Advances in Medical Sciences 62 (2017) 345–356

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Advances in Medical Sciences

journal homepage: www.elsevier.com/locate/advms

Review Article

Bacterial infections and hepatic encephalopathy in liver

cirrhosis–prophylaxis and treatment
 -Kaczmarska
Damian Piotrowski* , Anna Boron
Department of Infectious Diseases, Medical University of Silesia in Katowice, Bytom, Poland

A R T I C L E I N F O A B S T R A C T

Article history:
Received 30 March 2016 Infections are common among patients with liver cirrhosis. They occur more often in cirrhotic patient
Accepted 29 November 2016 groups than in the general population and result in higher mortality. One reason for this phenomenon is
Available online 14 May 2017 bacterial translocation from the intestinal lumen that occurs as a consequence of intestinal bacterial
overgrowth, increased permeability and decreased motility. The most common infections in cirrhotic
Keywords: patients are spontaneous bacterial peritonitis and urinary tract infections, followed by pneumonia, skin
Liver cirrhosis and soft tissue infections. Intestinal bacterial overgrowth is also responsible for hyperammonemia,
Bacterial infections which leads to hepatic encephalopathy. All of these complications make this group of patients at high risk
Antibiotics
for mortality. The role of antibiotics in liver cirrhosis is to treat and in some cases to prevent the
Prophylaxis
development of infectious complications. Based on our current knowledge, antibiotic prophylaxis should
Treatment
be administered to patients with gastrointestinal hemorrhage, low ascitic fluid protein concentration
combined with liver or renal failure, and spontaneous bacterial peritonitis as a secondary prophylaxis, as
well as after hepatic encephalopathy episodes (also as a secondary prophylaxis). In some cases, the use of
non-antibiotic prophylaxis can also be considered. Current knowledge of the treatment of infections
allows the choice of a preferred antibiotic for empiric therapy depending on the infection location and
whether the source of the disease is nosocomial or community-acquired.
© 2017 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346
2. Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346
2.1. Search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346
2.2. Inclusion and exclusion criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346
3. Review: The influence of the microbiota on liver disease: pathomechanisms of the microbiota . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 346
4. Bacterial complications in liver cirrhosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
4.1. Spontaneous bacterial peritonitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
5. Hepatic encephalopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 348
6. Diagnosis of bacterial infection in liver cirrhosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
7. Treatment of bacterial infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
8. Antibiotics in prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 350
8.1. Primary prophylaxis: patients hospitalized due to gastrointestinal hemorrhage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351
8.2. Primary prophylaxis: patients with low ascitic protein concentration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351
8.3. Secondary prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 351
8.4. Hepatic encephalopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352
9. Antibiotic prophylaxis and quinolone resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352
10. Alternative methods of infection prophylaxis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352
10.1. Probiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 352
10.2. Bile acids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
10.3. Prokinetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353

* Corresponding author at: Department of Infectious Diseases, Medical University of Silesia in Katowice, Aleja Legionów 49, 41-902 Bytom, Poland. Fax: +48 32 2819245.
E-mail address: dpiotrowski@sum.edu.pl (D. Piotrowski).

http://dx.doi.org/10.1016/j.advms.2016.11.009
1896-1126/© 2017 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.
346  -Kaczmarska / Advances in Medical Sciences 62 (2017) 345–356
D. Piotrowski, A. Boron

11. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353

Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
Financial disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353

Core tips: This paper is an assembly of current knowledge peer-reviewed journal regarding the influence presence of liver
regarding bacterial infections and other complications of liver cirrhosis and its association with bacterial infections. The
cirrhosis such as hepatic encephalopathy. It consists of previously duplicates were excluded; the excess of animal model studies
performed studies on the most common infections in the course of were excluded if there were available studies regarding the same
end-stage liver fibrosis. The article presents a summary of the issue performed on humans.
epidemiological studies results from different countries. It also Fig. 1 shows that there were found 120 full-text original articles.
includes guidelines for current indications for antimicrobial Five studies were excluded because they were duplicates. Low
prophylaxis. There has been discussed the current guidelines for clinical relevance to date was the reason for excluding another 22
empiric treatment of bacterial infections, that coexist with the liver studies. Finally, 19 articles were excluded due to not evaluable data.
cirrhosis. Finally there have been selected 74 original articles [10].

1. Introduction 3. Review: The influence of the microbiota on liver disease:

pathomechanisms of the microbiota
The human gastrointestinal tract is the largest surface covered
by the epithelium in the body [1]. This surface is exposed to The microbiota that can be found in the human gastrointestinal
multiple microorganisms, including intestinal bacteria, archaea, tract plays a pivotal role in maintaining the health of the host [2],
viruses and others such as protozoa [2]. The endogenous intestinal including but not limited to processing food, synthesizing
microbiota creates an ecological system that plays roles in vitamin vitamins, digesting indigestible polysaccharides [9,11,12] and
production, bile acid degradation, digestion, and immunity (both secreting bioactive metabolites that may affect the host's
local and general [3]), and together with the intestinal mucosa metabolism [12]. These organisms may also play a significant role
forms a barrier against pathogens [4]. There is a relationship in the pathogenesis of liver disease [2]. One possible complication
between the gut and the liver: blood with its intestinal content is small intestinal bacterial overgrowth (IBO). While pathogenesis
flows through the portal system and activates liver functions, while associated with the intestinal microbiota has not been clearly
the liver produces the bile that is secreted into the gut to make fat demonstrated, there is some evidence that alcohol metabolites and
digestion possible. pro-inflammatory cytokines allow the overgrowth of intestinal
Liver damage may be caused by various factors including but flora [13–16]. Alcohol results on qualitative change of the
not limited to viral infections, toxic damage and metabolic microbiota (in humans [17,18] and in animal models [19–21]).
diseases. Changes in the intestinal microbiota may induce or Other factors that contribute to bacterial overgrowth include the
worsen liver damage [5]. Liver cirrhosis is the tenth most common modulation of gastric acid secretion, decrease of intestinal motility,
cause of death in the Western world, and infections are among the lack of bile constituents, antimicrobial peptides, and portal
causes of acute decompensation of liver disease [6–8]. hypertension [15,19,22]. Changes in intestinal microbial composi-
This paper is a summary of the current knowledge of the tion may also have an influence on homeostasis. Among the factors
prophylaxis and treatment of bacterial infections in patients with that affect intestinal microbiota, environmental and genetic should
liver cirrhosis and other complications of liver disease, such as be mentioned [23]. The microbial inhabitants from populations
hepatic encephalopathy (HE) [9]. with similar cultural factors like hygiene, exposure to antibiotics,
chemicals, and diet are more similar than populations in different
countries [24]. Bacteria gain energy from the diet. There are also
2. Materials and methods
observations that microbiota can regulate nutrient harvest.
Increase in Firmicutes and decrease in Bacteroides were associated
2.1. Search strategy
with an intensified energy harvest [23]. Alcohol also results in
A broad search of the relevant literature for this topic was
conducted. Searches in PubMed, Embase, and the Web of Science
included but was not limited to the following search terms: “liver
cirrhosis AND prophylaxis”, “liver cirrhosis AND SBP”, “liver cirrhosis
AND infections”, “liver cirrhosis AND antibiotics”, “SBP prophylaxis”,
“spontaneous bacteremia AND liver AND prophylaxis OR treatment”,
“intestinal flora AND cirrhosis”, “norfloxacin AND prophylaxis”,
“ciprofloxacin AND prophylaxis”, and “rifaximine AND liver cirrhosis”,
“hepatic encephalopathy AND treatment”, “hepatic encephalopathy
AND prophylaxis”, “bacterial translocation”, “gut microbiota”, “TLR
AND cirrhosis”, “bacterial infection AND cirrhosis AND prevention”,
“infection diagnosis AND cirrhosis”. The articles that were found
had been published between 1994 and 2016. The inclusion and
exclusion criteria were set “a priori” (see below).

2.2. Inclusion and exclusion criteria

There were selected studies that matched following criteria:

