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Consensus and Guideline

Expert Consensus on Diagnosis and Treatment of End-Stage Liver Disease Complicated with Infections

Ning, Qin1,∗; Chen, Tao1; Wang, Guiqiang2,∗; Xu, Dong1; Yu, Yanyan2; Mao, Qing3; Li, Taisheng4; Li, Lanjuan5; Li, Jun6; Lu, Xiaoju7; Li, Jiabin8; Li, Zhiwei9; Zhang, Wenhong10; Xiao, Yonghong5; Meng, Qinghua11; Mi, Yuqiang12; Shang, Jia13; Yu, Yunsong14; Zhao, Yingren15; Zhao, Caiyan16; Zhao, Hong2; Huang, Jianrong5; Peng, Jie17; Tang, Hong7; Tang, Xiaoping18; Hu, Jinhua19; Hu, Bijie20; Guo, Wei1; Zheng, Bo21; Chen, Baiyi22; Zhang, Yuexin23; Wei, Jia24; Sheng, Jifang5; Chen, Zhi5; Wang, Minggui10; Xie, Qing25; Wang, Yuming3; Wang, Fu-Sheng19; Hou, Jinlin17; Duan, Zhongping26; Wei, Lai27; Jia, Jidong28;  Chinese Society of Infectious Disease of Chinese Medical Association

Editor(s): Wang, Haijuan

Author Information
Infectious Diseases & Immunity: July 2022 - Volume 2 - Issue 3 - p 168-178
doi: 10.1097/ID9.0000000000000055
  • Open

Abstract

Introduction

End-stage liver disease (ESLD) was first introduced in the 1980s but with no accurate definition.[1] To date, no consensus or guidelines for the diagnosis and management of patients with ESLD complicated by infections have been established. This consensus, raised mainly by experts from the Society of Infectious Diseases, Chinese Medical Association, provides data on principles as well as working procedures for the diagnosis and treatment of ESLD complicated by infections.

Definition of ESLD

The main feature of ESLD is that the liver function cannot meet the physiological needs of the body. Based on the hepatic morphology and function, ESLD refers to the end stage of chronic liver disease, regardless of etiology, with advanced liver injury, dysfunction, and decompensation. Its clinical disease forms include acute-on-chronic liver failure (ACLF), acute decompensation of liver cirrhosis, chronic liver failure (CLF), and decompensated hepatocellular carcinoma [Figure 1].[2,3] Infections in patients with ESLD are one of the most frequent complications that trigger and cause profound inflammation, extrahepatic organ dysfunction or failure, and eventually a marked increase in mortality.[4]

F1
Figure 1:
The main feature of ESLD is that the liver function cannot meet the physiological needs of the body. Based on the hepatic morphology and function, ESLD refers to the end stage of chronic liver diseases, regardless of etiology, with advanced liver injury, dysfunction, and decompensation. Its clinical disease forms include ACLF, ADC, CLF, and decompensated hepatocellular carcinoma. ACLF: Acute-on-chronic liver failure; ADC: Acute decompensation of liver cirrhosis; CLF: Chronic liver failure; ESLD: End-stage liver disease.

Epidemiology

Infections in patients with ESLD commonly occur in the abdominal, respiratory, biliary, and urinary tracts as well as in gastrointestinal, skin, and soft tissues. Local infections can progress to the bloodstream when appropriate treatment is not applied.[5] Spontaneous bacterial peritonitis (SBP) and pneumonia are two major types of infection in patients with ESLD.[6]

The pathogens mostly detected in patients with ESLD are Escherichia coli (25.9%–27.4%), Staphylococcus spp. (22%–23.4%), Pneumonia pediococcus (12.5%–13.7%), Enterococcus spp. (16.6%–23.9%), anaerobic bacteria (6.2%–7.8%), and fungi, including Candida (15%–17.1%). The pathogens causing abdominal infections include E. coli, Klebsiella pneumoniae, Staphylococcus aureus, Enterococcus faecium, Enterococcus faecalis, and occasionally, Mycobacterium tuberculosis.[7] Opportunistic pathogens are common in respiratory infections, and these include Pseudomonas aeruginosa, S. aureus, and fungi, including Candida and Aspergillus.[8]

Nosocomial infections are also relatively common in patients with ESLD owing to their immune defects, with an increasing incidence of carbapenem-resistant K. pneumoniae and Acinetobacter baumannii infections.[9]

Recommendation 1

Qualified medical organizations should establish an in-hospital pathogen monitoring system and clarify the prevalence of pathogens and drug resistance, which can guide empirical antibacterial treatment.

