Epidemiology and clinical characteristics of patients with carbapenem-resistant enterobacterales infections: experience from a large tertiary care center in a developing country

Carbapenem-resistant Enterobacterales (CREs) are a dominant threat to patient health in healthcare settings worldwide. CRE strains consistently have limited therapeutic options, often associated with increased toxicities, and require prolonged treatment, leading to a higher cost burden than carbapenem-susceptible strains [9]. In this study, 61.9% of carbapenem-resistant isolates were K. pneumoniae. Compared to each other, 38.1% were E. coli, according to a study by Chotiprasitsaku et al. that showed that 70.7% of the isolated CRE were K. pneumoniae [10].

Furthermore, the results of a study that was conducted to evaluate the importance of performing active surveillance tests for CRE showed that the most commonly isolated strains were K. pneumoniae (83.16%), followed by Enterobacter cloacae (9.76%) and E. coli (4.38%) [11]. Furthermore, K. pneumonia was predominant in 25.4% of the isolates compared to 18.4% of E. coli [12].

The majority of patients who showed CRE-positive specimens were males (n = 13, 61.9%), with a median age of 51 years (IQR 24–64). These results are somewhat similar to those of Gomides et al., who found that the average age of CRE cases was 52.42 ± 19.34 years (range 13–97 years), and males were more predominant (65.31%) than females (1.88:1), with a higher discharge rate in our study (82.1%) than in this study (5.3%) [11].

The comorbidities of patients with CRE isolates varied. Among them, malignancy was the most common (n = 80, 36.7%), which is consistent with a study conducted in India that showed a high prevalence of CRE among cancer patients [13]. Other reported comorbid diseases in our study were hypertension (n = 62, 28.4%), diabetes mellitus (n = 51, 23.4%), chronic kidney disease (n = 19, 8.7%), and other comorbidities, such as hypothyroidism, end-stage renal disease, liver cirrhosis, heart failure, organ transplants, inflammatory bowel disease, and rheumatoid arthritis.

In our study, the onset of CRE acquisition was also investigated. 56% of the patients had CRE-positive samples in the first three days of admission, which is considered present on admission and may be attributed to other hospital visits, as the hospital setting of the study setting hospital is a tertiary health care institution that receives referrals from other hospitals in the West Bank and Gaza.

In addition, 36.7% of the patients were cancer patients with recurrent chemotherapy treatment visits. In children with malignancy, 56% of E. coli and 37% of isolated K. pneumoniae were CRE [14].

Due to the limited availability of treatment options, infections caused by CRE are often associated with high rates of morbidity and mortality. We studied patient outcomes in terms of crude mortality, defined as in-hospital death within 30 days of a CRE positive result. The 30-day all-cause mortality after CRE positivity was found to be 17.9%, which is consistent with a study conducted in China in which mortality among patients was 17.2% [15], while a study investigating 60-day all-cause mortality in a tertiary care hospital in Cuba resulted in a mortality rate [16]. However, the results of this investigation as a case series of CRE infections between 2011 and 2014 in Lebanon showed a mortality rate of 27.5% in the hospital, which was higher than our findings [17]. Several variables, including the primary site of infection and antibiotic use 24 h before CRE infection, were potentially associated with mortality. Additionally, the mortality group experienced many comorbidities, such as sepsis, unsuccessful treatments, and respiratory failure.

Active surveillance testing (AST) to detect CRE colonized patients for proper patient isolation purposes and, in some cases, empiric antibiotic selection is applied in this hospital as a facility-specific policy in which patients with a high risk of MDRO are eligible for the criteria of AST (i.e., referred from another hospital, admitted to any hospital for more than 48 h in the last six months, previous history of MDRO, upon admission to the ICU, then weekly, rectal swabs are repeated or as required by the infection prevention and control team). As part of AST, rectal swabs represented most CRE isolates. The finding of a high prevalence of CRE isolation from rectal swabs was consistent with a study conducted at a university hospital that rectal concluded that CRE colonization is very common in high-risk patients from the ICU and hematopoietic stem cell transplantation (HSCT) departments and predominant colonization of carbapenem-resistant K. pneumonia [18]. Understanding colonization as a critical step in infection progression provides a reason to detect colonized patients and potentially design intervention measures to avoid subsequent infection [19]. Approximately 40.6% of the CRE-infected patients in our study were colonized with CRE prior to developing infection compared to the 65% rate in the study by Xia Chen et al. [20]. Moreover, some data suggest that active surveillance tests performed on admission may play a role in preventing the spread of resistant gram-negative organisms in healthcare institutions with regard to widespread cross-transmission and outbreaks [21].