observational or case-control studies, meta-analyses published in a Fig. 1. PRISMA 2009 flow diagram [10].
  -Kaczmarska / Advances in Medical Sciences 62 (2017) 345–356
D. Piotrowski, A. Boron
decrease of commensal bacteria (among others Lactobacillus). Its
chronic administration is the reason for decrease in production of
long-chain fatty acids (LCFAs) and therefore for reduction of
lactobacilli, for whom LCFAs are energy source [21]. Antibiotics are
another factor that causes dysbiosis by eliminating vulnerable
bacteria.
As the defense mechanism weakens, the probability of bacterial
translocation outside of the intestine rises. Bacterial translocation
occurs due to increased intestinal permeability and lowered
intestinal motility and can form the basis for the progression of
liver disease and the development of complications [2]. For
example, a greater probability of spontaneous bacterial peritonitis
(SBP) was observed when cirrhotic patients with and without
intestinal bacterial overgrowth were compared. Moreover, while
experimental intestinal bacterial overgrowth may result in
microbial translocation and liver inflammation [1], studies of
patients with decreased bacterial numbers due to antibiotic use
demonstrated that their liver disease was ameliorated and the
infectious complications in patients with advanced cirrhosis were
decreased [6]. The term “bacterial translocation” (BT) indicates the
migration of microorganisms and their products (also called
pathogen-associated molecular patterns or PAMPs) [i.e., endotox-
ins such as lipopolysaccharide (LPS), bacterial DNA, peptidogly-
cans, and lipoteichoic acid] across the intestinal barrier from the
intestine lumen to the mesenteric lymph nodes and extraintestinal
organs and sites [9,25]. Microbial products translocate through
disrupted tight junctions using paracellular route from the
intestinal lumen into extraintestianal tissues and organs; living
bacteria appear to translocate through the transcellular route
(transcytosis) [26].
The studies regarding intestinal permeability are mostly
performed in animal models. Fig. 2 illustrates the process in
animal model. There is deficiency of intestinal permeability studies
in human models; they are mostly focus on the paracellular
pathway, and not the transcytosis.
The composition of the microbiota is not constant throughout
the host's life and varies depending on age, diet, sanitation level
and antibiotic exposure [11,25]. When the host reaches maturity,
the microbiota remains stable until old age, when changes may
occur due to changes in diet and digestive physiology. The study of
Claesson et al. identified correlations between gut flora and diet in
the elderly and between gut flora and health status [27]. The
Fig. 2. Connection between alcohol, intestine and liver: bacterial overgrowth and
intestinal permeability are induced by alcohol directly or by acetaldehyde [2,25,26].
347
alteration of gastrointestinal tract flora has been studied in
patients with liver disease. Chen et al. [28] demonstrated that
Bacteroides and Lachnospiraceae were reduced in patients with
cirrhosis, while Proteobacteria, Fusobacteria, Enterobacteriaceae,
Veillonellaceae and Streptococcaceae were increased. Similar results
were reported by Bajaj et al. [29], who showed that Veillonellaceae
was abundant and present in higher numbers in cirrhotic patients
with hepatic encephalopathy compared to the group without HE.
This study also confirmed that the extensive Enterobacteriaceae
family (including Salmonella, Shigella, Yersinia pestis, Klebsiella and
Escherichia coli) was more numerous in cirrhotic patients [28,30]. It
should be noted that Escherichia coli is most common pathogen
that causes bacteremia and spontaneous bacterial peritonitis
(SBP).
Another interaction worth mentioning, especially in the context
of liver disease, is alcohol. Alcohol promotes the growth of Gram-
negative bacteria with a subsequent increase in endotoxin
synthesis. Moreover, Gram-negative bacteria also possess an
alcohol dehydrogenase and are able to metabolize alcohol to
acetaldehyde, which increases intestinal permeability.
Additionally, chronic alcohol feeding in mice results in
subclinical intestinal inflammation [31]. Similar findings were
confirmed in duodenal biopsies from patients with chronic alcohol
abuse [31]. When combined, these effects of alcohol lead to the
increased transfer of endotoxin to the portal system [9,16].
The increased intestinal permeability is observed in many
different conditions. Even high fat diet increases intestinal
permeability in humans [32]. If patient suffers from non-alcoholic
fatty liver disease (NAFLD), his intestine permeability will be
increased comparing to healthy individuals [33]. This kind of bowel
dysfunction may be a result of liver disease, but also of intestinal
inflammation. The intestinal inflammation often coexists in
patients with chronic liver disease [23] and in decompensated
cirrhosis may be the trigger for a further increase of intestinal
permeability [1].
Due to the influence of gut bacteria on the severity of liver
cirrhosis and its complications, intestinal decontamination may
improve liver disease intensity. The majority of conducted studies
investigating decompensated cirrhosis identified three main
factors that affected bacterial translocation: intestinal bacterial
overgrowth, increased intestinal permeability and inadequate
immunity [34]. Bacteria identified as the source of acquired
infections were exactly the same as the bacteria that overgrew in
the small intestine. Additionally, an increase in intestinal
permeability has been reported in liver cirrhosis due to variety
of factors, such as oxidative stress, alterations of enterocyte
mitochondrial function, structural changes [1], and weakening of
the secretory barrier due to deficiencies in bile, IgA, and
antimicrobial peptides [15].
Bacterial translocation affects not only patients with decom-
pensated liver cirrhosis but also patients in the non-cirrhotic
stages of liver disease. Bacterial translocation was found to be a
relevant factor in fibrogenesis [35] and inflammation [36]. The
endotoxemia is a consequence of the increased intestinal
permeability. As the bacterial products reach the liver through
portal system, they activate receptors including Toll-like receptors
(TLRs). The TLRs signaling pathway promotes liver inflammation
[37]. Among the TLRs family, TLR2 is a receptor for Gram-positive
bacteria that recognizes, inter alia, lipoproteins, peptidoglycan, and
lipoteichoic acid [38–40].
Central role in the innate immune response to bacterial
translocation is played by TLR4, which is a cellular receptor for
endotoxin. After binding LPS to TLR4, MyD88-dependent and
MyD88-independent (TRIF/IRF-3-dependent) pathways are acti-
vated for cells derived from bone marrow (including Kupffer cells)
and liver cells including hepatic stellate cells (HSCs) [41]. The result
348  -Kaczmarska / Advances in Medical Sciences 62 (2017) 345–356
D. Piotrowski, A. Boron
of activating TLRs is induction of synthesis of cytokines and
chemokines that leads to migration of inflammatory cells
(neutrophils, monocytes, and macrophages) into the liver.
Activated Kupffer cells produce variety of pro-inflammatory
cytokines (TNF-a, IL-6, IL-1), chemokines (CXCL1, CXCL2, CCL2,
CCL3, CCL4, CCL5), reactive oxygen species [36], and pro-fibrogenic
mediators, such as TGF-b and PDGF.
The excessive production of pro-inflammatory cytokines may
lead to the systemic inflammation. Pro-fibrogenic factors have an
influence on HSCs to transdifferentiate into myofibroblasts, and
produce extracellular matrix (ECM) proteins [42]. The excessive
production and deposition of ECM proteins cause hepatic fibrosis
[40,43], and therefore is responsible for the portal hypertension
progress.
4. Bacterial complications in liver cirrhosis
Bacterial translocation is a physiological process in healthy
conditions and it is crucial for host immunity. In cirrhosis,
“pathological” BT develops with increase in quantity of BT. In
humans there is a lack of access to mesenteric lymph nodes and
setting the “cut-off” for physiological BT [1]. Epithelial integrity is
essential in preventing the entry of potentially harmful substances
(bacteria or their products) into the portal circulation through
transcellular or paracellular pathways [44]. Study by Pijls et al.
showed the increased intestine permeability in patient with
compensated cirrhosis compared with control group. Cirrhotic
patients have an increased risk of developing bacterial infections
due to bacterial overgrowth and increased bacterial translocation
[45,46]. It must be noted that SBP is most likely caused by the
bacteria that have been translocated from intestine [1,15]. Bacterial
translocation causes also pro-inflammatory state that worsens the
hemodynamic status of patients with cirrhosis and leads to
decompensation. The immune activation (“cytokine storm”)
causes development of cirrhosis-associated immune dysfunction
that increases susceptibility to other infections [47–49]. The risk of
developing infections during hospitalization of cirrhotic patients
has been summarized; the probability of infection incidence at
admission is 25–35% [50], which is 4–5-fold higher than the risk for
the general population. The most common infections are urinary
tract infections and SBP, followed by pneumonia, soft tissue and
skin infections, and bacteremia [46]. The risk factors for infection
are liver cirrhosis, bleeding esophageal varices, low concentration
of ascitic fluid proteins, past SBP episodes, and hospitalization [46].
Cirrhotic patients have not only a risk of infection occurrence but
Table 1
Most common bacteria responsible for infections in cirrhosis [46].
Infection type
Spontaneous bacterial peritonitis and spontaneous bacteremia
UTI
Pneumonia
Skin and soft tissue infections
UTI: urinary tract infection.
also a risk of infections with increased severity. The probability of
death rises 3.8-fold and reaches 30% at 1 month and 63% at 1 year
in decompensated liver disease [51]. In advanced liver cirrhosis,
bacterial translocations affect the disease and aggravate hepatic
failure, encephalopathy and/or hepatorenal syndrome [51]
(Table 1).
4.1. Spontaneous bacterial peritonitis
We defined primary SBP as an infection of the ascitic fluid that
was formerly sterile with no intra-abdominal infection source [46].
The symptoms that accompany this diagnosis may include fever,
