18 J Contemp Med Sci | Vol. 8, No. 1, January-February 2022: 18–26 Review Epidemiology of Carbapenem Resistance Enterobacterales in Saudi Arabia: A Systematic Review Rawan S. Abou-assy1, Magda M. Aly1,3*, Reda H. Amashah1, Samyah D. Jastaniah1, Hany M. Al Deen2 1Department of Biology, College of Science, King Abdulaziz University, Jeddah, Saudi Arabia. 2Department of Microbiology, King Faisal Medical Complex, Taif, Makkah, Saudi Arabia. 3Department of Botany and Microbiology, Faculty of Science, Kafrelsheikh University, Kafrelsheikh Govvernorate, Egypt. *Correspondence to: (Email: mmmohammad@kau.edu.sa) (Submitted: 10 December 2021 – Revised version received: 26 December 2021 – Accepted: 17 January 2022 – Published online: 26 February 2022) Abstract The widespread of multidrug-resistant bacteria, particularly carbapenem-resistant Enterobacterales (CRE) bacteria, constitutes a major public health threat worldwide, owing to the limited therapeutic options. This review will describe and uncover the Saudi experience in the challenge against carbapenem resistance (CR). The different carbapenem resistance prevalence and carbapenemase genes detected from various bacterial species were mapped for Saudi regional distribution, based on Saudi published data during a period extended from 2017 to 2021. However, VIM, IMP, and KPC enzymes were usually reported with the predominance of OXA and NDM among Enterobacterales. Although SIM and GIM carbapenemases were uncommonly detected in our country. Collaborative efforts and raising awareness of the threat of carbapenem resistance are required to minimize the spread of multidrug-resistant bacteria. Keywords: Carbapenem, Enterobacteriaceae, Saudi Arabia, lactamase, resistant, carbapenemase ISSN 2413-0516 Introduction Carbapenem resistance (CR) bacteria is a significant and mounting health concern globally,1,2 this problem is aggra- vated by inadequate infection control in developing countries due to poor hygiene, resource and structural constraints, defi- cient surveillance data, and lack of awareness regarding noso- comial infections.3,4 It occurs mainly among Gram-negative pathogens such as Klebsiella pneumoniae, Pseudomonas aerug- inosa and Acinetobacter baumannii, and may be intrinsic or mediated by transferable carbapenemase-encoding genes,5,6 the most effective carbapenemases, in terms of carbapenem hydrolysis and globally spread, are KPC, VIM, IMP, NDM and OXA-48 genotypes.7 Carbapenem class antibiotics have been a mainstay of treatment for serious infections caused by Enterobacterales, but efficacy has been compromised by the widespread acquisi- tion of resistance genes to these critical drugs.8 Effective anti- microbial options for Carbapenem-Resistant Enterobacterales (CRE) are often lacking, and treatment typically requires reli- ance on drugs with a risk of toxicity or other safety concerns.9 Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a prominent cause of nosocomial infections associated with high rates of morbidity and mortality, particularly in immune-compromised individuals.10,11 Carbapenem resist- ance causes a broad spectrum of diseases including pneu- monia, urinary tract infections, bloodstream infections, skin, and soft tissue infections.12 This resistance is facilitated by complex factors, including the presence of mobile genetic ele- ments, the misuse of antimicrobial drugs, poor infection con- trol practices, and increased international travel.13 In healthcare settings, CRE is transmitted from person to person, often via the hands of healthcare personnel or through contaminated medical equipment.14 Additionally, sink drains and toilets are increasingly recognized as an environmental reservoir and CRE transmission source.15 Risk factors for CRE colonization and