Nutritional therapy

Risk screening: nutritional screening tools, such as the NRS-2002, are recommended for screening the nutritional risk [30].

Assessment: body composition, imaging, grip strength, subjective global assessment, Royal Free Hospital-Global Assessment and Nutritional Assessment for Liver Disease are recommended [31].

Intervention. Patients who cannot swallow and chew food should start tube feeding within 24–48 h after admission [32]. Supplemental parenteral nutrition should be provided when enteral nutrition is not feasible or the amount of intake is less than 60% of the basal energy expenditure [33]. Light-digestible food is preferred, with four to six meals per day. Late-night extra meals of carbohydrate-rich foods are recommended [34]. The energy supply should be at least 35 kcal/kg/d for nonobese and 25–35 kcal/kg/day for individuals with a BMI 30–40 kg/m2. The protein or amino acid supply is recommended to range from 1.2 to 1.5 g/kg/d. Avoid protein restriction in patients with hepatic encephalopathy [35]. Vegetable and dairy proteins are preferred in optimal daily protein, as well as branched-chain amino acid (BCAA). In all cases, hypoglycemia and vitamin deficiencies should be carefully treated [34].

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 [36, 37].

Thrombocytopenia management

Thrombocytopenia is very common in patients with ESLD complicated by infections. For patients with platelet counts < 20 × 109/L or platelet counts > 20 × 109/L with bleeding, and for invasive procedures, maintaining a platelet count above 50 × 109/L can reduce the risk of bleeding [38]. In addition, platelets can induce hepatocyte regeneration, potentially improving liver function in patients with liver disease [39]. At present, the clinical treatment mainly includes platelet infusion, avatrombopag, recombinant human thrombopoietin (rhTPO), recombinant human interleukin 11(rhIL-11), etc. Avatrombopag has proven efficacy in patients with liver disease. It significantly improves platelet count and reduces the proportion of patients receiving platelet transfusion or rescue due to bleeding in patients with liver disease undergoing elective invasive procedures [40]. The small sample research of rhTPO, rhIL-11 and leucogen suggested that it had a certain effect on the improvement of platelet count in patients with liver disease, and it was necessary to use thromboelastogram (TEG) to monitor the coagulation status of patients.

Immunomodulatory treatment

Albumin considerably increases the survival of patients with cirrhosis combined with SBP but without any other bacterial infections types [41].

Gamma globulin rapidly increases the level of serum IgG, which could potentially neutralize bacterial endotoxins, increase anti-inflammatory mediators, and enhance the organic ability of antibiotics [42].

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 [43]. Although granulocyte–macrophage colony-stimulating factor (GM-CSF) cannot considerably improve the prognosis of patients with sepsis, it may reduce the incidence of secondary infections [44,45,46]. Granulocyte colony-stimulating factor (GCSF) may improve the short-term survival of patients with liver failure [47]. A combination of GM-CSF and carbapenem is superior to carbapenem monotherapy in difficult-to-treat spontaneous bacterial peritonitis [48]. 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 [49, 50].

Etiological treatment

For hepatitis B-related ESLD, strong and high resistance barrier nucleoside (nucleotide) analog antiviral therapy, namely entecavir and tenofovir, is recommended; it improves short-term mortality by rapidly reducing the HBV DNA load and relieving immune injury [51, 52]. 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 [37]. For alcoholic-origin ESLD, patients should abstain from alcohol consumption as soon as possible and may be treated with metadoxine [53, 54].

Recommendation 5

Nutritional support (1, A) and hepatoprotective treatment (2, C) 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 (1, B).

Recommendation 7

Glucocorticoid treatment should be evaluated with caution in patients with severe infections (1, A).

Recommendation 8

Entecavir or tenofovir disoproxil fumarate is recommended as an anti-HBV treatment for HBV-related ESLD, renal function should be closely monitored. Tenofovir is not recommended for patients with renal or kidney dysfunction. DAA therapeutic regimens, sofosbuvir-velpatasvir or glecaprevir-pibrentasvir, should be selected based on the liver and kidney functions and the interaction between drugs in patients with HCV-related ESLD (1, A).

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 monitoring drug resistance data. During the process of empirical antibiotic treatment, the surveillance of indicators, such as inflammatory factors, and laboratory test findings facilitates 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 and biliary 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) [55]. 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 [56]. 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 Enterococcus faecalis and Enterococcus faecium, 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. [57, 58]. 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 [59].

TBP. Normally, anti-tuberculosis treatment is not recommended for patients with ESLD [60, 61]. The anti-tuberculosis treatment recommendation by the American Thoracic Society in 2003 could be referenced if treatment is necessary [62].

Biliary tract infection. 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 [63]. 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 3–5 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.

Recommendation 9

Empirical antibiotic treatment for ESLD complicated by abdominal and biliary tract infection was recommended in Table 3 (1, B).

Table 3 Empirical antibiotic treatment for ESLD complicated by abdominal and biliary tract infectionRespiratory 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 [64]. The antibiotic regimens for treating CAP include penicillin/enzyme inhibitor complexes, third-generation cephalosporins or their enzyme inhibitor complexes, cephamycin, and quinolones [65].

Mild or moderate HAP [66]. Patients with early onset (admission: after 5 days), short-term mechanical ventilation (after 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 [66]. 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.

Recommendation 10

Empirical antibiotic treatment for ESLD complicated by pulmonary infection was recommended in Table 4 (1, B).

Table 4 Empirical antibiotic treatment for ESLD complicated by pulmonary infection

CAP, community-acquired pneumonia; HAP, hospital-acquired pneumonia.

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. 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 [64, 67]. The incidence of sepsis caused by fungal urinary tract infections has gradually increased, which calls for appropriate antifungal treatment.

Recommendation 11

Empirical antibiotic treatment for ESLD complicated by urinary tract infections was recommended in Table 5 (1, B).

Table 5 Empirical antibiotic treatment for ESLD complicated by urinary tract infectionsBloodstream 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 [68, 69]. The course of antibiotic treatment should last 7–10 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 [8, 68, 69].

Recommendation 12

Primary and secondary 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 (1, A).

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 7–10 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.

Recommendation 13

Empirical antibiotic treatment for ESLD complicated by skin or soft tissue infections was recommended in Table 6 (1, B).

Table 6 Empirical antibiotic treatment for ESLD complicated by skin or soft tissue infectionsGastrointestinal 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 [72].

Recommendation 14

Empirical antibiotic treatment for ESLD complicated by gastrointestinal infections was recommended in Table 7 (1, B).

Table 7 Empirical antibiotic treatment for ESLD complicated by gastrointestinal infectionsPrinciple 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 [18].

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 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 have the risk of 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 Child–Pugh score C.

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. Thus, the blood concentration should then be monitored during administration. Linezolid can cause liver damage, thrombocytopenia, and lactic acidosis during long-term treatment.

Recommendation 15

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 (1, A).

Invasive fungal infection

Currently, three main types of antifungal regimens can be administered for ESLD [73].

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

Triazoles. Fluconazole, itraconazole, voriconazole, posaconazole and isavuconazole 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 liver function according to the Child–Pugh classification (Table 8) [59].

Table 8 Dose adjustment of common antifungal drugs in patients with liver injuryRecommendation 16

Echinocandins are the preferred anti-fungals 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. The use of amphotericin B should be avoided (1, A).