abdominal pain, vomiting, diarrhea or gastrointestinal bleeding,
signs of renal impairment, and hepatic encephalopathy. To
diagnose SBP, it is mandatory to demonstrate that polymorpho-
nuclear (PMN) count in the ascitic fluid is greater than or equal to
250 cells per mm3. Positive blood cultures could be found in SBP in
30–40% depending on study [50,52–54]. There is also possible to
get positive culture from ascitic fluid with PMN count less than
250 cells per mm3 in a patient without intra-abdominal infection.
This is called bacterascites [55]. Another complication worth
mentioning is secondary peritonitis. This complication is not
frequent (it occurs in approximately 5–10% of all cirrhosis and
ascites cases); however, it is characterized by a much higher
mortality rate compared to SBP (66% vs. 10% [56]). Runyon's criteria
have been proposed to distinguish SBP and secondary peritonitis.
The criteria assume the presence at least two of the following:
protein concentration in ascites higher than 10 g/L, glucose
concentration in ascitic fluid lower than 50 mg/dL (2.8 mmol/L),
and ascitic LDH concentration higher than the serum concentra-
tion [56,57]. Depending on the cause of secondary peritonitis,
other biochemical markers can be found in the ascitic fluid. For
example, high amylase activity may point to pancreatitis or gut
perforation as the cause of secondary peritonitis.
5. Hepatic encephalopathy
Hepatic encephalopathy is a complex disease that ranges from
mild symptoms (confusion) to coma; it may occur as a result of
liver failure (acute or chronic), portal hypertension and cirrhosis.
Hepatic encephalopathy is an important disease entity because the
risk of dying within one year exceeds 60% after development [58].
Additionally, the incidence of hepatic encephalopathy is quite
common–the risk of developing it reaches 15% in one year in
patients with liver cirrhosis and ascites [59]. The pathology of
Responsible bacteria
Escherichia coli, Klebsiella pneumoniae, Enterobacter spp., Streptococcus pneumoniae
Streptococcus viridans
Escherichia coli, Klebsiella pneumoniae,
Enterococcus faecalis,
Enterococcus faecium
Streptococcus pneumoniae,
Mycoplasma pneumoniae,
Legionella spp.,
Haemophilus influenze,
Klebsiella pneumoniae,
Pseudomonas aeruginosa,
Staphylococcus aureus
Staphylococcus aureus,
Streptococcus pyogenes,
Escherichia coli,
Klebsiella pneumoniae,
Pseudomonas aeruginosa
  -Kaczmarska / Advances in Medical Sciences 62 (2017) 345–356
D. Piotrowski, A. Boron
hepatic encephalopathy is multifactorial and among the others
includes the metabolism of ammonia. It is worth to note that
intestinal bacterial overgrowth is associated with higher ammonia
production and higher serum ammonia concentrations; however,
the decrease of ammonia clearance by the kidneys (which is also
affected in advanced cirrhosis) can also contribute to higher serum
ammonia concentrations [60]. Regardless of the reason for the
hyperammonemia, it influences the induction of encephalopathy
through the promotion of cerebral edema, modulation of the
blood–brain barrier and neuroinhibition [9,59,60].
Hepatic encephalopathy not related to cirrhosis-acquired
systematic infection may be a complication of intestine bacterial
overgrowth and subsequent hyperammonemia. Because the
causative agent is bacteria in the bowel, the treatment for hepatic
encephalopathy includes the reduction of intestinal flora or switch
of its composition. This can be achieved by treatment with non-
absorbable disaccharides such as lactulose, which reduces
ammonia generation from bacteria with a faster intestinal transit
time. Other treatments that have been found to be successful
include supplementation with branched-chain amino acids
(valine, leucine, and isoleucine), because they correct the
disproportion of branched-chain and aromatic amino acids and
reduce false neurotransmitter synthesis [61–63]. Antimicrobial
treatment should include non-absorbable or poorly absorbable
antibiotics such as norfloxacin and rifaximin. The mechanism for
their action is to eradicate bacterial overgrowth and lower
intestinal ammonia production. Various studies and meta-analyses
(inter alia by Lata et al. [64], Wu et al. [65], and Hadjihambi et al.
[66]) confirmed the efficacy of rifaximin in overt hepatic
encephalopathy treatment [9].
6. Diagnosis of bacterial infection in liver cirrhosis
Positive cultures from blood, urine or ascitic fluid are the perfect
laboratory tests to confirm a bacterial infection and to determine
the species of the pathogen. As mentioned above, there is a
possibility that bacteria isolation fails in numerous of infections. It
may be caused by culture media, which does not allow to form the
colony. The other possibility is the presence of nondividing
bacterial cells (for example after antibiotic therapy that caused a
block of bacterial division). Another cause is lack of bacteria, but
the presence of bacterial products–they can still cause a host
response, being undetectable in cultures [67].
The molecular methods are alternative to the cultures. Even if
pathogen is not detectable in culture, its DNA still can be found.
There is a possibility to detect bacterial DNA (a gene for 16S RNA)
using directed polymerase chain reaction [67]. DNA-DNA hybrid-
ization is another method to detect and identify pathogens [68,69].
These methods show better sensitivity and are faster – the results
could be delivered within a day [69].
The time of diagnosis is crucial for patients. Common clinical
symptoms, such as systemic inflammatory response syndrome
(SIRS), and basic laboratory tests: blood leukocyte count, C-
reactive protein (CRP), and procalcitonin (PCT) are routine markers
of infection in general population. These laboratory tests can be
also used for diagnosis infection in liver cirrhosis [70–73]. In 2015
study by Papp et al. [74] showed that presepsin can also be another
marker for infection in cirrhotic patients.
It seems that diagnosis of infection should be set up on the basis
of clinical symptoms and laboratory test (blood leukocyte count,
CRP, PCT). The next step should include samples collection (for
example blood, ascitic fluid) for cultures and the beginning of
empirical treatment. There is a possibility that the cultures are
negative. On the one hand, the diagnosis of sterile inflammation
could be set, on the other hand, molecular diagnostic could be used
for widening diagnosis.
349
7. Treatment of bacterial infections
Cirrhotic patients with severe infections should receive anti-
biotics by IV as soon as the diagnosis is confirmed, because delays
in treatment cause higher mortality [75]. The treatment (empirical
in the beginning) should cover a wide spectrum of possible
bacteria and not cause adverse events. Third-generation cepha-
losporins have been considered for many years to be a gold
standard for the empirical treatment of many infections in
cirrhotic patients due to their activity against Enterobacteriaceae
and non-enterococcal Streptococcus spp. and their good tolerance
[57]. The disadvantage of these antibiotics is the rising resistance of
bacteria to this drug group. It is most common in nosocomial
infections but is also observed in community-acquired infections
when patients are hospitalized or have contact with the health care
system prior to infection [76,77].
Third-generation cephalosporins are still recommended for
the empirical therapy of community-acquired SBP [46,78,79];
previous studies showed that amoxicillin with clavulanic acid
and ciprofloxacin provide similar results [80]. However, more
recent studies demonstrated that third-generation cephalospor-
ins were highly effective in treatment of SBP ten years ago, when
Gram-negative bacteria were responsible for most cases of SBP
and classification into community-acquired, health care-associ-
ated and nosocomial was not routinely used [81,82]. Multidrug-
resistant bacteria can be more frequently found in nosocomial
infections (20–35% of infections), but even in the group of
community-acquired SBP its prevalence can reach 4–16%
[50,78,81]. The use of cephalosporins should be restricted to
community-acquired infections [46]. The efficacy of traditionally
recommended therapy has been low in nosocomial infections
[83]. Broad-spectrum antimicrobial agents, such as carbapenems
with or without glycopeptides or piperacillin-tazobactam,
should be considered for the initial treatment not only of
nosocomial infections but also of healthcare-associated infec-
tions when the risk factors or severity signs for multi-resistant
bacteria are apparent [50,78,81]. A recent study by Piano et al.
[81] compared ceftazidime versus meropenem with daptomycin
and proved that meropenem with daptomycin was more effective
than ceftazidime (86.7% vs 25%, p < 0.001) in nosocomial SBP
treatment.
The other common infection in this patient group is urinary
tract infection. Third-generation cephalosporins and amoxicillin
combined with clavulanic acid are recommended for empirical
treatment of this community-acquired infection. Additionally,
quinolones and trimethoprim-sulfamethoxazole are included in
the empirical standard of treatment [46,78]. If the urinary infection
is not complicated, oral antibiotics may be used. Similarly,
quinolones are not recommended whether the patient is
undergoing long-term norfloxacin prophylaxis. Due to frequent
cross-resistance between quinolones and trimethoprim-sulpha-
metoxazol, this therapy is also not recommended in this group of
patients. Uncomplicated nosocomial UTI can be treated with
nitrofurantoin, but every UTI complicated by sepsis, severe sepsis
or septic shock should be treated with carbapenems regardless of
whether it was nosocomial or community-acquired [46,78].
Treatment of pneumonia should cover both typical and atypical
bacteria. Levofloxacin or moxifloxacin or the combination of a
macrolide with a third-generation cephalosporin or amoxicillin-
clavulanic acid is recommended [46] for community-acquired
infection. Nosocomial or health-care associated infection should
be treated with combination of ciprofloxacin with carbapenems or
with third-generation cephalosporin. In addition, it should be
considered, whether patient has risk factors for MRSA infection
(including recent antibiotics use, carriers of MRSA in the nasal
cavity, ventilator-associated pneumonia). In this case vancomycin
350  -Kaczmarska / Advances in Medical Sciences 62 (2017) 345–356
D. Piotrowski, A. Boron