infection have been identified as longer length of hospital stay, prior hospitalization, admission to ICU, renal dysfunction, neurological disorders, tracheostomy, mechanical ventilation, central venous catheter (CVC) use, urinary catheter use, nasogastric tube use, implementation of dialysis, prior use of any antibiotic, and specific use of carbapenems.16–18 The aim of this review was to shed light on all studies tackling Carbapenem resistance in Enterobacteriaceae, car- bapenem resistance A. baumannii (CRAB) and carbapenem resistance P. aeruginosa (CRPA) in the Saudi Arabia regions, with an indication for each region, description of studies time- line, the prevalence of carbapenem resistance, and CR- encoding genes detected based on Saudi data published over last 5 years from 2017 to 2021. This study enabled us to gain deep insight into the CR problem in Saudi Arabia, in addition to mapping the regional distribution of carbapenemase enzymes and CR prevalence for each region, which is strongly encouraged by epidemiologists to improve surveillance strate- gies to minimize the spread of CR gram negative bacteria such as previously described. Methods Literature Review PubMed, ScienceDirect and international Journals Online databases were searched to December 2021. The search key words used were carbapenem resistance in Saudi Arabia, Enterobacteriaceae, CRE, Escherichia coli, CREC, Klebsiella, CRKP, Pseudomonas aeruginosa, CRPA, Acinetobacter bau- mannii, CRAB, carbapenem, -lactam, -lactamase, resistant, carbapenemase, MBL, metallo-b-lactamase, VIM, NDM, OXA, oxacillinase, IMP, KPC to extract articles published only in English in an attempt to include up to date relevant data. Study Selection Criteria Only research articles reporting the prevalence or molecular genotyping frequency of carbapenem resistance in clinical pathogens isolated from patients and hospital environment or 19J Contemp Med Sci | Vol. 8, No. 1, January-February 2022: 18–26 R.S. Abou-assy et al. Review Epidemiology of Carbapenem Resistance Enterobacterales in Saudi Arabia: A Systematic Review showed the proportion of carbapenem resistant isolates of all Gram-negative isolates, or clinical data including patient demographics, underlying conditions, and antibiotic treat- ment in all Saudi Arabia regions. Only Studies elaborating bacteria study population, pathogens identified, phenotypic and genotypic methods used to detect carbapenem resistance were used. Patient populations of all hospital types were included while case reports and review articles were excluded from this systematic review as it has become conventional.19,20 Data Extraction A database was created in which study location, sample collec- tion period, bacterial species isolated, a number of isolates tested for CR, CR isolates, CR prevalence, ESBL & carbapene- mase genes, methods used to identify resistant isolates, refer- ences, and outcomes were included. Results The emergence and rapid spread of carbapenem-resistant Enterobacterales in Saudi Arabia encouraged scientific researchers and epidemiologists to investigate CR hospital associated infection prevalence and the genes involved in resistance to carbapenems. As described in Figure 1A the number of published articles per year was clearly increased and indicated by the highest number recorded in 2021. This is closely related to the dissemination of CRE throughout the country and the increased awareness of the importance of sur- veillance and control of multidrug-resistant bacteria in order to improve health quality. A high prevalence of carbapene- mase producers in Saudi Arabia was mainly identified as A. baumannii, followed by Pseudomonas aeruginosa, and Klebsiella pneumonia.21–26 The majority number of published research papers per carbapenemase type