Abstract
Background:
Carbapenem-resistant Enterobacterales (CRE) are a significant public health threat affecting human health globally. Unfortunately, the incidence of CRE has increased globally, raising the red flag for the need for an urgent plan for this serious and worrisome problem.
Objectives:
We aimed to identify the prevalence and genetic characterization of CRE in addition to determining antibiotic resistance profiles and the effect of independent variables on carbapenemase gene types.
Design:
The study is a retrospective cross-sectional study conducted at a tertiary care hospital in East Jerusalem.
Methods:
Data were collected from microbiology, molecular, and infectious diseases units from May 2019 till November 2023. Non-repetitive isolates that tested positive for CRE according to the CLSI (M100, S29, 2023) and American Society for Microbiology Diagnostic Microbiology Proceedings manual were included with no age exclusion.
Results:
A total of 599 CRE non-repetitive isolates were included, carbapenemase detected (C-CRE detected) genes were seen in 421 isolates, while the remaining 178 isolates were carbapenemase not detected (C-CRE not detected). The most common carbapenemase gene was bla NDM (347 isolates, 82.4%), followed by bla OXA-48 (55 isolates, 13.1%). The prevalence of CRE from total cultures (gram-negative, gram-positive, and no growth) during the study period was 2.4%, while the prevalence of CRE from Enterobacterales was 20.6%. The prevalence of CRE increased over the study years with a notable increase between 2020 and 2021, Klebsiella species were the most common carbapenem-resistant bacterial genera, while surveillance anal swab culture was the most dominant culture site from where CRE isolates were isolated. Antibiotic resistance varied according to carbapenemase gene type and bacterial genera.
Conclusion:
CRE is a growing problematic health issue that spotlights the urgent need for integrated, complete, and appropriate national antimicrobial stewardship and infection prevention and control programs.
Keywords: antibiotic resistance, carbapenem resistance, carbapenemase, prevalence
Plain language summary
How common are carbapenem-resistant enterobacterales (CRE), their genetic makeup, and antibiotic resistance in a Major Hospital in East Jerusalem (2019-2023)
Our goal is to understand how common CRE bacteria are, analyze their genetic makeup, and assess their resistance to antibiotics. We also want to examine how different factors influence the types of carbapenemase genes these bacteria carry. This research is based on past patient data from a major hospital in East Jerusalem. It looks at cases over a period of time to identify patterns and trends.
Introduction
Antimicrobial resistance (AMR) is a major global threat affecting human health. If no action is taken, it will cause 10 million deaths annually by 2050. 1 Unfortunately, the incidence of carbapenem-resistant Enterobacterales (CRE) has increased globally, raising the red flag for an urgent need for interventions to halt this climbing resistance. 2 CRE is defined as Enterobacterales resistant to at least one carbapenem (ertapenem, meropenem, doripenem, and imipenem) or producing a carbapenemase enzyme. 3 In general, CRE is classified into two main subgroups according to their mechanism of resistance: the non-carbapenemase-producing CRE and the carbapenemase-producing CRE that is further divided according to the Ambler classification into three groups: class A, class B, and class D ß-lactamases. 4 blaKPC, blaNDM, blaOXA-48-like, blaIMP, and blaVIM are the mainly targeted carbapenemase genes. 5 Distinguishing between both subgroups and at the molecular level of carbapenemases is crucial for guiding the treatment plan and applying proper infection prevention and control (IPC) measures.
CRE is mainly transmitted at healthcare facilities; it can lead to asymptomatic colonization mostly in the digestive system. However, it can spread to other persons or advance and cause infections such as lung infections, bloodstream infections, and skin soft tissue infections. 6
Immunocompromised patients, due to either inherent deficiencies in immune function or alterations in host defenses induced by chemotherapy or radiotherapy, are particularly more susceptible to such infections.7,8 Some studies also have shown a high prevalence of CRE colonization among cancer patients.8,9
Implementing multidisciplinary strategies that emphasize IPC measures—such as hand hygiene, use of proper personal protective equipment, active surveillance with anal or fecal cultures, and isolation of CRE patients—as well as empowering antimicrobial stewardship (AMS) programs and regulating over-the-counter antibiotic purchasing, is of pivotal importance for prevention of CRE spread.
Antibiotics endorsed by the Infectious Diseases Society of America for the treatment of infections caused by CRE are not available in Palestinian territories, which makes it challenging to treat such infections with the increase in antibiotic resistance; furthermore, research is scarce regarding AMR in general and CRE genes in specific. Therefore, we aimed to identify the prevalence, carbapenemase detection, and antibiotic resistance for CRE in a tertiary care hospital in East Jerusalem from 2019 to 2023.
Methods
Study design
This study is a retrospective cross-sectional study that was carried out between May 2019 and November 2023 at Augusta Victoria Hospital (AVH), a tertiary care hospital in East Jerusalem with a capacity of 171 beds known for its specialized services including comprehensive cancer and diabetes care, kidney care and dialysis, and skilled nursing and long-term care who come from all Palestinian regions including Gaza strip.
Data collection
Data were collected from the hospital’s system. All microbiology and molecular results from May 2019 till November 2023 were extracted from the hospital system in addition to all CRE reports, which were gathered from the infectious diseases unit department as Excel data sheets.
Population
Bacterial culture results were obtained from 2904 non-repetitive Enterobacterales isolates from clinical cultures and surveillance swab cultures of inpatients, including oncology patients, nephrology and dialysis patients, and patients who reside in the skilled nursing and long-term care from 2019 till 2023.
