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Gram-negative multidrug-resistant organisms were dominant in neurorehabilitation ward patients in a general hospital in southwest China

This study aimed to investigate the prevalence of and risk factors for multidrug-resistant organism (MDRO) infection in the rehabilitation ward of a general hospital in Southwest China. We analyzed rehabilitation patients with nosocomial infections caused by MDROs from June 2016 to June 2020. MDRO infection pathogens and associated antibiotic resistance were calculated. Possible risk factors for MDRO-related infection in the neurorehabilitation ward were analyzed using chi-square, and logistic regression. A total of 112 strains of MDRO were found positive from 96 patients. The MDRO test-positive rate was 16.70% (96/575). Ninety-five MDRO strains were detected in sputum, of which 84.82% (95/112) were gram-negative bacteria. Acinetobacter baumannii (A. Baumannii), Pseudomonas aeruginosa (P. aeruginosa), and Klebsiella pneumonia (K. pneumonia) were the most frequently isolated MDRO strains. The logistic regression model and multifactorial analysis showed that long-term (≥ 7 days) antibiotic use (OR 6.901), history of tracheotomy (OR 4.458), and a low albumin level (< 40 g/L) (OR 2.749) were independent risk factors for the development of MDRO infection in patients in the rehabilitation ward (all P < 0.05). Gram-negative MRDOs were dominant in rehabilitation ward patients. Low albumin, history of a tracheostomy, and long-term use of antibiotics were independent risk factors for MRDO infection and are worthy of attention.

Multidrug-resistant organisms (MDROs) threaten the health patients under not only intensive care but also rehabilitation [1][2][3] . Patients admitted to the rehabilitation ward of our hospital (a 2000-bed general hospital) mainly have conditions affecting the central nervous system. Most of the patients are transferred from the Department of Neurosurgery and Critical Care Unit and have consciousness disorders, paralysis or impaired deglutition. Prolonged bed rest and long-term antibiotic use in these patients increase their vulnerability to bacterial infection 4 . Moreover, patients generally stay in rehabilitation centers for a long time and share rehabilitation training facilities. MDRO infections can easily occur and spread among these patients 5 .
A pilot study from Germany found that among MDROs, gram-negative, extended spectrum beta-lactamase (ESBL)-producing bacteria the highest prevalence rates among patients undergoing neurologic rehabilitation (10.2%) and geriatric rehabilitation (22.7%) 1 . Additional reports have found that the incidence of MDRO infections is increasing, and positive patients have a significantly higher burden than negative patients and attain fewer rehabilitative benefits 6,7 .
Recent studies from China investigated the profile and the antibiotic resistance patterns of MDROs in the intensive care unit (ICU) or among cancer patients 3,8 . However, there is a lack of systematic epidemiological investigations on nosocomial MDRO infections in rehabilitation wards of general hospitals in China. Therefore, the current study aims to investigate the microbiological profiles of and risk factors for MDRO infection in the rehabilitation ward of our hospital, which will provide valuable information for reducing the rate of MDRO infection in rehabilitation wards.
Statistical methods. The data were entered into Microsoft Office Excel 2016, and the results were analyzed using the Statistical Package for the Social Sciences (SPSS 20.0, Chicago, USA). Count data (%) were compared by Fisher's exact test or the chi-square test as appropriate. Fisher's exact test was used if the expected count in  www.nature.com/scientificreports/ any cell was less than five. Multivariate analyses were performed to evaluate the most important associations between risk factors and infection acquisition. Therefore, logistic multifactorial regression analysis was performed. The odds ratio (OR) and its corresponding 95% confidence interval (CI) 13 for each factor was calculated to identify the level of association between the risk factor and the acquisition of MDRO 14 . A P value less than 0.05 indicates a significant difference.
Ethics consideration. This study protocol was approved by the Ethics Committee of the Second Affiliated Hospital of Chongqing Medical University. All methods were performed in accordance with the relevant guidelines and regulations. As the data are anonymous, the requirement for informed consent was waived by the Ethics committee of the Second Affiliated Hospital of Chongqing Medical University.