Pathogenesis

The pathophysiological characteristics of ESLD are markedly hampered liver function, liver microcirculation disturbance, local and systemic inflammatory responses, immune paralysis and disorders, and intestinal microecological imbalance, which are systemic risk factors for infection. The immune defects of systemic inflammatory response syndrome (SIRS), compensated anti-inflammatory response syndrome (CARS), and mixed antagonist response syndrome (MARS) play key roles in the development of infection in patients with ESLD. The ESLD-associated cascade of inflammatory cytokine storms, such as interleukin (IL)-6, IL-10, IL-8, IL-1α, tumor necrosis factor alpha (TNF-α), fibrinogen-like protein 2, monocyte chemotactic protein 1, and interferon γ, promotes the occurrence of infection.[10,11]

Procalcitonin (PCT) and C-reactive protein (CRP) are acute-phase serum proteins. The predictive power of the levels of CRP and PCT for detecting infection has been found to be similar in patients with and without cirrhosis. Elevated serum levels of PCT and CRP are correlated with the presence, course, and outcome of sepsis in patients with cirrhosis in the general population.[11]

Recommendation 2

The presence of SIRS, CARS, and MARS facilitates the prediction of infection in patients with ESLD. Changes in the levels of PCT, CRP, TNF-α, and IL-2 could reflect the infection stages.

Clinical manifestations

Abdominal infection

SBP is the most frequent abdominal infection in patients with ESLD, which may be asymptomatic or mildly symptomatic with abdominal distention with or without low-grade fever.[12] Fungal peritonitis is commonly observed in patients with compromised immunity and long-term use of broad-spectrum antibacterial drugs or glucocorticoids.[13] Diagnosis of tuberculous peritonitis (TBP) should be considered when conventional anti-infective treatment is ineffective. TBP may manifest as increased flexibility of the abdominal wall, with a large amount of ascites.[14]

Respiratory infection

Fever, cough, and sputum production are the major symptoms of respiratory infections, with or without rapid progression. Pulmonary fungal infections show polytropic symptoms and an occult onset, especially in patients who have been treated with antibiotics. Fever, cough, jelly-like sputum, and bloody sputum are specific to pulmonary aspergillosis infections.[15]

Biliary tract infection

The clinical manifestations of biliary tract infections are often atypical, and bacteriological confirmation is difficult to obtain. Pain in the upper abdomen or right upper abdomen, fever, nausea, vomiting, belching, acid reflux, and bloating are frequent symptoms.[16]

Gastrointestinal infection

Gastrointestinal infections in patients with ESLD have multiple clinical manifestations with a wide variety of pathogens, including diarrhea, abdominal pain, watery stools, or increased stool frequency.[15,17]

Urinary tract infection

Patients with ESLD complicated by upper urinary tract infections often show systemic symptoms, such as fever and chills, with or without accompanying back pain in the kidney area or the ureteral point. Patients with lower urinary tract infections usually complain of urethral irritation, such as frequent urination, urgency, dysuria, and discomfort. Changes in urine properties, including turbidity, odor, and gross hematuria, are often observed.[18,19]

Bloodstream infection (including catheter-related infection)

Primary and secondary bloodstream infections are classified according to whether the pathogens originate in the bloodstream or secondary to other local sites. Secondary bloodstream infections include pneumonia, urinary infections, peritonitis, and cellulitis. Catheter-related bloodstream infection is a common primary bloodstream infection in patients with ESLD. When blood stream infection occurs within 72 hours of catheter indwelling, the primary type should be considered. Fever and chills are the typical clinical manifestations.[20]

Skin and soft tissue infection

Skin and soft tissue infections are common in patients with ESLD. The main manifestations include redness, skin damage, and pressure sores.[15,21]

Other infections

Intracranial infection rarely occurs in patients with ESLD, with few reports of bacterial meningitis. Fever, headache, vomiting, and loss of consciousness are the main symptoms.[22]

Tibiofibular periostitis is uncommon and presents with local pain, swelling, and tenderness.[23]

Endocarditis shows non-specific systemic symptoms, such as hypothermia, fatigue, appetite loss, and weight loss. Heart murmurs can also be observed.[24]

Endophthalmitis manifests as eye pain, photophobia, tearing, blurred vision, conjunctival hyperemia, markedly reduced visual acuity, and flaky or blocky floating objects in the eye chamber.[25]

Recommendation 3

The clinical manifestations of ESLD complicated by infections at various sites are often atypical and require careful consultation and physical examination for accurate and early diagnosis.

