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Sepsis in patients with cirrhosis

Inflammatory phenotype of sepsis in acute-on-chronic liver failure

What is acute-on-chronic liver failure?

Patients with cirrhosis are often admitted to the hospital for an acute decompensation of the liver disease

[28].

Acutely decompensated cirrhosis refers to the development of ascites, encephalopathy, gastrointestinal hemor-

rhage, or any combination of these disorders

[28]. Acutely decompensated cirrhosis can be precipitated by disor-

ders such as bacterial infection (25% of cases), alcoholic hepatitis (16%), or gastrointestinal hemorrhage (16%)

[29]. There may be more than one precipitating disorder . Of note, 50% of cases of acutely decompensated cirrho-

sis develop without any clinically identifiable precipitating disorder.

In cirrhosis, the existence o f organ failures is recognized using the Chronic Liver Failure (CLIF) Consortium

Organ Failure scale which is a modification of the SOFA scale (

Table 12.4) [29,30]. Twenty percent of patients

admitted for acutely decompensated cirrhosis have acute-on-chronic liver failure (ACLF)

[29].Thisgroupof

patients includes those with single kidney failure (i.e., one organ system failure), those with single “nonkid-

ney” organ failure if it is a ssociated with kidney or brain dysfunction, and those with two organ failures or

more. According to the number of organ system failures at presentation, patients with acutely decompensated

cirrhosis are stratified into four prognostic grades (no ACLF and ACLF grades 1, 2, and 3)

[28,29].Among

patients with ACLF, the most prevalent failing organ systems are the kidney (56%), followed by the liver

(44%), coagulation (28%), and the brain (24%). Cardiovascular and respiratory failures are less frequent (17%

and 9%, respectively)

[29].

Patients with acutely decompensated cirrhosis have systemic inflammation

[29,31]. However, patients with

ACLF have a higher grade of systemic inflammation relative to those without ACLF, as indicated by higher blood

white-cell counts, and greater plasma levels of CRP levels and a broad variety of inflammatory mediato rs (both

pro- and antiinflammatory)

[29,31]. Of note, the blood levels of most blood markers of systemic inflammation

increase in parallel with the severity of ACLF

[31].

In contrast to patients without ACLF who have a very low short-term mortality (,5% at 28 days), those with

ACLF have a high 28-day mortality rate depending on the number of failing organs. Indeed, 28-day mortality

rate is 20%, 32%, and 80%, in ACLF grade 1, grade 2, and grade 3, respectively

[28,29] (Table 12.5).

According to the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)

[2], patients

with acutely decompensated cirrhosis precipitated by an infection can be divided into two groups. The first

group comprises patients without sepsis because they have low-grade systemic inflammation, no ACLF and their

risk of death is very low. The second group comprises patients with sepsis, because they have high-grade sys-

temic inflammation associated with ACLF and a high risk of dying at short term.

TABLE 12.4 The CLIF-C Organ Failure scoring system.

Scale

Organ system: marker 1 2 3

Liver: Bilirubin, mg/dL , 6 $ 6 and ,12 $ 12

Renal: Creatinine, mg/dL , 2 $ 2 and ,3.5 $ 3.5 or use of renal-replacement

therapy

Coagulation: INR , 2.0 $ 2.0 and ,2.5 $ 2.5

Brain: West-Haven grade for HE 0 1234 or use of endotracheal intubation

because of HE

Circulation MAP $ 70 mm Hg MAP , 70 mm Hg Use of vasopressor(s)

Respiration: PaO

/FiO

or SpO

/FiO

. 300 or .357 # 300 and .200 or # 357 and .214 # 200 or # 214 or use of mechanical

ventilation for reasons other than HE.

Kidney failure is defined by a subscore of 2 or more. For each of other the organ systems, failure is defined by a subscore of 3.

CLIF-C, chronic liver failure-consortium; INR, international normalized ratio; HE, hepatic encephalopathy; MAP, mean arterial pressure; Pao2, partial pressure of

arterial oxygen; Fio2, fraction of inspired oxygen; Spo2, oxygen saturation as measured by pulse oximetry.

Adapted from Jalan R, Saliba F, Pavesi M, Amoros A, Moreau R, Gine

s P, et al. Development and val-idation of a prognostic score to predict mortality in patients with acute-

on-chronic liver failure. J Hepatol. 2014;61:10381047.

