Key words : Bacterial infections, Fungal infections, Liver failure, Prognosis, Viral infections

Introduction

Despite the significant advancements in liver transplant, infectious complications continue to be the leading cause of morbidity and mortality in liver transplant recipients. In fact, infections are reported as the most common cause of mortality following liver transplant in many centers.¹

After liver transplant, approximately 80% of patients experience at least 1 infection in the first year. The incidence of bacterial infections during the first 3 months posttransplant ranges from 14% to 75%, with nosocomial bacterial infections being the most common source of infection during the early period (usually within the first month).^2,3

Early diagnosis of infectious diseases is crucial in patients who undergo solid-organ transplant (SOT). This is because infectious diseases progress more rapidly and are more severe in immunocompro-mised patients compared with immunocompetent patients. However, immunosuppressive therapy often obscures the signs and symptoms of infection, making early detection challenging. Furthermore, drug interactions and toxicities as a result of polypharmacy can complicate the treatment of infections.⁴ Therefore, it is essential to take preventive measures against infection. In cases where infection is present, empirical treatment should be based on the local microbiological data of the transplant center.⁵

In this study, we aimed to evaluate the risk factors before, during, and after liver transplant that facilitate the development of infections and to reveal the epidemiological data of our transplant center. By doing so, we aim to identify preventable risk factors for infection development, evaluate morbidity and mortality, and determine the most appropriate empirical antimicrobial agents based on the epidemiological data.

Materials and Methods

Study population

This was a single-center retrospective, observational study performed from July 28, 2012, to February 24, 2020. We included patients aged ≧18 years who had undergone liver transplant using either deceased donors or living donors. Donors for living-donor liver transplant were first- or second-degree relatives of the respective recipients. Patients who died within the first 48 hours after transplant, those who underwent additional transplant procedures outside the liver, and those with incomplete data were excluded from the study. Ethical approval for the study was obtained from the Ethics Committee of Ankara City Hospital (decision number E1/340/2020; February 13, 2020).

Demographic, clinical, and laboratory data of patients undergoing liver transplant were obtained from several sources, including the pretransplant evaluation forms of liver transplant candidates and donors, follow-up forms after liver transplant, and hospital electronic medical records. In addition, microorganisms and antimicrobial resistance patterns isolated in healthcare-associated infections were accessed from the Infline software system using the National Health Service Associated Infections Surveillance Network.

Special follow-up forms were created for each patient to evaluate their sex, age, ethnicity, marital status, blood group, comorbid diseases, height, weight, the primary disease resulting in transplant, Model for End-Stage Liver Disease (MELD) score, serum albumin level before transplant, biochemistry, complete blood count, C-reactive protein, TSH, hemoglobin A1c, and hemostasis parameters.

The following parameters were also evaluated: pretransplant history of esophageal varices, abdo-minal ascites, encephalopathy, portal vein thrombosis, liver cirrhosis, and the presence or absence of hepatocellular carcinoma. We also evaluated left heart ejection fraction before transplant, duration of stay in the clinic and intensive care unit before and after transplant (in days), prophylactic antibiotics before transplant and their duration (in days), whether the transplanted liver was from a living or deceased donor, and whether there was an ABO blood mismatch between the liver transplant recipient and the donor. We also analyzed the transplant technique (Roux-en-Y or duct to duct), duration of transplant, whether a stent was placed in the bile duct during transplant, and whether vascular grafts were used. Other data collected included presence of posttransplant reoperation (undergoing abdominal surgery for any reason), type of infection (bacterial, viral, and fungal), source of infection (intra-abdominal, blood circulation), type of microorganism growing in samples taken from clinical materials, antibacterial resistance profiles, carbapenem and antifungal usage, 30-day and 6-month mortality, and donor age, sex, blood type, and cause of death.

Classification of infection and colonization

We evaluated infections that required hospitalization. We used the infectious disease definitions provided by the Center for Disease Control and Prevention (CDC) and the National Health Service Safety Network. These infections included urinary tract infections, surgical site infections, pneumonia, intra-abdominal infections, and bloodstream infections. Infections outside this group and with a specific origin were defined as “other infections.” For our study, we considered symptomatic urinary tract infection as a urinary tract infection. If there was bacterial growth in the blood culture due to skin contamination, we considered it a bloodstream infection if the same skin-contaminated bacteria grew in 2 or more blood cultures taken at different times, accompanied by symptoms.⁶ Clinical events in which the evaluating physician diagnosed the patient with an infection and initiated antimicrobial treatment, but the source of the infection could not be determined and the microorganism could not be isolated, were defined as “infection with an undetermined source.”