Regarding clinical specimens, urine was the most common source of CRE isolates (n = 38, 12.7%), which was consistent with the findings of Daniel et al. (31.8%) [22] and Moghnieh et al. (31% of cases were found in urine) [23]. In a pediatric study that described the demographics and clinical data of patients under one year who showed CRE growth, K. pneumonia was predominant (60.4%), and sputum (37.5%) was the most common clinical sample compared to urinary cultures (25%) [24]. However, in a Tunisian study evaluating the occurrence and characterization of CRE pathogens, the highest CRE rate was isolated from blood samples (28%), followed by anal swabs (21.5%) and urine samples (18.4%) [25]. The discrepancy in rates may be attributed to the early detection of CRE pathogens in the studied hospital through AST and early implementation of infection prevention measures that help prevent the spread of pathogens to sterile body sites and the development of infection.

Associated healthcare risk factors that improve CRE infection include prolonged hospitalization, the existence of invasive devices, attendance in high-risk units such as an ICU, and previous exposure to broad-spectrum antibiotics [26]. Our study identified some possible risk factors that other investigators highlighted [27]. We found that 68 cases of CRE were isolated from ICU patients, which comprises an overall prevalence of 31.1% of all CRE cases. This may be explained by the longer hospital stay in this category and greater utilization of medical devices and broad-spectrum antibiotics, exposing them to greater risk than patients in other departments. A study carried out in Gaza (a nearby area) revealed that the ICUs had the highest resistance rate of Enterobacteriaceae to carbapenem, with 52.9% of all isolated Enterobacteriaceae [28]. In Morocco, Delaguio et al. found that most of CRE was isolated from the neonatal unit (14%), followed by the departments of urology-nephrology (11%) and plastic surgery (10%) [29].

Gram-negative bacteria, particularly CREs, are among the world’s most significant public health problems as a result of their extensive antibiotic resistance. Only last-line antibiotics such as colistin, fosfomycin, and tigecycline were effective against most of these isolates [30, 31].

Patients received multiple antimicrobial therapies according to clinical culture and sensitivity results; therefore, patients who were colonized with CRE in the form of nasal or rectal swabs did not receive antibiotics, as they did not have signs and symptoms of infection. The swabs were performed as part of active surveillance and isolation purposes. Therefore, not all samples were tested for all antibiotics, as active surveillance samples are excluded from sensitivity testing according to microbiology and CLSI guidelines [8]. For CRE strains in colonized patients, Lin et al. showed that compared to K. pneumonia, E. coli was more susceptible to gentamicin (59.3% vs. 21.1%) and amikacin (87.0% vs. 45.1%) [32]. For therapeutic purposes in our study and according to the results guidelines and observational studies for the management of CRE infection, patients with CRE were managed with a combined regimen [31, 33]. It was shown that the most widely used antibiotic among our patients with CRE was colistin (13.3%), which is still considered a viable and key treatment option for CRE infections [34]; colistin was also found to be the cornerstone for CRE management in other studies [16]. Other treatment options offered to patients were amikacin (9.6%) and tigecycline (4.6%). Meanwhile, meropenem was administered as a high-dose and extended infusion protocol in 4.1% and gentamycin in 2.7% of the regimens. On the other hand, a study conducted in Dammam showed that 37% of the patients were treated with tigecycline as a targeted therapy, followed by colistin 28%, amikacin 21%, and gentamicin 11% (16).