154 12. Sepsis and the liver

III. Cardiovascular system in liver failure

https://t.me/medicina_free

ACLF may be related to either infection, severe alcoholic hepatitis, gastrointestinal hemorrhage, or no clinically

identifiable mechanism. Accordingly, sepsis is one of the phenotypes of ACLF, which will be called hereafter

infection-related ACLF.

Infection-related acute-on-chronic liver failure versus acute-on-chronic liver failure unrelated to infection

Among patients with ACLF, the phenotype of those with acute infection is distinct from the phenotype of

those without infection

[32]. Infected patients have higher prevalence of cerebral failure (31% vs 17% in nonin-

fected patients), circulatory failure (34% vs 18%), and respiratory failure (20% vs 10%). The other distinctive fea-

tures of infection-related ACLF are a higher blood white-cell count, and greater plasma levels of CRP,

proinflammatory proteins (cytokines [TNF-α and IL-6], chemokine [IL-8]), and antiinflammatory cytokines (IL-10

and IL-1ra)

[32]. Finally, 90-day mortality rate is significantly higher in patients with infection-related ACLF than

in those with ACLF unrelated to infection (51% and 38%, respectively)

[32]. Together, these findings indicate that

systemic inflammation and severity are greater in infection-related ACLF than in ACLF unrelated to infection.

Pathophysiology of infection-related acute-on-chronic liver failure

As for sepsis in the general population, PAMPs and virulence factors produced by living, invading microbes,

and DAMPs that result from collateral tissue damage, can act in concert to induce and perpetuate inflammation

in patients with infection-associated ACLF

[28,33] (Fig. 12.5). Living bacteria often engage not only surface PRRs

but also intracellular PRRs, which could be perceived by the immune system as a signal of great danger and

therefore elicit an intense inflammatory response

[3]. In contrast, in patients with ACLF unrelated to infection,

the number of inducers of inflammation may be more limited. The inducers could be only DAMPs released by

necrotic liver cells in the context of alcoholic hepatitis or posthemorrhage ischemic hepatitis

[28]. PAMPs that

have translocated from the gut lumen could be the inducer of inflammation in 40% of cases of ACLF without

clinically identifiable trigger

[29,33]. These translocated PAMPs, which are not produced by living, invading

microbes, may elicit a less vigorous immune response than that elicited by PAMPs from living bacteria

[3].Of

note, the only translocated PAMP identified so far in blood from patients with cirrhosis is LPS, which is recog-

nized by a surface PRR (i.e., TLR4)

[33]. The differences in the number of inducers of inflammation, their origin

(invading microbe or not), and perhaps the engagement of intracellular PRRs may explain the higher grade of

inflammation and greater mortality in patients with ACLF related to infections.

TABLE 12.5 Definitions of the CLIF Consortium for organ system failures, acutely decompensated cirrhosis, and acute-on-chronic

liver failure (ACLF) used in the present study.

Definition of acutely decompensated cirrhosis

Acute development of ascites, hepatic encephalopathy, gastrointestinal hemorrhage, or any combination of these disorders

Definitions allowing patients stratification according to severity

Patients with acutely decompensated cirrhosis without ACLF

(1) Patients with no organ failure

(2) Patients with single failure (affecting any of the following: liver, coagulation, circulation, respiration) and serum creatinine levels ,

1.5 mg/dL without HE

(3) Patients with single cerebral failure and creatinine levels , 1.5 mg/dL

Patients with acutely decompensated cirrhosis and ACLF

ACLF grade 1 comprises:

(1) Patients with single kidney failure

(2) Patients with single liver, coagulation, circulatory or lung failure associated with creatinine levels ranging from 1.5 to 1.9 mg/dL or

HE grade 1 or 2, or both

(3) Patients with single brain failure with creatinine levels ranging from 1.5 to 1.9 mg/dL

ACLF grade 2 include patients with 2 organ failures

ACLF grade 3 include patients with 3 organ failures or more (maximum of 6).

Definitions according to the CLIF-Consortium organ failure scoring system see Table 12.4 and ref. [30].

CLIF, chronic liver failure, Pao

partial pressure of arterial oxygen; FiO

, fraction of inspired oxygen; SpO

, oxygen saturation as measured by pulse oximetry.

According to Moreau R, Jalan R, Gine

s P, Pavesi M, Angeli P, Cordoba J, et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute

decompensation of cirrhosis. Gastroenterology. 2013;144:1426-1437.

