3.1 Rates of Antimicrobial Resistance and Phenotypes from the Middle East/Arabian Gulf Region

Figure 2 presents data on the rates of antimicrobial resistance and DTR phenotypes among isolates of P. aeruginosa from the Arabian Gulf countries, and other countries or regions [20, 43, 57]. The highest resistance rates observed in each Arabian Gulf country, and the others presented, were to meropenem, ranging from 10.3% (UAE) to >40.0% in Oman and Qatar (higher than the other countries and regions) (Fig. 2). The meropenem resistance rates in Oman and Qatar are reflective of single center data and not necessarily indicative of the resistance status in the country as a whole. Colistin resistance was low (<2.2%) globally (Fig. 2). Amikacin resistance was <5% in Qatar, Saudi Arabia, and the UAE (similar to Southern Europe, North America and Southeast Asia), but higher in Kuwait (10.7%) and Oman (20.0%). There were lower rates of DTR-P. aeruginosa (10.9–13.2%) in North America, Saudi Arabia, and Southeast Asia; rates of 16% in Southern Europe and EMR; and rates of 19.0–25.9% elsewhere (data not collected in Oman or the UAE; Fig. 2). Published rates of antimicrobial resistance or susceptibility from the Arabian Gulf countries, and other countries or regions are presented in Supplementary Table 3 [8,9,10, 12,13,14,15,16,17,18,19,20, 23, 24, 26,27,28,29,30, 32,33,34, 36, 37, 41,42,43,44].

The rates of antimicrobial susceptibility among a collection of P. aeruginosa isolates from Middle East countries (Israel, Jordan, Kuwait, and Saudi Arabia) ranged from 62.8% (levofloxacin) to >90% (amikacin and colistin) [12], according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) 2020 breakpoints [54]. However, there was no susceptibility breakpoint, and only intermediate or resistance breakpoints, for colistin when using Clinical and Laboratory Standards Institute (CLSI) 2020 breakpoints [55]. Susceptibility to ceftazidime-avibactam and ceftolozane-tazobactam was >90% in the Middle East and Middle East-Africa regions [12, 13].

MDR rates among. P. aeruginosa were 30.6% and 38.1%, and the rate with a DTR phenotype was 7.4% for the Middle East region [12, 14]. Among MDR P. aeruginosa isolates, cefepime, meropenem and piperacillin-tazobactam susceptibility was 30–50%, which decreased to 0% among DTR isolates [12]. A 2016–2018 ATLAS surveillance study reported that no isolates of carbapenemase-producing P. aeruginosa collected in the Middle East-Africa region were resistant to colistin, whereas 32.3% were resistant to aztreonam, and ≥92.3% were resistant to the other tested agents, including amikacin, ceftazidime-avibactam, imipenem and meropenem [9]. These findings reflected the high proportions of MBL-positive isolates that were detected in all regions included in the study [9]. Rates of meropenem non-susceptibility were 25–35% among P. aeruginosa collected in the Middle East and Africa [12, 13, 15]. Among meropenem-non-susceptible respiratory P. aeruginosa isolates collected from adult intensive-care unit (ICU) patients in the Middle East-Africa region, susceptibility was 68.1% to ceftolozane-tazobactam, 34.9% to ceftazidime, and 28.2% to piperacillin-tazobactam [15].

In the above studies, the range of countries comprising the Middle East-Africa region (including Egypt, Israel, Jordan, Kenya, Kuwait, Lebanon, Morocco, Qatar, South Africa, and Tunisia) were from a wide range of social and economic settings. Antimicrobial susceptibility or resistance data and reports on P. aeruginosa isolates from the individual Arabian Gulf countries are described below. The main study findings are summarized in Table 1 and data presented in Supplementary Table 3.

3.1.1 Bahrain, Kuwait and Oman

More than 80% of ciprofloxacin-resistant P. aeruginosa isolates from Bahrain were also resistant to imipenem, meropenem and piperacillin-tazobactam; however, none were resistant to colistin [16, 17]. Similarly, high resistance rates to meropenem (≥87.5%) and low resistance rates to colistin (2.1%) were observed among MDR P. aeruginosa isolates from Kuwait (one of which was pandrug-resistant [PDR]; defined as resistant to all antimicrobial agents [5]) [18]. The rates of susceptibility to amikacin, ceftazidime, ciprofloxacin, imipenem and piperacillin-tazobactam were also notably lower in the study of MDR P. aeruginosa from Kuwait, compared with non-MDR isolates [18]. Conversely, P. aeruginosa from diabetic foot infections, collected in Kuwait, exhibited susceptibility rates of ≥65.7% to ceftazidime, meropenem, gentamicin, imipenem, and amikacin [19].