The culture and identification of microorganisms were conducted with the use of standard procedures, and the antibacterial susceptibility tests of the strains were conducted in accordance with the European Committee for Antimicrobial Susceptibility Testing.

For this study, bacteria classified as colonized or not classified by using the CDC and National Health Service Safety Network infection definitions were not included. We used the definition of multiple drug resistance (MDR) to assess the antibiotic resistance of bacteria. To establish an international standard terminology, we used the definition made by the CDC and the European Center for Disease Control and Prevention for MDR. According to this definition, MDR is when a microorganism is resistant to at least 1 drug in 3 or more antimicrobial categories, where each category is an effective antibiotic for the microorganism. These descriptions were made for Staphylococcus aureus, Enterococcus species, Enterobacteriaceae (except Salmonella species and Shigella species), Pseudomonas aeruginosa, and Acinetobacter species of epidemiological importance. Methicillin-resistant Staphylococcus aureus, carbapenemase-producing Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter species were considered as MDR microorganisms.⁷ Moreover, bacteria that secreted extended-spectrum beta-lactamases were labeled as ESBLs in terms of antimicrobial resistance profile. In our study, bacteria with positive ESBL release were included in the MDR microorganism group.

Each episode of infection was considered as an individual infection. If more than 1 microorganism was isolated in an episode of infection, it was classified as polymicrobial.

We categorized and evaluated infections that occurred after liver transplant into 3 groups. The first group (first month) included infections that developed within the first month after transplant, the second group (1-3 months) included infections that developed in the second and third months after the first month, and the third group (3-6 months) included infections that developed in the fourth, fifth, and sixth months.

We calculated the incidence of infection as ratio of patients who developed an infectious disease within a specific time period to the patient population included in the study. In our study, we evaluated the incidence of infection during the first month, first 3 months, and first 6 months.

Statistical analyses

We analyzed the obtained data using the IBM SPSS version 23 package program. For all statistical analyses, we considered P < .05 as significant, and we evaluated the relationships at a 95% confidence interval. The categorical data are expressed as frequency (percentage) and the continuous data as mean ± SD or median (minimum to maximum or range). We examined the suitability for normal distribution using the Kolmogorov-Smirnov test. We used logistic regression analysis to examine the risk factors affecting infections and Cox regression analysis to examine the risk factors affecting 1-month and 6-month mortality. We analyzed the relationships between categorical and numerical variables using the Mann-Whitney U test and Kruskal Wallis test. In contrast, we used the Fisher exact test and chi-square analysis to evaluate the relationships between categorical variables.

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Results

Recipient characteristics

We retrospectively examined the follow-up data of 118 patients who underwent liver transplant for 6 months posttransplant by using patient files and electronic medical records. After we excluded 2 patients because of lack of data and 3 patients who died within the first 48 hours and considered 1 patient only once because of retransplant, 112 patients were included in the study. Among these 112 patients, 67.9% (n = 76) were men, with a median age of 50 years (range, 20-66 y). Viral hepatitis-related liver cirrhosis was the most frequent indication for liver transplant (55.4%, n = 62), followed by cryptogenic liver cirrhosis and toxic hepatitis. The specific indications for liver transplant of recipients are presented in (Table 1).

Among included transplant recipients, 43% (n = 49) had at least 1 comorbid disease, with diabetes mellitus being the most common (35%, n = 22). In addition, 17% (n = 20) of patients included in the study had a previous infection within the month before transplant and received antibiotic prophylaxis appropriate to their specific infection.

Characteristics of donors

Our study included 112 living and deceased liver donors. Living-donor liver transplant procedures were performed with first- and second-degree relatives of the respective recipients. The mean age of the liver donors was 33.5 years (range 15-75 years), and 55.8% (n = 62) were male donors. Of 112 donors, 66.1% (n = 74) were living liver donors. Of the first-degree living donors, 14 were the recipient’s spouse, 4 were parents, 24 were children, and 15 were siblings. Among second-degree relative donors, 7 were cousins, 3 were uncles or aunts, and 7 were nephews. The main cause of death for deceased donors was intracranial hemorrhage (3.2%, n = 24).