155Sepsis in patients with cirrhosis

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Although systemic inflammation is certainly the primary cause of organ failures in infection-related ACLF, the

nature of the cause-to-effect relationship is still unclear

[28]. It has been suggested that organ failures are a result

of tissue hypoperfusion caused by circulatory dysfunction related to the induction of arteriolar iNOS in response

to cytokines or bacterial byproducts. The paradigm for this mechanism is the development of type 1 hepatorenal

syndrome, (an acute kidney injury that is specific for cirrhosis and is a form of ACLF)

[28]. NO produced by

iNOS may have a cardiac depressant effect contributing to sepsis-induced circulatory dysfunction. There is also

some evidence that PAMP-activated immune cells can cause collateral tissue damage (a process called immuno-

pathology)

[28]. It has been suggested that the development of organ failures may be related of metabolic

changes associated with systemic inflammation. Indeed, high-throughput metabolomics using blood samples col-

lected from a large series of patients with acutely decompensated cirrhosis revealed that, in those with ACLF ,

exaggerated systemic inflammatory responses were associated with reallocation of glucose to activated immune

cells, and a defect in mitochondrial fatty acid β-oxidation and energy production in peripheral organs, which

then may fail

[34].

Immunosuppression in cirrhosis and acute-on-chronic liver failure

Almost 30% of patients with ACLF who do not have infection at presentation develop this complication (i.e.,

new secondary infection) during short-term follow-up, indicating that these patients have immunosuppression.

Moreover, secondary infections are severe complications. Indeed, among patients with ACLF, 90-day mortality is

higher in those who develop secondary infection than in those who remain free of this complication during the

entire period of follow-up

[32].

Cirrhosis

Infection

(most often bacterial)

PAMPs

PRRs

Virulence

factors

Functional

feature recognition

Severe systemic

inflammation

Immune-mediated

tissue damage

NO production by

splanchnic arterioles

Renal hypoperfusion

Organ failure(s)

Acute-on-chronic

liver failure

Mitochondrial

dysfunction

Fatty acid oxidation

ATP synthesis

DAMPs

FIGURE 12.5 Pathophysiology of infection-related acute-on-chronic liver failure. Cirrhosis is associated with an increased risk of infec-

tion, in particular, the bacterial infections. Infections cause intense systemic inflammation that may elicit organ system failures through three

distinct mechanisms, which are not mutually exclusive. These include tissue hypoperfusion, tissue damage caused by an excessive immune

response of the host, and impaired mitochondrial production of energy (ATP).

156 12. Sepsis and the liver

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Some predictors of secondary infections have been identified in patients with ACLF, these predictors include

higher blood levels of inflammatory mediators (IL-6, IP-10 [CXC chemokine 10], interferon-α2, and IL-10), soluble

forms of CD206 (i.e., macrophage mannose receptor), and CD163 (i.e., scavenger receptor cysteine-rich type 1

protein M130), and quinolinate (a product of the tryptophan-kynurenine pathway)

[32,35]. Of note, IL-10 is an

antiinflammatory (i.e., immunosuppressive) cytokine

[25] and quinolinate is also known to induce immunosup-

pression

[36].

In patients with ACLF, certain subsets of circulating innate myeloid cells exhibit features of immunosuppres-

sion

[3740]. For example, in these patients, macrophages derived from circulating monocytes have a PGE

mediated defective production of proinflammatory cytokines in response to bacterial PAMP stimulation

[37].

Other studies have shown that patients with ACLF have increased frequenc y of CD14

monocytes expressing

the receptor tyrosine kinase MerTK [38,39] and of CD14

CD15

HLA-DR

myeloid-derived suppressor cells [40] ;

both monocyte subsets having suppressed innate responses to bacterial PAMPs. Another study found decreased

frequencies of other myeloid mononuclear cells (conventional dendritic cells [DCs] and plasmacytoid DCs) in

patients with severe alcoholic hepatitis, including patients who had ACLF

[41]. Finally, there are several studies

showing that circulating neutrophils from patients with decompensated cirrhosis have multiple defects involving

migration; bacterial recognition; and bacterial killing activities including engulfment and phagocytosis, degranu-

lation, the ability to rapidly produce a large amount of antimicrobial reactive oxygen species (respiratory burst),

and NET formation (reviewed in. ref.

[42]).