In Oman, extended-spectrum β-lactamase (ESBL) enzyme production was only detected in 2 of 2362 P. aeruginosa isolates collected [20]. The lowest rate of susceptibility among P. aeruginosa from Oman was to meropenem (58.0%), with ≥80.0% of isolates susceptible to amikacin, ceftazidime, ciprofloxacin, gentamicin and piperacillin-tazobactam. All isolates were susceptible to colistin. Another study in Oman found that 8.1% of all MDR isolates from a tertiary care teaching hospital were P. aeruginosa [21]. In the same hospital, the rate of CR P. aeruginosa in bacteremia was 22% between 2012 and 2016, with a rate of 43% reported in 2015 alone [22].

3.1.2 Qatar

Among P. aeruginosa from cystic fibrosis patients in Qatar, antimicrobial non-susceptibility ranged from 9.8% (piperacillin-tazobactam) to 41.0% (gentamicin); all isolates were susceptible to colistin [23]. Meropenem non-susceptibility was 11.5% and meropenem resistance was 58.3% among MDR isolates. Among the MDR subset, resistance rates ranged from 50.0% (piperacillin-tazobactam) to 100% (gentamicin, amikacin and cefepime), whereas none of the MDR isolates were resistant to colistin [23].

In a multi-hospital study, the rate of MDR isolates collected in Qatar between 2014 and 2015 was 8.1% (2.4% of which were PDR) [24]. The rate of MDR P. aeruginosa at one of these hospitals before the implementation of an antimicrobial stewardship program was 9.0% and was 5.5% after implementation [25]. Most MDR P. aeruginosa isolates were resistant to cefepime, ciprofloxacin, piperacillin-tazobactam and meropenem (>90%); in addition, aminoglycoside resistance was 50–75%, and 3.4% were colistin-resistant [25]. Non-susceptibility to ceftazidime-avibactam and ceftolozane-tazobactam was 31.2% and 37.1%, respectively, among MDR P. aeruginosa [26]. The authors attributed ceftazidime-avibactam and ceftolozane-tazobactam non-susceptibility rates among the MDR isolates in their study to the production of ESBL and VIM enzymes [26]. Among a smaller subset of eight MDR isolates that produced metallo-β-lactamases (MBLs), but not ESBLs, all were susceptible to aztreonam but resistant to the other agents studied [27].

3.1.3 Saudi Arabia

Two studies of P. aeruginosa isolates reported low resistance to ceftazidime-clavulanic acid (<10%) and high resistance to gentamicin (41%) [28, 29]. All isolates were susceptible to colistin. In a single-center study of 156 P. aeruginosa isolates, 22.4% were ceftazidime-resistant, of which 71.4% were ESBL-producers and 42.9% were MBL-producers [28]. Thirty-nine (19.5%) of 200 clinical P. aeruginosa isolates collected at another center were ceftazidime-resistant, most of which were also resistant to other tested agents; however, all isolates were susceptible to colistin [29]. In a single-center study of 33 MDR P. aeruginosa isolates, the rates of resistance to colistin and the carbapenems were 6.1% (colistin), 39.4% (doripenem), 81.8% (meropenem), and 90.9% (imipenem) [30]. In a multi-hospital study, the percentage of carbapenemase production among 39 ceftazidime- and carbapenem-resistant isolates of P. aeruginosa collected was 28.2% [31].

Another multicenter study statistically compared the overall resistance rates to tested agents among 121 P. aeruginosa isolates [32]. The rate of resistance to piperacillin-tazobactam (4.9%) was significantly lower than to ceftazidime, levofloxacin, aztreonam, ciprofloxacin, piperacillin, imipenem, ticarcillin and meropenem (P < 0.05). In contrast, the rate of resistance to meropenem (30.6%) was significantly higher than to piperacillin-tazobactam, amikacin, cefepime, gentamicin, ceftazidime, levofloxacin, aztreonam, ciprofloxacin, piperacillin and imipenem (P < 0.05). The overall MDR rate was 10.7% [32]. A higher rate of meropenem resistance was observed among respiratory isolates than among other infection types (41.5%; P < 0.05).