Results
The origin of MDRO specimens. After excluded 58 patients from the 633 patients who meet the inclusion criteria, a total of 575 nosocomial infection patients were finally analyzed ( Fig. 1). Meanwhile, there was a total of 3125 patients admitted in the neurorehabilitation center. After eliminating duplicate strains and colonization, 112 strains of MDRO were found positive from 96 patients. The MDRO test-positive rate was 16.70% (96/575). Different types of specimens were positive for MDROs, of which sputum accounted for 84.82% (95/112) and urine accounted for 9.82% (11/112). We also analyzed the distribution of infection types in patients of both groups and the result showed there was no significant differences (Supplementary Table 1). This result indicated that lung infections in patients in the rehabilitation ward were quite common ( Table 1).  (Table 3). Similarly, the resistance of K. pneumoniae to several antibiotics was 100% (12/12),  (Table 3). As only one E. cloacae strain was isolated, calculating the percentage of antibiotic sensitivity seems not applicable. The results also supported the idea that MRSA was still sensitive to Tetracycline and Vancomycin in most cases (Supplementary Table 3).

Association between patient characteristics and infection with MDROs.
Finally, we analyzed the risk factors for MDRO-related infection in neurorehabilitation ward. The results showed that patients in the rehabilitation ward with a history of ICU stay, a low albumin level, a history of mechanical ventilation, presence of a tracheostomy, an indwelling urinary catheter, indwelling nasogastric intubation, and long-term antibiotic use and those who were male were more likely to develop MDRO infection than patients with nosocomial infection but not infected with an MDRO (Table 4). However, further analysis of the above risk factors in the logistic regression analysis revealed that a low albumin level, presence of a tracheostomy, and long-term antibiotic use were the only independent risk factors (P < 0.05) for the development of MDRO-related infectious in patients in the neurorehabilitation ward (Table 5).

