# Molecular epidemiology of carbapenemase-producing Enterobacteriaceae and Acinetobacter baumannii in human infections around the Red Sea

Ayan Ragueh, Ibrahim Abdallah, Rachid Mouhoumed, Mohamed Aboubaker, Jean-Marc Rolain, Seydina Diene

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## To cite this version:

Ayan Ragueh, Ibrahim Abdallah, Rachid Mouhoumed, Mohamed Aboubaker, Jean-Marc Rolain, et al. Molecular epidemiology of carbapenemase-producing Enterobacteriaceae and Acinetobacter baumannii in human infections around the Red Sea. Journal of Infection and Public Health, 2025, 18 (4), pp.102692. 10.1016/j.jiph.2025.102692. hal-05005682

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## Review

# Molecular epidemiology of carbapenemase-producing *Enterobacteriaceae* and *Acinetobacter baumannii* in human infections around the Red Sea

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Ayan A. Ragueh<sup>a,b,c</sup>, Ibrahim S. Abdallah<sup>a</sup>, Rachid M. Mouhoumed<sup>a</sup>, Mohamed H. Aboubaker<sup>d</sup>, Jean-Marc Rolain<sup>b,c</sup>, Seydina M. Diene<sup>b,c,*</sup>

## ARTICLE INFO

Article history:

Received 22 October 2024

Received in revised form 30 January 2025

Accepted 3 February 2025

Keywords:

Red Sea countries

Molecular epidemiology

Enterobacteriaceae

Acinetobacter baumannii

Carbapenemases

## ABSTRACT

The emergence and global spread of carbapenemase-producing bacteria (CPB) is of great concern to public health. Carbapenemase enzymes, which can hydrolyse almost all β-lactams, can be readily transferred between bacterial species through recombinant plasmids, transposons, or integrons. Human infections caused by CPB have limited treatment options and are associated with high mortality rates. These enzymes are mainly identified among *Enterobacteriaceae* and non-fermenter bacteria such as *Acinetobacter baumannii* and are associated either with hospital- or community-acquired infections. Located at the crossroads of the Middle East, Europe, and Africa, the countries around the Red Sea are of interest due to their great diversity and mix of populations. This review aims to describe the epidemiology of carbapenem resistance in *Enterobacteriaceae* and *A. baumannii* around the Red Sea, with country-specific findings. In this study, we emphasise the urgent need to screen for and detect these enzymes to prevent their spread and to maintain control.

© 2025 The Author(s). Published by Elsevier Ltd on behalf of King Saud Bin Abdulaziz University for Health Sciences. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

## Contents

<table><tr><td>Introduction</td><td>1</td></tr><tr><td>Epidemiology of carbapenem-producing <i>Enterobacteriaceae</i> and <i>A. baumannii</i> (CPEA) in human infections in countries around the Red Sea</td><td>5</td></tr><tr><td>Conclusion.</td><td>7</td></tr><tr><td>Funding information.</td><td>7</td></tr><tr><td>Declaration of Competing Interest.</td><td>7</td></tr><tr><td>Acknowledgment</td><td>7</td></tr><tr><td>References.</td><td>7</td></tr></table>

## Introduction

Since the discovery and industrial production of antibiotics, their use has reduced morbidity and mortality in humans and helped save millions of lives [1]. However, over the past decade, the rise of

antimicrobial resistance has begun to pose a global challenge to disease control, as it has increased significantly in bacteria, reducing the effectiveness of many clinically important antibiotics. This resistance is associated with significant clinical and economic consequences, including longer hospital stays, higher hospital costs, increased antimicrobial expenditure, and higher mortality rates [2]. Carbapenems are some of the most effective antibiotics against multidrug-resistant (MDR) bacteria, and combined with their negligible toxicity to the host, have become the preferred antibiotics worldwide as a last resort option to treat infections caused by MDR bacteria [3]. Unfortunately,

<footnote><sup>a</sup> Université de Djibouti, Campus Balbala croisement RN2-RN5, 1904 Djibouti</footnote>

<footnote><sup>b</sup> MEPHI, APHM, Faculté de Pharmacie, Aix-Marseille University, 19-21 Boulevard Jean Moulin, Marseille 13385 CEDEX 05, France</footnote>

<footnote><sup>c</sup> IHU-Méditerranée Infection, 19-21 Boulevard Jean Moulin, Marseille 13385 CEDEX 05, France</footnote>

<footnote><sup>d</sup> Laboratoire de Biologie Médicale Mer-Rouge, Rue Moscou, Djibouti</footnote>

<footnote>* Correspondence to: MEPHI, IHU-Méditerranée Infection, Faculté de Pharmacie, Aix-Marseille University, 19-21 Boulevard Jean Moulin, Marseille 13385 CEDEX 05, France.</footnote>

<footnote>E-mail address: seydina.diene@univ-amu.fr (S.M. Diene).</footnote>
the effectiveness of carbapenem treatment is now in question due to the spread of carbapenemase enzymes, widely expressed by carbapenem-resistant Enterobacteriaceae isolates. The global spread of these carbapenemases poses an enormous challenges to global health systems [4]. According to the World Health Organization (WHO), the "priority pathogens" most threatening to human health include the Enterobacteriaceae (e.g. Klebsiella pneumoniae, Escherichia coli, Enterobacter cloacae, Serratia marcescens, and Proteus mirabilis) and non-fermenting gram-negative bacilli (i.e. Pseudomonas and Acinetobacter spp.) [5] because of their multidrug-resistance phenotype to a large number of antibiotics, including third-generation cephalosporins and carbapenems [6]. Due to its strategic geographical location and geopolitical significance, the Red Sea is a central hub for major international maritime routes, notably the Eurasian route, which is recognised as one of the world's key arteries for energy supply [7]. A channel for intense maritime traffic linking European ports to East Asia, the Red Sea extends for about 2000 kilometres from the Suez Canal in the north to the Bab al-Mandab Strait in the south, with a maximum width of 300 kilometres [8]. As such, it increases the geographical proximity between these coastal states. However, this proximity is not without consequences, particularly in terms of the spread of antimicrobial resistance, particularly the spread of carbapenemase genes, a phenomenon that is emerging and spreading from the Middle East, Europe, and Asia. The countries located around the Red Sea, including Egypt, Jordan, Sudan, Saudi Arabia, Yemen, Djibouti, and Somalia, are at the crossroads of crucial maritime flows and face health and security issues linked to these regional dynamics. In addition, parameters such as international tourism [9], regular religious pilgrimages to Saudi Arabia [10], migration, and medical tourism [11] accelerate this phenomenon. In this review, we present current knowledge regarding the spread of carbapenem-carrying bacteria in hospitals in countries bordering the Red Sea, and the molecular epidemiology of carbapenemase-producing Enterobacteriaceae (CPE) and carbapenem-resistant A. baumannii (CRAB) in each country.

