suitable for the systematic review. The articles included 17027 Enterobacteriaceae isolates, out of which 7592 isolates were identified as resistant bacteria. The studies included various resistant strains, such as Escherichia coli and Klebsiella pneumoniae, that were responsible for various clinical conditions, including urinary tract infections, blood infections, surgical site infections, and pneumonia. In addition, the review highlighted the dynamic nature of antibiotic resistance, with the identification of new resistant bacterial species and the emergence of resistance to newer antibiotic classes over the last decade. Continued surveillance, rational antibiotic use, and the development of alternative treatment options are crucial to address the evolving landscape of antibiotic resistance among Enterobacteriaceae bacteria in the country.


Introduction And Background
Antibiotic resistance often arises within a few years of introducing a new antibiotic [1].It occurs due to various mechanisms, including enzymatic inactivation or modification of antibiotics, alteration in bacterial target sites, permeability barriers to the antibiotic influx, active efflux pumps that extrude antibiotics from bacterial cells, and combinations of mechanisms [2][3][4].Over time, mutations that confer resistance tend to increase, and antibiotic use can amplify this rate of increase due to selection pressure.Additionally, other factors that contribute to the spread of antimicrobial resistance (AMR) include crowding, poor hygiene, overuse and misuse of antibiotics, and increased travel [3].
Enterobacteriaceae is most known for being antibiotic-resistant due to extended-spectrum β-lactamases (ESBLs) production, which can break down third-generation cephalosporins and aztreonam [9].ESBL organisms are treated with carbapenem, the last resort to treat multidrug-resistant gram-negative bacteria.With the increase in carbapenem use, carbapenem-resistant Enterobacteriaceae (CRE) has become a public health concern [10].The emergence and widespread dissemination of novel ESBLs and carbapenemases have contributed to a significant rise in AMR among Enterobacteriaceae worldwide over the past two decades [3,9,11,12].
Among carbapenemases-producing Enterobacteriaceae (CPEs), the most common resistance mechanism is the production of Klebsiella pneumoniae carbapenemase (KPC) enzymes.These enzymes are most frequently found in isolates of Klebsiella pneumoniae (K.pneumoniae).Many countries around the world have recorded outbreaks caused by KPC-producing K. pneumoniae [13].In Saudi Arabia, studies about AMR are limited and retrieved from separate institutions [14,15].By systematically reviewing the available literature, the review will provide a comprehensive overview of the prevalence and extent of antibiotic resistance among Enterobacteriaceae in Saudi Arabia.This information will help identify the magnitude of the problem and contribute to the understanding of the current AMR landscape in the country.Therefore, our study aimed to investigate the antibiotic resistance trend among Enterobacteriaceae in Saudi Arabia from 2003 to 2023.

Review Methodology
This systematic review complied with established criteria (Preferred Reporting Items for Systematic Reviews and Meta-Analyses, PRISMA) [16].

Search Strategy
The systematic review was conducted through a thorough literature search of PubMed, Medline, Ovid, Scopus, and Cochrane databases using the keywords in the abstract and title: Resistance AND Enterobacteriaceae AND Saudi Arabia.One researcher screened studies published from 2003 to 2023 examining the antibiotic resistance trend among Enterobacteriaceae in Saudi Arabia to select studies that matched the inclusion and exclusion criteria.
Then, key data points were retrieved from the final record of the included research.

Inclusion and Exclusion Criteria
All papers assessing the prevalence of resistance among Enterobacteriaceae in Saudi Arabia were included in the systematic review.We excluded published studies in languages other than English, narrative reviews, duplicated papers, studies published before 2003 or conducted on the timeframe for bacterial resistance before 2002, studies with insufficient data or findings, studies with irrelevant findings, studies that did not include clinical samples and studies for which full text was unavailable.

Screening and Data Extraction
A reference manager was used to check the output of the search technique for duplication.The author first screened the titles and abstracts of the relevant studies.Then, relevant full-text papers were examined and evaluated for inclusion criteria.The data was independently extracted in a Microsoft Excel (Microsoft® Corp., Redmond, WA) spreadsheet.The data included authors, year of publication, study design and period, objective, methodology, population characteristics, and results of resistance pattern (bacterial species, antibiotics classes, mechanism of resistance).