Discussion
Antibiotic resistance is an ongoing major public health challenge worldwide. Studies have noted that the prevalence rates of risk factors for MDRO infection have increased in recent years 13,15,16 . Therefore, MDRO infections have been regarded as a global health priority. As the study was conducted in a neurorehabilitation center, patients with acquired brain injury comprised the main inpatient population in our study. Usually, transfer to the rehabilitation ward indicates that the patient's condition is relatively stable. However, neurologic injury patients (e.g., acquired brain injury patients) have an increased risk of infection due to injury-related immune deficits 17 , the accumulation of comorbid conditions 18 , prolonged hospital stay, and severe functional and cognitive dysfunctions that increase dependence on caregivers 19 . Additionally, the interactive nature of rehabilitation wards, such as shared therapeutic facilities and close contact with therapists/nurses, provides opportunities for communicable diseases to spread 20,21 .
Our investigation revealed that the prevalence of MDRO infection among nosocomial infection patients in the neurorehabilitation ward was 16.70%. Specifically, 95 MDRO strains were detected in sputum, of which 95.79% were gram-negative bacteria, with A. baumannii (accounting for 45.26%), P. aeruginosa (accounting for 36.84%), and K. pneumonia (accounting for 12.64%) being the most prevalent. In contrast, a previous review study reported that among MDROs, ESBL-producing Enterobacterales (71.6%) and carbapenem-resistant (CR) Enterobacterales (6.9%) were the most prevalent in Asia, while multidrug-resistant P. aeruginosa (5.4%), multidrug-resistant A. baumannii (15.0%), and C. difficile (26.1%) were the most prevalent in North America 13,22 . Therefore, different study populations may have different MDRO prevalence, patient populations, and antibiotic susceptibility profiles. Only 4 strains (4.21%) of MRSA were detected in our study. This is not surprising, as the prevalence of MRSA showed a markedly decreasing trend from 69.0% in 2005 to 35.3% in 2017 based on data from the China Antimicrobial Surveillance Network (CHINET) 23 . Additionally, in the study by Heudorf and colleagues, the MRSA prevalence was only 1.3% among patients undergoing neurologic rehabilitation 24 . Another reason might be because of the specimen composition. In this study, sputum samples accounted for over 90%  25 .
It should be noted that antimicrobial susceptibility varied among the gram-negative MDRO isolates. For example, A. baumannii was resistant to mainly piperacillin, cephalosporin, and carbapenems (Meropenem and Imipenem) but was susceptible to cefoperazone/sulbactams, tigecycline and sulfonamides. In contrast, P. aeruginosa was 100% resistant to tigecycline and sulfonamides and over 70% resistant to carbapenems. We also found that K. pneumoniae was 100% resistant to carbapenems, aztreonam, amikacin, levofloxacin, ceftriaxone, and piperacillin. In recent years, carbapenem-resistant gram-negative bacteria, especially multidrug-resistant K. pneumoniae, have emerged as a new threat causing both nosocomial and community-acquired infections worldwide. In a study in cancer patients, researchers found that the isolated gram-negative MDROs were primarily sensitive to meropenem, imipenem, and amikacin, while they were primarily resistant to aztreonam, cephalosporins, and fluoroquinolones 8 . This might be partly attributed to the different pathological characteristics of patients in neurorehabilitation and oncology centers. The proportion of K. pneumoniae with carbapenem resistance has increased rapidly in not only undeveloped areas but Europe and North America 15 . Since carbapenems are often considered last-resort antibiotics for severe K. pneumoniae infection, treatment will become difficult if carbapenem resistance develops. Zhu et al. found that exposure to carbapenems is one of the main risk factors (OR 4.16) for carbapenem-resistant K. pneumoniae infection 15 . Therefore, clinical expertise suggests that restricting the use of carbapenems is helpful in reducing the development of MDROs.
The analysis of risk factors revealed that patients in the rehabilitation ward with a history of ICU stay, a low albumin level, a history of mechanical ventilation, presence of a tracheostomy, an indwelling urinary catheter, indwelling nasogastric intubation, and long-term antibiotic use as well as those who were male were more likely to develop MDRO infection. Logistic regression further confirmed that a low albumin level, presence of a tracheostomy, and long-term antibiotic use were independent risk factors. Despite warnings regarding overuse, antibiotics are overprescribed worldwide. Based on our results, long-term exposure (> 7 days) to antibiotics is   www.nature.com/scientificreports/ more likely to induce multidrug resistance in rehabilitation patients than short-term exposure. This is consistent with Hanna Renk's study in ICU patients 26 . The reason might be that antibiotics remove antibiotic-sensitive competitors, leaving resistant bacteria behind to reproduce as a result of natural selection. Limiting antibiotic therapy when feasible and optimizing antibiotic use duration have the potential to enhance patient care while preventing multidrug-resistant infections 27 . Infection and malnutrition have always been intricately linked 28 . Albumin levels lower than 40 g/L were recognized as a risk factor for MDRO infection in our study. This is inconsistent with the results of Schoevaerdts's study in older patients 29 . As a result of inadequate protein and caloric intake in stroke patients with dysphagia 30 , hypoalbuminemia is quite common in the rehabilitation ward. Early studies noted that serum albumin plays a role in antiplatelet aggregation activity and antioxidant and anti-inflammatory processes 31 . Additionally, low albumin levels impair the immune system. A recent study reported that human serum albumin alters the expression of specific genes that promote the survival and persistence of A. baumannii 32 . Moreover, hypoalbuminemia increases the apparent total volume of distribution (V (d)) and clearance 33 of time-dependent antibacterial, which may result in a failure to achieve pharmacodynamic targets 34 . Therefore, a maintained nutritional supply is of utmost importance to ensure adequate albumin production, especially in dysphagia patients in the rehabilitation ward.
A recent meta-analysis showed that an endotracheal tracheostomy obviously increased the risk of multidrugresistant bacterial infection 35 . This was also confirmed in our study, as MDRO-related infection was 4 times more common in rehabilitation patients with a tracheostomy than in those without. Previous studies demonstrated that patients who had a tracheostomy were more likely to develop lung infection by P. aeruginosa and carbapenem-resistant Klebsiella, both of which are common MDROs 36,37 . The presence of a tracheostomy tube not only increases flow resistance and breathing effort but also impairs the heating and humidification of inspired air 38 . Consequently, ciliary function is damaged, and respiratory infection recurs. Decannulation is a milestone of physical recovery for patients after being transferred to the rehabilitation center 39 . Based on previous guidelines and experience, the sooner patients are decannulated, the less their risks for acquiring pneumonia and MDRO infection are 35,40 . Zivi et al. demonstrated that early mobilization plays a critical role in reducing the time to decannulation 41 . Moreover, sufficient respiratory muscle performance, cough efficacy, swallowing status, and consciousness supports the cannula removal process in most patients 38,39 . Therefore, comprehensive rehabilitation strategies, including secretion management, respiratory muscle training, airway clearance techniques, swallowing exercises and pharyngeal electrical stimulation, have been suggested for tracheotomized patients in clinical practice [42][43][44] .
In summary, the prevalence of nosocomial infection due to a MDRO was relatively high in rehabilitation patients in our study. The most frequently isolated pathogens were gram-negative A. baumannii, P. aeruginosa, and K. pneumonia. The limitation of this study was that data were obtained from only one hospital; thus, there is a possibility that other types of pathogens were neglected. We suggest effective hygiene management in rehabilitation wards, and physicians should consider the epidemiological characteristics of local resistance patterns when initiating antimicrobial treatment.

Data availability
The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.