**Carbapenemases in gram-negative bacteria (GNB):** carbapenemases represent a wide range of enzymes that can be classified both functionally (Bush classification) and genetically (Ambler molecular classification) [12,13]. The most common molecular classification is based on the Ambler classification scheme, which assigns carbapenemases to three of Ambler's four classes (A, B, and D)[14]. According to the functional classification, carbapenemases belong to functional groups 2df, 2 f, 3a, and 3b [13]. Although the number of carbapenemase enzymes identified in GNB is very large, clinically relevant carbapenemases are known as the "big five": KPC (*K. pneumoniae* carbapenemase), NDM (New Delhi Metallo-β-lactamase), IMP (imipenem-resistant *Pseudomonas*), VIM (Verona integron-encoded metallo-β-lactamase), and OXA-48 (oxacillinase) [15].

**Class A carbapenemase-producing Enterobacteriaceae:** Enterobacteriaceae are a family of diverse Gammaproteobacteria that includes both common pathogens (such as *K. pneumoniae*, *E. coli*, *E. cloacae*, and *Salmonella enterica*) and rare pathogens (such as *P. mirabilis*, *Raoultella planticola*, and *Citrobacter freundii*) commonly associated with human infections with increasing resistance to antibiotics [16]. Since the first Class A carbapenemase was reported in 1990 from an *S. marcescens* isolate in the United Kingdom, several Class A carbapenemases have been reported, some of which are encoded on chromosomes (NmCA, SME, IMI-1, SFC-1) and others which are encoded on plasmids (KPC, IMI-2, GES derivatives such as GES-1, GES-2, GES-4, and GES-5). They all efficiently hydrolyse carbapenems and are partially inhibited by clavulanic acid [16]. The most commonly encountered and clinically significant enzyme in this group is KPC [17]. Originally reported in a clinical *K. pneumoniae* isolate, KPC enzymes are now readily detected in many members of the Enterobacteriaceae family [18], conferring resistance to all β-lactams (except monobactams). KPC-producing isolates are usually

associated with multidrug resistance and therefore severely limit treatment options, resulting in high mortality rates for associated infections [19]. The genes encoding for KPC enzymes can be found on mobile genetic elements such as transposons and various plasmids, facilitating their spread [4]. The global prevalence of KPC-producing isolates is on the rise, posing significant threats to clinical practice and public health [20,21]. Numerous studies have reported outbreaks of KPC-producing Enterobacteriaceae in different geographic regions, demonstrating the spread of these enzymes [22–25]. KPC-2 and KPC-3 are the most prevalent variants worldwide, likely due to their location on the Tn4401 transposon, which is found on conjugative plasmids that enable horizontal transfer, granting these enzymes an exceptional capacity to spread [26–28]. The increasing global distribution of KPC-producing isolates underscores the urgent need for effective surveillance and control measures.

**Class A carbapenemase-producing A. baumannii:** A. baumannii has emerged over the past two decades as an important opportunistic pathogen, particularly in healthcare settings. This non-fermenting gram-negative bacterium is primarily associated with life-threatening infections in severely debilitated patients and is the cause of many nosocomial infections [29]. Its ability to survive in hostile environments and to rapidly acquire antimicrobial resistance poses a challenge for healthcare workers worldwide. The primary resistance mechanism to β-lactams in A. baumannii is the production of β-lactamases including Class A β-lactamases (such as TEM, SHV, CTX-M, GES, and KPC enzymes), Class B metallo-β-lactamases (MBLs) (such as NDM enzymes), Class C cephalosporinases (such as Acinetobacter-derived cephalosporinases (ADCs)), and Class D oxacillinases (such as OXA-23, OXA-24, OXA-48, and OXA-58). However, other mechanisms including changes in the outer membrane proteins, the overexpression of multidrug efflux pumps, and alterations in the affinity or production of penicillin-binding proteins can also be associated with β-lactams in this bacterial species [30]. Class A carbapenemase enzymes are less common in A. baumannii compared to other types of carbapenemases, but have been reported in some isolates. Indeed, KPC enzymes, although primary associated with Enterobacteriaceae, have been reported in A. baumannii isolates. GES carbapenemases, especially the GES-14 variant, have been reported in this species [31–35].

