ACLF is an acute deterioration of chronic liver disease characterized by multiple organ failure and high short-term mortality, with 3-month and 1-year mortality rates being 53.7% and 67.4%, respectively (22). ACLF patients are highly susceptible to BIs because these patients display sepsis-like immune paralysis (23–25).
BIs play a critical role in the development and progression of ACLF because they exacerbate the inflammatory reaction via pathogen-associated molecular patterns (PAMPs) in the body. BIs also trigger the occurrence of ACLF in patients with cirrhosis (2, 8). The systemic inflammatory response induced by BIs leads to multiple extra-hepatic organ failures and further increases mortality in patients with ACLF (26). A worse clinical course and a lower 90-day probability of survival (49%) or a higher short-term mortality by 2- to 4- fold was reported in ACLF patients with concurrent BIs (either at diagnosis or during follow-up) than ACLF patients without BIs (8, 27). Our results also showed that irrespective of the grade level, once BIs occurred, ACLF patients were prone to a lower transplant-free survival than those without BIs. At the same time, our study confirmed that the frequency of BIs increased with higher ACLF grades, varying from 47.6–90%. The clinical course was quite different between HBV-ACLF patients with and without BIs. Patients without BIs showed a 2-fold higher improvement proportion relative to patients with BIs. On the other hand, patients with BIs showed a 2-fold higher worsening proportion relative to patients without BIs. Thus, in this study, we demonstrated that the occurrence of BIs exerted a negative impact on the severity level, clinical course, and mortality in HBV-ACLF patients, which was consistent with previous studies (6, 8).
For about 7.7% of patients, BIs were recorded as a precipitating factor of ACLF in this study. On the other hand, as ACLF developed or progressed, the incidence of BIs increased. To be specific, the incidence of BIs was 25.2% in patients admitted to our hospital, while 45.2% of patients developed BIs after HBV-ACLF diagnosis, which was consistent with previous studies (8, 9). In this study, bacterial peritonitis (33.65%) was the most prevalent infection site, followed by pneumonia (25.96%). Bacterial peritonitis is one of the most common infections in ACLF patients varying from 21.1–34.5% and is associated with a high risk of developing irreversible renal failure and hepatorenal syndrome (6, 8, 28). Pneumonia (25.96%) was the second most common infection site in this study, and the frequency of pneumonia varied from 7.7–45.0% in previous studies (2, 6, 8). Bloodstream infection (2.88%) was less common in this study relative to other studies (28). In our study, the mortality according to different BI sites was 19.23% in bacterial peritonitis, 14.42% in multi-site infection, 13.46% in pneumonia, 7.69% in unproven infection, 1.92% in bloodstream infection, 0% in biliary tract infection, and 0% in other infection.
The increased intestinal permeability was the main cause of bacterial translocation in patients with cirrhosis, and Escherichia coli was the major translocating bacteria (29). There were 20 cases of bacteria isolated from 14 patients in this study, including 14 (70% of the culture-positive episodes) cases of gram-negative bacteria and 6 (30% of isolates) cases of gram-positive bacteria. Bacteria were isolated from the ascitic fluid in 8 (40% of isolates) cases, blood in 7 (30% of isolates) cases, urine in 3 (15% of isolates) cases, and sputum in 3 (15% of isolates) cases. Only one (5% of isolates) bacteria obtained from the urine of a patient without prophylactic antibiotic treatment was confirmed to be MDR E. coli. The MDR rate in our study was lower than other studies (2, 6, 8, 30). Fungi were isolated from three BIs cases, but fungal infections were not evaluated in this study.
In this study, the univariate and multivariate analyses confirmed that platelet count and prophylactic antibiotics were both independent negative prognostic factors of BIs. A lower platelet count usually existed in patients with cirrhosis, which also indicated the correlation between the severity level of HBV-ACLF and the prevalence of BIs. Notably, prophylactic antibiotics were an independent negative prognostic factor in this study, which suggested that prophylactic antibiotics protected HBV-ACLF patients from BIs. The positive influence of prophylactic antibiotics was also demonstrated by the improvement in the transplant-free survival probability in this study. Although the severity level of ACLF was closely related to the incidence of BIs, our study further analyzed and found that prophylactic antibiotics played an apparent protective role against BIs, irrespective of the severity of HBV-ACLF as compared with patients without prophylactic antibiotics. This makes sense because the application of prophylactic antibiotics was an important method to limit potential damage and prevent recurrence of infection (11). However, delayed initiation of antibiotics can lead to the loss of crucial time and worse outcomes in HBV-ACLF patients. Additionally, cirrhosis patients were at high risk of nosocomial infections. Thus, the early administration of prophylactic antibiotics could improve the patient’s prognosis (31).
Several factors, including epidemiological, local microbiological, and risk factors for MDR, need to be considered when it comes to initiating antibiotics (32). MDR bacterial infections were the main concern for the use of prophylactic antibiotics or inappropriate antibiotics and were usually isolated in the intensive care unit and nosocomial episodes. It has been reported that the prevalence of MDR bacterial infections in patients with decompensated cirrhosis and with ACLF increased from 29–38% in culture-positive infections from 2011 to 2017–2018 in Europe (33). MDR bacterial infections is a serious event related to lower resolution rates and higher short-term mortality (8, 34). Recent studies have also reported increasing prevalence of gram-positive bacteria (33, 35, 36). However, the most frequently isolated bacteria in this study were gram-negative bacteria, which was consistent with other studies (2, 12). Additionally, the frequency of the MDR in this study was lower than in previous studies (2).
Previous studies have demonstrated MDR-covering strategies to be effective, as they yield a higher infection resolution rate or a higher chance of microbiological susceptibility as compared to classical antibiotics strategies, especially in nosocomial infections and severe infections (12, 33). However, in a randomized clinical trial when the infection was not complicated by sepsis, the benefit derived from the use of broad-spectrum antibiotics was blunted (12). We also need to recognize the toxicity and risk of secondary infection due to the application of broad-spectrum antibiotics. Third-generation cephalosporins have been recommended as an appropriate first-line prophylaxis in advanced cirrhosis patients because of antibiotic effectiveness and low hepatic and renal toxicity (12, 37). Emerging studies have revealed that the efficacy of third-generation cephalosporins has been reduced due to the spread of MDR bacterial infections (13, 14, 31). However, evidence has also shown that third-generation cephalosporins, as first-line antibiotics, achieved a recovery rate of approximately 75% in SBP patients and cefotaxime was the first choice in community-acquired infections (6) (38). Our results also suggested that the antibiotic efficacy of third-generation cephalosporins was higher than MDR antibiotics, indicating that third-generation cephalosporins are more appropriate prophylactic antibiotics for HBV-ACLF patients. Although there was no significant difference in the efficacy between third-generation cephalosporins and MDR-covering agents—most likely due to the limited number of patients in this study—further studies are needed to confirm this finding.
The major limitation of this study was the small number of patients enrolled, and as a result, a lack of power to demonstrate the efficacy of prophylactic antibiotics. Additionally, this was a retrospective study. Adequately powered randomized controlled trials are needed to show a high level of evidence for the efficacy of prophylactic antibiotics in HBV-ACLF patients and to confirm the efficacy of third-generation cephalosporins in prophylactic treatment. Mortality and adverse events and other clinically important outcomes should also be evaluated.