Table 2
Community-acquired infection–suggested empirical therapy for patients with liver cirrhosis [46,78,79,85,87].

Infection type Suggested empirical treatment Suggested treatment durationa

Spontaneous bacterial peritonitis First line treatment: 5 days
Cefotaxime 2 g BID iv or
Ceftriaxone 1 g QD or BID iv or
Amoxicillin + clavulanic acid 1,2 g TID or QID iv
Second line treatment:
Ciprofloxacin 200 mg BID iv or
Meropenem 1 g TID iv or
Piperacillin-tazobactam 4,5 g TID iv or
Imipenem 1 g TID combined with
Vancomycin 500 mg QID or 1 g BID iv or
Teicoplanin 6 mg/kg QD iv
UTI Uncomplicated infection: 5 to 7 days
Ciprofloxacin 500 mg BID po or
Cotrimoxazole 960 mg BID po or
Nitrofurantonine 50 mg QID po
Septic patients:
Cefotaxime 2 g BID iv or
Ceftriaxone 1 g QD or BID iv or
Amoxicillin + clavulanic acid 1,2 g TID or QID iv
Pneumonia Ceftriaxone 1 g QD or BID iv or 7 to 10 days
Amoxicillin + clavulanic acid 1,2 g TID or QID iv combined with macrolide
or
Levofloxacin 500 mg QD iv or po
Skin and soft tissue infections Amoxicillin + clavulanic acid 1,2 g TID or QID iv or
Ceftriaxone 1 g QD or BID with cloxacillin 2 g QID iv

BID: two times a day (Latin: bis in die), QD: once a day (Latin: quaque die), QID: four times a day (Latin: quarter in die), TID: three times a day (Latin: ter in die), UTI: urinary
tract infection.
a
Treatment duration – it may vary depending on the clinical state and laboratory results, see text for details.

or linezolid should be added to the previously mentioned 8. Antibiotics in prophylaxis

antimicrobial agents [46,78].
Treatment duration may vary depending on the clinical state
and laboratory results. A five-day treatment of SBP–that is caused
by Gram-negative bacteria sensitive to third-generation
cephalosporins–may be sufficient to achieve recovery in most
cases [79]. However, recovery should be confirmed by a reduction
of neutrophil count in control paracentesis (performed at least
48 hours after the first one). The therapy may be prolonged if
necessary [79,84]. Duration of community-acquired pneumonia
treatment is 7 to 10 days, while patient is hospitalized, and it can be
shorten to 5 to 7 for outpatient [85,86]. The uncomplicated UTI can
be treated also for 5 to 7 days [87].
Tables 2 and 3 summarize suggested empirical treatment for
both community-acquired and nosocomial infections.
Due to the risk of the bacteria developing antibiotic resistance,
prophylaxis should only be administered to patients with a very
high risk of acquiring bacterial infections [46]. As already
mentioned above, prolonged antibiotical prophylaxis may lead
to resistance of bacteria against antimicrobial agent. That is the
reason why antimicrobial prophylaxis is not recommended for
every cirrhotic patient. Additionally, current prophylaxis strategies
aim to protect patient from acquiring SBP, bacteremia or hepatic
encephalopathy. Currently, there are only a few indications for
long-term antibiotic prophylaxis in cirrhosis patients (see Table 4).
These indications were published by Fernández et al. in 2012 [46].
Since then there have been published new articles that show the
increase of multidrug-resistant bacteria in patients on quinolone

Table 3
Nosocomial infection-suggested empirical therapy for patients with liver cirrhosis [32,78,79].

Infection type Suggested empirical treatment Suggested treatment

durationa
Spontaneous bacterial Meropenem 1 g TID iv 5 days
peritonitis With or without daptomycin 6 mg/kg QD or
Piperacillin-tazobactam 4,5 g TID iv or
Imipenem 1 g TID combined with
Vancomycin 500 mg QID or 1 g BID iv or
Teicoplanin 6 mg/kg QD iv
UTI Carbapenems iv 5 to 7 days
Pneumonia Meropenem 1 g TID iv or 7 to 10 days
Ceftazidime 2 g TID iv
Combined with ciprofloxacin 400 mg TID iv
In case of patients at-risk-of-MRSA pneumonia (recent antibiotics use, Carriers of MRSA in the nasal cavity,
ventilator-associated pneumonia):
Vancomycin iv or linezolid
Skin and soft tissue Meropenem 1 g TID iv or
infections Ceftazidime 2 g TID iv
Combined with glycopeptide

QD: once a day (Latin: quaque die), TID: three times a day (Latin: ter in die), UTI: urinary tract infection.
a
Treatment duration – it may vary depending on the clinical state and laboratory results, antibiotic resistance of bacteria – see text for details.
  -Kaczmarska / Advances in Medical Sciences 62 (2017) 345–356
D. Piotrowski, A. Boron 351

Table 4
Indications of antibiotic prophylaxis in cirrhosis [46].