Collectively, these findings suggest that immunosuppression in ACLF is complex. Indeed, ACLF is associated

with increased blood levels of immunosuppressive molecules (e.g., IL-10, quinolinate) and defective functions of

innate myeloid cells, including neutrophils, monocytes, and dendritic cells, which may play a role in the develop-

ment of secondary infections that complicate ACLF. Of note, lymphocytes have not yet been extensively studied

in patients with ACLF. These immune cells should be investigated in ACLF because, as mentioned earlier, their

alteration has been shown to be involved in immunosup pression associated with protracted sepsis in the general

population

[5].

Clinical features and management of sepsis syndromes in patients with cirrhosis

Patients with decompensated cirrhosis are at increased risk to develop spontaneous or secondary bacterial

infections. Around one-third of patients are infected at admission or develop this complication during hospitali-

zation; this is five times greater than the rate of infections observed in the general population. Spontaneous bacte-

rial peritonitis (SBP), urinary-tract infections, pneumonia and bacteremia are the most frequent infections

[4347]. Clinical risk factors for infections are upper gastrointestinal bleedi ng, poor liver function, low protein

ascites, prior spontaneous infections and hospitalization. Some genetic polymorphisms also predispose to SBP

[43,48,49].

Bacterial infections are also a key pro gnostic determinant in patients with cirrhosis. Infections frequently com-

plicate with sepsis are the main precipitating event of ACLF in Western countries and may precipitate or compli-

cate variceal hemorrhage by increasing portal pressure and altering hemostasis

[32,43,49]. Not surprisingly,

infections are together with hepatocellular carc inoma the main causes of death in cirrhosis. Consequently, early

diagnosis and prompt and adequate empirical antibiotic treatment of infection is key in the management of these

patients

[43,49].

Spontaneous bacterial peritonitis

SBP is the most characteristic and one of the most frequent bacterial infections observed in cirrhosis (25%

40% of all infectious episodes reported in different series). It is defined as the infection of the ascites fluid in the

absence of an identifiable intraabdominal source of infection. Its prevalence is 2% in patients undergoing total

paracentesis and around 10%15% in hospitalized patients with ascites

[43,49,50].

Altered gut microbiota, increased intestinal permeability, bacterial translocation, and immunosuppression

(acquired or secondary to genetic susceptibility) are the pathophysiological substrates for SBP, spontaneous bac-

teremia, and spontaneous bacterial empyema. Some genetic polymorphisms (NOD2 variants, mannose-binding

lectin deficiency and TLR2 polymorphisms) also increase the risk of SBP through immune dysfunction

[43,50].

Besides this immunodeficient state, circulating levels of inflammatory cytokines increase markedly in infected

157Sepsis in patients with cirrhosis

III. Cardiovascular system in liver failure

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patients with cirrhosis, especially in those with ACLF. This “cytokine storm,” as mentioned earlier, is the sub-

strate of sepsis and the main contributor to organ failure

[28,51].

Diagnosis

SBP can be asymptomatic in the initial stages of the disease. Fever, chills, tachycardia, vomiting, ileus or diar-

rhea, and abdominal pain and tenderness are classical signs of the infection. Encephalopathy and renal dysfunc-

tion are also frequently observed in these patients. SBP can also trigger variceal bleeding or complicate with

septic sho ck. Prompt diagnostic paracentesis should be performed in the presence of any of these abnormalities

and also in all cirrhotic patients with ascites at the time of hospital admission. Any delay in diagnostic paracent-

esis and in the initiation of appropriate therapy result in fatal outcomes in patients with SBP increasing threefold

mortality

[43,49,50]. Ascites fluid analysis shows a neutrophil count $ 250 cells/mm3 with or without positive

cultures. In patients with hemorrhagic ascites, a subtraction of one neutrophil per 250 blood red cells should be

made. Both blood and ascites cultures must be obtained at the time of SBP diagnosis. Ascites fluid should be

inoculated directly into blood culture bottles at the bedside. Immediately afterwards appropriate empirical antibi-

otic therapy must be initiated

[43,49].

Cultures are positive in around 50% of cases. Enterobacteriaceae (Escherichia coli and Klebsiella pneumoniae), and

nonenterococcal streptococci (Streptococcus viridans and Streptococcus pneumoniae) are the most frequent bacteria

responsible for SBP. Anaerobes seldom cause this infection. Their isolation should lead to exclude a secondary

peritonitis

[43,49,50].

Although the type of bacteria causin g SBP is similar to that observed in the past two decades, susceptibility to

the different antibiotic families has dramatically changed during this period. Nowadays, most isolates exhibit

resistance to third-generation cephalosporins and quinolones, antibiotics frequently prescribed in the treatment

of SBP in the 80s and 90s

[45,47,5254].