Strategy for Data Synthesis
A summary table was created using data from relevant studies to provide a qualitative interpretation of the findings and study components.

Risk of Bias Assessment
In this systematic review, the risk of bias assessment was conducted among non-randomized studies of interventions (NRSI).We used the ROBINs-1 tool to assess NRSIs [17].The assessments were conducted and the outcome assessed was the resistance pattern during 2002-2021.The judgment options were low, moderate, serious, and critical, and the overall risk of bias was reached using signaling questions.Issues that occurred while conducting the assessments due to unspecified study designs were corrected by discussion among the authors, and the most suitable judgment was agreed upon for these studies.The risk of bias revealed the overall quality of the included studies.Most studies need more reporting of study design details, including sample type, microbiological investigations, and antimicrobial susceptibility testing methods.Given the serious risk of bias observed within six of our included studies, our findings suggest the need for further investigational studies with more carefully designed and rigorously conducted studies involving larger sample sizes in the future.

Results
As described in Figure 1, 22 articles were considered suitable for the systematic review.

Overview of the Included Studies
The included papers were published between 2004 and 2023 in different hospital settings in Saudi Arabia in different cities (Riyadh, Alkharj, Taif, Dammam, Jeddah, Alhassa, Bisha, Jazan, and Makkah) or regions (Western Region, Eastern Saudi Arabia, and Northern borders).The study duration was between 2002 and 2021 (Table 1).The study design varied among the included studies; four of the papers utilized a crosssectional study design, three relied on retrospective analysis, two were prospective studies, and only one study involved a pooled analysis.Other studies did not report a definitive study design.The studies included diverse patient populations within the age range of 1 to 93 years, and most of them were intensive care patients.Species: E. coli (14) and K. pneumoniae Ampicillin (17) Amoxicillin/ clavulanic acid (3) Piperacillin/ Tazobactam (7) Cefoxitin ( 3) Ceftazidime ( 17) Cefepime ( 17) Imipenem (0) Meropenem (0) Amikacin ( 1) Gentamicin ( 5) Ciprofloxacin ( 13) Tigecycline (0) Nitrofurantoin ( 4)    The articles included 17027 isolates of Enterobacteriaceae bacteria, out of which 7592 isolates were identified as resistant bacteria.The most frequently collected specimens were blood (15 studies), urine (13 studies), wound specimens (13 studies), sputum (10 studies), and pus (two studies).Additionally, other sources include vaginal swabs, cerebrospinal fluid, tissue, pus, respiratory infection, endotracheal tube, rectal swabs, and endotracheal tube.Some studies focused on specific patient groups, such as those with diabetic foot infections or catheter-associated urinary tract infections (UTIs).
Moreover, ESBL production was a prominent focus in the included studies, with reported prevalence rates ranging from 1.6% to 87%.CREs were also identified and reported in several studies.Additionally, some studies highlighted the coexistence of multiple resistance mechanisms, such as the presence of both metallo-beta-lactamase (MBL) and ESBL in a subset of isolates.All details are described in Table 1.

Risk of Bias Assessment
The risk of bias revealed the overall quality of the included studies, according to the ROBINS-I tool (