**Class B carbapenemase-producing Enterobacteriaceae:** Unlike Class A carbapenemases, which were first reported in Enterobacterales, the first acquired Class B β-lactamases were detected in *Bacillus cereus* isolates in 1966. They are also known as metallo-β-lactamases (MBL) due to the need for one or two zinc ions (Zn(II)) at the active site for catalytic activity [36,37]. They can hydrolyse all β-lactams with the exception of monobactam. However, their activity is inhibited by the chelating agent ethylenediaminetetraacetic acid (EDTA), and not by clavulanic acid [38]. Metallo-β-lactamases (MBLs) are primarily represented by several types of enzymes including VIM, IMP, GIM (German imipenemase), and SIM (Seoul imipenemase). These enzymes are typically found within diverse integron structures, where they exist as gene cassettes. The mobility of these MBL genes is significantly enhanced when the integrons become incorporated into plasmids or transposons. This association facilitates the efficient transfer of MBL genes between different bacterial species [39]. IMP-1 was the first MBL reported in *Serratia marcescens* in Japan in 1991 [40]. VIM-1 was first isolated in Verona, Italy, in 1997 [41]. Since then, the IMP and VIM types have spread all over the world and have been found in different gram-negative bacterial species [42–44]. NDM-1 (New Delhi metallo-β-lactamase) has emerged as one of the most clinically significant carbapenemases in recent years. Its discovery in 2008 occurred in a *K. pneumoniae* isolate from a Swedish patient with a history of hospitalisation in New Delhi, India [45]. Since then, NDM carbapenemases have been the focus of worldwide attention due to their rapid dissemination among Enterobacteriaceae and Acinetobacter spp
<table><caption>**Table 1**
Reported studies on carbapenemase-producing Enterobacteriaceae (CPE) and carbapenem-resistant A. baumannii (CRAB) in countries bordering the Red Sea.</caption><thead><tr><th>Country</th><th>Year</th><th>Organisms</th><th>Setting</th><th>Source of isolates</th><th>Identified carbapenemases</th><th>Number of positive isolates / total tested</th><th>Ref.</th></tr></thead><tbody><tr><td rowspan="20">EGYPT</td><td>2013</td><td>K. pneumoniae</td><td>H</td><td>Faeces</td><td>NDM, VIM</td><td>5/113</td><td>[61]</td></tr><tr><td>2011</td><td>K. pneumoniae</td><td>H</td><td>Blood, urine, respiratory tract</td><td>KPC</td><td>14/20</td><td>[62]</td></tr><tr><td>2014</td><td>E. coli, K. pneumoniae, A. baumannii</td><td>H</td><td>Blood, urine, pus, sputum</td><td>VIM</td><td>22/65</td><td>[63]</td></tr><tr><td>2016</td><td>E. coli, K. pneumoniae</td><td>H</td><td>Rectal swabs</td><td>OXA-48, NDM-1,VIM</td><td>100/413</td><td>[64]</td></tr><tr><td>2014</td><td>E. coli, K. pneumoniae</td><td>H</td><td>Urine, sputum, burn swab, wound swab</td><td>NDM-1, NDM-5</td><td>22/65</td><td>[65]</td></tr><tr><td>2014–2016</td><td>A. baumannii</td><td>H</td><td>Blood, urine, sputum endotracheal secretion, wound swab, pus, CSF</td><td>IMP, SIM, GIM</td><td>280/280</td><td>[66]</td></tr><tr><td>2014–2016</td><td>E. coli, K. pneumoniae</td><td>H</td><td>Blood, urine, stool, wound swab</td><td>OXA-48, NDM1,VIM, KPC</td><td>29/185</td><td>[67]</td></tr><tr><td>2013–2015</td><td>K. pneumoniae</td><td>H</td><td>NA</td><td>NDM</td><td>46/46</td><td>[68]</td></tr><tr><td>2010–2015</td><td>A. baumannii</td><td>H</td><td>BAL, urine, blood, sputum, wound, tissue</td><td>NDM, VIM, OXA-58, OXA-51, OXA-23</td><td>74/74</td><td>[69]</td></tr><tr><td>2015–2016</td><td>A. baumannii</td><td>H</td><td>Urine, blood, sputum, wound swab</td><td>OXA-23, OXA-51</td><td>50/50</td><td>[70]</td></tr><tr><td>2015</td><td>K. pneumoniae, Enterobacter, spp</td><td>H/C</td><td>VAP, blood, wound swab, urine</td><td>VIM, KPC, OXA-48</td><td>47/75</td><td>[71]</td></tr><tr><td>2010–2011</td><td>A. baumannii</td><td>H</td><td>NA</td><td>OXA-23, OXA-40, OXA-58</td><td>34/34</td><td>[72]</td></tr><tr><td>2015</td><td>S. marcescens</td><td>H</td><td>Blood</td><td>IMP, VIM</td><td>15/40</td><td>[73]</td></tr><tr><td>2019</td><td>A. baumannii</td><td>H</td><td>Wound swab, respiratory secretions, blood, urine, body