was OXA, from all genotyping studies, OXA-48 variant in Enterobacteriaceae and OXA-23 variant in A. baumannii, and P. aeruginosa, followed by NDM-1 (all the collected studies except two.27,28 However, low number of published articles (8 studies) has reported the detection of VIM genes.22,24,28–33 Detection of VIM genes was reported in 5 studies while IMP was reported by El-Badawy, Abdelwahab et al. 2019, Shah, Yasir et al. 2019, Jawhar, AlRashed et al. 2020, Khater, AlFaki et al. 2020, Alqahtani, Tickler et al. 2021)30,31,28,34,24 and KPC genes was reported in 5 studies21,24,27,34,35 as described in Figure 1B. Furthermore, until now no studies reported the presence of SIM and GIM genes in the collected bacterial isolates from Saudi Arabia. Saudi Arabia is divided into 13 administrative regions, and geographically these regions are distributed in five major areas of the country (central, eastern, northern, southern and western areas). Most of the studies about CRE were conducted in the central, and western areas and small data came from the eastern, southern, and northern areas. The results according to the literature search and study selection indicate that a total of 24 studies met the inclusion criteria and were included for final review, of these 3 (12.5%) reported extended studies for more than three regions or shared with other countries, 8 (33.3%) reported from the central area, 7 (29%) reported from the western area, 2 (8.3%) reported from the eastern area, 3 (12.5%) reported from the south area, and one (4.2%) reported from north area (Figure 1C). There was no data reported from Fig. 1 (A) Number of published papers reporting CRE bacteria in Saudi Arabia from 2017 to 2021, (B) Number of published papers per carbapenemase genes in Saudi Arabia from 2017 to 2021, and (C) Number of published papers per Saudi regions from 2017 to 2021. A B C Najran, Tabuk and North border regions. Also, 18 studies (75%) reported genotype including carbapenemase or β-lacta- mase genes distribution and 16 studies (66.7%) reported clin- ical CR surveillance data. Two studies reported systematic reviews of CR from Saudi Arabia13,36 and three studies reported CR cases37–39 (excluded from this study). The regional distribu- tion of the different carbapenemases gene prevalence were mapped in Saudi Arabia from five years up to date (Figure 2), and regional distribution CR prevalence in Enterobacterales over several Saudi regions were mapped (Figure 3). Extended Studies from All Saudi Arabia There is a wide modern study to determine the prevalence of carbapenem resistance gram-negative genes in Gulf Coop- eration Council hospitals including Saudi Arabia (Table 1).24 The results indicate the rates of carbapenem resistance genes varied across the GCC hospitals and even among hospitals in the same country and this result was confirmed by the study of Al-Abdely et al. (2021)40 which explained the circu- lating strain causing outbreaks in this specific region. In 20 J Contemp Med Sci | Vol. 8, No. 1, January-February 2022: 18–26 Epidemiology of Carbapenem Resistance Enterobacterales in Saudi Arabia: A Systematic Review Review R.S. Abou-assy et al. Fig. 2 Percentage of epidemiology of carbapenem resistance Enterobacterales in Saudi Arabia regions.21,23–26 CRE, carbapenem resistance Enterobacterales; CSE, carbapenem sensitive Enterobacterales. Fig. 3 Molecular classification of carbapenem resistance K. pneumoniae genes distribution over Saudi Arabia regions.21,24,29,32,40 Table 1. Participating cities, CR prevalence and molecular classification of CR isolates in (Alqahtani, Tickler et al. 2021)24 study City Number of isolates CR isolates CR prevalence (%) Carbapenemase genes detected Dammam 266 49 18.4% OXA-48 (14.3%), NDM (4.1%) Khamis Mushait 250 50 