Indication Suggested treatment Duration

Primary prophylaxis in
gastrointestinal bleeding
Primary prophylaxis in
patient with low protein
ascites (< 15 g/L)
Secondary prophylaxis
Norfloxacin 400 mg BID po or 7 days
Ceftriaxone 1 g QD iv (in advances cirrhosis: at LEAST 2 of following: ascites, jaundice, HE,
malnutrition)
Norfloxacin 400 mg BID po Until LTx or death
(Child–Pugh score  9 points with serum bilirubin  3 mg/dL and/or impaired renal function:
Creatinine  1.2 mg/dL, BUN  25 mg/dL or Sodium  130 mmol/L)
Norfloxacin 400 mg BID po Until LTx or death

BID: two times a day (Latin: bis in die), HE: hepatic encephalopathy, LTx: liver transplantation.

prophylaxis [79,88]. This should be the reason for defining new
prophylactic strategies in cirrhosis [88], whether to shorten
quinolone prophylaxis, as it might be not working after some
period of time, or to find new ways to prevent SBP or bacteremia in
cirrhotic patients.
8.1. Primary prophylaxis: patients hospitalized due to gastrointestinal
hemorrhage
The first group consists of patients with gastrointestinal
bleeding, because they are at risk of developing SBP during the
course of the bleeding or for a short period of time after the
bleeding. The first week after admission is crucial, because half of
observed patient develop infections during the beginning of
hospitalization [52]. Moreover, hemostasis changes and increases
in the blood pressure in the portal system may be induced by
infection [89], resulting in a vicious cycle. Multiple studies have
demonstrated the benefit of using oral or intravenous antibiotics in
cirrhotic patients with gastrointestinal hemorrhages. The admin-
istration of amoxicillin, amoxicillin with clavulanic acid, ceftriax-
one, ceftazidime, cefotaxime, ciprofloxacin, norfloxacin, and
ofloxacin decreased the diagnosed infection rate (10–20%)
compared to the control group (45–66% [46,90]). The reduced
risk of infection improved the survival rate, bleeding control, and
lowered the probability of rebleeding [91]. The use antibiotic
prophylaxis is advised in any case with gastrointestinal hemor-
rhage. The first choice is oral norfloxacin (400 mg BID) due its
administration simplicity and low cost. However, the study by
Fernandez et al. [92] indicated that more aggressive treatment
with ceftriaxone (1 g QD for seven days) in patients with
gastrointestinal bleeding and severe liver failure (defined as at
least two of the following: ascites, severe malnutrition, jaundice or
encephalopathy) was a better choice than norfloxacin. The risk of
developing possible infections, proven infections and SBP or
bacteremia was higher in the norfloxacin group than in the
ceftriaxone group (33% vs. 11%, p = 0.003; 26% vs. 11%, p = 0.03; 12%
vs. 3%, p = 0.03, respectively). The Baveno V consensus conference
recommended the administration of antibiotic prophylaxis at the
time of admission either before or immediately after endoscopy
[9].
8.2. Primary prophylaxis: patients with low ascitic protein
concentration
Another group of patients who should receive antibiotic
prophylaxis consists of patients with low ascitic fluid protein
concentrations (below 10–15 g/L), because their risk of developing
a first SBP episode is high (20% within one year [93]) compared to
patients with higher ascitic protein concentrations (who did not
develop SBP over a 2 year follow-up period [93]). This criterion
itself does not indicate that patients require antibiotic prophylaxis;
indeed, another criterion is required: advanced liver failure
(defined as at least nine points in the Child–Pugh score with at
least three points for serum bilirubin concentration) or impaired
kidney function (defined as creatinine serum concentration of at
least 1.2 mg/dL, BUN greater than or equal to 25 mg/dL or sodium
serum concentration less than or equal to 130 mmol/L). In a study
where the above criteria were met, Fernandez et al. [92]
randomized patients to norfloxacin prophylaxis (400 mg QD for
one year) or a placebo. The risk of developing SBP or hepatorenal
syndrome after the 1 year follow-up was reduced in the
norfloxacin group (7% vs. 61%, 28% vs. 41%, p = 0.02, respectively).
Short-term survival was also improved in the norfloxacin group
(94% vs. 62%).
A study by Terg et al. [94] showed that ciprofloxacin
administered orally in a dose of 500 mg daily could be used
instead of norfloxacin.
Rolachon et al. [95] confirmed that patients benefited from
ciprofloxacin. This study was designed to observe whether 750 mg
of ciprofloxacin taken orally once a week would result in the
development of SBP in cirrhotic patients. The main inclusion
criterion was a low ascitic protein concentration (below 15 g/L).
Seven of sixty included patients had a previous history of SBP. After
randomization only one person with a history of SBP was included
in the placebo group, while the remaining six patients were
randomized into the ciprofloxacin group. Despite the imbalance in
SBP history and higher risk of SBP recurrence in the ciprofloxacin
group, only one patient developed SBP in the treated group vs.
seven patients in the placebo group (3.6% vs. 22%, p < 0.05).
One prospective case-control study by Da nulescu et al. [96]
compared the efficacy of rifaximin prophylaxis over a period of six
months (1 case of SBP in the rifaximin group and 4 cases of SBP in
the no prophylaxis group). However, while the study included 46
patients with higher ascitic fluid concentrations (>14 g/dL), all of
them were at high risk for developing SBP (Child–Pugh C, the
presence of ascites).
8.3. Secondary prophylaxis
The third group that benefits from antibiotic prophylaxis
consists of patients who previously underwent an SBP episode
because the risk of SBP recurrence is high (68% in one year in
patients receiving no or placebo prophylaxis). Norfloxacin reduced
the risk of infection to 20–25% and 3% if the SBP was caused by
Gram-negative bacteria (compared to 60% in the placebo group).
For these patients, norfloxacin (400 mg QD) was a better choice
than a quinolone dose once a week [97] due to the lower risk of SBP
recurrence; moreover, norfloxacin slowed down the selection of
resistant bacteria. Singh et al. [98] showed that administration of
oral trimethoprim-sulfamethoxazole (960 mg QD) 5 days a week
was also efficient for the prevention of SBP or spontaneous
bacteremia (27% in the placebo group vs. 3% in the treatment
group, p = 0.012). This trial stratified patients by serum bilirubin
(>3 mg/dL), ascitic fluid proteins (<1 g/dL) and creatinine (>2 mg/
dL) to ensure that high-risk patients would be similarly distributed
into the two groups. While this approach represented a clear
advantage, the study included both patients who previously had an
SBP episode and patients with no history of SBP. Therefore, the
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D. Piotrowski, A. Boron
interpretation of the results in the context of primary/secondary
prophylaxis may be hindered. However, trimethoprim-sulfameth-
oxazole may be considered as an alternative therapy for patients
unable to take quinolones.
Rifaximin was also studied for the prevention of SBP. The
efficacy of this non-absorbable antibiotic was compared to
norfloxacin prophylaxis and no prophylaxis. Lutz et al. [99]
divided 152 patients into three groups (norfloxacin, rifaximin
and no prophylaxis). The patients were observed for up to 16 weeks
during treatment. During the follow-up period, there were 24 cases
of SBP in the no prophylaxis group (out of 120 patients, 20%), 8
cases in the rifaximin group (out of 32 patients, 25%) and no cases
in the norfloxacin group. The difference between rifaximin and
norfloxacin was significant (p = 0.02); the difference between
norfloxacin and no prophylaxis was also significant (p = 0.04). The
SBP occurrence in the no prophylaxis group and rifaximin group
was considered to be comparable. In contrast, Hanouneh et al.
[100] performed a retrospective study of 404 cirrhotic patients
who were protected against SBP by rifaximin. However, this study
did not compare rifaximin to norfloxacin and excluded patients
with a high risk of developing SBP. Treatment with rifaximin for a
median time of 4.2 months allowed 89% of the patients to remain
SBP-free; this rate was 68% in the non-rifaximin group (p = 0.002).
Based on our current knowledge, rifaximin prophylaxis for SBP
may be reasonable in some subgroups of cirrhotic patients.
However, systemic prophylaxis is more effective and should be
considered as a standard of care [9]. Due to increase of multidrug-
resistant strains during quinolone prophylaxis, the usage of
rifaximin instead may be considered especially in patients with
confirmed presence of quinolone-resistant bacteria.
8.4. Hepatic encephalopathy
The next group that benefitted from the use of both antibiotic
and non-antibiotic prophylaxis consisted of patients with hepatic
encephalopathy. A total of 15% of cirrhotic patient with ascites have
a probability of developing hepatic encephalopathy within one
year [91]; the probability of mortality in these patients is more
than 60% within one year after the occurrence of hepatic
encephalopathy [58]. There is controversy concerning whether
rifaximin is effective for prophylaxis for SBP; however, a number of
studies have shown its efficacy in preventing hepatic encephalop-
athy. Large randomized trials by Bass et al. [101] (299 patients),
Sharma et al. [102] (120 patients), and Sidhu et al. [103] (94
patients) demonstrated the efficacy of rifaximin at different end-
points using rifaximin or rifaximin combined with non-absorbable
disaccharides. The results included decreased recurrent hepatic
encephalopathy and hospitalization rates, improvement in aster-
ixis, and lower mortality and hospitalization duration, respectively.
A retrospective analysis by Neff et al. [104] involved 203 patients
who received rifaximin or rifaximin with lactulose and were
observed for one year; these patients had a hepatic encephalopa-
thy rate of 81% and 67%, respectively. Additionally antibiotic
treatment may also lead to the development of subsequent
infections. Another retrospective analysis by Neff et al. [105] (211
patients) showed no Clostridium difficile infection after long-term
rifaximin uptake. The comparison of adverse events that occurred
during rifaximin or lactulose treatment were described in a meta-
analysis by Dong et al. [106] that revealed that rifaximin treatment
(390 of patients) was safer for the treatment of hepatic
encephalopathy than non-absorbable disaccharides (342 patients).
The comparison of these two groups showed a lower risk of
diarrhea (RR: 0.11, 95% CI: 0.04–0.31; p < 0.0001) and abdominal
pain (RR: 0.34, 95% CI: 0.14–0.83; p = 0.02). Another approach has
been used to decide which treatment method (rifaximin or
lactulose) will be suitable for the patient. Although both non-
absorbable disaccharides and rifaximin play significant roles in