Clinical cultures (blood, urine, skin, sputum, body fluids, and cerebrospinal fluid) were ordered by clinicians according to each patient’s medical condition status. Surveillance cultures were obtained from patients at risk of multidrug-resistant organism (MDRO) colonization. According to AVH’s policy, surveillance swabs (nasal and anal swabs) should be obtained from:
1- Patients who are transferred from other hospitals.
2- Patients who were hospitalized in the past 6 months for more than 24–48 h).
3- Patients who need admission to the intensive care unit (ICU): before admission to the ICU, once weekly while in the ICU, and before transmission to other hospital wards.
4- Patients who are known to have MDRO from previous admission surveillance swab results.
Inclusion criteria
This study includes 599 non-repetitive Enterobacterales isolates from patients aged between 14 days to 90 years old who tested positive for CRE according to the Proceeding of Clinical Microbiology, American Society for Microbiology (ASM), and the Clinical and Laboratory Standard Institute, CLSI (M100, S29, 2023). Susceptibility in Enterobacterales positive clinical cultures according to lab’s protocol should be done to gentamycin, ciprofloxacin, amikacin, meropenem, imipenem, ceftriaxone, ceftazidime, piperacillin/tazobactam, chloramphenicol, cefazolin, piperacillin, trimethoprim/sulfamethoxazole, ertapenem, ceftazidime/avibactam, ampicillin, and colistin, while surveillance cultures susceptibility only to amikacin, ceftazidime, meropenem, ertapenem, ceftazidime avibactam, and colistin are done. Briefly, the resistance profile of ertapenem, meropenem, and imipenem was performed for all members of the Enterobacterales family. Any bacteria with a non-susceptible profile were tested with The Modified Carbapenem Inactivation Method (mCIM) for the presence of a carbapenemase. All mCIM positive strains were further tested by multiplex (Plymerase Chain Reaction) PCR for the presence of the following genes: KPC, NDM, OXA-48, IMI, and VIM. The multiplex PCR assay used in this study was a laboratory-validated method that involved the utilization of primers approved for carbapenemase detection by the Israeli Ministry of Health. This was not a commercial “of-the-shelf” kit, but rather an established and validated in-house assay based on published protocols.10,11 MIC50 or MIC90 was not done.
Exclusion criteria
Repeated isolates obtained from clinical cultures at the same site for same single patient within a month were excluded. In addition, repeated isolates from surveillance swabs within 6 months were excluded. Multiple repeated isolates for the same patient from different body sites were counted as one isolate.
Outcomes
The study evaluated the prevalence of CRE in total cultures that were done at the study period and positive Enterobacterales cultures, as well as the genetic characteristics of carbapenamase gene in the CRE isolates across demographics, geographic regions, and referral hospitals. It also determined antibiotic resistance in prevalent bacterial genera and assessed carbapenemase gene types.
Statistical analysis
All data were analyzed using Stata software (version 17), StataCorp LLC, Texas, United States. Continuous data such as age and categorical data (geographic region, name of referral hospital, gender, bacterial genera, and CRE gene types) were presented using frequency distribution, counts, and percentages. Mean values and number of observations for each variable are provided in the appendix tables (Appendices 1 and 2). Multiple regression analysis for the effect of independent variables on carbapenemase gene types is provided in Appendix 3.
CRE prevalence was calculated by dividing the number of CRE isolates by total Enterobacterales culture results.
Chi square was conducted to observe the significance of year-to-year changes in the CRE prevalence from total Enterobacterales (Appendix 4).
Patient’s age was categorized according to the Federal Food and Drug Administration into three categories: pediatrics, adults, and geriatrics. The pediatric category was further divided into subpopulations: Neonates (from birth through the first 28 days of life), Infants (from 29 days to less than 2 years), Children (from 2 years to less than 12 years), and Adolescents (aged 12 through 21; up to but not including the 22nd birthday) 12 . Adults were defined as individuals aged 22 to less than 65 years, and geriatrics as those aged 65 and older.
Patients were categorized by diagnosis into solid tumors, hematological malignancies, kidney diseases, long-term care, and others.
Geographic distribution for the isolated CRE genes that are represented by the districts was categorized according to Palestinian region classification: North region, which includes districts of Jenin, Qalqilya, Nablus, Salfit, Tubas, and Tulkarm. The middle region includes districts of Ramallah, Jerusalem, Bethlehem, and Jericho. The southern region includes Hebron and Gaza Strip.
Referring hospitals before admission to AVH were divided into four categories: non-governmental organizations (NGOs), public hospitals, private hospitals, and other institutions where patients were either from overseas or whose referral hospital name was not available.
Results
Table 1 describes the number of bacterial cultures (gram-positive cultures, Enterobacterales cultures, other gram-negative cultures, and cultures with no growth) in each year and the total for all cultures that were used to calculate the prevalence of CRE.
Table 1.
Number of non-repetitive cultures that were done at AVH during the study period.
| Culture results | Year | |||||
|---|---|---|---|---|---|---|
| 2019 | 2020 | 2021 | 2022 | 2023 | Total | |
| Gram-positive isolates | 226 | 232 | 314 | 326 | 262 | 1360 |
| Enterobacterales isolates | 531 | 478 | 554 | 716 | 625 | 2904 |
| Other gram-negative isolates | 223 | 182 | 229 | 230 | 189 | 1053 |
| No growth cultures | 3141 | 3822 | 4121 | 4507 | 3686 | 19,277 |
| Total cultures | 4121 | 4714 | 5218 | 5779 | 4762 | 24,594 |
AVH, Augusta Victoria Hospital.