20.0% OXA-48 (14.0%), NDM; OXA-48 (6.0%) Riyadh 73 49 67.3% OXA-48 (51.0%), NDM (2.0%) NDM; OXA-48 (6.1%) VIM; OXA-48 (2.0%), VIM (6.1%) 21J Contemp Med Sci | Vol. 8, No. 1, January-February 2022: 18–26 R.S. Abou-assy et al. Review Epidemiology of Carbapenem Resistance Enterobacterales in Saudi Arabia: A Systematic Review Table 2. Participating hospitals, carbapenem resistance prevalence and molecular classification of 456 isolates of K. pneumoniae in (Al-Abdely, AlHababi et al. 2021)40 study Saudi Hospital name CRKP prevalence Carbapenemase genes detected 1. King Salman Bin Abdulaziz Hospital, Riyadh 96% NDM-1 (11%), OXA48 (89%) 2. King Khalid Hospital and Prince Sultan Center for Health Service, Al Kharj 53% NDM-1 (33%), OXA48 (67%) 3. King Fahd Specialist Hospital, Buraydah 90% NDM-1 (22%), OXA48 (44%), NDM-1 +OXA48 (33%) 4. Regional Laboratory and Blood Bank, Microbiology Department, Dammam 100% OXA48 (100%) 5. Gurayat General Hospital 96% NDM-1 (32%), OXA48 (50%), NDM-1 +OXA48 (18%) 6. Hael General Hospital 83% OXA48 (100%) 7. Arar Central Hospital 100% NDM-1 (33%), OXA48 (67%) 8. Asir Hospital 93% NDM-1 (25%), OXA48 (71%), NDM-1 +OXA48 (4%) 9. King Fahd Hospital, Al Baha 100% OXA48 (83%), NDM-1 +OXA48 (17%) 10. King Faisal Medical Complex, Taif 80% NDM-1 (17%), OXA48 (67%), NDM-1 +OXA48 (17%) 11. King Abdulaziz Specialist Hospital, Taif 100% NDM-1 (13%), OXA48 (88%) 12. King Fahad Hospital, Madina Munawara 84% NDM-1 (16%), OXA48 (70%), NDM-1 +OXA48 (4%) 13. Hera General Hospital, Jeddah 80% NDM-1 (25%), OXA48 (35%), NDM-1 +OXA48 (50%) Table 3. Review of carbapenem resistance studies which include more than 3 regions in Saudi Arabia Regions Number of isolates CR prevalence (%) Carbapenemase genes detected Organism Methods used Refs. Gulf Cooperation Council 529 of rectal swabs 26.1% One gene; OXA-48 (59.4%), NDM (13.8%), VIM (6.5%) & IMP (0.7%) Two genes; OXA-48 & NDM (8.7%), OXA-48 & VIM (6.5%), NDM & KPC (1.5%) & OXA-48 & KPC (0.7%) – XpertCarba-R Assay Alqahtani et al. ( 2021)24 Five regions include Central, North, East, South & West 519 of Entero- bacterales 84.7% OXA-48 (71.2%), NDM-1 (20.7%) & NDM+OXA-48 (8%). K. pneumoniae (90%), K. oxytoca (0.5%), E. coli (4%), E. cloacae (2.5%) & Others E-test XpertCarba-R Assay Al-Abdely et al. (2021)40 Five hospitals in the east, west and center regions 635 of P. aeruginosa 28.2% for imipen- em 23.0% for mer- openem 18.7% for meropenem & imipenem Carbapenemase genes; GES (9%), VIM (3.4%), NDM (6%) & OXA48 (0.5%) ESBL genes; PER (1.1%) & VEB (1.1%) Carbapenemase and ESBL genes; VIM + PER (1.1%), VIM + VEB (0.5%) P. aeruginosa VITEK-II PCR Al Hassinah et al. (2020)22 addition to the other two studies, Table 2 illustrated the presence of carbapenem resistance genes in Enterobacte- riaceae and P. aeruginosa isolates in more than 3 regions in Saudi Arabia (Table 3).22,40 Epidemiology of Central Area In the last five years, there are eight published studies related to clinical CR infection from a central area (Table 4), six of them detect the carbapenemase genes distribution among specific hospitals,28,34,35,41–43 other three studies give a preva- lence rated to CR dissemination,34,35,44 two studies focus on CRKP,34,43 and one study detect CRG in P. aeruginosa and A. baumannii.28 Epidemiology of Western Area The western area includes the Makkah region that had two largest cities (Makkah and Jeddah) with the highest popula- tion outside the central region. Millions of Muslims from across the globe arrive annually in Makkah to perform pil- grimage and Umrah. These mass gatherings could be a good environment for spreading multi-drug resistant organisms around the world.13,45 There were seven studies published in the last five years from the western region of Saudi Arabia, three of them from Makkah city,21,33,46 two studies from Jeddah city,27,31 one study from Taif 30 and one study from Al-Madinah.47 Five of these studies detect the carbapene- mase genes dissemination ratios and four studies give a CR surveillances,47 and one study focus on CRKP33 while two studies detect the CRG genes in P. aeruginosa CRPA. Other studies focus on CRAB30,31 while carbapenem resistance Klebsiella quasipneumoniae in Jeddah was described by Hala et al. (2019).27 Epidemiology of Eastern Area There were two genotypic studies published recently from the western region of Saudi Arabia.32,48 The first one aimed to assess different genotypic and phenotypic methods to detect carbapenemases; however, each has a limitation, Talal (2019)32 study evaluated the performance of modified Carbapenem Inactivation Method (mCIM) test in Enterobacteriaceae in 22 J Contemp Med Sci | Vol. 8, No. 1, January-February 2022: 18–26 Epidemiology of Carbapenem Resistance Enterobacterales in Saudi Arabia: A Systematic Review Review R.S. Abou-assy et al. Ta bl e 4. R ev ie w o f c ar ba pe ne m re si st an ce st ud ie s i n Ce nt ra l, W es te rn , E as te rn , N or th er n an d So ut he rn a re as o f S au di A ra bi a Ar ea (c ity ) Nu m be r o f is ol at es CR p re va le nc e (% ) Ca rb ap en em as e ge ne s Or ga ni sm M et ho ds u se d Re fs . 1. R iy ad h & Q as si m 16 2, 66 5 23 .2 % – En te ro ba ct er al es (1 4% ), E. c ol i ( 6. 4% ), K. p ne um on ia e (9 .6 % ), A. b au m an ii (1 9. 5% ) & P. a er ug in os a (1 9. 2% ) VI TE K- II BD P ho en ix M ic ro Sc an p lu s M ut ai r e t a l. (2 02 1) 44 2. R iy ad h 1, 86 4 7. 6% ES BL (5 3. 3% ), KP C (1 1. 5% ), O XA -4 8 (1 .3 % ) & N D M (0 .6 7% ) – VI TE K- II Xp er tC ar ba - R a ss ay A le id an e t a l. (2 02 1) 35 3. R iy ad h – – P. ae ru gi no sa ; O XA -2 3 (5 5% ), O XA 4 0 (5 % ), O XA 1 0 (7 .5 % ), O XA 4 8 (3 .7 5% ), IM P (1 .2 5% ), VI M (4 6% ), O XA -1 (2 2% ) & G IM (1 5% ) A. b au m an ni i; O XA -2 3 (8 5. 7% ), O XA 4 0 (1 7% ), VI M (1 1. 4% ), IM P (1 7% ), G IM (2 .8 % ), O XA -1 (2 .8 % ) & O XA -4 8 (2 .8 % ) P. ae ru gi no sa (8 0 is ol at es ) A. b au m an ni i ( 35 is ol at es ) E- te st VI TE K- II PC R Ja w ha r e t a l. (2 02 0) 28 4. A l-Q uw ay iy ah 54 1 Al l s am pl es 78 o f K. p ne um on ia e 6. 7% fo r a ll sa m pl es 46 .2 % fo r K. p ne um on ia e O XA -4 8 (7 7. 8% ), N D M (1 3. 9% ), KP C (5 .6 % ), IM P (2 .8 % ), & O XA -4 8 & N D M (1 3. 9% ) K. p ne um on ia e VI TE K- II D 70 C M H T PC R Kh at er e t a l. (2 02 0) 34 5. R iy ad h – – – K. p ne um on ia (4 7% ), E. c ol i ( 31 % ), En te ro ba ct er sp . ( 5. 3% ), Ci tro ba ct er sp . (5 .3 % ), Kl uy ve ra As co rb at a (5 .3 % ), & Pr ot eu s ( 5. 3% ) – A lz om or e t a l. (2 01 9) 50 6. R iy ad h – – Ch ro m os om al ; C TX -M -1 5 (9 0% ), N D M -1 (2 0% ), N D M -5 (4 0% ), & O XA -1 81 (4 0% ) Pl as m id ; C TX -M -1 5 (1 00 % ), N D M -1 (2 0% ), N D M -5 (3 0% ), C TX -M -1 7 (1 0% ), TE M -1 8 (9 0% ), O XA -1 (4 0% ), O XA -1 81 (4 0% ), & C M V- 42 (8 0% ) E. c ol i M ic ro br ot h di lu tio n m et ho d PC R W G S A bd E l G ha ny e t a l. (2 01 8) 41 7. R iy ad h – – O XA -4 8 (5 8. 1% ) N D M (4 1. 9% ) C TX -M -1 (7 7. 4% ) C TX -M -9 (9 .6 % ) T EM -1 (7 4. 2% ) O XA -1 (5 4. 8% ) S H V- 1 (4 .4 % ) K. p ne um on ia e (2 1 is ol at es ), & E . c ol i ( 10 is ol at es ) E- te st Im ip en em + E D TA st rip M H T PC R A l-A ga m y e t a l. (2 01 8) 42 8. R iy ad h – – O XA -4 8 (6 7. 6% ), N D M -1 (1 2. 7% ), C TX -M -1 5 (6 6. 