Microbiological etiology of recipients

In the first 6 months after transplant, the incidence of infection was 71.4% (n = 80), with a total of 151 infection episodes. The most common cause of these infection episodes was unknown origin (n = 43, 28.4%), followed by intra-abdominal infections (n = 39, 25.8%) and pneumonia (n = 22, 14.5%). (Table 2) shows the infection rates that developed during 3 separate periods after transplant. Intra-abdominal infections were the most common infections in the first 1, 3, and 6 months of infection, and their source could be identified. The most common infectious agents were bacteria (n = 78, 95.1%), with Klebsiella species (n = 20, 25.9%), Acinetobacter species (n = 18, 23.3%), and Enterococcus species (n = 12, 15.5%) being the most frequently isolated microorganisms (Table 3).

The most frequently observed pathogens in the peritoneal fluid were Klebsiella species (7 of 26, 26.9%). Similarly, the pathogen distribution in blood culture revealed Klebsiella species (9 of 25, 36%) as the most commonly isolated, followed by Acinetobacter species (6 of 25, 24%). In diagnostic tracheal aspirate cultures, the most frequently observed pathogens were Acinetobacter species (5 of 10, 50%).

Antibiogram data were obtained for 72 of the 78 bacteria isolated from infection sites during the 6-month follow-up of patients. When antibiotic resistance profiles were evaluated, 52.8% (n = 38) were found to be MDR. Among the MDR bacteria, 52.6% (n = 20) were resistant to carbapenem and 39.5% (n = 15) were ESBL positive (Table 4). At any point during the 6-month follow-up, 58.9% (n = 66) of patients received carbapenem treatment. A significant relationship was found between carbapenem use and carbapenem-resistant bacterial isolation (P = .002).

Patients who had an infection in the month before transplant had a higher risk of MDR microorganism and carbapenem-resistant microorganism growth in the first and sixth months after transplant (odds ratio [OR] = 16.979, P = .007 and OR = 10.155, P = .027, respectively). However, there were no significant risk factors for mortality (OR = 2.441, P = .238 and OR = 3.458, P = .077) (Table 5).

Recipients in the infection group had significantly higher total bilirubin, creatinine, direct bilirubin, and international normalized ratio levels, longer preoperative and postoperative intensive care unit stay, and increased presence of encephalopathy than recipients in the group without infection. Factors affecting the development of infection at 1 and 6 months after transplant are shown in (Table 6) and (Table 7). When we examined risk factors for infection using binary logistic regression analysis as a univariable model, the analysis demonstrated that a high MELD score increased the risk of developing infection in the sixth month (OR = 1.066, P = .035).

During the first 6 months, 25.9% (n = 29/112 study patients) developed intra-abdominal infections. Patients who underwent longer operations and reoperations had a higher risk of developing intra-abdominal infections (OR = 1.5, P = .019 and OR = 6, P = .03 respectively). In the first 6 months posttransplant, 10 patients died. We observed a significant relationship between infection and mortality in the first month posttransplant (P = .048), but no significant relationship was observed between infection and mortality in the first 6 months (P = .173). Also, there was a significant correlation between mortality and isolating MDR bacteria and carbapenem-resistant microorganisms within 6 months (P < .001 and P < .001, respectively) (Table 8). However, assessment with Cox regression analysis showed that having an infection in the first month posttransplant and within 6 months did not constitute a significant risk factor for mortality (OR = 6.284, P = .081 and OR = 3.679, P = .217, respectively). Conversely, infections caused by MDR and carbapenem-resistant microorganisms within the first 6 months posttransplant were significant risk factors for mortality (OR = 16.459, P < .001 and OR = 13.638, P < .001, respectively).