Previously, aminoglycosides were highlighted as the main line in CRE treatment, since they could be the only antimicrobials to which CRE isolates showed in vitro sensitivity [35, 36]. However, high resistance rates to aminoglycosides have been reported in some studies in which only 20.4% of the CRE isolates were gentamicin susceptible [37]. Another study found that only 10.4% and 13.0% of CRE pathogens were susceptible to amikacin and gentamicin, respectively [38]. Furthermore, Wu et al. reported an amikacin resistance rate of 29% and a gentamycin resistance rate of 76% for isolated CRE [39]. However, our study showed higher susceptibility of CRE to amikacin and gentamicin, with differences between E. coli and K. pneumonia (76.2% and 33.6% for CR– E. coli and 35.1% and 53.1% for K. pneumonia, respectively). Concerning ciprofloxacin and trimethoprim-sulfamethoxazole (94%), a Bahraini study showed that 79% of all CRE isolates were resistant to trimethoprim-sulfamethoxazole, and 94% of the isolates tested were ciprofloxacin resistant [40]. This was in agreement with our study, which showed that 85.7% of the E. coli isolates were resistant to trimethoprim-sulfamethoxazole, while 74.1% of the K. pneumonia isolates showed resistance to trimethoprim-sulfamethoxazole. For ciprofloxacin, the highest resistance rate was observed with E. coli (66.7%), which was lower than that observed in an earlier Bahraini study [40] and then the rate reported in a Chinese study (95% for K. pneumoniae and 88% for E. coli) [39].

The minimum inhibitory concentration (MIC) of an antibiotic is defined as the lowest needed concentration of that antibiotic to prevent visible growth of bacteria or bacteria. Regarding the interpretation of meropenem MIC for E. coli and K. pneumonia and according to the CLSI breakpoints, when MIC exceeds 4 µg/mL, the bacteria are considered resistant to carbapenems [41]. Among the isolated samples, 85.7% of CR-E. coli had a MIC of more than 16 µg/mL, while 84.3% of the samples of CR-K. pneumonia showed a MIC of more than 16 µg/mL. A study on CRE in children with cancer found that all isolates were resistant to carbapenem, with a MIC  8 µg/mL in 153 (55%) [14]. Previously, it was common practice to treat CRE-causing infections with high meropenem MICs (8–16 mcg / ml) using extended-infusion meropenem in combination with another drug, often polymyxin or aminoglycosides [34]. However, subsequent observational and RCT data revealed that these regimens were associated with higher rates of mortality and nephrotoxicity compared to newer β-lactam-β-lactamase inhibitor agents to treat CRE infections. As a result, the IDSA panel’s most recent guidelines do not recommend the use of extended infusion carbapenems, with or without a second drug, to treat CRE when meropenem non-susceptibility is confirmed [42, 43].

Overuse and inappropriate use of broad-spectrum antimicrobials, which aid in the development of various resistance mechanisms by these pathogens, along with the lack of effective antibiotic stewardship programs, have helped hasten the cycle of emerging resistance; that is, the lack of well-established infection prevention and control practices are all factors that have contributed to the persistence and spread [44]. The increasing incidence of infections caused by Gram-negative bacteria from MDR creates substantial difficulty in optimal empirical antibiotic selection for critically ill patients [44]. Containing the spread of MDR gram-negative bacilli, predominantly CRE, is challenging, and the adoption of multimodal infection control care bundles is vital to prevent outbreaks and catastrophic sequela [45].

Strengths and limitations

Although this paper is the first in Palestine to study the topic of CRE isolates, our study has several limitations. First, it is a retrospective descriptive study in which data were collected from a single center that studied only two carbapenems-resistant species; thus, it may not be representative of other centers. Second, it did not assess the change in antibiotic resistance throughout the year or year over year. Finally, due to limited resources in developing countries, molecular testing for CRE is unavailable at our institution, and the results of colistin sensitivity were not feasible to collect during the study period.