Differential diagnosis

Secondary peritonitis constitutes the main differential diagnosis of SBP. A secondary peritonitis should be sus-

pected when at least two of the following are present in ascites fluid: glucose levels , 50 mg/d L, protein concen-

tration . 10 g/L, LDH concentration . normal serum levels (Runyon’s criteria). These criteria have a specificity

of 90% for the diagnosis of secondary peritonitis. Gram’s stain of a smear of sediment of ascites fluid is also use-

ful in identifying patients with gut perforation in whom multiple types of bacteria are frequently seen. These sub-

jects also present high levels of amylase and bilirubin in ascites. Prompt abdominal computed tomography and

early indication of surgery are also important in the management of patients with secondary peritonitis

[43,49].

Bacterascites is diagnosed in the patients with normal ascites fluid neutrophil count but positive ascites fluid

culture. It may represent a transient and spontaneously reversible colonization of ascites that does not require

treatment but also the first step in the development of SBP, especially in patients who are symptomatic. In all

patients with bacterascites, a new paracentesis must be done within 2448 hours to rule out an episode of SBP.

Those who are symptomatic require antibiotic therapy

[50].

Treatment

Empirical antibiotic schedules

Diagnosis of SBP constitutes an indication to immediately initiate an appropriate empirical antibiotic treat-

ment. Each hour of delay in starting adequate antibiotic therapy increases mortality, especially in severe cases

[43,49]. Third-generation cephalosporins, that were antibiotics extensively used in the past decades in the treat-

ment of SBP, are nowadays frequently ineffective in this setting given the alarming increase in antibiotic resis-

tance observed in the healthcare environment in patients with decompensated cirrhosis

[45,47,5254]. Risk of

SBP caused by multidrug-resistant organisms is especially high in nosocomial episodes

[45,5254].

Severity of SBP (i.e., presence of ACLF), site of infection acquisition, and local epidemiological pattern of anti-

biotic resistance should be considered when deciding the empirical antibiotic treatment in patients with SBP

[43,48,49]. Current guidelines only recommend the use of classical β-lactams (3rd generation cephalosporins and

amoxicillin-clavulanic acid) in nonsevere infections acquired in the community. Empirical strategies active

against resistant strains should be used in the rest of cases. Carbapenems should be started empirically in

areas with a high prevalence of extended spectrum beta-lactamase producing Enterobacteriaceae. The addition

of antibiotics active against multidrug-resistant gram-positive organisms is recommended in areas with a

relevant rate of infections caused by vancomycin-susceptible enterococci; vancomycin-resistant enterococci or

158 12. Sepsis and the liver

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methicillin-resistant Staphylococcus aureus (Table 12.6, Fig. 12.6) [43,48,49,54]. Several studies have demonstrated

the efficacy of adapting empirical antibiotic strategies to the local pattern of antibiotic resistance. In a single-

center investigation, the combination of meropenem plus daptomycin was more effective than ceftazidime alone

in the empirical treatment of nosocomial SBP (infection resolution: 87% vs 25%), with no increase in the rate of

second infections caused by multidrug resistant organisms

[55]. Two large-scale observational studies have also

shown that the use of empirical antibiotic strategies covering multi-drug resistant organisms improve short-term

prognosis in patients with decompensated cirrhosis or ACLF

[45,47].

Dosing strategies aimed at optimizing the antibiotics’ pharmacokinetic and pharmacodynamics are currently

recommended in the treatment of patients with cirrhosis and severe infections. These strategies consist of the use

of high antibiotic doses within the first 4872 hours after the diagnosis of infecti on and in the administration of

time-dependent antibiotics (β-lactams) in continuous or extended infusions. This therapeutic strategy achieves

high and sustained concentrations of the drug in the source of infection. Concentrations achieved are several

times over the minimum inhibitory concentration and over the mutagenic window, increasing the likelihood of

therapeutic success and decreasing the risk of resistance selection

[48,54,56].

After microbiological isolation, immediate deescalation is mandatory in order to prevent further antibiotic

resistance (

Fig. 12.6). Epidemiological surveillance data could guide the deescalation process in the absence of

positive blood or ascites fluid cultures

[54].

The efficacy of the initial antibiotic therapy should be checked by a new paracentesis 2 days after diagnosis.