hepatic encephalopathy prophylaxis and treatment, they differ
based on the price for a month's therapy. Assuming various doses
of lactulose (from 40 to 60 g daily) and rifaximin (800 to 1200 mg
daily), their average cost per month is currently 167–250 PLN and
551–827 PLN, respectively [9].
The presented studies results confirmed that rifaximin is safe,
burdened with fewer side effects than non-absorbable disacchar-
ides. In 2010, FDA approved rifaximin as a drug for HE treatment
[29].
Two randomized trials assessed rifaximin versus placebo in
patients with minimal HE [103,107]. There were 136 patients
treated for 8 weeks with rifaximin or placebo, their minimal HE at
the beginning was the first episode of HE ever. Two patients from
placebo group and one from rifaximin group developed overt HE.
Data from these trials were inconclusive. The application of this
drug in overt HE is recommended, it should be also discussed the
rifaximin administration as a first-line for minimal HE or HE
prophylaxis. Available studies showed that the usage of rifaximin is
at worst as effective as non-absorbable disaccharides but with
fewer adverse events.
9. Antibiotic prophylaxis and quinolone resistance
Despite the fact that current studies show benefits from
antibiotic prophylaxis in selected groups of patients, prolonged
antibiotic usage leads to the emergence of resistant bacteria. The
recurrence of SBP in patients with quinolone prophylaxis is caused
more often by Gram-positive cocci (mainly streptococci in up to
50% of SBP cases vs. 16% in a group that did not receive norfloxacin
prophylaxis). Moreover, Gram-negative bacilli resistant to quino-
lones can also lead to the development of SBP or urinary tract
infections. Overall, depending on the study 26% to 38% [108,109] of
SBP cases were caused by quinolone-resistant Gram-negative
bacteria. These studies also showed a high percentage (44–72%) of
bacteria resistant to trimethoprim-sulfamethoxazole [109]. Thus,
this antibiotic should not be considered as an alternative to
norfloxacin [9]. The use of other antimicrobial drug, for example
rifaximine, should be considered.
10. Alternative methods of infection prophylaxis
To reduce the risk of the development of resistant bacteria,
limited use of antibiotics should be considered. Because these
medications are important for cirrhotic patients and patients
benefit from their use (as discussed above), this is not a discussion
concerning whether to use antibiotics or nothing at all. Instead, we
will analyze whether other non-antibiotic medications may be
useful for the treatment of cirrhotic patients. Because the primary
agents of infection in cirrhotic patients are intestinal bacteria, most
current therapies focus on intestinal bacterial overgrowth,
increased intestinal permeability and subsequent bacterial trans-
location, and decreased immunity.
The authors have found several studies that showed benefits
from using probiotics, bile acids, and prokinetics. Unfortunately,
those studies are relatively old (they were published between 2000
and 2008) and are only partially based on humans. Even these ones
focused on soft endpoints like presence of endotoxemia or the
bacterial composition of the stool. The results were optimistic, and
perhaps this could become a base for further research.
10.1. Probiotics
Therapy with Lactobacillus spp. in rat models (Bauer et al. [110]
and Wiest et al. [111]) showed no reduction in bacterial
translocation or SBP development. Rayes et al. [112] added fiber
  -Kaczmarska / Advances in Medical Sciences 62 (2017) 345–356
D. Piotrowski, A. Boron
to Lactobacillus spp. and observed a lower rate of postoperative
bacterial infections in the fiber-Lactobacillus group than in the
intestinal decontamination alone group. The studies performed on
rats fed ethanol compared to rats fed ethanol and Lactobacilli by
Forsyth et al. [113] showed the reduced endotoxemia in the group
fed with ethanol and treated with Lactobacillus. The lower
endotoxemia was correlated with reduced intestinal and liver
inflammation.
The beneficial effect of probiotics in viral hepatitis has not been
widely studied. One interesting study by Chen et al. [114]
demonstrated that the prebiotic lactitol increased the number of
beneficial bacteria and caused a reduction in serum endotoxin
concentrations in patients with hepatitis B and C compared to the
control group. The endotoxemia was decreased through an
increase in Lactobacillus and Bifidobacterium with the potential
to inhibit pathogenic bacterial overgrowth.
Liver function improvement was observed in studies by Liu
et al. [115] and Lata et al. [116], where treatment with probiotics
resulted in an improvement and reduction in the Child–Pugh class
in 50% of studied patients and a reduction in endotoxemia.
The rationale underlying treatment with probiotics is their
ability to reduce the amount of ammonia flowing through the
portal vein [117]. This is especially important in patients with
hepatic encephalopathy. The effects of treatment with Enterococ-
cus faecium SF68 compared to treatment with lactulose showed
similar results during the treatment period and the maintenance of
therapeutic effects during the follow-up period in the probiotic
group.
10.2. Bile acids
Bile acids were studied in rat models because they showed
bacteriostatic potential that might lead to a decrease in intestinal
bacterial overgrowth. Lorenzo-Zuniga et al. [118] reported that oral
administration of cholylsarcosine and cholylglycine led to the
elimination of intestinal bacterial overgrowth, a reduction in
bacterial translocation, a reduction of endotoxemia, and improve-
ment in the survival rate.
10.3. Prokinetics
Because the intestinal bacterial overgrowth is partially second-
ary to decreased bowel motility, it is reasonable to use prokinetics
to shorten the time of intestinal bacterial stay. Study by Perez-
Paramo et al. [119] conducted on propranolol (a b-adrenergic
blocker), and Zhang et al. [120] on cisapride (performed in rats
model) showed a decrease in intestinal bacterial overgrowth and
bacterial translocation without influence on ascites infection rates
[119] and decreased intestinal transit time, intestinal bacterial
overgrowth and bacterial translocation [120]. These results may
also be a trigger for future studies on prokinetics.
11. Conclusions
The human body is a suitable host for trillions of micro-
organisms. The largest surface covered by the epithelium is the
intestine, which is home to a large number of bacteria. Although
some of the bacteria live in symbiosis with us, providing vitamins,
degrading bile acids, and improving immunity, the bacteria can
also cause a variety of infectious diseases when they translocate
from the lumen of the intestine to other organs and sites. The
balance between intestinal bacteria and the host is important, but
in some clinical cases it is also fragile.
The role of antibiotics in infectious complications of liver
cirrhosis cannot be underestimated. A number of studies and trials
have proven their efficacy in lowering mortality and preventing
353
infections. However, antimicrobial treatment (especially in long-
term prophylaxis) may result in the emergence of resistant
bacteria. This fact has led to research into the discovery of new
antimicrobial agents that may be effective against resistant
bacteria or reduce the selection of resistant strains. In this context,
a new non-absorbable antimicrobial agent (rifaximin) is under
investigation. The varied results from rifaximin studies require
deeper analysis, perhaps by selecting specified groups of patients
who may achieve the best results in terms of prophylaxis.
Another approach to the prophylaxis of liver cirrhosis
complications involves non-antibiotic agents, including probiotics,
prokinetics and bile acids. Some of these agents have already
proven their efficacy in preventing infectious complications, while
others require additional studies.
Conflict of interest
The authors declare no conflict of interest.
Financial disclosure
The authors have no funding to disclose.
References
[1] Wiest R, Lawson M, Geuking M. Pathological bacterial translocation in liver
cirrhosis. J Hepatol 2014;60:197–209, doi:http://dx.doi.org/10.1016/j.
jhep.2013.07.044.
[2] Quigley EMM, Stanton C, Murphy EF. The gut microbiota and the liver.
Pathophysiological and clinical implications. J Hepatol 2013;58:1020–7, doi:
http://dx.doi.org/10.1016/j.jhep.2012.11.023.
[3] Abt MC, Artis D. The intestinal microbiota in health and disease: the influence
of microbial products on immune cell homeostasis. Curr Opin Gastroenterol
2009;25:496–502, doi:http://dx.doi.org/10.1097/MOG.0b013e328331b6b4.
[4] Vollaard EJ, Clasener HAL. Colonization resistance. Antimicrob Agents
Chemother 1994;38:409–14.
[5] Cesaro C, Tiso A, Del Prete A, Cariello R, Tuccillo C, Cotticelli G, et al. Gut
microbiota and probiotics in chronic liver diseases, Digestive and Liver.
Disease 2011;43:431–8, doi:http://dx.doi.org/10.1016/j.dld.2010.10.015.
[6] Leber B, Spindelboeck W, Stadlbauer V. Infectious complications of acute and
chronic liver disease. Semin Respir Crit Care Med 2012;33:80–95, doi:http://
dx.doi.org/10.1055/s-0032-1301737.
[7] Bartoletti M, Giannella M, Caraceni P, Domenicali M, Ambretti S, Tedeschi S,
et al. Epidemiology and outcomes of bloodstream infection in patient with
cirrhosis. J Hepatol 2014;61:51–8, doi:http://dx.doi.org/10.1016/j.
jhep.2014.03.021.
[8] Moreau R, Jalan R, Gines 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:e1429, doi:
http://dx.doi.org/10.1053/j.gastro.2013.02.042.
[9] Piotrowski D, Boron  -Kaczmarska A. Antybiotyki w marskosci wa˛troby.
Hepatologia 2015;15:120–7.
[10] Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, et al.
Preferred reporting items for systematic review and meta-analysis protocols
(PRISMA-P) 2015: elaboration and explanation. BMJ 2015;349(1):g7647, doi:
http://dx.doi.org/10.1136/bmj.g7647.
[11] Backhed F. Programming of host metabolism by the gut microbiota. Ann Nutr
Metab 2011;58:44–52, doi:http://dx.doi.org/10.1159/000328042.
[12] Marques TM, Wall R, Ross RP, Fitzgerald GF, Ryan CA, Stanton C. Programming
infant gut microbiota: influence of dietary and environmental factors. Curr
Opin Biotechnol 2010;21:149–56, doi:http://dx.doi.org/10.1016/j.
copbio.2010.03.020.
[13] Szabo G, Bala S, Petrasek J, Gattu A. Gut-liver axis and sensing microbes. Dig
Dis 2010;28:737–44, doi:http://dx.doi.org/10.1159/000324281.
[14] Abu-Shanab A, Quigley EM. The role of the gut microbiota in non-alcoholic
fatty liver disease. Nat Rev Gastroenterol Hepatol 2010;7:691–701, doi:http://
dx.doi.org/10.1038/nrgastro.2010.172.
[15] Teltschik Z, Wiest R, Beisner J, Nuding S, Hofmann C, Schoelmerich J, et al.
Intestinal bacterial translocation in rats with cirrhosis is related to
compromised Paneth cell antimicrobial host defense. Hepatology
2012;55:1154–63, doi:http://dx.doi.org/10.1002/hep.24789.
[16] Hartmann P, Seebauer CT, Schnabi B. Alcoholic liver disease: the gut