2% ), & C TX -M -1 4 (2 1% ) K. p ne um on ia e E- te st VI TE K- II PC R (u z Za m an , A lro da yy an et a l. 20 18 )43 9. M ak ka h – – VI M (3 1% ), & G ES (8 .6 % ) Ps eu do m on as a er ug in os a PC R M LS T (A l-Z ah ra ni , I br ah im et a l. 20 21 )33 10 . M ed in a 15 ,7 08 38 .4 % fo r Im ip en em 46 .1 % fo r M er op en em – K. p ne um on ia e VI TE K- II A l-Z al ab an i et a l. (2 02 0) 47 (C on tin ue d) 23J Contemp Med Sci | Vol. 8, No. 1, January-February 2022: 18–26 R.S. Abou-assy et al. Review Epidemiology of Carbapenem Resistance Enterobacterales in Saudi Arabia: A Systematic Review Ta bl e 4. R ev ie w o f c ar ba pe ne m re si st an ce st ud ie s i n Ce nt ra l, W es te rn , E as te rn , N or th er n an d So ut he rn a re as o f S au di A ra bi a Ar ea (c ity ) Nu m be r o f is ol at es CR p re va le nc e (% ) Ca rb ap en em as e ge ne s Or ga ni sm M et ho ds u se d Re fs . 11 . J ed da h 28 6 of K le bs ie l- la sp p – KP C- 2 Kl eb sie lla sp p. VI TE K- II Br ot h M i- cr od ilu tio n PC R W G S H al a et a l. (2 01 9) 27 12 . T ai f 45 o f A ci ne to - ba ct er sp p. 71 % O XA -5 1 (1 00 % ), IM P (8 7. 5% ), N D M (6 2. 5% ), O XA -2 3 (5 9. 4% ), VI M (9 .3 % ), & O XA -4 0 (3 .1 % ) A. b au m an ni i VI TE K- II D is k di ffu si on ER IC -P CR E l-B ad aw y et a l. (2 01 9) 30 13 . J ed da h 13 5 of A. b au m an ni i 55 .6 % O XA -5 1 (1 00 % ), O XA -2 3 (9 2% ), IM P (8 4% ), N D M -1 (1 .3 % ), O XA -2 4/ 40 (5 .3 % ), VI M (9 2% ), TE M (8 4% ), & S H V (1 0. 7% ) A. b au m an ni i VI TE K- II PC R Sh ah e t a l. (2 01 9) 31 14 . M ak ka h 86 4 A ll sa m - pl es 12 0 of E nt er o- ba ct er ia ce ae 21 .7 % O XA -4 8 (1 00 % ), N D M -1 (8 4. 7% ), & K PC (7 3. 1% ) K. p ne um on ia e (8 0. 7% ) E. c lo ac ae (7 .7 % ) E . c ol i ( 7. 7% ) P. m ira bi lis (3 .8 % ) VI TE K- II D is k PC R K ha n et a l. (2 01 9) 21 15 . M ak ka h 4, 80 3 of G ra m ne ga tiv e ba ci lli 58 .2 3% - A. b au m an ni i ( 99 .1 3% ) P. ae ru gi no sa (6 2. 4% ) K. p ne um on ia (3 8% ) E. c ol i ( 5. 59 % ) VI TE K- II Fa id ah e t a l. (2 01 7) 46 16 . M ak ka h – – VI M (3 1% ), & G ES (8 .6 % ) Ps eu do m on as a er ug in os a M ul tip le x PC R M LS T A l-Z ah ra ni e t a l. (2 02 1) 33 17 . A l- Q at if 75 3 of p at ie nt s 20 8 of C lin ic al Su rf ac es 2. 8% o f p at ie nt s 36 % o f C lin ic al Su rf ac es O XA -6 6/ O XA -2 3 /a rm A (3 7% ), O XA -6 9/ O XA -2 3/ G ES -1 1 (4 .2 % ), O XA -9 4/ N D M -1 (2 .1 % ), O XA -6 6/ O XA -2 3 (9 .5 % ), & O XA -5 1/ O XA -2 3 (1 % ) A. b au m an ni i BD P ho en ix PC R W G S A l-H am ad e t a l. (2 02 0) 48 18 . D am m am – – O XA -4 8 (D om in an t) , N D M (s ec on d CR E ge ne d is se m in a- tio n) , & V IM (l ow p re va le nc e) – m CI M PC R Ta la l ( 20 19 )32 19 . A l-J ou f 61 7 of E nt er o- ba ct er al es 32 % – K. p ne um on ia e (6 3% ), P. m ira bi lis (2 9% ), & E . c ol i ( 8% ) BD P ho en ix B an dy a nd Ta nt ry (2 02 1) 25 20 . J iz an 50 10 % fo r i m ip en em 12 % fo r m er op e- ne m C TX -M (7 0% ), SH V (1 6% ), TE M (1 2% ), & N D M -1 (0 % ). E. c ol i ( 50 % ), K. p ne um on ia e (4 0% ), A. b au m an ii (4 % ), P. ae ru gi no sa (4 % ), & E. c lo ac ae (2 % ) CD T VI TE K- II PC R S ob ia e t a l. (2 02 1) 26 21 . A bh a 27 6 of K . p ne u- m on ia e 61 .7 % fo r M er op en em 44 .5 % fo r Im ip en em – K. p ne um on ia e VI TE K- II A l B sh ab sh e e t a l. (2 02 0) 49 22 . A bh a 54 o f K . p ne u- m on ia e 63 % fo r I m ip en em 57 .4 % fo r M er op e- ne m O XA -4 8 (8 1. 