From 2019 to 2023, 599 CRE isolates out of 2904 gram-negative Enterobacterales met the inclusion criteria, with 46 isolates in 2019, 67 isolates in 2020, 88 isolates in 2021, 215 isolates in 2022, and 183 isolates in 2023.
The overall prevalence of CRE was (599/24,594, 2.4%) among all cultures and (599/2904, 20.62%) among Enterobacterales cultures. Prevalence of CRE from the positive Enterobacterales cultures each year was 8.66% in 2019, 14.02% in 2020, 15.88% in 2021, 30.03% in 2022, and 29.28% in 2023. However, in 2019, 2020, 2022, and 2023, the prevalence of CRE (from all cultures: gram-positive, gram-negative, and no growth each year) was 1.12%, 1.42%, 1.69%, 3.72%, and 3.84%, respectively (Figure 1).
Figure 1.
Prevalence of CRE over the study years 2019–2023.
A significant increase from year to year is demonstrated in the results via Chi-square Appendix 4.
CRE, Carbapenem-resistant Enterobacterales.
From the 599 CRE isolates, C-CRE detected genes were found in 421 isolates, while the remaining 178 were C-CRE not detected. C-CRE detected mainly harbored bla NDM (347 isolates, 82.4%), followed by bla OXA-48 (55 isolates, 13.1%), bla NDM + OXA-48 (7 isolates, 1.7%), bla KPC (6 isolates, 1.4%), and bla VIM (6 isolates, 1.4%; Table 2.
Table 2.
Characteristics of CRE.
| Variable | C-CRE detected | C-CRE not detected | Total | ||||
|---|---|---|---|---|---|---|---|
| Total N = 421 | N = 178 | ||||||
| KPC (blaKPC gene) | NDM (blaNMD gene) | NDM+ | OXA-48 (bla OXA-48 gene) | VIM (bla VIM gene) | |||
| OXA-48 | |||||||
| N = 6 | N = 347 | N = 7 | N = 55 | N = 6 | N = 599 | ||
| N (%) | N (%) | N (%) | N (%) | N (%) | N (%) | N (%) | |
| Year | |||||||
| 2019 | 0 (%) | 26 (56.5%) | 2 (4.3%) | 9 (19·6) | 0 (0%) | 9 (19.6%) | 46 (100%) |
| 2020 | 3 (4.5%) | 39 (58.2%) | 0 (%) | 2 (3%) | 1 (15%) | 22 (32.8%) | 67 (100%) |
| 2021 | 1 (1.1%) | 41 (46.6%) | 3 (3.4%) | 5 (5.7%) | 0 (0%) | 38 (43.2%) | 88 (100%) |
| 2022 | 1 (0.5%) | 124 (57.7%) | 1 (0.5%) | 22 (10.2%) | 1 (0.5%) | 66 (30.7%) | 215 (100%) |
| 2023 | 1 (0.5%) | 117 (63.9%) | 1 (0.6%) | 17 (9.3%) | 4 (2.2%) | 43 (23.5%) | 183 (100%) |
| Bacteria | |||||||
| Citrobacter | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 7 (100%) | 7 (100%) |
| Enterobacter | 0 (0%) | 15 (51.7%) | 0 (0%) | 3 (10.3%) | 4 (13.8%) | 7 (24.1%) | 29 (100%) |
| Escherichia | 2 (1%) | 129 (67.2%) | 5 (2.6%) | 25 (13%) | 1 (0.5%) | 30 (15.6%) | 192 (100%) |
| Klebsiella | 4 (1.1%) | 202 (54.8%) | 2 (0.5%) | 27 (7.3%) | 1 (0.3%) | 133 (36%) | 369 (100%) |
| Morganella | 0 (0%) | 1 (100%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 1 (100%) |
| Providencia | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 1 (100%) | 1 (100%) |
| Culture type | |||||||
| Surveillance anal swab culture | 5 (1.1%) | 283 (64.6%) | 7 (1.6%) | 44 (10.1%) | 4 (0.9%) | 95 (21.7%) | 438 (100%) |
| Clinical cultures | 1 (0.6%) | 64 (39.8%) | 0 (0%) | 11 (6.8%) | 2 (1.2%) | 83 (51.6%) | 161 (100%) |
| Blood culture | 0 (0%) | 10 (37%) | 0 (0%) | 3 (11.1%) | 0 (0%) | 14 (51.9%) | 27 (100%) |
| Body fluids culture | 0 (0%) | 0 (0%) | 0 (0%) | 2 (40%) | 0 (0%) | 3 (60%) | 5 (100%) |
| Cerebrospinal fluid culture | 0 (0%) | 1 (100%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 1 (100%) |
| Skin culture | 0 (0%) | 15 (42.9%) | 0 (0%) | 2 (5.7%) | 1 (2.8%) | 17 (48.6%) | 35 (100%) |
| Sputum culture | 0 (0%) | 8 (32%) | 0 (0%) | 2 (8%) | 0 (0%) | 15 (60%) | 25 (100%) |
| Urine culture | 1 (1.5%) | 30 (44.1%) | 0 (0%) | 2 (2.9%) | 1 (1.5%) | 34 (50%) | 68 (100%) |
| Sex | |||||||
| Female | 1 (0.4%) | 169 (59.5%) | 0 (0%) | 33 (11.6%) | 2 (0.7%) | 79 (27.8%) | 284 (100%) |
| Male | 5 (1.6%) | 178 (56.5%) | 7 (2.2%) | 22 (7%) | 4 (1.3%) | 99 (31.4%) | 315 (100%) |
| Age categories | |||||||
| Neonates | 0 (0%) | 8 (100%) | 0 (0%) | 0 (0%) | 0 (0%) | 0 (0%) | 8 (100%) |
| Infants | 0 (0%) | 8 (40%) | 0 (0%) | 4 (20%) | 1 (5%) | 7 (35%) | 20 (100%) |
| Children | 1 (2.4%) | 21 (51.2%) | 2 (4.9%) | 9 (22%) | 2 (4.9%) | 6 (14.6%) | 41 (100%) |
| Adolescents | 1 (2.8%) | 19 (54.3%) | 0 (0%) | 3 (8.6%) | 0 (0%) | 12 (34.3%) | 35 (100%) |
| Adults | 3 (0.6%) | 284 (59.7%) | 5 (1%) | 38 (8%) | 2 (0.4%) | 144 (30.3%) | 476 (100%) |