microbiome and liver cross talk. Alcoholism: Clin Exp Res 2015;39(5):763–
75, doi:http://dx.doi.org/10.1111/acer.12704.
[17] Leclercq S, Matamoros S, Cani PD, Neyrinck AM, Jamar F, Starkel P, et al.
Intestinal permeability, gut-bacterial dysbiosis, and behavioral markers of
alcohol-dependence severity. Proc Natl Acad Sci U S A 2014;111(42):4485–
93, doi:http://dx.doi.org/10.1073/pnas.1415174111.
354  -Kaczmarska / Advances in Medical Sciences 62 (2017) 345–356
D. Piotrowski, A. Boron
[18] Mutlu EA, Gillevet PM, Rangwala H, Sikaroodi M, Naqvi A, Engen PA, et al.
Colonic microbiome is altered in alcoholism. Am J Physiol Gastrointest Liver
Physiol 2012;302(9):966–78, doi:http://dx.doi.org/10.1152/ajpgi.00380.2011.
[19] Yan AW, Fouts DE, Brandl J, Starkel P, Torralba M, Schott E, et al. Enteric
dysbiosis associated with a mouse model of alcoholic liver disease.
Hepatology 2011;53:96–105, doi:http://dx.doi.org/10.1002/hep.24018.
[20] Bull-Otterson L, Feng W, Kirpich I, Wang Y, Qin X, Liu Y, et al. Metagenomic
analyses of alcohol induced pathogenic alterations in the intestinal
microbiome and the effect of Lactobacillus rhamnosus GG treatment. PLoS
ONE 2013;8(1):e53028, doi:http://dx.doi.org/10.1371/journal.pone.0053028.
[21] Chen P, Torralba M, Tan J, Embree M, Zengler K, Starkel P, et al.
Supplementation of saturated long-chain fatty acids maintains intestinal
eubiosis and reduces ethanol-induced liver injury in mice. Gastroenterology
2015;148(1):203–14, doi:http://dx.doi.org/10.1053/j.gastro.2014.09.014.
[22] Inagaki T, Moschetta A, Lee YK, Peng L, Zhao GX, Downes M, et al. Regulation
of antibacterial defense in the small intestine by the nuclear bile acid
receptor. Proc Natl Acad Sci USA 2006;103:3920–5, doi:http://dx.doi.org/
10.1073/pnas.0509592103.
[23] Llorente C, Schnabl B. The gut microbiota and liver disease. Cell Mol
Gastroenterol Hepatol 2015;1(3):275–84, doi:http://dx.doi.org/10.1016/j.
jcmgh.2015.04.003.
[24] Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras
M, et al. Human gut microbiome viewed across age and geography. Nature
2012;486(7402):222–7, doi:http://dx.doi.org/10.1038/nature11053.
[25] Koutsounas I, Kaltsa G, Spyros IS, Bamias G. Markers of bacterial translocation
in end-stage liver disease. World J Hepatol 2015;7(20):2264–73, doi:http://
dx.doi.org/10.4254/wjh.v7.i20.2264.
[26] Wiest R, Lawson M, Geuking M. Reply to: bacterial translocation in liver
cirrhosis: site and role in fibrogenesis. J Hepatol 2014;61(3):710–1, doi:
http://dx.doi.org/10.1016/j.jhep.2014.06.004.
[27] Claesson MJ, Jeffery IB, Conde S, Power SE, O’Connor EM, Cusack S, et al. Gut
microbiota composition correlates with diet and health in the elderly. Nature
2012;488:178–84, doi:http://dx.doi.org/10.1038/nature11319.
[28] Chen Y, Yang F, Lu H, Wang B, Chen Y, Lei D, et al. Characterization of fecal
microbial communities in patients with liver cirrhosis. Hepatology
2011;54:562–72, doi:http://dx.doi.org/10.1002/hep.24423.
[29] Bajaj JS, Ridlon JM, Hylemon PB, Thacker LR, Heuman DM, Smith S, et al.
Linkage of gut microbiome with cognition in hepatic encephalopathy. Am J
Physiol Gastrointest Liver Physiol 2012;302:G168–75, doi:http://dx.doi.org/
10.1152/ajpgi.00190.2011.
[30] Lu H, Wu Z, Xu W, Yang J, Chen Y, Li L. Intestinal microbiota was assessed in
cirrhotic patients with hepatitis B virus infection. Intestinal microbiota of
HBV cirrhotic patients. Microb Ecol 2011;61:693–703, doi:http://dx.doi.org/
10.1007/s00248-010-9801-8.
[31] Chen P, Starkel P, Turner JR, Ho SB, Schnabl B. Dysbiosis-induced intestinal
inflammation activates tumor necrosis factor receptor I and mediates
alcoholic liver disease in mice. Hepatology 2015;61(3):883–94, doi:http://dx.
doi.org/10.1002/hep.27489.
[32] Teixeira TF, Souza NC, Chiarello PG, Franceschini SC, Bressan J, Ferreira CL,
et al. Intestinal permeability parameters in obese patients are correlated with
metabolic syndrome risk factors. Clin Nutr 2012;31(5):735–40, doi:http://dx.
doi.org/10.1016/j.clnu.2012.02.009.
[33] Miele L, Valenza V, La Torre G, Montalto M, Cammarota G, Ricci R, et al.
Increased intestinal permeability and tight junction alterations in
nonalcoholic fatty liver disease. Hepatology 2009;49(6):1877–87, doi:http://
dx.doi.org/10.1002/hep.22848.
[34] Benten D, Wiest R. Gut microbiome and intestinal barrier failure–The
“Achilles heel” in hepatology? J Hepatol 2012;56:1221–3, doi:http://dx.doi.
org/10.1016/j.jhep.2012.03.003.
[35] Gabele E, Dostert K, Hofmann C, Wiest R, Scholmerich J, Hellerbrand C, et al.
DSS induced colitis increases portal LPS levels and enhances hepatic
inflammation and fibrogenesis in experimental NASH. J Hepatol 2011;55
(6):1391–9, doi:http://dx.doi.org/10.1016/j.jhep.2011.02.035.
[36] Seki E, Schnabl B. Role of innate immunity and the microbiota in liver fibrosis:
crosstalk between the liver and gut. J Physiol 2012;590(Pt 3):447–58, doi:
http://dx.doi.org/10.1113/jphysiol.2011.219691.
[37] Schnabl B, Brenner DA. Interactions between the intestinal microbiome and
liver diseases. Gastroenterology 2014;146(6):1513–24, doi:http://dx.doi.org/
10.1053/j.gastro.2014.01.020.
[38] Aliprantis AO, Yang RB, Mark MR, Suggett S, Devaux B, Radolf JD, et al. Cell
activation and apoptosis by bacterial lipoproteins through toll-like receptor-
2. Science 1999;285:736–9, doi:http://dx.doi.org/10.1126/
science.285.5428.736.
[39] Yoshimura A, Lien E, Ingalls RR, Tuomanen E, Dziarski R, Golenbock D. Cutting
edge: recognition of Gram-positive bacterial cell wall components by the
innate immune system occurs via Toll-like receptor 2. J Immunol
1999;163:1–5.
[40] Aoyama T, Palk YH, Seki E. Toll-Like Receptor Signaling and Liver Fibrosis.
Gastroenterology Research and Practice. Article ID 192543 2010, doi:http://
dx.doi.org/10.1155/2010/192543.
[41] Inokuchi S, Tsukamoto H, Park E, Liu ZX, Brenner DA, Seki E. Toll-like receptor
4 mediates alcohol-induced steatohepatitis through bone marrow-derived
and endogenous liver cells in mice. Alcohol Clin Exp Res 2011;35:1509–18,
doi:http://dx.doi.org/10.1111/j.1530-0277.2011.01487.x.
[42] Bataller R, Brenner DA. Liver fibrosis. J Clin Invest 2005;115:209–18, doi:
http://dx.doi.org/10.1172/JCI200524282.
[43] Friedman SL. Mechanisms of hepatic fibrogenesis. Gastroenterology
2008;134(6):1655–69, doi:http://dx.doi.org/10.1053/j.gastro.2008.03.003.
[44] Pijls KE, Koek GH, Elamin EE, de Vries H, Masclee AAM, Jonkers DMAE. Large
intestine permeability is increased in patients with compensated liver
cirrhosis. Am J Physiol Gastrointest Liver Physiol 2014;306:G147–53, doi:
http://dx.doi.org/10.1152/ajpgi.00330.2013.
[45] Jalan R, Fernandez J, Wiest R, Schnabl B, Moreau R, Angeli P, et al. Bacterial
infections in cirrhosis: a position statement based on the EASL Special
Conference 2013. J Hepatol 2014;60:1310–24, doi:http://dx.doi.org/10.1016/j.
jhep.2014.01.024.
[46] Fernandez J, Gustot T. Management of bacterial infections in cirrhosis. J
Hepatol 2012;56:S1–S12, doi:http://dx.doi.org/10.1016/S0168-8278(12)
60002-6.
[47] Yan K, Garcio-Tsao G. Novel prevention strategies for bacterial infections in
cirrhosis. Expert Opin Pharmacother 2016;17(5):689–701, doi:http://dx.doi.
org/10.1517/14656566.2016.1145663.
[48] Dirchwolf M, Podhorzer A, Marino M, Shulman C, Cartier M, Zunino M, et al.
Immune dysfunction in cirrhosis: distinct cytokines phenotypes according to
cirrhosis severity. Cytokine 2016;77:14–25, doi:http://dx.doi.org/10.1016/j.
cyto.2015.10.006.
[49] Wasmuth HE, Kunz D, Yagmur E, Timmer-Stranghöner A, Vidacek D, Siewert
E, et al. Patients with acute on chronic liver failure display ‘sepsis-like’
immune paralysis. J Hepatol 2005;42(2):195–201, doi:http://dx.doi.org/
10.1016/j.jhep.2004.10.019.
[50] Fernandez J, Acevedo J, Castro M, Garcia O, de Lope C, Roca D, et al. Prevalence
and risk factors of infections by multiresistant bacteria in cirrhosis: a
prospective study. Hepatology 2012;55:1551–61, doi:http://dx.doi.org/
10.1002/hep.25532.
[51] Arvaniti V, D’Amico G, Fede G, Manousou P, Tsochatzis E, Pleguezuelo M, et al.
Infections in patients with cirrhosis increase mortality four-fold and should
be used in determining prognosis. Gastroenterology 2010;139(4):1246–56,
doi:http://dx.doi.org/10.1053/j.gastro.2010.06.019.
[52] Tandon P, Garcia-Tsao G. Bacterial infections, sepsis, and multiorgan failure in
cirrhosis. Semin Liver Dis 2008;28:26–42, doi:http://dx.doi.org/10.1055/s-
2008-1040319 Gastroenterology 139 (2010) 1246–1256.
[53] Dang Y, Lou J, Yan Y, Yu Y, Chen M, Sun G, et al. The role of the neutrophil Fcg
receptor I (CD64) index in diagnosing spontaneous bacterial peritonitis in
cirrhotic patients. Int J Infect Dis 2016;49:154–60, doi:http://dx.doi.org/
10.1016/j.ijid.2016.06.021.
[54] Bal CK, Daman R, Bhatia V. Predictors of fifty days in-hospital mortality in
decompensated cirrhosis patients with spontaneous bacterial peritonitis.
World J Hepatol 2016;8(12):566–72, doi:http://dx.doi.org/10.4254/wjh.v8.
i12.566.
[55] Bruns T, Peter J, Reuken PA, Grabe DH, Schuldes SR, Brenmoehl J, et al. NOD2
gene variants are a risk factor for culture-positive spontaneous bacterial
peritonitis andmonomicrobial bacterascites in cirrhosis. Liver Int 2012;32
(2):223–30, doi:http://dx.doi.org/10.1111/j.1478-3231.2011.02561.x.
[56] Soriano G, Castellote J, Alvarez C, Girbau A, Gordillo J, Baliellas C, et al.
Secondary bacterial peritonitis in cirrhosis: a retrospective study of clinical
and analytical characteristics, diagnosis and management. J Hepatol
2010;52:39–44, doi:http://dx.doi.org/10.1016/j.jhep.2009.10.012.
[57] European Association for the Study of the Liver. EASL clinical practice
guidelines on the management of ascites, spontaneous bacterial peritonitis,
and hepatorenal syndrome in cirrhosis. J Hepatol 2010;53:397–417, http://
dx.doi.org/10.1016/j.jhep.2010.05.004.
[58] Jepsen P, Ott P, Andersen PK, Sorensen HT, Vilstrup H. Clinical course of
alcoholic liver cirrhosis: a Danish population-based cohort study. Hepatology
2010;51(5):1675–82, doi:http://dx.doi.org/10.1002/hep.23500.
[59] Kimer N, Krag A, Gluud LL. Safety effiacy, and patient acceptability of
rifaximin for hepatic encephalopathy. Patient Preference Adherence
2014;8:331–8, doi:http://dx.doi.org/10.2147/PPA.S41565.
[60] Mardini H, Record C. Pathogenesis of hepatic encephalopathy: lessons from
nitrogen challenges in man. Metab Brain Dis 2013;28(2):201–7, doi:http://dx.
doi.org/10.1007/s11011-012-9362-2.
[61] Bajaj JS. Review article: the modern management of hepatic encephalopathy.
Aliment Pharmacol Ther 2010;31(5):537–47, doi:http://dx.doi.org/10.1111/
j.1365-2036.2009.04211.x.
[62] Prakash R, Mullen KD. Mechanisms, diagnosis and management of hepatic
encephalopathy. Nat Rev Gastroenterol Hepatol 2010;7(9):515–25, doi:
http://dx.doi.org/10.1038/nrgastro.2010.116.
[63] Riordan SM, Williams R. Gut flora and hepatic encephalopathy in patients
with cirrhosis. N Engl J Med 2010;362(12):1140–2, doi:http://dx.doi.org/
10.1056/NEJMe1000850.