Discussion

Infections in liver transplant recipients are significant factors in determining transplant success.⁸ In our study, although not all infections were risk factors for mortality when evaluated without categorizing them as mild or severe, infections caused by antibiotic-resistant bacteria were found to be a risk factor for mortality, consistent with the literature (P < .001). Several studies have demonstrated that severe infections caused by sepsis, bacteremia, fungal infection, and antibiotic-resistant bacteria increase mortality.^9-12

During the 6-month follow-up of our transplant recipients, a total of 151 infection episodes occurred, with 58.2% (n = 88) of these occurring in the first month. Our study findings align with those of other studies, which have shown that most infection episodes after liver transplant develop within the first month.^8,13,14 About 80% of patients who undergo liver transplant experience at least 1 episode of infection in the first year after transplant.¹⁵ Liver transplant recipients are more susceptible to infections compared with other SOT recipients because of the technical complexity of surgical procedures and abdominal surgery-related complications.^8,9 Most studies that have evaluated infections after liver transplant have reported “intra-abdominal infection” as the most common infection.^8,9,16 In our study, when infection episodes were evaluated based on infection sources, intra-abdominal infections were the most common among the infections in both the first month and the sixth month (33% and 36%, respectively), whereas pneumonia ranked second.

Bacterial infections are known to be the most common after liver transplant, but the incidence of bacterial infections varies among studies.^8,13,17 In our study, bacteria (n = 78, 95.1%) were the most frequently detected microorganisms, consistent with the literature. However, the incidence of bacterial infections was higher compared with the literature.

When bacterial infections were evaluated independently, 78 bacteria were isolated, with gram-negative bacteria the majority (80.7%, n = 63). Klebsiella species (n = 20, 25.9%) were the most frequently isolated bacteria. In different studies in the literature, gram-positive microorganisms were shown to be more frequently isolated in infections that develop in 1, 3, and 6 months after transplant.^18-21 In their study, Karapanagiotou and colleagues evaluated the intensive care unit follow-up of patients after transplant and found that gram-negative microorganisms were more common, with A baumannii being the most frequently isolated.²² In a study by Shi and colleagues, bacteremia in the first 6 months after liver transplant was evaluated, and gram-negative bacteria were more common (69.7%). The most frequently isolated bacteria were S maltophilia, Enterobacteriaceae, O anthropi, Pseudomonas species, and A baumannii.¹² The isolated bacteria vary depending on the local epidemiological data of the transplant center. Awareness of the epidemiological data of transplant centers will lead to rational, empirical treatment approaches and increase the success of treatment.

In SOT recipients, various factors related to the type of surgical procedure, hospitalization, and donor-related factors increase the risk of MDR microorganisms. Most bacterial infections in patients with SOT are healthcare-related and often involve MDR microorganisms that are acquired during hospitalization before or after transplant.²¹ In our study, 52.8% of the 72 isolated bacteria that had antibiotic sensitivity testing were MDR microorganisms, and the most common pattern was carbapenem resistance 20 (52.6%) isolates. Zhong and colleagues evaluated MDR gram-negative bacterial infections in the first 6 months after liver transplant and showed that 56% of the patients with isolated gram-negative bacteria were MDRs, with ESBL being the most common resistance pattern.²³ In a study evaluating bacterial antibiotic resistance in infections developed in chronic liver diseases, ESBL was found to be the most common pattern of resistance.²⁴ Depending on local epidemiological factors, MDR patterns may vary in different cities or among hospitals in the same city.

In a study evaluating bacterial infections in patients who underwent liver transplant between 2014 and 2018 in Turkey, Enterobacteriaceae were isolated in 34.5% of patients. The most frequently isolated bacteria among Enterobacteriaceae was Klebsiella species (61.2%), and all isolated Klebsiella species were shown to be positive for carbapenemase release.²⁵ According to Central Asian and Eastern European Antimicrobial Resistance Surveillance (CAESAR) 2018 data, the carbapenem resistance rate for Acinetobacter species and Klebsiella pneumoniae isolated from blood and cerebrospinal fluid in our country were 92% and 34%, respectively. Data from CAESAR showed an increase in carbapenem resistance in our country in 2018 compared with 2017.²⁶

In our study, the most common detection of carbapenem resistance among MDR microorganisms (52.6%) supports the problem of carbapenem resistance in our country. Carbapenem-resistant Acinetobacter species infection has been associated with high morbidity and mortality in SOT recipients.^27-29

In studies that only evaluated liver transplant, carbapenem-resistant Acinetobacter species infection has been shown to increase mortality.^30,31 In our study, 55% (n = 11) of the carbapenem-resistant microorganisms were Acinetobacter species and 30% (n = 6) were K pneumoniae. Carbapenem-resistant K pneumoniae (CRKP) has been an important cause of intensive care-acquired infections and has been shown to increase mortality, especially in SOT recipients.³²