fluid, drains</td><td>KPC, VIM, NDM, SPM, OXA-23, OXA-51</td><td>206/206</td><td>[74]</td></tr><tr><td>2017</td><td>A. baumannii</td><td>H</td><td>ICU</td><td>OXA-23, NDM, GES</td><td>30/50</td><td>[75]</td></tr><tr><td>2018–2019</td><td>K. pneumoniae, E. coli, E. cloacae</td><td>H/C</td><td>Pus, blood, sputum, urine, stool</td><td>NDM, VIM, KPC, OXA-48, IMP, SPM</td><td>93/115</td><td>[76]</td></tr><tr><td>2019–2020</td><td>K. pneumoniae, E. coli, A. baumannii</td><td>H</td><td>VAP</td><td>NDM, VIM, IMP, SPM</td><td>43/57</td><td>[77]</td></tr><tr><td>2019</td><td>K. pneumoniae</td><td>H/C</td><td>Sputum, urine</td><td>NDM, VIM, IMP</td><td>17/37</td><td>[78]</td></tr><tr><td>2013</td><td>E. aerogenes</td><td>H</td><td>Blood</td><td>NDM</td><td>1/46</td><td>[79]</td></tr><tr><td>2021</td><td>K. pneumoniae, E. coli, A. baumannii</td><td>H</td><td>Urine, blood, sputum</td><td>KPC, OXA-48, NDM, VIM</td><td>67/71</td><td>[80]</td></tr><tr><td>2012</td><td>A. baumannii</td><td>H</td><td>NA</td><td>OXA-23, OXA-24, OXA-58, GES</td><td>25/40</td><td>[81]</td></tr><tr><td>2018–2019</td><td>K. pneumoniae, E. coli, E. cloacae, S. marcescens, C. freundii</td><td>H/C</td><td>Urine, sputum, wound swab, blood, ascitic fluid</td><td>KPC, NDM, OXA-48</td><td>50/775</td><td>[82]</td></tr><tr><td>2012</td><td>K. pneumoniae</td><td>H</td><td>ICU</td><td>NDM</td><td>1/2</td><td>[83]</td></tr><tr><td>2013</td><td>K. pneumoniae, E. coli, A. baumannii</td><td>H</td><td>Blood, urine, wound swab, fluid aspirates (pericardial, pleural, ascitic)</td><td>NDM, OXA-48</td><td>50/229</td><td>[84]</td></tr><tr><td>2015</td><td>A. baumannii</td><td>H</td><td>Pus, sputum, urine</td><td>OXA-23</td><td>32/40</td><td>[85]</td></tr><tr><td>2022</td><td>K. pneumoniae</td><td>H</td><td>Urine, blood, sputum wound, ICU</td><td>KPC, NDM, OXA-48, VIM, IMP</td><td>57/86</td><td>[86]</td></tr><tr><td>2019</td><td>K. pneumoniae, E. coli</td><td>H</td><td>Cutaneous wound aspirates, blood, catheter tips, sputum</td><td>NDM, VIM, IMP, KPC</td><td>30/150</td><td>[87]</td></tr><tr><td>2019–2021</td><td>K. pneumoniae</td><td>H</td><td>Blood, pus, urine, sputum, CSF, CVP, peritoneal fluid</td><td>KPC, NDM, OXA-48</td><td>105/119</td><td>[88]</td></tr><tr><td>2022–2023</td><td>E. coli, K. pneumoniae, A. baumannii</td><td>H</td><td>Urine, blood, sputum, pus, rectal swab, throat swab, stool</td><td>NDM, VIM, IMP, KPC, OXA-48</td><td>91/108</td><td>[89]</td></tr><tr><td>2021–2023</td><td>K. pneumoniae, E. coli</td><td>H</td><td>NA</td><td>NDM, OXA-48</td><td>107/107</td><td>[90]</td></tr><tr><td>2020–2021</td><td>K. pneumoniae, E. coli, A. baumannii</td><td>H/C</td><td>Urine, respiratory samples, blood, other</td><td>NDM, OXA-48</td><td>51/151</td><td>[91]</td></tr><tr><td>2014–2016</td><td>K. pneumoniae</td><td>H</td><td>Urine, blood, sputum, wound, other</td><td>KPC, VIM, NDM, IMP, OXA-48</td><td>79/117</td><td>[92]</td></tr><tr><td>2011</td><td>A. baumannii</td><td>H</td><td>ICU</td><td>NDM</td><td>1/1</td><td>[93]</td></tr><tr><td>2014</td><td>K. pneumoniae, E. coli, S. marcescens, M. morganii</td><td>H</td><td>Blood, respiratory samples, urine, pus, wound</td><td>OXA-48, NDM-1</td><td>65/128</td><td>[94]</td></tr><tr><td rowspan="10">JORDAN</td><td>2019–2021</td><td>K. pneumoniae</td><td>H</td><td>Urine, blood, pus, sputum</td><td>KPC, NDM, IMP, OXA-48</td><td>26/179</td><td>[95]</td></tr><tr><td>2013–2014</td><td>K. pneumoniae, E. coli, E. cloacae</td><td>H</td><td>Urine, pus, fluid, wound, sputum</td><td>NDM, OXA-48, VIM, IMP</td><td>28/2759</td><td>[96]</td></tr><tr><td>2012–2013</td><td>K. pneumoniae</td><td>H</td><td>Respiratory tract</td><td>NDM, OXA-48</td><td>7/296</td><td>[97]</td></tr><tr><td>2010</td><td>A. baumannii</td><td>H</td><td>Respiratory samples of bronchoalveolar lavage, endotracheal aspirate, sputum</td><td>OXA-23, OXA-51</td><td>74/149</td><td>[98]</td></tr><tr><td>2010–2020</td><td>A. baumannii</td><td>H/C</td><td>Urine, respiratory samples, blood, wound pus, body fluid, tissue</td><td>OXA-23, OXA-51</td><td>478/622</td><td>[99]</td></tr><tr><td>2016</td><td>A. baumannii</td><td>H/C</td><td>Clinical specimens</td><td>OXA-23, OXA-51, NDM, GES, KPC</td><td>45/45</td><td>[100]</td></tr><tr><td>2013–2014</td><td>K. pneumoniae</td><td>H</td><td>Urine, blood, pus, wound, catheter line, bone, pleural fluid drain</td><td>KPC</td><td>10/75</td><td>[101]</td></tr><tr><td>NA</td><td>K. pneumoniae, E. cloacae, A. baumannii</td><td>H</td><td>Blood</td><td>KPC, NDM, VIM</td><td>27/101</td><td>[102]</td></tr><tr><td>2018</td><td>A. baumannii</td><td>H</td><td>NA</td><td>OXA-51, OXA-23, NDM</td><td>78/86</td><td>[103]</td></tr></tbody></table>