| Geriatrics | 1 (5.3%) | 7 (36.9%) | 0 (0%) | 1 (5.3%) | 1 (5.3%) | 9 (47.4%) | 19 (100%) |
| Diagnosis | |||||||
| Kidney disease | 0 (0%) | 44 (62.8%) | 0 (0%) | 10 (14.3%) | 3 (4.3%) | 13 (18.6%) | 70 (100%) |
| Long term care | 1 (2%) | 11 (22%) | 0 (0%) | 0 (0%) | 0 (0%) | 38 (76%) | 50 (100%) |
| Liquid tumor | 0 (0%) | 47 (78.3%) | 0 (0%) | 1 (1.7%) | 0 (0%) | 12 (20%) | 60 (100%) |
| Solid tumor | 5 (1.2%) | 240 (59%) | 5 (1.2%) | 43 (10.6%) | 3 (0.7%) | 111 (27.3%) | 407 (100%) |
| Others | 0 (0%) | 5 (41.7%) | 2 (16.7%) | 1 (8.3%) | 0 (0%) | 4 (33.30%) | 12 (100%) |
| Geographic distribution | |||||||
| North region | 1 (1%) | 63 (60.6%) | 2 (1.9%) | 13 (12.5%) | 0 (0%) | 25 (24%) | 104 (100%) |
| Middle region | 1 (0.5%) | 82 (45.1%) | 2 (1.1%) | 14 (7.7%) | 4 (2.2%) | 79 (43.4%) | 182 (100%) |
| South region | 2 (1.7%) | 80 (68.4%) | 1 (0.8%) | 7 (6%) | 2 (1.7%) | 25 (21.4%) | 117 (100%) |
| Gaza | 2 (1%) | 122 (62.2%) | 2 (1%) | 21 (10.7%) | 0 (0%) | 49 (25%) | 196 (100%) |
CRE, Carbapenem-resistant Enterobacterales.
CRE was increasing over the years, the C-CRE not detected were isolated from 2019 to 2023, and more than half of these isolates were isolated in the last 2 years. bla NDM was the most prevalent gene over the study years. The majority of bla NDM and bla OXA-48 genes were also isolated in the last 2 years (Table 2).
Klebsiella was the most dominant genera, 369 isolates out of 599 CRE isolates (61.6%) were Klebsiella, 54.74% of them harbored bla NDM, 7.32% harbored bla OXA-48, while 36.04% were C-CRE not detected. Escherichia coli was the second most frequent genera, with 192 isolates out of 599 CRE (32.1%). bla NDM was harbored by 67.19% of the isolated E. coli, 13.02% harbored bla OXA-48, and 15.63% were C-CRE not detected (Table 2).
Surveillance anal swab culture was the most dominant culture site from where CRE isolates were isolated (438/599, 73.1%), NDM gene was most prevalent (64.61%) in surveillance anal swab cultures, while C-CRE not detected accounted for 21.69% of total surveillance cultures. Other genes such as bla KPC, bla OXA-48, and bla VIM were dominant in surveillance cultures compared to clinical cultures, but bla NDM + OXA-48 were only seen in surveillance anal swab cultures. On the other hand, clinical cultures (161/599, 26.9%) were almost equal in terms of carbapenemase or non-carbapenemase detection, 51.55% were C-CRE not detected, and the rest were C-CRE detected with NDM gene dominating other genes. The most common source for clinical cultures was urine followed by skin cultures, blood, and sputum cultures. Body fluids and cerebrospinal fluids cultures accounted for nearly 1% of the total cultures (Table 2).
CRE isolates were isolated almost equally from males and females 284 females and 315 males. bla NDM accounted for more than 50% in both genders. bla KPC and bla VIM were dominating in males, while bla NDM + OXA-48 was only seen in males (Table 2).
CRE was distributed among all age categories; however, the majority of CRE isolates were most seen among adults; more than half of these isolates harbored bla NDM (59.66%) followed by C-CRE not detected (30.25%). Neonates only harbored bla NDM, which was also the most prevalent gene in all age categories except for geriatrics where C-CRE not detected accounted for nearly half of the CRE isolates. bla NDM + OXA-48 was only seen among children and adults (Table 2).
The majority of patients had solid tumors (407/599, 67.9%), followed by chronic kidney diseases (69/599, 11.5%), hematological malignancies (60/599, 10%), and (50/599, 8.3%) patients were long-term care facility residents. The remaining (12/599, 2%) patients had other diseases (transplant, chronic anemia diseases). bla NDM and C-CRE not detected were isolated from patients with all included diagnoses. While bla OXA-48 was not seen among patients requiring long-term care, bla KPC was only isolated from patients with solid tumors and patients requiring long-term care. While bla NDM + OXA-48 was only seen among patients with solid cancer and with other diagnoses. bla VIM was detected in patients diagnosed with solid tumors and kidney diseases (Table 2).