Bergamasco and colleagues cited SOT as an independent risk factor for CRKP.³³ In a study evaluating 1249 patients who underwent SOT in China, 56% (n = 38) of 68 patients who developed an episode of K pneumoniae infection in the first 3 months after transplant had CRKP, and K pneumoniae infection was shown to increase mortality.³⁴ In our study, similar to the literature, the presence of carbapenem-resistant microorganisms increased mortality in liver transplant recipients. In parallel with the increase in carbapenem use, there has been an increase in the incidence of carbapenemase-producing K pneumoniae worldwide for the past 10 years.³⁵

Studies have shown that carbapenem exposure increases the release of carbapenemase in bacteria.^28,35-37 In 58.9% (n = 66) of our patients, carbapenem use was detected at any time during the 6-month follow-up period, and a statistically significant relationship was found between carbapenem exposure and carbapenem resistance. Because excessive use of carbapenems in empirical treatment leads to an increase in carbapenem resistance, our antibiotic treatment alternatives are decreasing in severe infections. Therefore, more rational use of carbapenems should be ensured in this patient group.

Our study found that pretransplant elevated creatinine and bilirubin levels, coagulation disorders, presence of encephalopathy, high MELD scores, history of infection in the last month before transplant, length of operation and presence of reoperation, and length of stay in the intensive care unit before and after transplant were significantly associated with infections.

The strength of our study is its importance in terms of showing the frequency of infections with MDR microorganisms after transplant and its effect on mortality. This study had several limitations. It was a retrospective study with a single-center design, and the sample size of liver transplant recipients was relatively small. These factors could have resulted in overestimations of the incidence of infections. Multicenter prospective studies would be more beneficial.

Conclusions

Multidrug-resistant infections are emerging as a potential cause of morbidity and mortality in liver transplant recipients. Our study found that MDR infections, particularly, carbapenem-resistant microorganisms, were statistically significant factors associated with mortality. As a result, infection control measures are crucial, especially for patients undergoing SOT.

Factors such as high pretransplant levels of bilirubin and creatinine in the recipient, presence of encephalopathy, impaired coagulation parameters, high MELD scores, long stays in the intensive care unit before and after the operation, and extended reoperation and operation times were associated with an increased risk of infection.

In cases of suspected infection in transplant recipients, initiating empirical treatment based on local epidemiological data would benefit both treatment success and rational antibiotic use. In addition, it would prevent antibiotic resistance.

References:

1. Baganate F, Beal EW, Tumin D, et al. Early mortality after liver transplantation: Defining the course and the cause. Surgery. 2018;164(4):694-704. doi:10.1016/j.surg.2018.04.039
   CrossRef - PubMed
   
2. Ayvazoglu Soy EH, Akdur A, Yildirim S, Arslan H, Haberal M. Early postoperative infections after liver transplant. Exp Clin Transplant. 2018;16 Suppl 1(Suppl 1):145-148. doi:10.6002/ect.TOND-TDTD2017.P36
   CrossRef - PubMed
   
3. Heldman MR, Ngo S, Dorschner PB, Helfrich M, Ison MG. Pre- and post-transplant bacterial infections in liver transplant recipients. Transpl Infect Dis. 2019;21(5):e13152. doi:10.1111/tid.13152
   CrossRef - PubMed
   
4. Fishman JA. From the classic concepts to modern practice. Clin Microbiol Infect. 2014;20 Suppl 7:4-9. doi:10.1111/1469-0691.12593
   CrossRef - PubMed
   
5. Pouch SM, Patel G; American Society of Transplantation Infectious Diseases Community of Practice. Multidrug-resistant Gram-negative bacterial infections in solid organ transplant recipients-Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33(9):e13594. doi:10.1111/ctr.13594
   CrossRef - PubMed
   
6. Horan TC, Andrus M, Dudeck MA. CDC/NHSN surveillance definition of health care-associated infection and criteria for specific types of infections in the acute care setting. Am J Infect Control. 2008;36(5):309-332. doi:10.1016/j.ajic.2008.03.002
   CrossRef - PubMed
   
7. Magiorakos AP, Srinivasan A, Carey RB, et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect. 2012;18(3):268-281. doi:10.1111/j.1469-0691.2011.03570.x
   CrossRef - PubMed
   
8. Kim YJ, Kim SI, Wie SH, et al. Infectious complications in living-donor liver transplant recipients: a 9-year single-center experience. Transpl Infect Dis. 2008;10(5):316-324. doi:10.1111/j.1399-3062.2008.00315.x
   CrossRef - PubMed
   
9. Lim S, Kim EJ, Lee TB, et al. Predictors of postoperative infectious complications in liver transplant recipients: experience of 185 consecutive cases. Korean J Intern Med. 2018;33(4):798-806. doi:10.3904/kjim.2017.230
   CrossRef - PubMed
   
10. Olivari D, Mainardi V, Rando K, et al. Risk factors of mortality after liver transplantation in Uruguay. Transplant Proc. 2018;50(2):499-502. doi:10.1016/j.transproceed.2017.12.036
    CrossRef - PubMed
    
11. Elkholy S, Mogawer S, Hosny A, et al. Predictors of mortality in living donor liver transplantation. Transplant Proc. 2017;49(6):1376-1382. doi:10.1016/j.transproceed.2017.02.055
    CrossRef - PubMed
    
12. Shi SH, Kong HS, Xu J, et al. Multidrug resistant gram-negative bacilli as predominant bacteremic pathogens in liver transplant recipients. Transpl Infect Dis. 2009;11(5):405-412. doi:10.1111/j.1399-3062.2009.00421.x
    CrossRef - PubMed
    
13. Chiereghin A, Petrisli E, Ravaioli M, et al. Infectious agents after liver transplant: etiology, timeline and patients' cell-mediated immunity responses. Med Microbiol Immunol. 2017;206(1):63-71. doi:10.1007/s00430-016-0485-7
    CrossRef - PubMed
    
14. Mukhtar A, Abdelaal A, Hussein M, et al. Infection complications and pattern of bacterial resistance in living-donor liver transplantation: a multicenter epidemiologic study in Egypt. Transplant Proc. 2014;46(5):1444-1447. doi:10.1016/j.transproceed.2014.02.022
    CrossRef - PubMed
    
15. Romero FA, Razonable RR. Infections in liver transplant recipients. World J Hepatol. 2011;3(4):83-92. doi:10.4254/wjh.v3.i4.83
    CrossRef - PubMed
    
16. Kim SI, Kim YJ, Choi JY, et al. Strategies to reduce infectious complication using epidemiologic data analysis in liver transplant recipients. Transplant Proc. 2013;45(8):3061-3064. doi:10.1016/j.transproceed.2013.08.072
    CrossRef - PubMed
    
17. Vera A, Contreras F, Guevara F. Incidence and risk factors for infections after liver transplant: single-center experience at the University Hospital Fundacion Santa Fe de Bogota, Colombia. Transpl Infect Dis. 2011;13(6):608-615. doi:10.1111/j.1399-3062.2011.00640.x
    CrossRef - PubMed
    
18. Antunes M, Teixeira A, Fortuna P, et al. Infections after liver transplantation: a retrospective, single-center study. Transplant Proc. 2015;47(4):1019-1024. doi:10.1016/j.transproceed.2015.03.009
    CrossRef - PubMed
    
19. Kawecki D, Chmura A, Pacholczyk M, et al. Bacterial infections in the early period after liver transplantation: etiological agents and their susceptibility. Med Sci Monit. 2009;15(12):CR628-637.
    CrossRef - PubMed
    
20. Kawecki D, Pacholczyk M, Lagiewska B, et al. Bacterial and fungal infections in the early post-transplantation period after liver transplantation: etiologic agents and their susceptibility. Transplant Proc. 2014;46(8):2777-2781. doi:10.1016/j.transproceed.2014.08.031
    CrossRef - PubMed
    
21. Gagliotti C, Morsillo F, Moro ML, et al. Infections in liver and lung transplant recipients: a national prospective cohort. Eur J Clin Microbiol Infect Dis. 2018;37(3):399-407. doi:10.1007/s10096-018-3183-0
    CrossRef - PubMed
    
22. Karapanagiotou A, Kydona C, Papadopoulos S, et al. Infections after orthotopic liver transplantation in the intensive care unit. Transplant Proc. 2012;44(9):2748-2750. doi:10.1016/j.transproceed.2012.09.004
    CrossRef - PubMed
    
23. Zhong L, Men TY, Li H, et al. Multidrug-resistant gram-negative bacterial infections after liver transplantation - spectrum and risk factors. J Infect. 2012;64(3):299-310. doi:10.1016/j.jinf.2011.12.005
    CrossRef - PubMed
    
24. Jain M, Varghese J, Michael T, et al. An insight into antibiotic resistance to bacterial infection in chronic liver disease. J Clin Exp Hepatol. 2017;7(4):305-309. doi:10.1016/j.jceh.2017.05.003
    CrossRef - PubMed
    
25. Cinar G, Kalkan IA, Azap A, et al. Carbapenemase-producing bacterial infections in patients with liver transplant. Transplant Proc. 2019;51(7):2461-2465. doi:10.1016/j.transproceed.2019.02.050
    CrossRef - PubMed
    
26. Organization WH. Central Asian and Eastern European Surveillance of Antimicrobial Resistance: Annual report 2018. 2018.
    CrossRef - PubMed
    
27. Liu H, Ye Q, Wan Q, Zhou J. Predictors of mortality in solid-organ transplant recipients with infections caused by Acinetobacter baumannii. Ther Clin Risk Manag. 2015 21;11:1251-1257. doi:10.2147/TCRM.S91277
    CrossRef - PubMed
    
28. de Gouvea EF, Martins IS, Halpern M, et al. The influence of carbapenem resistance on mortality in solid organ transplant recipients with Acinetobacter baumannii infection. BMC Infect Dis. 2012;12:351. doi:10.1186/1471-2334-12-351
    CrossRef - PubMed
    
29. Reddy P, Zembower TR, Ison MG, Baker TA, Stosor V. Carbapenem-resistant Acinetobacter baumannii infections after organ transplantation. Transpl Infect Dis. 2010;12(1):87-93. doi:10.1111/j.1399-3062.2009.00445.x
    CrossRef - PubMed
    
30. Kim YJ, Kim SI, Lee YD, et al. Carbapenem-resistant Acinetobacter baumannii bacteremia in liver transplant recipients. Transplant Proc. 2018;50(4):1132-1135. doi:10.1016/j.transproceed.2018.01.043
    CrossRef - PubMed
    
31. Zhang W, Wang W, Kang M, et al. Bacterial and fungal infections after liver transplantation: microbial epidemiology, risk factors for infection and death with infection. Ann Transplant. 2020;25:e921591. doi:10.12659/AOT.921591
    CrossRef - PubMed
    
32. Mouloudi E, Massa E, Piperidou M, et al. Tigecycline for treatment of carbapenem-resistant Klebsiella pneumoniae infections after liver transplantation in the intensive care unit: a 3-year study. Transplant Proc. 2014;46(9):3219-3221. doi:10.1016/j.transproceed.2014.09.160
    CrossRef - PubMed
    
33. Bergamasco MD, Barroso Barbosa M, de Oliveira Garcia D, et al. Infection with Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae in solid organ transplantation. Transpl Infect Dis. 2012;14(2):198-205. doi:10.1111/j.1399-3062.2011.00688.x
    CrossRef - PubMed
    
34. Wu D, Chen C, Liu T, Wan Q. Risk factors for acquisition of carbapenem-resistant Klebsiella pneumoniae and mortality among abdominal solid organ transplant recipients with K. pneumoniae Infections. Med Sci Monit. 2020;26:e922996. doi:10.12659/MSM.922996
    CrossRef - PubMed
    
35. Pan H, Lou Y, Zeng L, et al. Infections Caused by carbapenemase-producing Klebsiella pneumoniae: microbiological characteristics and risk factors. Microb Drug Resist. 2019;25(2):287-296. doi:10.1089/mdr.2018.0339
    CrossRef - PubMed
    
36. Kim SY, Jung JY, Kang YA, et al. Risk factors for occurrence and 30-day mortality for carbapenem-resistant Acinetobacter baumannii bacteremia in an intensive care unit. J Korean Med Sci. 2012;27(8):939-947. doi:10.3346/jkms.2012.27.8.939
    CrossRef - PubMed
    
37. Kang JS, Yi J, Ko MK, Lee SO, Lee JE, Kim KH. Prevalence and risk factors of carbapenem-resistant Enterobacteriaceae acquisition in an emergency intensive care unit in a tertiary hospital in Korea: a case-control study. J Korean Med Sci. 2019;34(18):e140. doi:10.3346/jkms.2019.34.e140
    CrossRef - PubMed