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<table><caption>Table 1 (continued)</caption><thead><tr><th>Country</th><th>Year</th><th>Organisms</th><th>Setting</th><th>Source of isolates</th><th>Identified carbapenemases</th><th>Number of positive isolates / total tested</th><th>Ref.</th></tr></thead><tbody><tr><td rowspan="10">KSA</td><td>2012</td><td>A. baumannii</td><td>H</td><td>ICU</td><td>OXA-23, OXA-40, VIM, SPM</td><td>64/64</td><td>[104]</td></tr><tr><td>2014</td><td>A. baumannii</td><td>H</td><td>Rectal swab</td><td>OXA-23</td><td>37/45</td><td>[105]</td></tr><tr><td>2017–2019</td><td>K. pneumoniae, E. coli, E. cloacae</td><td>H</td><td>Blood, sputum, urine, swab, wound, fluid, tissue, nephrostomy, pus, respiratory samples</td><td>OXA-48, NDM</td><td>180/180</td><td>[106]</td></tr><tr><td>2017</td><td>K. pneumoniae, E. coli, E. cloacae, P. mirabilis</td><td>H</td><td>Respiratory tract, urinary tract, gastrointestinal tract, wound infections</td><td>KPC, OXA-48, NDM</td><td>26/120</td><td>[107]</td></tr><tr><td>2014–2018</td><td>K. quasipneumoniae</td><td>H</td><td>Tracheostomy wound</td><td>KPC-2</td><td>1/286</td><td>[108]</td></tr><tr><td>2012</td><td>K. pneumoniae, E. coli, E. cloacae, E. aerogenes, A. baumannii</td><td>H</td><td>NA</td><td>OXA-48, NDM, VIM, OXA-23</td><td>196/242</td><td>[109]</td></tr><tr><td>2011–2013</td><td>K. pneumoniae, E. coli, E. aerogenes</td><td>H</td><td>Blood, respiratory, urine, wound</td><td>OXA-48, NDM</td><td>4/11</td><td>[110]</td></tr><tr><td>2011</td><td>K. pneumoniae</td><td>H</td><td>ICU</td><td>OXA-48, NDM, VIM</td><td>60/60</td><td>[111]</td></tr><tr><td>2013</td><td>K. pneumoniae, E. coli, E. cloacae</td><td>H</td><td>Respiratory, urine, blood, pus</td><td>OXA-48, NDM, VIM</td><td>54/54</td><td>[112]</td></tr><tr><td>2011–2012</td><td>K. pneumoniae</td><td>H</td><td>Respiratory, surgical wound, rectal swabs, urine, blood, abdominal drainage</td><td>OXA-48, NDM</td><td>48/71</td><td>[113]</td></tr><tr><td>2014</td><td>A. baumannii</td><td>H</td><td>Blood, body fluid, cerebrospinal fluid respiratory specimen, wound, urine</td><td>OXA-23, GES</td><td>21/753</td><td>[114]</td></tr><tr><td rowspan="10">SUDAN</td><td>2015</td><td>K. pneumoniae</td><td>H</td><td>Urine</td><td>NDM</td><td>1/1</td><td>[115]</td></tr><tr><td>2011</td><td>K. pneumoniae</td><td>H</td><td>NA</td><td>OXA-48, NDM</td><td>9/9</td><td>[116]</td></tr><tr><td>2017</td><td>A. baumannii</td><td>H</td><td>ICU</td><td>OXA-23</td><td>5/8</td><td>[117]</td></tr><tr><td>2017</td><td>A. baumannii</td><td>H</td><td>Blood, tissue biopsy, peritoneal fluid, sputum, urine, wound, catheter tip</td><td>IMP, VIM, NDM, OXA-23, OXA-40, OXA-51</td><td>32/45</td><td>[118]</td></tr><tr><td>2011</td><td>A. baumannii</td><td>H</td><td>ICU</td><td>VIM, OXA-23, OXA-40</td><td>29/32</td><td>[119]</td></tr><tr><td>2020–2021</td><td>K. pneumoniae</td><td>H</td><td>NA</td><td>OXA-48, NDM, VIM</td><td>64/86</td><td>[120]</td></tr><tr><td>2014</td><td>A. baumannii</td><td>H</td><td>NA</td><td>OXA-23</td><td>10/10</td><td>[121]</td></tr><tr><td>2017</td><td>A. baumannii</td><td>H</td><td>NA</td><td>OXA-23</td><td>30/35</td><td>[122]</td></tr><tr><td>2012–2014</td><td>A. baumannii</td><td>H</td><td>Blood, skin wound</td><td>OXA-23, OXA-51</td><td>100/107</td><td>[123]</td></tr><tr><td>2014</td><td>K. pneumoniae</td><td>H</td><td>Blood, sputum, wound, urine</td><td>OXA-48, NDM-1</td><td>16/16</td><td>[124]</td></tr><tr><td>2015</td><td>K. pneumoniae</td><td>H</td><td>Blood, urine, sputum, wound swabs tracheal aspirate, body fluid</td><td>OXA-48, NDM, VIM</td><td>49/54</td><td>[125]</td></tr><tr><td rowspan="10">YEMEN</td><td>2012</td><td>A. baumannii</td><td>H/C</td><td>VAP</td><td>OXA-23, OXA-51</td><td>12/12</td><td>[126]</td></tr><tr><td>2021</td><td>K. pneumoniae, E. coli</td><td>H</td><td>NA</td><td>OXA-48, NDM</td><td>200/200</td><td>[127]</td></tr><tr><td>2016–2017</td><td>K. pneumoniae, E. coli, A. baumannii</td><td>H</td><td>Blood, urine, wound swabs, sputum, tips of catheters, other bodily fluids</td><td>NDM-1, NDM-5, NDM-6, IMP, OXA-48, VIM</td><td>121/206</td><td>[128]</td></tr><tr><td>2015–2016</td><td>K. pneumoniae</td><td>H/C</td><td>Blood, urine, wound swabs</td><td>NDM, VIM, OXA-48, GES</td><td>44/117</td><td>[129]</td></tr><tr><td>2018–2019</td><td>K. pneumoniae, E. coli, E. cloacae</td><td>H</td><td>Urine, wound swabs, sputum, stool, plural fluid, other bodily fluids</td><td>GIM-1, SIM-1</td><td>5/385</td><td>[130]</td></tr><tr><td>2022</td><td>E. coli</td><td>C</td><td>Urine</td><td>OXA-23, OXA-51</td><td>12/60</td><td>[131]</td></tr><tr><td>2015–2016</td><td>K. pneumoniae, E. coli, P. mirabilis, P. vulgaris</td><td>H</td><td>Urine, wound swabs, sputum, blood, tissue aspirates, ear swab, CSF</td><td>NDM, VIM, IMP</td><td>72/200</td><td>[132]</td></tr><tr><td>2017</td><td>K. pneumoniae</td><td>H</td><td>Blood, urine, sputum, wound swab</td><td>OXA-48, NDM, KPC, IMP</td><td>46/60</td><td>[133]</td></tr><tr><td>2016–2020</td><td>K. pneumoniae</td><td>H</td><td>Blood, urine, sputum, pus, wound swab</td><td>NDM-1, NDM-5, OXA-48</td><td>35/68</td><td>[134]</td></tr><tr><td>2017–2018</td><td>A. baumannii</td><td>H</td><td>Blood, urine, sputum, wound, cerebrospinal fluid, and catheter tips</td><td>OXA-23, OXA-58, NDM-1, GES-11</td><td>40/42</td><td>[135]</td></tr><tr><td>2017–2019</td><td>A. baumannii</td><td>H</td><td>Sputum, blood, urine, wound swab, central-line catheter and tips</td><td>OXA-23, NDM, GES</td><td>22/38</td><td>[136]</td></tr><tr><td rowspan="3">DJIBOUTI</td><td>2016</td><td>K. pneumoniae, E. coli, E. cloacae</td><td>H</td><td>Urine, sputum, aspiration, blood, ear swab, pus, catheter, ventricular drain</td><td>NDM-1, NDM-5, OXA-48, OXA-181, OXA-232</td><td>27/27</td><td>[137]</td></tr><tr><td>2013</td><td>K. pneumoniae, E. cloacae</td><td>H</td><td>Urine, pus, blood, sputum, vaginal swab, ascites fluid</td><td>NDM</td><td>10/10</td><td>[138]</td></tr><tr><td>2013</td><td>A. baumannii</td><td>H</td><td>Sputum, tracheal aspiration</td><td>OXA-23, OXA-51</td><td>3/3</td><td>[139]</td></tr><tr><td rowspan="3">SOMALIA</td><td>2020</td><td>K. pneumoniae, E. coli, A. baumannii</td><td>H</td><td>Urine, pus, blood, respiratory samples</td><td>OXA-23, OXA-48 NDM</td><td>20/256</td><td>[140]</td></tr><tr><td>2019</td><td>E. coli</td><td>H</td><td>Urine</td><td>OXA-48</td><td>2/142</td><td>[141]</td></tr><tr><td>2019</td><td>K. pneumoniae, A. baumannii</td><td>H</td><td>NA</td><td>NDM, VIM, OXA-23, OXA-48</td><td>11/317</td><td>[142]</td></tr></tbody></table>