P. aeruginosa isolates from three different ICUs in one hospital showed the lowest rates of resistance to the class of aminoglycosides (amikacin [18.8%], tobramycin [20.0%] and gentamicin [31.7%]), while 30.0% of isolates were resistant to colistin [33]. The study recorded a multidrug resistance rate of 60.9% among P. aeruginosa [33]. Similarly, the resistance rates among P. aeruginosa isolates from seven ICUs ranged from 8.9% (cefepime) to 41.1% (imipenem). The rate of meropenem resistance was 27.8% [34]. In that ICU study, 36.7% of 90 P. aeruginosa isolates collected were MDR [34]. A higher rate of 93.1% MDR P. aeruginosa isolates were associated with ventilator-associated pneumonia (VAP) in another ICU study in Saudi Arabia [35].

3.1.4 United Arab Emirates

A total of 1969 P. aeruginosa were collected in a cross-sectional multicenter study, of which 23.9% of isolates were identified as carbapenem-non-susceptible [36]. Among a subset of 37 carbapenem-non-susceptible isolates that underwent molecular characterization, 10.8% of isolates were MDR and 37.8% were XDR. No study isolates were characterized as PDR because all were susceptible to colistin [36]. A single-center study of 31 P. aeruginosa isolates reported rates of resistance ranging from 16.1% (gentamicin) to 51.6% (meropenem) [37]. High susceptibility was reported to ceftazidime-avibactam and ceftolozane-tazobactam among all P. aeruginosa isolates (93.5% and 96.8%, respectively).

3.2 Studies on Molecular Resistance Mechanisms from the Middle East/Arabian Gulf Regions

Figure 3 (data shown in Supplementary Table 4) shows the distribution of β-lactamase genes among P. aeruginosa from the Arabian Gulf countries, and other countries or regions. The variety of documented VIM and GES genes appears to be greater in the countries of the Arabian Gulf, compared with the other countries and regions. In contrast, fewer IMP-type genes were reported in the Arabian Gulf, compared with North America, Latin America, and Southeast Asia. Fewer types of NDM and KPC genes were documented among P. aeruginosa in the Arabian Gulf and the other countries and regions (Fig. 3, Supplementary Table 4). Molecular characterization studies conducted in the individual Arabian Gulf countries are described below.

Fig. 3

Distribution of β-lactamase genes among P. aeruginosa from the Arabian Gulf countries and other countries/regions (2010–2021) (genotype data from each country/region are shown in Supplementary Table 4). Circles show the genotype number of each β-lactamase gene detected in a country or region and ‘type’ represents an identified β-lactamase gene that has not been sub-typed. EMR, Eastern Mediterranean Region; inc, including; excl, excluding; NDM, New Delhi metallo-β-lactamase; VIM, Verona integron-encoded metallo-β-lactamase; IMP, imipenemase; GES, Guiana extended-spectrum; KPC, Klebsiella pneumoniae carbapenemase; and UAE, United Arab Emirates

3.2.1 Bahrain, Kuwait and Qatar

The upregulated expression of genes mexB, mexD, mexF and mexY was identified in 8% of tested ciprofloxacin-resistant P. aeruginosa isolates [17]. The same isolates also showed a decrease in ciprofloxacin minimum inhibitory concentration (MIC) by the efflux pump inhibitor carbonyl cyanide 3-chlorophenylhydrazone. Among imipenem-resistant P. aeruginosa isolates collected from community, hospital, and ICU patients in Bahrain, 52.5% carried MBL genes; mostly VIM-type (90.4%) [16]. One isolate was NDM‑1-positive, and one isolate carried both VIM and NDM‑1 genes.

Data on the β-lactamase genes carried by P. aeruginosa isolates in Kuwait are scarce. A global antimicrobial surveillance study that included countries in the Middle East-Africa region showed that 11 isolates of VIM-2-positive and 3 VIM-4-positive P. aeruginosa were collected in Kuwait [8].

Among 75 MDR (defined according to [5]) P. aeruginosa isolates from two centers in Qatar, 96.0% possessed class C and/or class D β-lactamases, while MBLs were detected in 26.7% of the isolates (blaVIM-2, blaVIM-5 and blaIMP-2) [27]. One (1.3%) isolate co-carried both blaVIM-2 and blaIMP-1 and all four β-lactamase classes were pre