[64] Lata J, Hulek P, Fejfar T, Spicák J, Drastich P, Marecek Z, et al. Rifaximin in the
treatment of hepatic encephalopathy. Vnitr Lek 2002;48(6):578–82.
[65] Wu D, Wu SM, Lu J, Zhou YQ, Xu L, Guo CY. Rifaximin versus Nonabsorbable
Disaccharides for the Treatment of Hepatic Encephalopathy: A Meta-
Analysis. Gastroenterology Research and Practice 2013; Article ID 236963,
http://dx.doi.org/10.1155/2013/236963.
[66] Hadjihambi A, Khetan V, Jalan R. Pharmacotherapy for hyperammonemia.
Expert Opin Pharmacother 2014;15(12):1685–95, doi:http://dx.doi.org/
10.1517/14656566.2014.931372.
[67] Lleo MM, Ghidini V, Tafi MC, Castellani F, Trento I, Boaretti M. Detecting the
presence of bacterial DNA by PCR can be useful in diagnosing culture-
negative cases of infection, especially in patients with suspected infection
  -Kaczmarska / Advances in Medical Sciences 62 (2017) 345–356
D. Piotrowski, A. Boron
and antibiotic therapy. FEMS Microbiol Lett 2014;354(2):153–60, doi:http://
dx.doi.org/10.1111/1574-6968.12422.
[68] Moraes SR, Siqueira Jr. JF, Colombo AP, Rjcas IN, Ferreira MC, Domingues RM.
Comparison of the effectiveness of bacterial culture, 16S rDNA directed
polymerase chain reaction, and checkerboard DNA-DNA hybridization for
detection of Fusobacterium nucleatum in endodontic infections. J Endodont
2002;28(2):86–9.
[69] Enomoto H, Inoue S, Matsuhisa A, Aizawa N, Imanishi H, Saito M.
Development of a new in situ hybridization method for the detection of
global bacterial DNA to provide early evidence of a bacterial infection in
spontaneous bacterial peritonitis. J Hepatol 2012;56(1):85–94, doi:http://dx.
doi.org/10.1016/j.jhep.2011.06.025.
[70] Acevedo J, Fernandez J, Castro M, Roca D, Gines P, Arroyo V. Early markers of
bacterial infection in liver cirrhosis. J Hepatol 2010;52:S65, doi:http://dx.doi.
org/10.1016/S0168-8278(10)60147-X.
[71] Lin ZY, Chuang WL, Dai CY, Yu ML, Chen SC, Hsieh MY. Clinical application of
serum C-reactive protein measurement in the detection of bacterial infection
in patients with liver cirrhosis. Kaohsiung J Med Sci 2002;18(3):121–6.
[72] Acevedo J, Fernandez J, Filella X, Castro M, Roca D, Gines P. Diagnostic
capacity and prognostic value of procalcitonin in cirrhotic patients with
bacterial infection. Hepatology 2010;52:905A.
[73] Qu J, Feng P, Luo Y, Lü X. Impact of hepatic function on serum procalcitonin for
the diagnosis of bacterial infections in patients with chronic liver disease.
Medicine 2016;95(30):1–7, doi:http://dx.doi.org/10.1097/
MD.0000000000004270.
[74] Papp M, Tornai T, Tornai D, Vitalis Z, Tornai I, Lakatos PL. Presepsin as a new
biomarker for old expectations in the diagnosis and prognosis of bacterial
infection in cirrhosis. United European Gastroenterology Journal.
Conference: 23rd United European Gastroenterology Week Barcelona Spain.
Date of Publication: October 2015, http://dx.doi.org/10.3748/wjg.v22.
i41.9172.
[75] Kumar A, Zarychanski R, Light B, Parrillo JE, Maki D, Simon D, et al. Early
combination antibiotic therapy yields improved survival compared with
monotherapy in septic shock: a propensitymatched analysis. Crit Care Med
2010;38:1773–85, doi:http://dx.doi.org/10.1097/CCM.0b013e3181eb3ccd.
[76] Cheong HS, Kang CI, Lee JA, Moon SY, Joung MK, Chung DR, et al. Clinical
significance and outcome of nosocomial acquisition of spontaneous bacterial
peritonitis in patients with liver cirrhosis. Clin Infect Dis 2009;48:1230–6,
doi:http://dx.doi.org/10.1086/597585.
[77] Acevedo JG, Fernandez J, Castro M, Garcia O, de Lope CR, Navasa M, et al.
Current efficacy of recommended empirical antibiotic therapy in patients
with cirrhosis and bacterial infection. J Hepatol 2009;50(Suppl 1):S5, doi:
http://dx.doi.org/10.1016/S0168-8278(09)60008-8.
[78] Botwin GJ, Morgan TR. Bacterial infections in cirrhosis. Hepatol Int 2014;8
(Suppl 2):S467–74, doi:http://dx.doi.org/10.1007/s12072-014-9522-z.
[79] Salerno F, La Mura V. Treatment of spontaneous bacterial peritonitis. Dig Dis
2015;33:582–5, doi:http://dx.doi.org/10.1159/000375358.
[80] Angeli P, Guarda S, Fasolato S, Miola E, Craighero R, Del Piccolo F, et al. Switch
therapy with ciprofloxacin vs. intravenous ceftazidime in the treatment of
spontaneous bacterial peritonitis in patients with cirrhosis: similar efficacy
at lower cost. Aliment Pharmacol Ther 2006;23:75–84, doi:http://dx.doi.org/
10.1111/j.1365-2036.2006.02706.x.
[81] Piano S, Fasolato S, Salinas F, Romano A, Tonon M, Morando F. The empirical
antibiotic treatment of nosocomial spontaneous bacterial peritonitis: results
of a randomized, controlled clinical trial. Hepatology 2016;63(4):1299–309,
doi:http://dx.doi.org/10.1002/hep.27941.
[82] Rimola A, Garcia-Tsao G, Navasa M, Piddock LJ, Planas R, Bernard B, et al.
Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a
consensus document, International. Ascites Club. J Hepatol 2000;32:142–53,
doi:http://dx.doi.org/10.1016/S0168-8278(00)80201-9.
[83] de Mattos AA, Costabeber AM, Lionço LC, Tovo CV. Multi-resitant bacteria in
spontaneous bacterial peritonitis. A new step in management? World J
Gastroenterol 2014;20(39):14079–86, doi:http://dx.doi.org/10.3748/wjg.
v20.i39.14079.
[84] Fernandez J, Navasa N, Planas R, Montoliu S, Monfort D, Soriano G, et al.
Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal
syndrome and improves survival in cirrhosis. Gastroenterology
2007;133:818–24, doi:http://dx.doi.org/10.1053/j.gastro.2007.06.065.
[85] Lopardo G, Basombrio A, Clara L, Desse J, de Vedia L, di Libero E, et al.
Neumonia adquirida de la comunidad en adultos. Recomendaciones sobre su
atencion. Medicina 2015;75:245–57.
[86] Postma DF, van Werkhoven CH, Huijts SM, Bolkenbaas M, Oosterheert JJ,
Bonten MJM. New trends in the prevention and management of community-
acquired pneumonia. Netherlands J Med 2012;70(8):337–48.
[87] van Nieuwkoop C, van’t Wout JW, Assendelft WJJ, Elzevier HW, Leyten EMS,
Koster T, et al. Treatment duration of febrile urinary tract infection (FUTIRST
trial): a randomized placebo-controlled multicenter trial comparing short (7
days) antibiotic treatment with conventional treatment (14 days). BMC Infect
Dis 2009;9(131):1–9, doi:http://dx.doi.org/10.1186/1471-2334-9-131.
[88] Salerno F, Borzio M, Pedicino C, Simonetti R, Rossini A, Boccia S, et al., The
impact of infection by multidrug resistant agents in patients with cirrhosis. A
multicenter prospective study. Liver Int 2016; doi:10.1111/liv.13195.
[89] Gómez-Hurtado I, Such J, Sanz Y, Francés R. Gut microbiota-related
complications in cirrhosis. World J Gastroenterol 2014;20(42):15624–31,
doi:http://dx.doi.org/10.3748/wjg.v20.i42.15624.
355
[90] Hou MC, Lin HC, Liu TT, Kuo BI, Lee FY, Chang FY, et al. Antibiotic prophylaxis
after endoscopic therapy prevents rebleeding in acute variceal hemorrhage:
a randomized trial. Hepatology 2004;39:746–53, doi:http://dx.doi.org/
10.1002/hep.20126.
[91] Chavez-Tapia NC, Barrientos-Gutierrez T, Tellez-Avila FI, Soares-Weiser K,
Uribe M. Antibiotic prophylaxis for cirrhotic patients with upper
gastrointestinal bleeding. Cochrane Database Syst Rev 2010;9:CD002907,
doi:http://dx.doi.org/10.1002/14651858.CD002907.pub2.
[92] Fernandez J, Ruiz del Arbol L, Gomez C, Durandez R, Serradilla R, Guarner C,
et al. Norfloxacin vs ceftriaxone in the prophylaxis of infections in patients
with advanced cirrhosis and hemorrhage. Gastroenterology 2006;131:1049–
56, doi:http://dx.doi.org/10.1053/j.gastro.2006.07.010.
[93] Garcia-Tsao G. Bacterial infections in cirrhosis: treatment and prophylaxis. J
Hepatol 2005;42:S85–92, doi:http://dx.doi.org/10.1016/j.jhep.2004.12.006.
[94] Terg R, Fassio E, Guevara M, Cartier M, Longo C, Lucero R, et al. Ciprofloxacin
in primary prophylaxis of spontaneous bacterial peritonitis: a randomized,
placebo-controlled study. J Hepatol 2008;48:774–9, doi:http://dx.doi.org/
10.1016/j.jhep.2008.01.024.
[95] Rolachon A, Cordier L, Bacq Y, Nousbaum JB, Franza A, Paris JC, et al.
Ciprofloxacin and long-term prevention of spontaneous bacterial peritonitis:
results of a prospective controlled trial. Gastroenterol 1994;106:A970.
[96] Danulescu RM, Ciobica  A, Stanciu C, Trifan A. The role of rifaximine in the
prevention of the spontaneous bacterial peritonitis. Rev Med Chir Soc Med
Nat Iasi 2013;117(2):315–20.
[97] Bauer TM, Follo A, Navasa M, Vila J, Planas R, Clemente G, et al. Daily
norfloxacin is more effective than weekly rufloxacin in prevention of
spontaneous bacterial peritonitis recurrence. Dig Dis Sci 2002;47:1356–61,
doi:http://dx.doi.org/10.1023/A:1015386901343.
[98] Singh N, Gayowski T, Yu VL, Wagener MM. Trimethoprim-sulfamethoxazole
for the prevention of spontaneous bacterial peritonitis in cirrhosis: a
randomized trial. Ann Intern Med 1995;122:595–8, doi:http://dx.doi.org/
10.7326/0003-4819-122-8-199504150-00007.
[99] Lutz P, Parcina M, Bekeredjian-Ding I, Nischalke HD, Nattermann J,
Sauerbruch T, et al. Impact of rifaximin on the frequency and
characteristics of spontaneous bacterial peritonitis in patients with liver
cirrhosis and ascites. Public Library Sci 2014;9(4):e93909, doi:http://dx.doi.
org/10.1371/journal.pone.0093909.
[100] Hanouneh MA, Hanouneh IA, Hashash JG, Law R, Esfeh JM, Lopez R, et al. The
role of rifaximin in the primary prophylaxis of spontaneous bacterial
peritonitis in patients with liver cirrhosis. J Clin Gastroenterol 2012;46:709–
15, doi:http://dx.doi.org/10.1097/MCG.0b013e3182506dbb.
[101] Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB, et al. Rifaximin
treatment in hepatic encephalopathy. N Engl J Med 2010;362(12):1071–81,
doi:http://dx.doi.org/10.1056/NEJMoa0907893.
[102] Sharma BC, Sharma P, Lunia MK, Srivastava S, Goyal R, Sarin SK. A
randomized, double-blind, controlled trial comparing rifaximin plus
lactulose with lactulose alone in treatment of overt hepatic encephalopathy.
Am J Gastroenterol 2013;108(9):1458–63, doi:http://dx.doi.org/10.1038/
ajg.2013.219.
[103] Sidhu SS, Goyal O, Mishra BP, Sood A, Chhina RS, Soni RK. Rifaximin improves
psychometric performance and health-related quality of life in patients with
minimal hepatic encephalopathy (the RIME Trial). Am J Gastroenterol
2011;106(2):307–16, doi:http://dx.doi.org/10.1038/ajg.2010.455.
[104] Neff GW, Jones M, Broda T, Jonas M, Ravi R, Novick D, et al. Durability of
rifaximin response in hepatic encephalopathy. J Clin Gastroenterol 2012;46
(2):168–71, doi:http://dx.doi.org/10.1097/MCG.0b013e318231faae.
[105] Neff GW, Jones M, Jonas M, Ravinuthala R, Novick D, Kaiser TE, et al. Lack of
Clostridium difficile infection in patients treated with rifaximin for hepatic
encephalopathy: a retrospective analysis. J Clin Gastroenterol 2013;47
(2):188–92, doi:http://dx.doi.org/10.1097/MCG.0b013e318276be13.
[106] Dong W, Shu-Mei W, Jie L, Ying-Qun Z, Ling X, Chuan-Young G. Rifaximin
versus nonabsorbable disaccharides for the treatment of hepatic
encephalopathy: a meta-analysis. Gastroenterology Research and Practice
2013;Articles ID 236963, http://dx.doi.org/10.1155/2013/236963.
[107] Bajaj JS, Heuman DM, Wade JB, Gibson DP, Saeian K, Wegelin JA, et al.
Rifaximin improves driving simulator performance in a randomized trial of
patients with minimal hepatic encephalopathy. Gastroenterology 2011;140
(2):478–87, doi:http://dx.doi.org/10.1053/j.gastro.2010.08.061.
[108] Cereto F, Herranz X, Moreno E, Andreu A, Vergara A, Fontanals D, et al. Role of
host and bacterial virulence factors in Escherichia coli spontaneous bacterial
peritonitis. Eur J Gastroenterol Hepatol 2008;20:924–9, doi:http://dx.doi.
org/10.1097/MEG.0b013e3282fc7390.
[109] Cereto F, Molina I, González A, Del Valle O, Esteban R, Guardia J, et al. Role of
immunosuppression in the development of quinolone-resistant Escherichia
coli spontaneous bacterial peritonitis and in the mortality of E. coli
spontaneous bacterial peritonitis. Aliment Pharmacol Ther 2003;17:695–701,
doi:http://dx.doi.org/10.1046/j.1365-2036.2003.01491.x.
[110] Bauer TM, Fernandez J, Navasa M, Vila J, Rodes J. Failure of Lactobacillus spp. to
prevent bacterial translocation in a rat model of experimental cirrhosis. J
Hepatol 2002;36:501–6, doi:http://dx.doi.org/10.1016/S0168-8278(02)
00003-X.
[111] Wiest R, Chen F, Cadelina G, Groszmann RJ, Garcia-Tsao G. Effect of
Lactobacillus-fermented diets on bacterial translocation and intestinal flora
in experimental prehepatic portal hypertension. Dig Dis Sci 2003;48:1136–
41, doi:http://dx.doi.org/10.1023/A:1023729115659.
356  -Kaczmarska / Advances in Medical Sciences 62 (2017) 345–356
D. Piotrowski, A. Boron
[112] Rayes N, Seehofer D, Hansen S, Boucsein K, Muller AR, Serke S, et al. Early
enteral supply of lactobacillus and fiber versus selective bowel
decontamination: a controlled trial in liver transplant recipients.
Transplantation 2002;74:123–7.
[113] Forsyth CB, Farhadi A, Jakate SM, Tang Y, Shaikh M, Keshavarzian A.
Lactobacillus GG treatment ameliorates alcohol-induced intestinal oxidative
stress, gut leakiness, and liver injury in a rat model of alcoholic
steatohepatitis. Alcohol 2009;43:163–72, doi:http://dx.doi.org/10.1016/j.
alcohol.2008.12.009.
[114] Chen C, Li L, Wu Z, Chen H, Fu S. Effects of lactitol on intestinal microflora and
plasma endotoxin in patients with chronic viral hepatitis. Infect 2007;54:98–
102, doi:http://dx.doi.org/10.1016/j.jinf.2005.11.013.
[115] Liu Q, Duan ZP, Ha DK, Bengmark S, Kurtovic J, Riordan SM. Synbiotic
modulation of gut flora: effect on minimal hepatic encephalopathy in
patients with cirrhosis. Hepatology 2004;39:1441–9, doi:http://dx.doi.org/
10.1002/hep.20194.
[116] Lata J, Novotny I, Príbramská V, Jurankova J, Fric P, Kroupa R, et al. The effect of
probiotics on gut flora, level of endotoxin and Child-Pugh score in cirrhotic
patients: results of a double blind randomized study. Eur J Gastroenterol
Hepatol 2007;19:1111–3, doi:http://dx.doi.org/10.1097/
MEG.0b013e3282efa40e.
[117] Solga SF. Probiotics can treat hepatic encephalopathy. Med Hypotheses
2003;61:307–13, doi:http://dx.doi.org/10.1016/S0306-9877(03)00192-0.
[118] Lorenzo-Zuniga V, Bartoli R, Planas R, Hofmann AF, Vinado B, Hagey LR, et al.
Oral bile acids reduce bacterial overgrowth, bacterial translocation, and
endotoxemia in cirrhotic rats. Hepatology 2003;37:551–7, doi:http://dx.doi.
org/10.1053/jhep.2003.50116.
[119] Perez-Paramo M, Munoz J, Albillos A, Freile I, Portero F, Santos M, et al. Effect
of propranolol on the factors promoting bacterial translocation in cirrhotic
rats with ascites. Hepatology 2000;31:43–8, doi:http://dx.doi.org/10.1002/
hep.510310109.
[120] Zhang SC, Wang W, Ren WY, He BM, Zhou K, Zhu WN. Effect of cisapride on
intestinal bacterial and endotoxin translocation in cirrhosis. World J
Gastroenterol 2003;9:534–8, doi:http://dx.doi.org/10.3748/wjg.v9.i3.534.