CRE was distributed in all geographic regions; however, Gaza Strip followed by the middle region has a higher prevalence of CRE compared to other regions. bla NDM was the most common in all geographic regions. All genes were distributed in all geographic regions except for bla VIM, which was only seen in the middle and south regions (Table 2).
Public hospitals were the main referral sites for C-CRE detected isolates; 278 isolates out of 421 C-CRE detected (66%) were isolated from patients referred to AVH from public hospitals, followed by NGOs (108/421, 25.6%). bla NDM was the dominant gene in all referral settings; other genes, as bla KPC, bla VIM, and bla OXA-48, were most prevalent in public referral hospitals, while bla NDM + OXA-48 was only detected in isolates that were referred to AVH from public hospitals (Figure 2).
Figure 2.
Link between C-CRE detected genes and different referral hospitals.
CRE, Carbapenem-resistant Enterobacterales.
Isolates that harbored bla OXA-48 had higher susceptibility to the carbapenems compared to other carbapenemases. Isolates that harbored bla NDM + OXA-48, bla NDM, and bla VIM had lower susceptibility to amikacin (42.9%, 45.9%, and 50%, respectively) compared to isolates that harbored bla KPC and bla OXA-48 (66.7% and 68.6%, respectively). Gentamycin isolates, which harbored bla KPC and bla NDM, showed lower susceptibility (0%, 36.2% respectively) compared to bla OXA-48, bla NDM + OXA-48, and bla VIM (64.7%, 50%, and 100%, respectively). Susceptibility to ciprofloxacin was seen in 4.4% of isolates that harbored bla NDM, and 25% of isolates that harbored bla OXA-48. In addition, when looking at resistance to trimethoprim/sulfamethoxazole, lower susceptibility rates were seen among isolates that harbored bla VIM, bla KPC, bla NDM, and bla OXA-48; susceptibility to isolates that harbored bla NDM + OXA-48 was not tested (Table 3).
Table 3.
Antibiotic resistance according in C-CRE detected and C-CRE not detected.
| Antibiotic name | C-CRE detected genes | C-CRE not detected | ||||
|---|---|---|---|---|---|---|
| KPC N = 6 |
NDM N = 347 |
OXA-48 N = 55 |
NDM+ OXA-48 N = 7 |
VIM N = 6 |
N = 178 |
|
| Amoxicillin/clavulanic acid | 0% | 1.6% | 0% | N/T | 66.7% | 8.5% |
| 0/1 | 1/64 | 0/11 | N/T | 4/6 | 7/82 | |
| Amikacin | 66.7% | 45.9% | 68.6% | 42.9% | 50% | 39.5% |
| 4/6 | 157/342 | 35/51 | 3/7 | 3/6 | 70/177 | |
| Trimethoprim/Sulfamethoxazole | 0% | 12.5% | 27.3% | N/T | 0% | 8.4% |
| 0/1 | 8/64 | 3/11 | N/T | 0/2 | 7/83 | |
| Piperacillin/tazobactam | 0% | 1.40% | 0% | N/T | 0% | 18.4% |
| 0/1 | 1/71 | 0/11 | N/T | 0/2 | 16/87 | |
| Meropenem | 0% | 2.6% | 24.1% | 0% | 50% | 8.5% |
| 0/6 | 9/345 | 13/54 | 0/7 | 3/6 | 15/177 | |
| Imipenem | 0% | 3.7% | 25% | 0% | 25% | 11% |
| 0/1 | 5/136 | 6/24 | 0/1 | 1/4 | 11/100 | |
| Gentamycin | 0% | 36.2% | 64.7% | 50% | 100% | 27.6% |
| 0/2 | 38/105 | 11/17 | 1/2 | 2/2 | 27/98 | |
| Ertapenem | 0% | 0.3% | 9.3% | 0% | 33.3% | 0% |
| 0/6 | 1/342 | 5/54 | 0/7 | 2/6 | 0/177 | |
| Ciprofloxacin | 0% | 4.4% | 25% | N/T | 0% | 3.4% |
| 0/1 | 66/69 | 3/12 | N/T | 0/2 | 3/88 | |
| Chloramphenicol | N/T | 46.2% | 83.3% | N/T | 50% | 39.5% |
| N/T | 18/39 | 5/6 | N/T | 1/2 | 17/43 | |
| Ceftriaxone | 0% | 1.5% | 18.2% | N/T | 0% | 4.8% |
| 0/1 | 1/65 | 2/11 | N/T | 0/2 | 4/84 | |
| Ceftazidime/avibactam | N/T | 5.6% | 66.7% | 0% | N/T | 37.5% |
| N/T | 1/18 | 2/3 | 0/7 | N/T | 6/16 | |
| Ceftazidime | 0% | 0.9% | 25.5% | N/T | 16.7% | 3.4% |
| 0/6 | 3/347 | 14/55 | N/T | 1/6 | 6/178 | |
First (in bold) line represents the percentage of susceptibility. Second line represents the number of susceptible isolates/number of tested isolates.
CRE, carbapenem-resistant Enterobacterales; N, number of isolates; N/T, Not tested.