H: Hospital, C: Community, NA: Not Available, ICU: Intensive Care Unit, VAP: Ventilator-associated pneumonia, BAL: bronchoalveolar lavage, CSF: Cerebrospinal Fluid.

[46]. The dissemination of NDM-1 producing bacteria has now been documented worldwide. Most outbreaks have been linked to population movements between the Indian subcontinent and other regions, with some cases also being connected to the Balkans and Middle East [22,46]. This widespread distribution highlights the global nature of antimicrobial resistance and the challenges it poses to public health systems internationally.

**Class B carbapenemase-producing A. baumannii:** Class B carbapenemases, also known as metallo-β-lactamases (MBLs), are an important group of enzymes contributing to carbapenem resistance

in A. baumannii. Class B imipenemase (IMP) was the first MBL identified in A. baumannii in Europe. IMP-2 was discovered in an Italian A. baumannii isolate as the first gene cassette on a Class 1 integron [39]. Since then, various MBL enzymes have been reported in A. baumannii globally, including VIM and SIM (first reported in Korea) enzymes. Some other significant MBLs have been reported in A. baumannii and are often found within integron structures. More recently, they have been reported in NDM enzymes, firstly in A. baumannii in 2010 and since then in various parts of the world [47–49]. In some cases, these MBL genes in A. baumannii are
typically found as gene cassettes within Class 1 integrons and are often associated with plasmids or transposons, facilitating their spread. MBL-producing *A. baumannii* isolates often exhibit multidrug resistance phenotypes and pose significant challenges for treatment and infection control. The co-existence of multiple carbapenemase types (e.g., OXA-type and MBLs) in *A. baumannii* has been increasingly reported.

**Class D carbapenemase-producing Enterobacteriaceae:** Class D β-lactamases, commonly known as OXA enzymes or oxacillinases, encompass over 400 distinct enzymes. However, only a subset of these enzymes possesses carbapenemase activity. These are specifically referred to as carbapenem-hydrolysing Class D β-lactamases (CHDLs). They are serine-based enzymes, and use a serine residue in their active site for their β-lactam hydrolysis. Interestingly, while resistant to conventional inhibitors, CHDLs can be inhibited in vitro by sodium chloride (NaCl). This characteristic is relatively unique among β-lactamases and has potential implications for laboratory detection and possibly therapeutic approaches [50]. Although the first Class D carbapenemase identified was the OXA-23 enzyme in *A. baumannii*, additional carbapenem-hydrolysing CHDLs have also been found in *Enterobacteriaceae*. The most prevalent CHDL in *Enterobacteriaceae*, the OXA-48 carbapenemase, was identified in a *K. pneumoniae* isolate from Turkey in 2001 [51]. The blaOXA-48 gene has been reported in many countries around the world, most often from *K. pneumoniae* isolates. It appears that OXA-48 producers have now spread in Turkey, the Middle East, and North African [52,53].