Discussion
AMR poses a serious public health emergency, which is primarily attributed to the overuse of antibiotics [40,41].The resistance patterns observed in a specific strain of bacteria reflect a combination of inherent (intrinsic) and acquired resistance mechanisms.While intrinsic mechanisms are universally present, acquired mechanisms may exist only in certain geographical areas, leading to heterogeneous prevalence within those areas.Additionally, within a particular healthcare facility, only specific wards or units may be affected by these acquired mechanisms.Consequently, the implementation of effective surveillance, coupled with timely and accurate reporting of local epidemiology, plays a vital role in providing clinicians with crucial information for the appropriate management of patients [42].Therefore, this systematic review aimed to investigate the antibiotic resistance trend among Enterobacteriaceae in Saudi Arabia from 2003 to 2023.
Enterobacteriaceae bacteria are widely distributed and have a broad range of hosts.These bacteria have the potential to cross-infect and transmit between medical staff and patients.Additionally, they can acquire genetic material, such as plasmids or transposons, from external sources, enabling the horizontal transfer of drug-resistant genes.This, in turn, contributes to the extensive dissemination of drug-resistant bacteria [43,44].
Bacteria that belong to the Enterobacteriaceae family are responsible for causing several nosocomial infections and community-acquired infections.Particularly, it contributes to UTIs, respiratory infections, osteomyelitis, soft tissue infections, and endocarditis [5].We highlighted several species of Enterobacteriaceae that have been implicated in various clinical conditions in the last two decades.These infections included blood infections, catheter-associated UTIs and UTIs, diabetic foot infections, surgical site infections, and pneumonia.
It is a well-known fact that pathogens can develop drug resistance under the pressure of antibiotic selection.This can lead to a reduction in the effectiveness of antibiotics against infectious pathogens.Furthermore, the irrational use of antibiotics has resulted in many pathogens developing multidrug resistance, which is a cause of great concern in the medical community [47].In recent years, the widespread utilization of βlactamases has resulted in the elimination of the effectiveness of most cephalosporins against Enterobacteriaceae.As a result, carbapenems have become crucial in the treatment of clinical infections caused by these resistant bacteria.Unfortunately, the incidence of CREs has been steadily increasing over the years [48,49].Among the included studies, ESBL production was frequently reported among Enterobacteriaceae, with prevalence rates ranging from 4.8% to 87% [18,[20][21][22][23][24]26,30,33,34,38].
The trend of increasing the rate of resistance towards carbapenems over the years was noted in the included studies.In a study published in 2013, the resistance rate to both imipenem and meropenem was recorded at 15.5%.However, as time progressed, this resistance rate gradually climbed to a staggering 100% [20,33,[35][36][37][38][39].
Despite colistin being considered the last-line drug for treating gram-negative bacteria [50], there has been a trend in resistance to colistin in recent years among the mentioned studies.Notably, a study conducted in 2017 revealed that all isolates were susceptible to colistin, indicating its effectiveness at that time [20].However, subsequent studies conducted between 2017 and 2020 showed a significant rise in colistin resistance rates.One study reported a resistance rate of 2.1%, while another study found an alarming increase to 17.8% [38,39].These findings highlight the growing challenge of colistin resistance and the urgent need for effective strategies to combat it.
One limitation of this study is that the included studies were limited to a specific time frame and geographical area (Saudi Arabia from 2003 to 2023).Therefore, the findings may not be representative of the global or long-term trends in antibiotic resistance among Enterobacteriaceae.

Conclusions
The systematic review highlights the trend of antibiotic resistance among Enterobacteriaceae in Saudi Arabia.The studies included various resistant strains, such as E. coli and K. pneumoniae, that were responsible for various clinical conditions, including UTIs, blood infections, surgical site infections, and pneumonia.The review highlighted the dynamic nature of antibiotic resistance, with the identification of new resistant bacterial species and the emergence of resistance to newer antibiotic classes over the last decade.The study also revealed high resistance rates to several classes of antibiotics, including penicillins, cephalosporins, carbapenems, fluoroquinolones, sulfonamides, aminoglycosides, beta-lactam antibiotics, and macrolides.The emergence of new resistant bacterial species underscores the evolving landscape of antibiotic resistance and the need for continuous monitoring and adaptation of treatment guidelines.The findings emphasize the importance of rational antibiotic use and the development of alternative strategies to combat multidrug resistance.

Clinical implications
These findings highlight the urgent need for effective strategies to combat antibiotic resistance in Saudi Arabia.The data provide valuable insights into the prevailing resistance patterns and can guide healthcare professionals in selecting appropriate antimicrobial therapies.Continued surveillance, rational antibiotic use, and the development of alternative treatment options are crucial to address the evolving landscape of antibiotic resistance among Enterobacteriaceae bacteria in the country.

FIGURE 1 :
FIGURE 1: PRISMA flow diagram of study selection for the systematic review PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses