Zhong Lin, Yang Jiayin | Multicenter Expert Consensus on the Diagnosis and Treatment of Multidrug-resistant Bacterial Infections after Liver Transplantation
update time:2025-02-18 Reading times: 49 +
update time:2025-02-18 Reading times: 49 +
Original work by Wang Shouping et al. Published in Journal of Basic and Clinical General Surgery of China
17:30, February 14, 2025, Sichuan Province
Wang Shouping1, 2, Wang Pusen3, Lü Tao1, Yang Jian1, Kong Lingxiang1, Xu Gang1, Song Jiulin1, Xie Kunlin1, Zhao Dong3, Que Weitao3, Huang Yiming3, Tang Jianxin3, Fang Taishi3, Jiang Zhongyi3, Gao Wei4, Dong Chong4, Chen Gang5, Zhu Lan5, Guo Wenzhi6, Tao Ruolin6, Fu Zhiren7, Song Shaohua7, Chen Changbin8, Wang Yuanyuan8, Yang Liang9, Li Guangming10, Yi Huimin11, Zhang Zhongwei2, Zhong Lin3, Yang Jiayin1
Wang Shouping, Wang Pusen, Lü Tao, Yang Jian, Kong Lingxiang, Xu Gang, Song Jiulin, Xie Kunlin, Zhao Dong, Que Weitao, Huang Yiming, Tang Jianxin, Fang Taishi, Jiang Zhongyi, Gao Wei, Dong Chong, Chen Gang, Zhu Lan, Guo Wenzhi, Tao Ruolin, Fu Zhiren, Song Shaohua, Chen Changbin, Wang Yuanyuan, Yang Liang, Li Guangming, Yi Huimin, Zhang Zhongwei, Zhong Lin, Yang Jiayin. Multicenter Expert Consensus on the Diagnosis and Treatment of Multidrug - resistant Bacterial Infections after Liver Transplantation. Journal of Basic and Clinical Hepatobiliary Surgery, 2025, 32(1): 1 - 8. doi: 10.7507/1007 - 9424.202501074
Zhong Lin, Professor, Doctoral Supervisor, Dean of the Institute of Organ Transplantation, Southern University of Science and Technology, Director of the Organ Transplantation Center and General Surgery Department of the Third People's Hospital of Shenzhen, Chief Scientist of the Key Research and Development Project (formerly 973) of the Ministry of Science and Technology of China for Transplantation Infections. Currently, he is a member of the Organ Transplantation Physician Branch of the Chinese Medical Doctor Association, a member of the Organ Transplantation Society of the Chinese Medical Association, Deputy Director of the Tumor Infection Professional Committee of the Chinese Anti - Cancer Association, and President of the Organ Donation and Transplantation Physician Branch of the Shenzhen Medical Doctor Association.
Yang Jiayin, Professor, Doctoral Supervisor, Director of the Organ Transplantation Center and General Surgery Department of West China Hospital, Sichuan University, Director of the Key Laboratory of Transplantation Engineering and Transplantation Immunology of the National Health Commission. He is a leading talent in scientific and technological innovation of the "National High - level Talent Special Support Program" and the chief expert of major projects of the Ministry of Science and Technology. Currently, he is the Vice - President of the Organ Transplantation Physician Branch of the Chinese Medical Doctor Association, a standing member of the Organ Transplantation Society of the Chinese Medical Association, Deputy Leader of the Liver Transplantation Group and Pediatric Transplantation Group of the Organ Transplantation Society of the Chinese Medical Association, President of the Sichuan Provincial Cancer Society, President of the Organ Transplantation Physician Branch of the Sichuan Provincial Medical Doctor Association, and Director of the Organ Transplantation Quality Control Center of Sichuan Province.
Liver transplantation is the most effective treatment for end - stage liver disease, and multidrug - resistant bacterial infection after liver transplantation is one of the important causes of death in liver transplant recipients. How to effectively identify and prevent and treat multidrug - resistant bacterial infections is the key to improving the quality of life of liver transplant recipients. West China Hospital of Sichuan University took the lead in organizing multiple medical centers across the country and combined with the mature experience in related fields at home and abroad to formulate the "Multicenter Expert Consensus on the Diagnosis and Treatment of Multidrug - resistant Bacterial Infections after Liver Transplantation" around the epidemiological characteristics of multidrug - resistant bacterial infections after liver transplantation, the treatment and selection of antibacterial drugs, and the prevention and control measures of multidrug resistance.
Liver transplantation is currently the only effective treatment for end - stage liver disease. With the vigorous development of surgical techniques, new immunosuppressants, tumor down - staging, peri - operative management, and infection prevention and control [1], the 1 - year survival rate after liver transplantation is close to 90%, and the 5 - year survival rate after transplantation exceeds 70% [2]. However, postoperative infection remains one of the main causes of graft dysfunction and death of liver transplant recipients [3 - 5].
Approximately 55% of liver transplant recipients will develop infections of varying degrees within 1 year after transplantation [6]. The 1 - year survival rate of recipients without postoperative infection can reach 90%, while that of recipients with infection is reduced to 67% [7]. Bacterial infection is the most common type of infection in liver transplant recipients after transplantation [6]. With the widespread use of antibacterial drugs, the drug resistance of bacteria has been continuously enhanced, especially multidrug - resistant organism (MDRO) infection, which has become one of the increasingly serious medical problems worldwide and seriously threatens the clinical outcomes of liver transplant recipients. Therefore, effectively preventing and treating MDRO infection in liver transplant recipients after transplantation has become the core problem to be solved urgently in the field of liver transplantation. Based on this, West China Hospital of Sichuan University, in cooperation with multiple medical centers across the country, has formulated the "Multicenter Expert Consensus on the Diagnosis and Treatment of Multidrug - resistant Bacterial Infections after Liver Transplantation".
The proportion of MDRO infection in bacterial infections among liver transplant recipients after transplantation is 50% - 70% [8]. The 30 - day, 90 - day, 180 - day, and 365 - day mortality rates of liver transplant recipients with MDRO infection are significantly higher than those without MDRO infection [9]. For example, the 60 - day mortality rate of liver transplant recipients with carbapenem - resistant Acinetobacter baumannii (CRAB) infection can reach 46.4% [10], and the 1 - year survival rate of those with carbapenem - resistant Klebsiella pneumoniae (CRKP) infection is less than 30% [7], which seriously affects the prognosis of liver transplant recipients. It has also been found that compared with common bacterial infections, MDRO infections after liver transplantation often have insidious onset, rapid progression, and high mortality, and most patients die of multiple organ failure caused by severe MDRO infection [10 - 13].
MDRO [14] refers to bacteria that are simultaneously resistant to three or more classes of commonly used clinical antibiotics, including pan - drug resistance and pan - sensitive resistance. When MDRO is detected after liver transplantation, it is necessary to comprehensively analyze whether it is a pathogenic bacterium or a colonizing bacterium. Only when it is a pathogenic bacterium can it be diagnosed as MDRO infection after liver transplantation.
Liver transplant recipients are extremely susceptible to pathogenic microorganisms, especially bacterial infections, due to factors such as liver function failure, long - term consumption of the primary disease, underlying diseases (such as diabetes), complex surgical operations, typical and atypical immunosuppressive states, and recipients of liver malignancies after down - staging through targeted and/or immunotherapy (who often require a high intensity of immunosuppression after transplantation). There are also infections such as fungi, viruses, and parasites.
According to the data of the China Antimicrobial Resistance Surveillance Network (www.chinets.com) from January to June 2024, the situation of bacterial resistance remains severe. The detection rates of carbapenem - resistant Gram - negative bacilli remain high. For example, the resistance rates of CRKP, carbapenem - resistant Escherichia coli (CREC), carbapenem - resistant Pseudomonas aeruginosa (CRPA), and CRAB to imipenem and meropenem are 18.2% and 18.6%, 3.1% and 3%, 22% and 17.7%, 73.1% and 72.7% respectively; the detection rate of methicillin - resistant Staphylococcus aureus (MRSA) is about 30%; the detection rate of vancomycin - resistant Enterococci (VRE) is also on the rise.
MDRO infections after liver transplantation include Gram - negative and Gram - positive bacterial infections, with Gram - negative bacterial infections being more common. Gram - negative bacteria [6, 15 - 16] mainly include CRAB, carbapenem - resistant Enterobacteriaceae (CRE, mainly including CRKP, CREC, etc.), extended - spectrum β - lactamases (ESBLs) - producing Enterobacteriaceae, CRPA, etc.; Gram - positive bacteria [9, 17] mainly include MRSA and VRE. The sources of MDRO infection include the donor, the recipient themselves, and the intensive care unit (ICU) environment. In recent years, the number of cases of donor - derived infection has gradually increased, especially MDRO infections such as CRKP, which mostly occur within 1 month after liver transplantation. The main infection sites are the lower respiratory tract, abdomen, and bloodstream, as well as the urinary system, wounds, etc., and multi - site infections can also occur [18 - 21]. This indicates that the situation of MDRO infection in liver transplant recipients after transplantation is severe.
The risk factors for MDRO infection after liver transplantation run through the entire peri - operative period (pre - operative, intra - operative, and post - operative) [9, 22 - 23]. Domestic and foreign studies [9, 16, 22 - 27] have found that the main risk factors for MDRO infection after liver transplantation include age, renal function, use of a large amount of immunosuppressants, pre - operative use of broad - spectrum antibacterial drugs, whether there is colonization or infection of drug - resistant bacteria before transplantation, model for end - stage liver disease score, liver function (coagulation time, hepatic encephalopathy, etc.), operation time, intraoperative blood transfusion volume, intraoperative blood loss, anhepatic period, endotracheal intubation time, nutritional factors, ICU stay time, and postoperative biliary complications.
The results of a Meta - analysis [24] showed that grade II - IV hepatic encephalopathy, renal insufficiency, patients with drug - resistant bacteria colonization before transplantation, implementation of tracheal intubation, use of antibacterial drugs before transplantation, and re - operation after transplantation are risk factors for MDRO infection after liver transplantation. The study by Wang Dong et al. [16] further elaborated that the risk of MDRO infection after liver transplantation increases 3.430 - fold when the postoperative tracheal intubation time is ≥ 48 h, and the risk of MDRO infection in patients with an ICU stay time of ≥ 7 d after transplantation increases 9 - fold. A retrospective, multicenter study by Martin - Mateos et al. [9] involving 960 liver transplant patients found that admission to the ICU 0 - 3 months before transplantation, infection with MDRO 0 - 3 months before transplantation, and an increase in the intraoperative transfusion volume of concentrated red blood cells are independent risk factors for MDRO infection. However, the current problem is that there is a lack of large - sample, multicenter studies to elaborate on the risk factors for MDRO infection after liver transplantation, and there is a lack of a MDRO infection prediction model for early warning and identification of high - risk patients.
Liver transplant recipients are more special (they often have combined liver - kidney and heart - lung insufficiency under the immunosuppressive state), and when their condition is critical, they may need advanced life - support technologies (including blood purification, artificial liver, extracorporeal membrane oxygenation, intra - aortic balloon counter - pulsation, etc.). These situations make the selection, dosage, impact on liver and kidney function, and pharmacokinetics of antibacterial drugs more complex.
The "three musketeers" of antibacterial drugs for the treatment of carbapenem - resistant Gram - negative bacilli (CRE, CRPA, CRAB, etc.) infections in clinical practice - tigecycline (tetracycline class), polymyxin (polypeptide class), and ceftazidime/avibactam (enzyme inhibitor combination) - still have certain problems in treatment. The "new three musketeers" - eravacycline, etc. (tetracycline class), SPR206, etc. (polymyxin B analogues), and cefepime/taniborbactam, etc. (new enzyme inhibitor combinations) - may provide new treatment options for carbapenem - resistant Gram - negative bacilli infections. However, currently, there is a lack of multicenter and large - sample studies on the treatment of MDRO infections, especially those covering the use of both the classic "three musketeers" and new antibacterial drugs (such as new tetracycline drugs).
Currently, for the treatment of MDRO infection after liver transplantation, the drug - use plan is selected according to the pathogen and the infection site. Commonly referred to guidelines or expert consensuses include: the "2024 Infectious Diseases Society of America (IDSA) Guidelines for the Treatment of Infections Caused by Antibiotic - Resistant Gram - Negative Bacteria" [28], the "Guidelines for the Diagnosis, Treatment, and Prevention and Control of Carbapenem - Resistant Gram - Negative Bacilli Infections" [29], the "Technical Specifications for the Diagnosis and Treatment of Drug - Resistant Bacterial Infections after Organ Transplantation (2019 Edition)" [30], the "2024 IDSA Clinical Practice Guidelines for Complicated Intra - abdominal Infections" [31], and the "Chinese Expert Consensus on the Management of Surgical Site Infections in Solid Organ Transplantation (2022 Edition)" [32].
Principles of antibiotic application [30]:
Klebsiella pneumoniae is one of the important opportunistic pathogens and nosocomial infection - causing bacteria.
Pseudomonas aeruginosa is widely present in nature and is also a common opportunistic pathogen in nosocomial infections.
ESBLs are enzymes that inactivate most penicillins, cephalosporins, and aztreonam. They are usually sensitive to carbapenems and do not inactivate non - β - lactam drugs (such as ciprofloxacin, sulfonamides, etc.). Any Gram - negative bacterium may carry the ESBLs gene, with Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, and Proteus mirabilis being the most common [46]. The treatment plan is shown in Table 3.
The preferred regimens are vancomycin, linezolid, daptomycin, and teicoplanin. The alternative regimens are tigecycline, ceftaroline, and telavancin.
The preferred regimens are linezolid and daptomycin. The alternative regimens are penicillin - based combination preparations (such as high - dose ampicillin - tazobactam, ampicillin - sulbactam, etc.) if sensitive to penicillins, teicoplanin (limited to the VanB genotype of VRE), and tigecycline.
With the assistance of clinical microbiology, determining the minimum inhibitory concentration of MDRO strains, rapidly detecting carbapenemases (including phenotypic and genotypic detection), and conducting combined drug - sensitivity testing can guide the precise antibacterial treatment of MDRO infections [31]. Phenotypic detection methods for carbapenemases include the Carba NP test, modified carbapenem inactivation test, ethylenediaminetetraacetic acid carbapenemase inactivation test, carbapenemase inhibitor enhancement test, and time - of - flight mass spectrometry. These methods mostly have disadvantages such as long time - consuming and complicated operation. Genotypic detection methods include enzyme - linked immunosorbent assay and molecular detection techniques. The traditional gene identification methods are PCR and DNA sequencing. The traditional PCR method requires a costly thermal cycling instrument, is complex to operate, and is time - consuming. The Sanger DNA sequencing method has high requirements for primer specificity, is expensive, and has complex post - data analysis. West China Hospital of Sichuan University, in collaboration with the team of Zhong Lin from the Third People's Hospital of Shenzhen, etc., has studied the Enzymatic Recombinase Amplification (ERA) technology and developed a kit for rapidly detecting five carbapenem - resistant genes, KPC, NDM, IMP, VIM, and OXA - 48, based on the ERA method. Currently, multi - center clinical trials are being carried out. At present, some new antibacterial drugs for MDRO infections have not been officially included in routine drug - sensitivity tests, which to some extent limits the selection of antibacterial drugs. At the same time, in medical institutions with the conditions, monitoring the blood concentration of antibiotics during their use is recommended, which helps to ensure the effective blood drug concentration of antibiotics and avoid adverse drug reactions, especially for drugs with a narrow therapeutic window (including polymyxins and aminoglycosides).
During anti - infection treatment, evaluate the recipient's infection control status, immune status, and the function of affected organs. Under the condition of ensuring good transplanted liver function and controllable infection, minimize and individually adjust the anti - rejection plan. If the infection is severe and life - threatening, immunosuppressants can be reduced or discontinued.
The effective implementation of infection control measures is of great significance for the prevention and control of MDRO infections. Hand hygiene, contact prevention, environmental hygiene cleaning, active screening, and antibacterial drug management are strongly recommended as basic measures for the prevention and control of MDRO infections at home and abroad [29, 47 - 48]. Some researchers [49] have also proposed establishing a multi - disciplinary collaboration team to standardize the prevention and control of MDRO infections, promoting informatization construction to form a closed - loop of infection control management, and implementing comprehensive and whole - process infection control management at the hospital and department levels under the guidance of a multi - disciplinary collaboration team, which helps to reduce the MDRO infection rate.
Sub - standard ward air quality will aggravate nosocomial infections in liver transplant wards.
Active screening, isolation, and other bundled measures are essential for the prevention and control of nosocomial MDRO infections. Usually, screening is carried out first, followed by isolation. Liver transplant recipients are a special group. When the liver is damaged, their ability to "capture" bacteria escaping from the intestine is reduced, leading to changes in their intestinal microbiome related to infection [50 - 51]. Therefore, routine active anal swab screening should be carried out, and fecal culture can also be used to detect drug - resistant bacteria. If the test result is positive, isolation in a single - room ward or a centralized ward is required, but there is currently no recommendation on whether to perform intestinal de - colonization.
Probiotics refer to some active microorganisms that are beneficial to the host. Common probiotics include lactic acid bacteria and Bifidobacterium. They help prevent infections, especially in the intestine, upper respiratory tract, etc., by regulating the balance of the intestinal flora, enhancing the intestinal barrier function, regulating the immune response, inhibiting the growth of pathogenic bacteria, and reducing antibiotic - associated diarrhea. West China Hospital of Sichuan University, in collaboration with the team of Zhong Lin from the Third People's Hospital of Shenzhen, etc., has independently developed a new type of probiotic and at the same time developed a probiotic capsule with independent intellectual property rights. Currently, multi - center clinical trials are being carried out.
With the advent of the big data era, artificial intelligence methods, especially prognostic prediction models constructed based on machine learning combined with clinical data, have powerful prediction capabilities and are increasingly being applied in the field of liver transplantation [52]. They have also shown good application prospects in predicting postoperative pulmonary infections and sepsis in liver transplant recipients [53 - 54]. However, the generalization ability of artificial intelligence prognostic prediction models still faces major challenges. Currently, there is no application of artificial intelligence in predicting MDRO infections after liver transplantation. In the future, it is necessary to build a database of liver transplant recipients across medical institutions and regions, develop an applicable MDRO infection prediction model, early identify liver transplant recipients at risk of MDRO colonization or infection, and achieve early intervention and precision medicine to improve the prognosis of transplant recipients.
MDRO infections after liver transplantation seriously affect the prognosis of liver transplant recipients and pose great challenges to clinical treatment. Through new rapid detection technologies such as ERA, early identification of MDRO - infected or colonized patients, timely use of antibiotics, and precise treatment combined with drug - sensitivity and enzyme type. In the future, new technologies such as artificial intelligence data analysis and supervision, laser air disinfection and sterilization, and new intestinal probiotics are needed to reduce the incidence of MDRO infections and improve the prognosis of liver transplant recipients.
Important statements and references are omitted.