Escherichia had higher susceptibility to imipenem and meropenem compared to the other bacterial genera (Enterobacter, Escherichia, and Citrobacter). On the other hand, Klebsiella had lower susceptibility to amikacin (37.7%) compared to the other bacterial genera. Meanwhile, susceptibility to gentamycin was close in Klebsiella and Escherichia (31.2% and 36.4% respectively). A total of 3% of Klebsiella, 12% of Escherichia, and 27.3% of Enterobacter were susceptible to ciprofloxacin, while 8.6% of Klebsiella, 20% of Escherichia, and 18.2% of Enterobacter were susceptible to trimethoprim/sulfamethoxazole. Susceptibility to ceftazidime/avibactam was not seen in all four tested Escherichia isolates (0%), while the susceptibility was 26.7% in Klebsiella and 33.3% in the three tested Enterobacter species (Table 4).
Table 4.
Antibiotic resistance among different bacterial species.
| Antibiotic | Genus | |||
|---|---|---|---|---|
|
Citrobacter
N = 7 |
Enterobacter
N = 27 |
Escherichia
N = 192 |
Klebsiella
N = 369 |
|
| Amoxicillin/clavulanic acid | N/T | 0% | 5.2% | 5.4% |
| N/T | 0/1 | 1/19 | 7/129 | |
| Amikacin | 100% | 86.2% | 80.3% | 37.7% |
| 7/7 | 25/29 | 151/188 | 137/363 | |
| Trimethoprim/Sulfamethoxazole | N/T | 18.2% | 20% | 8.6% |
| N/T | 2/11 | 4/20 | 11/128 | |
| Piperacillin/tazobactam | N/T | 0% | 11.5% | 9.0% |
| N/T | 0/11 | 3/26 | 12/133 | |
| Meropenem | 0% | 10.3% | 11.1% | 4.1% |
| 0/7 | 3/29 | 21/189 | 15/368 | |
| Imipenem | 0% | 6.7% | 18.0% | 4.8% |
| 0/1 | 1/15 | 11/61 | 9/186 | |
| Gentamycin | 100% | 64.3% | 36.4% | 31.2% |
| 1/1 | 9/14 | 20/55 | 48/154 | |
| Ertapenem | 0% | 3.6% | 3.1% | 3.0% |
| 0/7 | 1/28 | 6/191 | 11/365 | |
| Ciprofloxacin | N/T | 27.3% | 12% | 3% |
| N/T | 3/11 | 3/25 | 4/134 | |
| Chloramphenicol | N/T | 50% | 46.2% | 45.1% |
| N/T | 3/6 | 6/13 | 32/71 | |
| Ceftriaxone | N/T | 0% | 14.3% | 3.1% |
| N/T | 0/11 | 3/21 | 4/129 | |
| Ceftazidime/avibactam | N/T | 33.3% | 0% | 26.7% |
| N/T | 1/3 | 0/4 | 8/30 | |
| Ceftazidime | 0% | 3.4% | 8.9% | 1.4% |
| 0/7 | 1/29 | 17/192 | 5/369 | |
First (in bold) line represents the percentage of susceptibility. Second line represents the number of susceptible isolates/number of tested isolates.
N, number of isolates; N/T, not tested.
A regression analysis was also conducted as part of the data exploration process (Appendix 3).
Discussion
CRE prevalence was 2.4% overall and 20.62% among Enterobacterales-positive cultures. This is significant due to CRE’s resistance to multiple antibiotics, limiting treatment options and increasing mortality rates, while also posing transmission risks in hospitals. In Palestinian territories, a low-middle-income country, antibiotic stewardship remains limited and not very well practiced, leading to an increased risk of colonization or infection with multidrug-resistant pathogens. This likely accounts for the high CRE prevalence observed in our results. Other contributing factors provide further insight into this result, including the weakened immune system of the study’s population, which necessitates long-term hospitalization and recurrent antibiotic exposure, taking into account.
This study was conducted at AVH, which serves as a major tertiary referral center for oncology and nephrology patients with weakened immune systems from across the West Bank and Gaza. Its multidisciplinary team and advanced resources attract a heterogeneous patient population from various geographic regions and demographic backgrounds. This diversity contributes to the generalizability of our findings to a broader context, despite being based at a single institution.
Between 2019 and 2023, the prevalence of CRE rose from 1.12% to 3.84% of total cultures, and from 8.66% to 29.28% of total Enterobacterales. A significant increase was seen between 2021 and 2022 (Figure 1, Appendix 4), likely due to the COVID-19 pandemic, which strained hospital resources, led to gaps in IPC, and increased misuse of broad-spectrum antibiotics like meropenem, in addition to the lack of national regulations on antibiotics that contributes to rising resistance.
Our results show 70.28% (421/599) of carbapenemase detection from total CRE isolates (Table 2). Research suggests that C-CRE detected are more virulent than C-CRE detected, with more virulent genes associated with toxins and a greater ability to hydrolyze carbapenems. 13 Distinguishing between C-CRE detected and C-CRE not detected is crucial for effective clinical management and antibiotic selection, as C-CRE detected infections are less likely to respond to empirical antibiotics with higher mortality and poorer outcomes.14,15 Differentiating these resistance mechanisms is also vital for effective infection prevention measures, as C-CRE not detected are generally less transmissible than C-CRE detected, which are found on mobile genetic elements, allowing for faster transmission between patients. 16
bla NDM gene is dominating in our results (347/421, 82.4%), followed by bla OXA-48 (55/421, 13.1%) and the remaining (7/421, 1.66%) harboring bla NDM + OXA-48 and (6/421, 1.4%) for each of KPC and VIM genes. The majority of the carbapenemase genes were isolated in the last 2 years, which is consistent with the increase in CRE prevalence (Table 2). According to Center for Disease Control (CDC), most of the increase in CRE in the USA is related to the increase in the carbapenemase genes, which increases the transmissibility between bacteria and thus amplifies the spread of CRE. 17
Carbapenem-resistant Klebsiella (CR-K) was the most common isolate at 61.60%, followed by carbapenem-resistant Escherichia (CR-E) at 32.05%, supporting findings from Aeish et al. 2023 where 61.9% of CRE were Klebsiella species and 38.1% were Escherichia species (Table 2). 18 Enterobacter species were not common in our results with only (29/599, 4.84%) of CRE isolates. However, it is important to highlight that four out of six VIM genes were expressed by Enterobacter species.