**Class D carbapenemase-producing A. baumannii:** OXA enzymes are more frequently found in *A. baumannii* and, to a lesser extent, in *P. aeruginosa* and some *Enterobacteriaceae*. They play a crucial role in the MDR resistance phenotype in *A. baumannii*. The first case of an OXA-like enzyme was reported in an MDR clinical strain of *A. baumannii* isolated in 1985 in Scotland [54]. Initially named ARI-1 (*Acinetobacter* resistant to imipenem), it was later renamed OXA-23 once its sequence had been determined [55]. OXA carbapenemases have since been classified into nine major subgroups based on amino acid homologies, which highlights the significant genetic diversity within the OXA family and contributes to their varied resistance profiles [39]. Among OXA carbapenemases, OXA-23-like enzymes, in particular, have been associated with numerous outbreaks and sporadic cases worldwide [56–59].

## Epidemiology of carbapenemase-producing Enterobacteriaceae and A. baumannii (CPEA) in human infections in countries around the Red Sea

As represented in Table 1 and Fig. 1, a high number of carbapenemase-producing *Enterobacteriaceae* and *A. baumannii* have been reported in recent years in the different countries around the Red Sea, associated either with hospital-acquired or community-acquired infections. The rising resistance rates to carbapenems in most countries around the Red Sea are particularly concerning, as these antibiotics are among the most effective treatments for combating antimicrobial resistance (AMR), especially in *Enterobacteriaceae* and *A. baumannii*. This increasing resistance severely limits available treatment options. A larger number of studies have been conducted in Egypt and Saudi Arabia, probably due to their bigger populations and more developed infrastructure, which provides greater material and human resources for identifying carbapenemases within their communities (Fig. 1B). Class B enzymes (e.g. NDM) and Class D enzymes (e.g. OXA-23 and OXA-48) are the most commonly reported enzymes in studies across these countries (Fig. 1C). While these enzymes are now globally distributed, Class B carbapenemases show a high prevalence in Southern Europe and Asia, whereas Class D enzymes are more common in Mediterranean countries [60]. The geographical position of the countries around the Red Sea may explain this high presence of these genes in these countries.

**Egypt:** since 2011, a total of 34 studies have been conducted in several cities across the country, describing eight different carbapenemase types from various clinical samples associated with human infections in inpatient and outpatient units, demonstrating the spread of these genes throughout the country (Fig. 1). As shown in Table 1, the isolation sources of these CPEA isolates include different clinical specimens such as blood, urine, sputum, endotracheal secretion, wound swabs, pus, cerebrospinal fluid (CSF), stool, bronchoalveolar lavage (BAL), and respiratory tract samples. Among the reported Class A carbapenemases, KPC enzymes were detected in *Enterobacteriaceae* isolates predominantly in *K. pneumoniae* [62,67,71,76,80,86,92] and *E. coli* [67,80,86], whereas the GES enzyme was reported in *A. baumannii* isolates from hospital-acquired infections [81]. Class B metallo-β-lactamases such as NDM enzymes were detected in *Enterobacteriaceae* (e.g. *K. pneumoniae* [64,68,77-79,82,83,84,87,90], *E. coli* [64,77,83,90], *S. marcescens* [82], *C. freundii* [82], and *E. aerogenes* [79]), and in *A. baumannii* isolates [67,77,84,93,143] in various human samples either in hospital-acquired and community-acquired infections. VIM was also found in *Enterobacteriaceae* (*K. pneumoniae* [61,63,67], *S. marcescens* [73], *Enterobacter* spp. [71], and *M. morganii* [94]), and in *A. baumannii* [66,69,74]. IMP was also present in *Enterobacteriaceae* (*K. pneumoniae* [77,91] and *S. marcescens* [73]), and in *A. baumannii* [66,77,78]. GIM was present only at *K. pneumoniae* [77] and *A. baumannii* [66]. The SPM gene was found in *K. pneumoniae* [76,77] and *A. baumannii* [74]. Finally, SIM was only found in *A. baumannii* [66]. In Class D, the OXA-48 enzyme was the most reported carbapenemase in human infections associated with OXA-48-producing *Enterobacteriaceae*, especially *K. pneumoniae* [64,67,76,80,82,83,89,92,94,144], *E. coli* [64,67,76,80,84,89,91,94,144], *E. aerogenes* [76], *P. mirabilis* [76], *S. marcescens* [94], and *M. morganii* [94]), but also with OXA-producing *A. baumannii* [84], in which the OXA-23 enzyme has been reported [69,70,72,74,75,81,85].

**Jordan:** in Jordan, between 2010 and 2023, nine studies were conducted on carbapenemase-producing bacteria from different species mostly associated with human infections (Table 1). The reported Class A KPC-producing *K. pneumoniae* [95,96,101,102] and *A. baumannii* [100] isolates were all from clinical samples from hospitalised patients (Table 1). The GES carbapenemase was reported only in *A. baumannii* in 2016 from cancer patients [100]. In Class B, NDM-producing *Enterobacteriaceae* were reported including *K. pneumoniae* [95-97], *E. coli* [96], and *E. cloacae* [96], as well as NDM-producing *A. baumannii* [100]. However, VIM, IMP and SPM carbapenemases were reported in *K. pneumoniae*, *E. cloacae*, *E. coli* [96], and *A. baumannii* [100] isolates, respectively. In Class D, the oxacillinase OXA-48 was described in several studies in *K. pneumoniae* [95-97], whereas the pandemic OXA-23 carbapenemase was detected in clinical *A. baumannii* isolates [98-100,103].