Diagnosis

High-risk factor assessment and clinical manifestation

The risk factors include immune dysfunction, genetic susceptibility, and intestinal bacterial ectopic and iatrogenic elements.[6] The symptoms were presented in the clinical manifestations section above.

Laboratory examination

Infections can be diagnosed on the basis of the peripheral blood leukocyte count and classification and PCT and CRP levels. Interferon gamma release assay is helpful for diagnosing tuberculosis and the 1-3-β-D glucosidase test and Galactomannan test for diagnosing fungal infections. Routine tests for hydrothorax and ascites are recommended to localize infection sources.[4,8,26] The levels of cytokines, such as IL-6 and TNF-α, are expected to be useful in the diagnosis of ESLD complicated by infection and monitoring disease progression.[6,27]

Imaging examination

Ultrasonography, radiography, computed tomography, and magnetic resonance imaging can be used for clinical diagnosis.

Pathogen identification

Pathogens should be appropriately cultured in secretions, body fluids (pleural fluid, ascites fluid, and joint fluid), blood, bone marrow, or tissues in the early stages. Although the rate of positive ascites culture is relatively low, it is recommended to perform ascites culture before antibiotic administration. Blood culture bottles, including aerobic and anaerobic cultures, should be used for ascites culture. Neutrophil ascites is a variant of SBP that shows a negative ascites culture. The second-generation sequencing method can screen and identify a variety of bacteria by analyzing DNA extracted from tissues, swabs, and aspirates.

Recommendation 4

The diagnostic procedures include comprehensive assessment of high-risk factors, confirmation of symptoms and signs, and use of laboratory tests, such as imaging examinations and pathogenic tests. Timely collection of tissues, body fluids, blood, and other specimens for pathogen cultures should be emphasized.

Management

Nutritional treatment

Risk screening. Nutritional screening tools, such as the NRS-2002, are recommended for screening the nutritional risk.[28]

Assessment. Body composition examination, imaging technique examination, grip strength examination, and other techniques, such as subjective global assessment, Royal Free Hospital-Global Assessment, and nutritional assessment for liver disease, are recommended.[29]

Intervention. Patients who cannot swallow and chew food should start tube feeding within 24 to 48 hours after admission.[30] Supplemental parenteral nutrition should be provided when enteral nutrition is unreachable or the amount of intake is less than 60% of the basal energy expenditure.[31] Light-digestible food is preferred, with four to six meals per day. Late-night extra meals of carbohydrate-rich foods are recommended.[32] The energy supply for patients with ESLD complicated by infection is suggested to range from 25 to 35 kcal·kg−1·day−1. The protein or amino acid supply is recommended to range from 1.2 to 1.5 g·kg−1·day−1. The protein intake of patients with hepatic encephalopathy is suggested to range from 0.5 to 1.2 g·kg−1·day−1. After alleviation of hepatic encephalopathy, 0.5 g·kg−1·day−1 to the standard amount can be supplied with oral branched-chain amino acids.[33,34] In all cases, hypoglycemia and vitamin deficiencies should be carefully treated.[35]

Hepatoprotective treatment

Hepatoprotective agents include glycyrrhizin acid derivatives, polyene phosphatidylcholine, glutathione, N-acetylcysteine, silymarin, S-adenosylmethionine, and ursodeoxycholic acid. In general, the administration of one to two hepatoprotective agents with different working mechanisms is recommended.

Immunomodulatory treatment

Albumin considerably increases the survival of patients with cirrhosis combined with SBP, but without any other bacterial infections beyond abdominal infection.[36,37]

Gamma globulin rapidly increases the level of serum IgG, which could potentially neutralize bacterial endotoxins, increase anti-inflammatory mediators, and enhance the host ability of antibiotics.[37]

Thymosin α1, alone or in combination with ulinastatin, markedly reduces the 28-day mortality in patients with sepsis. It decreases the incidence of infection in patients with ACLF, CLF, and cirrhosis with SBP.[38,39] Although granulocyte-macrophage colony-stimulating factor cannot considerably improve the prognosis of patients with sepsis, it may reduce the incidence of secondary infections.[40] Granulocyte colony-stimulating factor may improve the short-term survival of patients with liver failure.[41] The benefits of glucocorticoid treatment in patients with ESLD complicated by infections are inconclusive, and such treatment may potentially lead to the spread of infection; thus, careful monitoring is required when applied.[41,42]

Etiological treatment

For hepatitis B-related ESLD, strong and high resistance barrier nucleoside (nucleotide) analog antiviral therapy, including entecavir and tenofovir, is recommended; it improves short-term mortality by rapidly reducing the HBV DNA load and relieving immune injury.[43] If direct antiviral therapy is required in patients with HCV-related ESLD, an appropriate direct antiviral agent (DAA) therapeutic regimen should be selected by evaluating the liver and kidney functions and the interaction between drugs.[44] For alcoholic-origin ESLD, patients should abstain from alcohol consumption as soon as possible and be treated with metadoxine.[45]

Recommendation 5

Nutritional support and hepatoprotective treatment reduce the infection risks and promote recovery in patients with ESLD.

Recommendation 6

Albumin, gamma globulin, and thymosin α1 can be administered via appropriate methods in patients with ESLD complicated by infection.

Recommendation 7

Glucocorticoid treatment should be evaluated with caution in patients with severe infections.

Recommendation 8

Entecavir or tenofovir is recommended as an anti-HBV treatment for HBV-related ESLD, in which renal function should be closely monitored. Tenofovir is not recommended for patients with renal or kidney injuries. DAA therapeutic regimens should be selected on the basis of the liver and kidney functions and the interaction between drugs in patients with HCV-related ESLD.

Antibiotic treatment

Before evaluating the antibiotic susceptibility of pathogens, empirical antibiotic treatment should be determined according to the infection sites, clinical manifestations, pathogen source (nosocomial or community-acquired infection), antibiotic history, response to previous treatments, local bacterial prevalence, and monitored drug resistance data. During the process of empirical antibiotic treatment, the surveillance of indicators, such as inflammatory factors and laboratory test findings, facilitate the evaluation of the efficacy and adjustment of therapeutic strategies. As soon as the pathogenic data are obtained, empirical antibiotic treatment should be altered to targeted antibiotic treatment. For patients with inconclusive pathogenic data, further detection of pathogens or adjustment of empirical antibiotic treatment should be adopted according to the efficacy of treatment and disease progression.

Abdominal infection

SBP. When SBP is diagnosed, active elimination of ascites (release of ascites, diuresis, and supplementation with albumin) and empirical antibiotic therapy should be initiated. Empirical antibiotic treatment should cover potential SBP-related pathogens (E. coli, K. pneumoniae, and Enterococcus spp.), and the pharmacokinetics of selected regimens should preferentially meet abdominal infection (ascites antibiotic concentration of >MIC90 of pathogenic microorganisms).[46,47] For community-associated SBP, β-lactam/β-lactamase complex, cephalosporin, and oxacephem can be empirically selected to target extended-spectrum β-lactamase (ESBL)-producing strains, while carbapenems (meropenem and biapenem) can be selected for severe infections.[48] ESBL-producing strains need to be targeted for healthcare-associated SBP (HA-SBP). Owing to the increasing proportion of gram-positive bacteria in patients with HA-SBP, such as enterococci and staphylococci, linezolid or teicoplanin may be necessary in combination treatment. Tigecycline can be used to treat refractory peritonitis.

Spontaneous fungal peritonitis (SFP). The incidence of SFP is relatively low (0%–13%) in patients with ESLD, mainly occurring in those with long-term application of broad-spectrum antibiotics or compromised immunity, such as patients with diabetes or long-term steroid use. The major strains include Candida albicans and Aspergillus spp.[49,50] For ESLD complicated by SFP, echinomycin is preferred, and fluconazole or voriconazole may be used as a treatment alternative; however, the reduction in dosage should be determined according to the patients’ model for end-stage liver disease (MELD) grade or estimated glomerular filtration rate.[51]

TBP. Normally, anti-tuberculosis treatment is not recommended for patients with ESLD.[52,53] The anti-tuberculosis treatment recommendation by the American Thoracic Society in 2003 could be referenced if treatment is necessary.[54]

Recommendation 9

Empirical antibiotic treatment for ESLD complicated by abdominal infection [Table 1].

Table 1 - Empirical antibiotic treatment for end-stage liver disease complicated with abdominal infection
Type of infection Recommended therapeutic regimen
Community-acquired infection Third generation cephalosporin; piperacillin; tazobactam
Nosocomial infection Carbapenems; or combined with vancomycin, linezolid, daptomycin (in case of highly prevalence of multi-drug resistant Gram-positive bacteria, or with sepsis)

Respiratory infection

Pulmonary infection is a major respiratory infection in patients with ESLD. Community-acquired pneumonia (CAP) and hospital-acquired pneumonia (HAP) should be well distinguished.[47,55] The antibiotic regimens for treating CAP include penicillin/enzyme inhibitor complexes, third-generation cephalosporins or their enzyme inhibitor complexes, cephalosporins, and quinolones.[6,46]

Mild or moderate HAP.[56] Patients with early onset (admission: within 5 days), short-term mechanical ventilation (within 4 days), no high-risk factors, stable vital signs, and no marked organ dysfunction are classified to have mild or moderate HAP. The potentially involved pathogens include Enterobacteriaceae, Haemophilus influenzae, Streptococcus pneumoniae, and methicillin-sensitive S. aureus. The following antibiotic regimens can be selected: third-generation cephalosporins (not necessarily including anti-Pseudomonas activity), β-lactam/β-lactamase inhibitors, and fluoroquinolones.

Severe HAP.[56] Severe pneumonia is diagnosed if a patient meets one of the following major criteria or more than three of the secondary criteria. The major criteria include the following: (1) need for tracheal intubation for mechanical ventilation and (2) septic shock requiring vasoactive drug therapy even after active fluid resuscitation. The secondary criteria include the following: (1) respiratory rate of ≥30 beats/min; (2) oxygenation index of ≤250 mmHg (1 mmHg = 0.133 kPa); (3) multiple lobe infiltration; (4) loss of consciousness and/or disorientation; (5) blood urea nitrogen level of ≥7.14 mmol/L; and (6) systolic blood pressure of <90 mmHg, requiring active fluid resuscitation. Patients with late onset (admission: within 5 days, mechanical ventilation: within 4 days) and high-risk factors are considered to have severe pneumonia, even if they do not fully meet the prescribed standards. The potential pathogens include P. aeruginosa, methicillin-resistant S. aureus (MRSA), Acinetobacter spp., Enterobacter spp., and anaerobic bacteria. Quinolones or aminoglycosides can be selected as antibiotic treatments in combination with one of the following agents: anti-pseudomonas β-lactams, such as ceftazidime, cefoperazone, piperacillin, ticarcillin, or mezlocillin; broad-spectrum β-lactam/β-lactamase inhibitors, such as ticarcillin/clavulanic acid, cefoperazone/sulbactam sodium, and piperacillin/tazobactam; carbapenems, such as imipenem, meropenem, and biapenem; and glycopeptide or linazolamide (for MRSA) when necessary. Effective antifungal agents should be used when there is a high likelihood of fungal infection.[57]

Recommendation 10

Empirical antibiotic treatment for ESLD complicated by pulmonary infection [Table 2].

Table 2 - Empirical antibiotic treatment for end-stage liver disease complicated with pulmonary infection
Type of infection Recommended therapeutic regimen
CAP Third generation cephalosporin; piperacillin tazobactam
HAP Mild to moderate HAP: third-generation cephalosporin/enzyme inhibitor; piperacillin tazobactam
Severe HAP: carbapenems alone; or combination of vancomycin, teicoplanin, and linezolid; or tigecycline
CAP: Community-acquired pneumonia; HAP: Hospital-acquired pneumonia.

Biliary tract infection

The principles for the management of ESLD complicated by biliary tract infection are as follows: (1) early bile culture and drug susceptibility test, (2) timely empirical antibiotic treatment, (3) appropriate antibiotic treatment according to the severity, (4) biliary concentration of regime distribution, (5) absence of liver and kidney injuries, and (6) combined antibiotic treatment when necessary.

Presently, etiological data on biliary tract infections in patients with ESLD are still lacking. Studies on Chinese patients with non-ESLD cholecystolithiasis indicate that gram-negative bacteria accounted for 70%–75% of overall infections. The major strains were E. coli, K. pneumoniae, and P. aeruginosa. Gram-positive bacterial infections, mainly E. faecium and E. faecalis infections, have shown a rapid increase in recent years.[56,58] For mild biliary tract infections, piperacillin, piperacillin/tazobactam, and cefoperazone/sulbactam are recommended. Alternatively, second- or third-generation cephalosporins, ampicillin, or aminoglycosides could be selected in combination with metronidazole or tinidazole. If the clinical symptoms do not improve after 3 to 5 days of treatment, the disease is considered to be complicated by gram-positive bacterial infection. This requires a change or combination treatment with antibiotics that are sensitive to gram-positive bacteria, such as vancomycin and teicoplanin. For severe biliary tract infections, carbapenems (meropenem or biapenem), vancomycin, and teicoplanin are recommended. Local removal and drainage of the biliary tract infection site are important, and surgical intervention may be timely considered when necessary.[59,60]

Recommendation 11

Empirical antibiotic treatment for ESLD complicated by biliary tract infections [Table 3].

Table 3 - Empirical antibiotic treatment for end-stage liver disease complicated with biliary tract infection
Type of infection Recommended therapeutic regimen
Community-acquired infection Piperacillin tazobactam; ceftriaxone + levofloxacin
Nosocomial infection Ceftazidime or meropenem + levofloxacin or vancomycin or teicoplanin or linezolid

Urinary tract infection

The main pathogen causing a simple urinary tract infection is E. coli. Nitrofurantoin, cotrimoxazole, fluoroquinolone, third-generation cephalosporin, and amoxicillin/clavulanic acid have been selected as empirical antibiotic treatments.[6] However, enterococcal infections are markedly increasing in patients with complex urinary tract infections. For mild to moderate infections, fluoroquinolones and third-generation cephalosporins can be selected as empirical treatments. For severe infection or failure of empirical treatment, fluoroquinolone (if not used for initial treatment), piperacillin/tazobactam, third-generation cephalosporin/enzyme inhibitor, carbapenem (imipenem, meropenem, or biapenem), or combination treatment with glycopeptides is the preferred choice.[6,61,62] The incidence of sepsis caused by fungal urinary tract infections has gradually increased, which calls for appropriate antifungal treatment.[63,64]

Recommendation 12

Empirical antibiotic treatment for ESLD complicated by urinary tract infections [Table 4].

Table 4 - Empirical antibiotic treatment for end-stage liver disease complicated with urinary tract infections
Type of infection Recommended therapeutic regimen
Community-acquired infection Simple infection: nitrofurantoin; cotrimoxazole; ciprofloxacin
With sepsis: third-generation cephalosporin; piperacillin tazobactam
Nosocomial infection Simple infection: amoxicillin/clavulanic acid; piperacillin/tazobactam, third generation cephalosporin/enzyme inhibitor
With sepsis: meropenem alone or + teicoplanin or vancomycin

Bloodstream infection

Bloodstream infections are critical, and once a clinically suspected diagnosis is established, empirical antibiotic therapy should be started as soon as possible. Before starting an empirical antibiotic treatment for secondary bloodstream infections, the primary lesion, host immune status, infection source, and clinical epidemiology should be evaluated first.[65,66] The course of antibiotic treatment should last 7 to 10 days after fever cessation. Patients with migratory lesions need continued treatment until the disappearance of lesions, and surgical drainage or debridement may be indispensable. Catheter-related pathogen cultures should be actively performed for suspected primary bloodstream infections. Catheter removal and prompt empirical antibiotic treatment are the main strategies used during the course.[67–69]

Recommendation 13

Secondary and primary bloodstream infections should be distinguished in patients with ESLD. Original infection sites should be identified for secondary bloodstream infections, which will guide the strategy of antibiotic treatment. Catheter removal and prompt empirical antibiotic treatment are the main strategies used for primary bloodstream infections.

Skin or soft tissue infection

The common pathogens of skin and soft tissue infections in patients with ESLD are S. aureus, Streptococcus pyogenes, P. aeruginosa, Enterobacteriaceae, and anaerobic bacteria.[70,71] For local infections, only topical antibacterial regimens, such as mupirocin ointment or fusidic acid cream, are administered for 7 to 10 days. Deep soft tissue infections, such as cellulitis, mostly caused by S. aureus or S. pyogenes, can be treated with intravenous cefazolin. For MRSA, vancomycin, linezolid, and daptomycin treatments are required.[6,72]

Recommendation 14

Empirical antibiotic treatment for ESLD complicated by skin or soft tissue infections [Table 5].

Table 5 - Empirical antibiotic treatment for end-stage liver disease with skin or soft tissue infection
Type of infection Recommended therapeutic regimen
Community-acquired infection Mild infection: topical antibacterial drugs, such as mupirocin, fusidic acid
Moderate to severe infection: piperacillin tazobactam, third generation cephalosporin + oxacillin
Nosocomial infection Third-generation cephalosporin or meropenem + oxacillin or vancomycin or teicoplanin or daptomycin or linezolid

Gastrointestinal infection

Individualized antibiotic treatment according to risk factors is preferred for patients with ESLD complicated by gastrointestinal infections. Broad-spectrum antibiotic regimens covering gram-negative bacteria could be selected as an empirical treatment. For severe infections, the combined administration of antibiotics covering gram-negative and gram-positive organisms is recommended.[73–77]

Recommendation 15

Empirical antibiotic treatment for ESLD complicated by gastrointestinal infections [Table 6].

Table 6 - Empirical antibiotic treatment for end-stage liver disease with gastrointestinal infection
Type of infection Recommended therapeutic regimen
Community-acquired infection Piperacillin tazobactam; third generation cephalosporin
Nosocomial infection Third-generation cephalosporin or meropenem alone or + vancomycin or teicoplanin or daptomycin or linezolid

Principle of antibiotic treatment for ESLD

Drug-induced liver injury is a major concern in the selection of antibiotics for patients with ESLD. Some liver injury is induced by antibiotic regimens in a dosage-related or dosage-independent manner, including hepatocyte necrosis or cholestasis. Another concern is adverse reactions, such as coagulation disturbances and hematopoietic disorder.[78–81]

β-Lactams. Most β-lactam agents are safe and are mainly excreted by the liver and kidneys. Most of them can be used at normal dosages in patients with ESLD; however, the dosage needs to be adjusted in patients with renal insufficiency. Among penicillin derivatives, amoxicillin/clavulanic acid, penicillinase-resistant penicillin (including oxacillin and flucloxacillin), mezlocillin, sulfacillin, and carbenicillin may cause transaminase level elevation or cholestasis. Most cephalosporins can be safely used in patients with ESLD at a conventional dosage. For patients with an obvious tendency to bleed, we recommend avoiding the use of structural drugs containing tetrazolium ring structures to reduce the risk of bleeding, such as cefoperazone, head mycin (cefmetazole or cefminox), and oxycephalosporin (latamoxef or flomoxef). Carbapenems (imipenem, meropenem, and biapenem), which are mostly excreted by the kidneys, can be safely used at normal dosages in patients with ESLD.

Quinolones. Quinolones are excreted by the liver and kidneys and can be safely used in patients with ESLD. However, some individuals risk elevated transaminase levels and cholestasis. In these patients, administration of quinolones, such as fleroxacin, enoxacin, lomefloxacin, gatifloxacin, and moxifloxacin, should be avoided.

Aminoglycosides. Aminoglycosides, which are mainly excreted by the kidneys, can be safely used at a conventional dosage in patients with ESLD but have limited use in patients with renal impairment.

Macrolides. Most macrolides are metabolized by the liver, causing potential hepatotoxicity, especially erythromycin esters. The use of macrolides, beyond azithromycin and clarithromycin, should be avoided in patients with ESLD.

Tetracyclines. Tetracyclines can cause liver steatosis or cholestasis and should generally be avoided. Doxycycline and minocycline can be used appropriately because of their relatively low hepatotoxicity. Tigecycline should be used at a reduced dosage in patients with a score of C in the Child–Pugh classification.

Antituberculosis regimens. Isoniazid, rifamycin, and pyrazinamide have obvious hepatic toxicities; their use should then be avoided in patients with ESLD.

Other antibacterial regimens. Clindamycin, lincomycin, and most nitroimidazoles (metronidazole and ornidazole) are metabolized by the liver and have certain hepatotoxicity, which requires dosage adjustment in patients with ESLD. Sulfonamides are mostly hepatotoxic and should be avoided in patients with ESLD. Although vancomycin is mainly excreted by the kidneys, its concentration in patients with cirrhosis is markedly increased; the blood concentration should then be monitored during administration. Linezolid can cause liver damage, thrombocytopenia, and lactic acidosis during long-term treatment.

Recommendation 16

β-Lactams (penicillins, most cephalosporins, and carbapenems), aminoglycosides, partial quinolones (levofloxacin and ciprofloxacin), and glycopeptide antibiotic regimens have minor hepatotoxicity and are thus preferred in patients with ESLD.

Invasive fungal infection

Currently, three main types of antifungal regimens can be administered for ESLD.[82]

Polyenes. Amphotericin B and its derivatives should be used with caution in patients with ESLD because of some hepatotoxicity.

Triazoles. Fluconazole, itraconazole, voriconazole, and posaconazole are partly metabolized in the liver. Voriconazole has relatively less hepatotoxicity than other triazoles and can then be used with an adjusted dosage and a monitored liver function.