The implementation of active surveillance is very critical in protecting the healthcare facility from MDROs and preventing outbreaks through early detection of asymptomatic carriers. At AVH, one of the few hospitals that have such an active policy in place, the majority of CRE cases—73.1% (438/599)—are detected from surveillance swabs. This reflects strong infection prevention measures and adherence to the CRE surveillance policy, while also placing an increased pressure on the healthcare personnel, particularly the IPC team that leads the efforts in the active surveillance, enforcing contact precautions, supporting AMS, staff training, outbreak response, and environmental cleaning.
Our results align with Aiesh et al. 2023, 18 which found 61.3% of CRE in rectal swabs. As for the clinical cultures, urine was the most common site for CRE isolation, which complement the results of other studies.19,20
CRE isolates were found across all age groups, but the majority (79.5%) occurred in adults, likely due to the higher number of Enterobacterales-positive cultures in that group (mean value = 0.824) (Appendix 2). The bla NDM gene was present in over half of the CRE isolates in adults and was the only gene found in neonates (Table 2). Our results differ from Han et al. 2020, who found that 70% of adult CRE isolates harbored bla KPC. 21 However, they align with Datta et al. 2016, identifying bla NDM as the sole carbapenemase gene in neonates. 22
CRE prevalence varies across Palestinian regions, with gene distribution differing geographically. The Gaza Strip and middle region show the highest rates. In Gaza, the high prevalence could be attributed to poor infrastructure, political instability, and limited resources. 23 The middle region's high CRE prevalence may be linked to 40% of Enterobacterales-positive cultures from patients there (Appendix 2). Certain genes, such as bla VIM, are more prevalent in the middle and south regions. Geographic variation may arise from antibiotic selection pressure, different prescription practices, and varying medical resources. Since no studies have explored these factors in Palestinian territories, further research is needed.
We mapped the geographic distribution of CRE isolates and linked them to referral hospitals. Markedly, 66% (278/421) of C-CRE detected isolates were from patients referred from public hospitals. bla NDM was the dominant gene in all referral settings; other genes were also most prevalent in public referral hospitals. These results could be justified by the lack of compliance and low implementation of IPC measures in public hospitals, either due to a lack of knowledge or educational programs. In addition, weak economy, political instability, poor public hospital infrastructure, and an overwhelmed health system may contribute to the spread of CRE.
In the Palestinian territories, antibiotics for treating CRE are limited and not available, making the treatment plan challenging and antimicrobial sensitivity testing essential. CRE were historically susceptible to aminoglycosides, but many now possess aminoglycoside-modifying enzymes that limit their effectiveness.24,25 At AVH, aminoglycosides are used to treat CRE infections if sensitivity exists, either alone or in combination with other antibiotics. Our study found that CR-K isolates were only 37.7% susceptible to amikacin and 31.2% to gentamycin, which are lower than the local results of Aiesh et al. 2023. 18 For the CR-E species, susceptibility rates were 80.3% and 36.4% susceptible to amikacin and gentamycin, respectively, which are close to the results of Aiesh et al. 2023. 18 At the molecular level (Table 3), our results show a 42.9%, 45.9%, and 50% susceptibility to amikacin in isolates that harbored bla NDM + OXA-48, bla NDM, and bla VIM, respectively, and higher susceptibility in isolates that harbored bla KPC and bla OXA-48 (66.7%, 68.6%, respectively). Instead, isolates that harbored bla KPC and bla NDM had the lower rates of susceptibility to gentamycin compared to other genes.
Ciprofloxacin and trimethoprim/sulfamethoxazole are limited as treatment options at AVH for sensitive CRE due to rising resistance. Our results show that CR-K isolates have 8.6% trimethoprim/sulfamethoxazole susceptible and 3% ciprofloxacin susceptible; CR-E shows 20% and 12% susceptibility, respectively (Table 4). These results are close to other studies.18,26 At the molecular level (Table 3), isolates that harbored bla NDM and bla OXA-48 were 12.5% and 27.3% susceptible to trimethoprim/sulfamethoxazole, respectively, while they were 4.4% and 25% susceptible to ciprofloxacin, respectively.
Novel β-lactams/β-lactamase inhibitors treat multidrug-resistant gram-negative bacteria, but resistance is emerging. 27 In our study, susceptibility to ceftazidime-avibactam was seen in 26.7% of CR-K 0% of the four CR-E that were tested, and 33.3% of the three tested carbapenem-resistant Enterobacter. Although the number of studied Escherichia and Enterobacterales is limited, it provides useful insight. Susceptibility to ceftazidime-avibactam was obvious in isolates that harbored bla NDM + OXA-48 (0%) but higher in those with bla NDM (5.6%) and bla OXA-48 (66.7%). Our results differ from a study showing lower CR-Klebsiella pneumonia resistance in cancer patients to ceftazidime-avibactam. 28
Colistin according to CDC is not recommended for treating infections caused by CRE; however, it could be used as an alternative agent for uncomplicated cystitis due to concerns about clinical effectiveness and concerns about accuracy of susceptibility testing. In AVH, colistin is used as a last resort when no alternatives are sensitive. Resistance to colistin was not included in the results because colistin susceptibility using the disk elution to all CRE isolates was introduced only in 2023.