Failure of treatment should be suspected if there is worsening of clinical condition, neutrophil count increases in

ascites fluid or there is no relevant reduction in neutrophil count (at least 25%). Antibiotic treatment should be

maintained for at least 57 days

[43,49,50].

Antibiotic strategies for extensively drug-resistant bacteria

Extended or pan-drug-resistant bacteria resist many if not all currently available antibiotics. Carbapenemase-

producing Enterobacteriaceae can be nowadays treated with ceftazidime-avibactam, a new cephalosporin-β-lacta-

mase inhibitor combination. Avibactam inactivates class A, class C and partially class D (OXA-48) carbapene-

mases but has no activity against metallo-β-lactamases (class B: VIM and NDM). These last extended-drug-

resistant bacteria strains are usually susceptible to aztreonam. SBP caused by methicillin-resistant S. aureus,

Pseudomonas aeuruginosa (resistant to carbapenems, ceftazidime and quinolones) should be treated with

TABLE 12.6 Main multidrug-resistant organisms (MDROs), reservoir and therapeutic options.

Gram-positive cocci Gram-negative bacilli

MDRO Methicillin-resistant S. aureus

Vancomycin-

resistant

enterococci

ESBL-producing

Enterobacteriaceae

Carbapenemase-

producing

Enterobacteriaceae

Carbapenem-resistant

non-fermentative

Enterobacteriaceae

Main

species

S. aureus E. faecium E. coli, K.

pneumoniae

E. coli, K.

pneumoniae

Pseudomonas

aeruginosa

Acinetobacter

baumanii

Resistance

mechanism

Target modification Target

modification

β-lactam

hydrolysis

β-lactam hydrolysis Restricted

outer

permeability

Efflux

pumps

β-lactam

hydrolysis

β-lactam

hydrolysis

Reservoir Oropharynx Intestinal tract Intestinal tract Intestinal tract Intestinal

tract

Intestinal

tract

Therapeutic

options

Vancomycin, teicoplanin,

daptomycin, linezolid, tedizolid

tigecycline, ceftaroline, ceftobiprole,

razupenem

Daptomycin,

linezolid,

tedizolid

tigecycline,

razupenem

Carbapenems,

temocillin

Ceftazidime-

avibactam,

Aztreonam-

tazobactam

Cefiderocol

Ceftolozane-

tazobactam

Cefiderocol

Eravacycline

Tigecycline,

colistin

Ceftazidime-

avibactam,

Cefiderocol

Eravacycline

S. aureus, Staphylococcus aureus, E. faecium, Enterococcus faecium, E. coli, Escherichia coli, K. pneumonia, Klebsiella pneumonia, P. aeruginosa, Pseudomonas aeruginosa, A.

baumannii, Acinetobacter baumannii.

159Sepsis in patients with cirrhosis

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ceftolozane-tazobactam. Infections caused by vancomycin-resistant enterococci require the use of linezolid, dapto-

mycin, or tigecycline

[54,56].

Fortunately, new antibiotics active against extended- or pan-drug-resistant bacteria will be available in the

next years. Among new compounds active against gram-negative multidrug-resistant organisms we have

aztreonam-tazobactam with activity against all type of beta-lactamases (A to D); cefiderocol, active against class

A, B, and C carbapenem-resistant Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii, and

eravacycline, active against carbapenem-resistant Enterobacteriaceae and A. baumannii. Ceftaroline and ceftobi-

prole display activity against methicillin-resistant S. aureus, while razupenem, a new carbapenem, is effective

against both methicillin-resistant S. aureus and vancomycin-resistant Enterococci. New glycopeptides such as ori-

tavancin and new oxazolidinones such as tedizolid phosphate are active against methicillin-resistant S. aureus

and vancomycin-resistant Enterococci.

Intravenous albumin

SBP frequently accentuates circulatory dysfunction and precipitates type 1 hepatorenal syndrome [49]. The

administration of 20% albumin (1.5 g/kg body weight at diagnosis, followed by 1 g/kg on day 3) decreases the

incidence of type 1 hepatorenal syndrome and reduces short-term mortality (from 30% to 10%)

[57]. Current

guidelines recommend the administration of albumin in all patients with SBP (level of evidence I, strong recom-

mendation)

[43,49]. Improvement in effective arterial blood volume and in systemic hemodynamics, attenuation

of endothelial dysfunction and immunomodulation are the mechanisms behind these positive effect of albumin

in SBP.