**Kingdom of Saudi Arabia (KSA):** in total, 24 articles have been published to date dealing with carbapenemase-producing bacteria detecting eight different carbapenemases in KSA (Table 1, Fig. 1B). While the initial report of a carbapenem-resistant *K. pneumoniae* outbreak in KSA was documented in 2010 at a tertiary care hospital's intensive care unit, with 20 of the 1706 *K. pneumoniae* detected being CRKP, the genetic basis for this carbapenem resistance remains undetermined [145]. Since that initial report, numerous comprehensive studies have been conducted across various regions, hospitals, and time periods in the country. These investigations have identified multiple carbapenemase genes and their associated risk factors (Fig. 1C). For instance, one epidemiological review in 2019 was published on the specific mechanisms of carbapenem resistance in *A. baumannii* in hospitals in different parts of the country [146]. Interestingly, KPC-2 was the only reported Class A carbapenemase in *K. quasipneumoniae* isolates in KSA in 2019 from tra cheostomy wound infection of a septic patient [107,108]. The GES enzyme (the GES-11 variant) was reported from *A. baumannii* strain
<figure><img src="image_4.png" /><figcaption>**Fig. 1.** Distribution of type of carbapenemase, number of studies, and carbapenemase types per country around the Red Sea. (A): Carbapenemase types described in each country; (B): The number of reported studies per country dealing with carbapenemase-producing gram-negative bacteria; (C): The number of carbapenemase types reported in each country.</figcaption></figure>

isolated from frequent-hand-touch surfaces in surgical units of a hospital in the eastern region of KSA [114]. In Class B, NDM was found to be carried by *Enterobacteriaceae* such as (K. pneumoniae [106,107,109,110–113,116,120,124,125,127], E. coli [106,107,112,127], E. cloacae [106,109], and E. aerogenes [109]), as well as in CR-NF A. baumannii [118]. Other Class B carbapenemases such as SPM and IMP have been identified in A. baumannii [104,119]. Furthermore, VIM has been reported to be present both in K. pneumoniae [111] and A. baumannii [104,119,147]. In Class D, among the oxacillinases, several studies have found the OXA-48 type in *Enterobacteriaceae* (K. pneumoniae [106,108–111,113,114,116,119,120,124], E. coli [106,107,109,110,112], E. cloacae [109], and E. aerogenes [109]). OXA-23 has also been found in A. baumannii [104,105,109,114,118,119,121,122,123,126,147].

**Yemen:** in Yemen, few studies (three published articles) have been conducted in hospital settings identifying various carbapenem-resistance genes in clinical isolates of *Enterobacteriaceae* (K. pneumoniae, E. coli, and E. cloacae), including NDM types (such as NDM-1 and NDM-5), and OXA-type (such as OXA-48, OXA-181, and OXA-232) [137,138] (Table 1, Fig. 1B and C). The OXA-23 carbapenemase gene has also been found in three A. baumannii isolates from sputum and tracheal aspirate samples [138,139] (Table 1).

**Sudan:** nine studies were identified in Sudan in the given period (Fig. 1B), reporting different carbapenemase-producing *Enterobacteriaceae* isolates, including K. pneumoniae, E. coli, E. cloacae, P. mirabilis, and P. vulgaris (Table 1). Almost all these isolates were from hospital settings, with the exception of one study which, curiously, described 12 E. coli isolates from community-acquired infections that produced OXA-23 carbapenemase (Table 1), despite the fact that this gene has thus far only been reported in *Acinetobacter* species.

Interestingly, different variants of carbapenemase, 12 in total (i.e. KPC, GES-11, NDM-1, NDM-5, NDM-6, IMP, VIM, GIM-1, SIM-1, OXA23, OXA-48, OXA-51, and OXA-58) have been reported in this country (Table 1). Clinical K. pneumoniae isolates carrying Class A carbapenemase genes such as KPC [133] and GES [129] have been described from clinical samples including blood, urine, and wound swabs. In Class B, NDM, VIM, IMP, and SIM were also found in clinical isolates of K. pneumoniae, E. coli, E. cloacae, P. mirabilis, and P. vulgaris [130,132–134]. The OXA-48 Class D enzyme was present in both *Enterobacteriaceae* and A. baumannii isolates [128]. Moreover, OXA-23 and OXA-58 were detected in A. baumannii isolates from hospitals [135,136].

**Djibouti:** very few reports, to our knowledge two articles (Fig. 1B), have been described dealing with carbapenem resistance either in Djibouti hospitals or communities. The first reports of carbapenemase-producing isolates from patients in the city of Djibouti were in 2019 and 2020, reporting *Enterobacteriaceae* and A. baumannii isolates associated with hospital-acquired infections. Clinical isolates of K. pneumoniae and E. coli carrying the carbapenemase OXA-48 and NDM enzymes were described in various clinical samples including urine, pus, blood, and respiratory samples [140,141] (Table 1). The pandemic OXA-23 carbapenemase was also reported in clinical A. baumannii isolates from a urine sample from a hospitalised patient [140].

**Somalia:** despite the lack of epidemiological reports on multi-drug-resistant (MDR) bacteria in this country due to the ongoing civil war, a 2021 study conducted in a German hospital identified Somali patients carrying carbapenem-resistant isolates. These patients were infected either with K. pneumoniae or A. baumannii isolates harbouring the NDM, VIM, OXA-23, and OXA-48 enzymes [142].
## Conclusion

The global spread of carbapenem-resistant gram-negative bacilli associated with infectious diseases has become a critical health concern in recent years, with the Middle East, Europe, and Africa emerging as hotspots for carbapenemase-producing bacteria. The countries surrounding the Red Sea, situated at the intersection of these regions, serve as a good example of the widespread dissemination of these resistant bacteria. This review underscores the troubling dissemination of carbapenemase-producing gram-negative bacilli, especially *Enterobacteriaceae* and *A. baumannii* isolates, in healthcare settings across the region. Given the current situation, it is imperative to implement robust surveillance programmes, enhance infection control measures, and develop rapid and accurate detection methods for this resistance in both clinical and environmental settings. These steps are crucial to preventing outbreaks and limiting the spread of these multidrug-resistant pathogens across these countries surrounding the Red Sea.

## Funding information

This work was supported by the Agence Nationale de la Recherche (ANR, fr: National Agency for Research), (reference: Fondation Méditerranée Infection 10-IHU-03) and by the University of Djibouti.

## Declaration of Competing Interest

The authors declare no competing interests.

## Acknowledgment

We are grateful the University of Djibouti for his support.

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