Conclusion
CRE represents an escalating serious public health concern, emphasizing the urgent need to raise awareness about MDROs among healthcare providers and the general public to ensure appropriate antibiotic utilization. Additionally, there is a critical need for a systemic implementation of national AMS programs and for strengthening the IPC programs in the Palestinian hospitals.
Strengths and limitations
This is the first 5-year study on CRE molecular prevalence in Palestinian territories. Single-center results limit generalizability although our study includes patients from almost all the Palestinian territories; a multicenter study is needed. In addition, since our results were retrospective observational, we could not assess the cause of the difference in the numbers of susceptibility tested isolates. Moreover, the susceptibility percentage could be biased by the small number of tested isolates. Finally, annual antibiotic resistance trends were not evaluated.
Supplemental Material
Supplemental material, sj-docx-1-tai-10.1177_20499361251375354 for Prevalence, molecular carbapenemase detection, and antibiotic resistance of carbapenem-resistant Enterobacterales in a tertiary care hospital in East Jerusalem (2019–2023): a retrospective study by Lilian AbuHadba, Mousa Hindiyeh, Ali Sabateen, Sameh Hallaq, Anton Handal, Hammam Rjoub and Abeer Karmi in Therapeutic Advances in Infectious Disease
Supplemental material, sj-docx-2-tai-10.1177_20499361251375354 for Prevalence, molecular carbapenemase detection, and antibiotic resistance of carbapenem-resistant Enterobacterales in a tertiary care hospital in East Jerusalem (2019–2023): a retrospective study by Lilian AbuHadba, Mousa Hindiyeh, Ali Sabateen, Sameh Hallaq, Anton Handal, Hammam Rjoub and Abeer Karmi in Therapeutic Advances in Infectious Disease
Acknowledgments
The study was made possible with the full support of Bethlehem University and Augusta Victoria Hospital.
Footnotes
ORCID iDs: Lilian AbuHadba 
https://orcid.org/0000-0003-4840-6694
Mousa Hindiyeh
https://orcid.org/0000-0003-2191-0874
Sameh Hallaq
https://orcid.org/0000-0002-5118-5928
Hammam Rjoub
https://orcid.org/0009-0009-3615-7564
Abeer Karmi
https://orcid.org/0009-0003-6996-4051
Supplemental material: Supplemental material for this article is available online.
Contributor Information
Lilian AbuHadba, Birzeit University, Ramallah, Palestine; Bethlehem University, Bethlehem, Palestine.
Mousa Hindiyeh, Augusta Vitoria Hospital, East Jerusalem, Israel.
Ali Sabateen, Augusta Vitoria Hospital, East Jerusalem, Israel.
Sameh Hallaq, Al-Quds University, Jerusalem, Palestine.
Anton Handal, Caritas Baby Hospital, Bethelehm, Palestine.
Hammam Rjoub, Augusta Vitoria Hospital, East Jerusalem, Israel.
Abeer Karmi, Al-Quds University, Jerusalem, Palestine; Bethlehem University, Bethlehem, Palestine.
Declarations
Ethics approval and consent to participate: The study was approved by the Ethics Committee at Augusta Victoria Hospital, in coordination with Bethlehem University. Ethics approval number: 28/GLD/2023.
Informed consent was not sought for the present study, as the IRB waived it, since this is a retrospective study involving de-identified patient data from existing medical records and laboratory databases.
Consent for publication: Not applicable.
Author contributions: Lilian AbuHadba: Conceptualization; Data curation; Investigation; Methodology; Writing – original draft.
Mousa Hindiyeh: Conceptualization; Data curation; Investigation; Methodology; Resources; Validation; Writing – review & editing.
Ali Sabateen: Conceptualization; Data curation; Investigation; Resources; Writing – original draft.
Sameh Hallaq: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Software; Validation; Writing – review & editing.
Anton Handal: Data curation; Investigation; Resources; Software; Writing – original draft.
Hammam Rjoub: Data curation; Investigation; Resources; Software; Writing – original draft.
Abeer Karmi: Conceptualization; Investigation; Methodology; Project administration; Supervision; Validation; Writing – review & editing.
Funding: The authors received no financial support for the research, authorship, and/or publication of this article.
Competing interests: All authors declare that: (i) no support, financial or otherwise, has been received from any organization that may have an interest in the submitted work; and (ii) there are no other relationships or activities that could appear to have influenced the submitted work.
Availability of data and materials: Not applicable.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplemental material, sj-docx-1-tai-10.1177_20499361251375354 for Prevalence, molecular carbapenemase detection, and antibiotic resistance of carbapenem-resistant Enterobacterales in a tertiary care hospital in East Jerusalem (2019–2023): a retrospective study by Lilian AbuHadba, Mousa Hindiyeh, Ali Sabateen, Sameh Hallaq, Anton Handal, Hammam Rjoub and Abeer Karmi in Therapeutic Advances in Infectious Disease
Supplemental material, sj-docx-2-tai-10.1177_20499361251375354 for Prevalence, molecular carbapenemase detection, and antibiotic resistance of carbapenem-resistant Enterobacterales in a tertiary care hospital in East Jerusalem (2019–2023): a retrospective study by Lilian AbuHadba, Mousa Hindiyeh, Ali Sabateen, Sameh Hallaq, Anton Handal, Hammam Rjoub and Abeer Karmi in Therapeutic Advances in Infectious Disease