Liver transplantation

SBP carries a very poor prognosis. Current hospital mortality ranges from 10% to 20% despite infection resolu-

tion. The 1-year probability of survival after an episode of SBP is approximately 30%50%. Therefore, patients

recovering from an episode of SBP should be considered as potential candidates for liver transplantation

[43,49].

Sepsis or shock?

Risk factors for MDROs?

Carbapenem + GPC coverage

YES

Ertapenem

TGC

Pneumonia, peritonis, meningis?

YES

Re-evaluaon of anbioc treatment at 48 h

Posive cultures

Adjust to microbiological results

(monotherapy if possible)

Negave

Adjust to

colonizaon data

- Change carbapenems by TGC

- Stop daptomycin, linezolid or

glycopepde if no isolaon of

MRSA, VSE or VRE

Rectal/nasal colonizaon

by MDROS?

YES

FIGURE 12.6 Empirical antibiotic schedules suggested in cirrhotic patients with sepsis or shock. Empirical treatment is decided accord-

ing to the severity of infection, the presence of risk factors for MDROs and the local epidemiology. Broad-spectrum antibiotics are prescribed

in the most severe infections covering all possible pathogens. Antibiotic schedules are re-evaluated after completing 48 of therapy, considering

also the data on epidemiological surveillance. # Glycopeptides, daptomycin in infections with high risk of bacteremia (catheter, endocarditis)

or linezolid in pneumonia, cellulitis or meningitis. MDROs multidrug-resistant organisms; TGC, third-generation cephalosporins; MRSA;

methicillin-resistant S. aureus; VSE, vancomycin-susceptible enterococci; VRE, vancomycin-resistant enterococci.

160 12. Sepsis and the liver

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Bacterial infections unrelated to SBP

Infections other than SBP represent more than two-thirds of the infectious episodes occurring in patients with

decompensated cirrhosis. Urinary-tract infections, pneumonia, skin soft tissue infections, and bacteremia are the

most frequent ones

[43,45,47,49,58]. Endovascular infections (endocarditis and “endotipsitis”[infection of a trans-

jugular intrahepatic portosystemic shunt stent]), secondary peritonitis, meningitis, and ost eoarticular infections

are infrequent but show the highest hospital mortality rates (30 to 60%)

[49]. As mentioned earlier, the pathogen-

esis of spontaneous bacteremia and spontaneous bacterial empyema is identical to that exposed for SBP. Urinary-

tract infections, pneumonia, and secondary bacteremia are also favored by urinary catheterization, endotracheal

intubation, central line insertion, and invasive procedures, respectively

[43,49].

Diagnosis

Diagnosis of non-SBP infections is based on clinical and analytical grounds and requires a complete work-up,

including a blood analysis with C-reactive protein and procalcitonin levels, blood cultures, urinary sediment and

culture, chest X-ray, diagnostic thoracocentesis and pleural fluid culture (in the presence of pleural effusion), and

gram-stain and culture of sputum or bronchial aspirate

[48,54]. Diagnostic criteria of the main non-SBP infections

are the following: urinary tract infection: abnormal urinary sediment ( . 1020 leukocytes/field) and positive uri-

nary culture ($105 CFU) or uncountable leukocytes per field if negative cultures; spontaneous bacteremia: posi-

tive blood cultures and no cause of bacteremia; secondary bacteremia: (1) catheter-related infection (positive

blood and catheter cultures), (2) bacteremia occurring within 24 hours after an invasive procedure; pneumonia:

clinical signs of infection and new infiltrates on chest X-ray; spontaneous bacterial empyema: neutrophil count in

pleural fluid $ 500/mm

(250/mm

if positive culture) and skin and soft tissue infections: clinical sign s of infec-

tion associated with swelling, erythema, heat, and tenderness in the skin. The diagnosis of the rest of infections is

made according to conventional criteria

[43,49].

Novel molecular methods are now commercially available to rapidly identify the bacteria responsible for infec-

tion. Assays based on microarrays or multiplex PCR and on matrix-assisted laser desorption/ionization time-of-

flight mass spectrometry permit a faster identification of resistant bacteria

[54].