5% ), N D M (7 .4 % ), & V IM (1 .8 % ) K. p ne um on ia e VI TE K- II E- te st PC R A l-Z ah ra ni a nd A la si ri (2 01 8) 29 D 70 C, Ca rb ap en em as e D et ec tio n Se t; M H T, M od ifi ed H od ge te st ; U TI , U rin ar y Tr ac t I nf ec tio n; M LS T, M ul ti Lo cu s Se qu en ci ng T yp es ; W G S, W ho le G en om e Se qu en ci ng ; m CI M , m od ifi ed C ar ba pe ne m In ac tiv at io n M et ho d. 24 J Contemp Med Sci | Vol. 8, No. 1, January-February 2022: 18–26 Epidemiology of Carbapenem Resistance Enterobacterales in Saudi Arabia: A Systematic Review Review R.S. Abou-assy et al. reference to molecular methods. Their obtained results con- firm that mCIM test is a simple tool for the reliable confirma- tion of carbapenemase activity with 97.3% sensitivity in Enterobacteriaceae, especially in clinical microbiological labo- ratories with limited resources.32 The second study isolated environmental and clinical CRAB to assess the potential envi- ronmental contamination by this pathogen from frequent- hand-touch surfaces of intensive care unit (ICU), medical, and surgical units were randomly sampled for a month-long period, and the CRAB identified were compared to clinical isolates of the same period.48 Epidemiology of Northern Area Data regarding the CR patterns of Enterobacterales in the northern regions are scarce, there was one surveillance non-genotypic report from Al-Jouf. Bandy and Tantry (2021) analyzed the antibiograms of Enterobacterales identified from January 2019 to December 2019.25 In total, 617 Enterobacter- ales were identified. K. pneumoniae exhibited 62.5%, 62%, and 58.3% resistance towards ertapenem, imipenem, and mero- penem, respectively. In E. coli and K. pneumoniae, seasonal variation in the antimicrobial resistance rate was observed for imipenem and meropenem and the resistance were signifi- cantly higher in winter. Furthermore, the K. pneumoniae mer- openem resistance rate was significantly higher in samples received from intensive care units than from other units.25 Epidemiology of Southern Area In the last five years, there were just three studies from southern regions, Saudi Arabia. Two of them from Abha city.29,49 The earlier study aims to identify the prevalence of CRKP and the most common types of cabapenemases between late April and September in 2015.29 The results of this study indicate that increasing age and intensive care unit admission were associated with CRKP isolation, the major type of carbapenemases in the southern region was OXA-48 with 81.5% and it seems to reach an endemic level, NDM was the second most frequent carbapenemase by 7.4% of isolates, this study refers OXA-48 and NDM carbapenem resistance strains dissemination in Saudi Arabia to receives large numbers of visitors and migrant workers from OXA-48 and NDM endemic countries such as Turkey, India, and Pakistan every year.29 The Third studies aimed to examine K. pneumo- niae infections in the ICU of Aseer Central Hospital and to determine their antimicrobial susceptibility and their rela- tionship to patients’ clinical outcomes from patients with var- ious infections.49 Conclusion Carbapenem-resistant Enterobacterials (CRE) is a growing threat and serious health concern spreading in Saudi Arabia and worldwide. This dilemma has been documented in many parts of the country and may challenge local health authori- ties. However, data is still scarce in certain local areas as well as in the Eastern, Northern border, Tabuk, and Najran regions. OXA-48 β-lactamase and NDM-1 β-lactamase are a prevalent gene responsible in CR strains in Saudi Arabia. The high rates of resistant Enterobacterials in Saudi Arabia call for compre- hensive surveillance programs to understand the origins and extent of the CR problem in depth as a major step to con- trolling the menace, developing a local antibiogram database coupled with nationwide antimicrobial stewardship and an infection prevention program might help in improving the knowledge of CR patterns. Multiple complex risk factors associated with CR infec- tion to the hospital environment, patient comorbidities, dura- tion of hospital admission, ICU complexity, intercurrent illness and the usage of antimicrobial agents contribute to the spread of CR infection. 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