Echinocandin. Echinomycin is commonly used for the treatment of ESLD, with less hepatotoxicity. There is no need to reduce the dosage for mild liver dysfunction; meanwhile, the dosage should be adjusted for moderate and severe liver dysfunctions. Antifungal drugs and dosage adjustments are recommended on the basis of the liver function according to the Child–Pugh classification [Table 7].[83]

Table 7 - Dose adjustment of antifungal regimens for liver incompetency
Child-Pugh category

Antifungal drugs Normal liver function A (5–6 points) B (7–9 points) C (≥10 points)
Amphotericin B Initial treatment 1–5 mg administration, increase 5 mg daily or every other day, when the increase is 0.6 times to 0.7 mg/kg, the dose can be suspended. Not recommended Not recommended Not recommended
Fluconazole 400 mg (qd) 400 mg (qd) 400 mg (qd) 200–400 mg (qd)
Itraconazole 200 mg q12 h d1 200 mg q12 h d1 200 mg q12 h d1 200 mg q12 h d1
200 mg/d 200 mg/d 200 mg/d 200 mg/d
Voriconazole 6 mg/kg q12 h d1 6 mg/kg q12 h d1 6 mg/kg q12 h d1 Not recommended
4 mg/kg q12 h 2 mg/kg q12 h 2 mg/kg q12 h
Posaconazole 200 mg q 8 h 200 mg q 8 h 200 mg q 8 h 200 mg q 8 h
Caspofene 70 mg qd d1 70 mg qd d1 70 mg qd d1 Not recommended
50 mg qd 50 mg qd 35 mg qd
Mikafen 100 mg/d 100 mg/d 100 mg/d 100 mg/d
Anifen 100 mg/d 100 mg/d 100 mg/d 100 mg/d

Recommendation 17

Echinocandins are initially recommended for sensitive fungal infections in patients with ESLD. Triazoles (fluconazole and voriconazole) can be used with dosage adjustment; however, close monitoring of the liver function is necessary. Therefore, the use of amphotericin B should be avoided.

Intestinal microecology

Intestinal microecological disorder contributes to infection in patients with ESLD, which is an effective intervening aspect.[84,85] Intestinal selective decontamination treatment involves the removal of overproduced intestinal gram-negative bacilli and fungi with narrow-spectrum antibiotics.[86] Rifaximin is a non-absorbable broad-spectrum antibacterial agent that reduces bacterial counts in the small intestine, bacterial translocation, and incidence of abdominal infection.[87]Lactobacillus exerts a protective effect on the intestinal mucosa by lowering the pH of the intestine, preventing colonization by pathogenic bacteria, regulating intestinal immunity, and improving intestinal function. Prebiotics and live Lactobacillus products can markedly reduce the incidence of spontaneous peritonitis in patients with cirrhosis. Fecal bacterial transplantation considerably improves survival and reduces the incidence of abdominal infections in patients with liver failure.[88]

Recommendation 18

Probiotics and synbiotics are effective adjuvant treatments for ESLD complicated by infection. Fecal bacterial transplantation and selective intestinal decontamination can effectively reduce the risk of SBP.

Blood purification

Different modes of blood purification (bilirubin absorption, plasma exchange, and molecular absorption recycling system) can be adopted to remove inflammatory mediators and toxins, improve the internal environment, promote immune reconstitution, stabilize hemodynamics, and facilitate synergistic antibiotic treatment. Beyond comprehensive medical treatment, blood purification treatment, such as Li's artificial liver system, could be selected, as appropriate.[88–91]

Recommendation 19

Blood purification can effectively remove inflammatory mediators and toxins in patients with ESLD complicated by infection.

Prognosis

The prognosis of ESLD complicated by infection is associated with the severity of liver disease and infection. The severity of liver disease and infection, as well as related predictive models, can be used to determine the prognosis of ESLD complicated by infection. It is recommended to use a combination of the APASL ACLF research consortium score, Tongji prognosis prediction model, Chronic Liver Failure Consortium organ failure score, Child–Turcotte–Pugh score, MELD score, and PCT and CRP levels to evaluate the prognosis of infection in patients with ESLD.[92–98]

Prevention

Precautions for ESLD complicated by infection include the following[99,100]: (1) active treatment of primary liver diseases: Recovery of primary liver function facilitates the prevention and treatment of infection in patients with ESLD. (2) Emphasis on supportive treatment: Competent nutritional and immunological conditions prevent infection in patients with ESLD. (3) Early diagnosis of infection: Early antibiotic treatment based on the early diagnosis of infection contributes to the control of infection. (4) Rational application of antibiotics: Antibiotics should be selected on the basis of empirical determinants and drug susceptibility. Prophylactic and joint application of antibiotics should be strictly controlled on the basis of clinical indications. (5) Regular air ventilation of wards, prevention of pathogen propagation among medical staff, and strict control of invasive operations are important procedures that prevent in-hospital infection.

Conflicts of Interest

None.

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Keywords:

Consensus; Diagnosis; End stage of liver disease; Infection; Therapy

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