Treatment

Antibiotic treatment

Prompt initiation of adequate antibiotic therapy is essential in the management of patients with cirrhosis and

non-SBP infections, especially in those with sepsis or ACLF. The choice of initial empirical antibiotics should be

based first on the severity of infection and second on the type and origin of infection and on the local epidemio-

logical pattern of antibiotic resistance. As occurs in patients with SBP, third-generation cephalosporins are nowa-

days limited to the empirical treatment of nonsevere infections acquired in the community. Broad-spectrum

antibiotics capable to cover all potential pathogens according to local epidemiological pattern of multidrug-

resistant organisms should be used in the rest of cases

[43,49]. This strategy is supported by a recent study that

demonstrates the efficacy of adapting empiric antibiotic strategies to the local pattern of resistance. In this investi-

gation, the administr ation of broad-spectrum antibiotics was more effective than third-generation cephalosporins

or amoxicillin-clavulanic acid in the empirical treatment of healthcare-associated infections

[59].

Once the causative organism is identified, antibiotic regimen should be narrowed to decrease the likelihood of

emergence of antibiotic resistance. Duration of antimicrobial treatment has not been formally investigated or

defined in non-SBP infections in cirrhosis. However, short-term treatments (710 days) are recommended in the

majority of patients in order to minimize the development of antibiotic resistance, except for infections caused by

S. aureus, intracellular strains, fungal infection, abscesses, parap neumonic empyema, biofilm formation, or infec-

tions with predefined duration of treatment

[43,48,49,54].

Intravenous albumin

Three studies have evaluated the clinical impact of human albumin in this setting and all three have failed to

demonstrate an improvement in survival

[6062]. Therefore, albumin administration cannot be recommended

nowadays in the treatment of infections unrelated to SBP as the beneficial effect observed in patients with cirrho-

sis and SBP is not extensive to patients with other infections

[43,49].

161Sepsis in patients with cirrhosis

III. Cardiovascular system in liver failure

https://t.me/medicina_free

Management of septic shock

Due to lack of specific studies in ci rrhosis, current guidelines defined in the general population should be fol-

lowed

[28,63]. A pro mpt (within the first 6 hours) protocoled resuscitation of sepsis-induced hypoperfusion with

predefined targets (mean arterial pressure $ 6065 mm Hg and normalization of lactate levels) is recommended.

Whether albumin or crystalloids should be used in the resuscitation process is still undefined. A strict monitoring

of patients’ responsiveness to fluid replacement is necessary to avoid fluid overload, peripheral edema, and

anasarca.

Current guidelines only recommend stress dose steroids in patients with vasopressor-unresponsive septic

shock in the general population

[28,63]. The clinical impact of stress dose steroids on the outcome of cirrhotic

patients with septic shock is unclear. A small uncontrolled cohort study suggested that hydrocortisone (50 mg IV

every 6 hours) could shorten the duration of shock resolution and improve survival in these patients

[64].

However, a subsequent RCT did not confirm these beneficial effects of steroids in cirrhotic patients with septic

shock

[65]. A large double-blind European randomized clinical trial is currently underway to address this topic.

Prevention of bacterial infections

Antibiotic prophylaxis in cirrhosis must be restricted to selected patients at a very high risk for the develop-

ment of SBP in order to prevent the development of antibiotic resistance [43,48,49,66]. Two recent randomized

clinical trials suggest that albumin administration can prevent SBP and non-SBP infections in patients with

decompensated cirrhosis

[62,67]. Infection control practices (hand hygiene, barrier precautions, and the imple-

mentation of bundles on prevention and control of ventilator-associated pneumonia and catheter-related infec-

tions) are also important in the prevention of bacterial infections in cirrhosis, especially in critical care

[54].

Fungal infections

Invasive fungal infections may occur in the immune-compromised host, including those patients with

advanced cirrhosis. Candida spp. accounts for the great majority of these infections, followed by invasive asper-

gillosis. However, the risk of fungal infections is substantially lower than that reported for bacterial strains,

except for patients with severe alcoholic hepatitis treated with steroids

[32,68].

Conclusions

Sepsis is defined as a life-threatening organ system dysfunction caused by a dysregulated immune host

response to infection. Organ dysfunction is an acute change in the SOFA organ subscore of 2 points or more,

which is associated with an in-hospital mortality of more than 10%. The liver is one of the organ systems whose

dysfunction can mediate poor outcome of infection. However, the liver is also an organ generating protective

responses against infection. Sepsis is one of the phenotypes of ACLF, which complicates acutely decompensated

cirrhosis. In patients with cirrhosis, infection should be promptly recognized and treated with empiric large-

spectrum antimicrobial therapies.

Acknowledgments

We thank Ferran Aguilar and Pere Lluis Leon for assistance with figures.

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