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Spontaneous Bacterial Peritonitis in Patients
with Cirrhosis and Ascites
S. Piano, F. Morando, and P. Angeli
J.-L. Vincent (ed.), Annual Update in Intensive Care and Emergency Medicine 2011
DOI 10.1007/978-3-642-18081-1, ˇ Springer Science+Business Media LLC 2011
Introduction: Definition and Epidemiology
Spontaneous bacterial peritonitis (SBP) is a bacterial infection of ascitic fluid
developed in patient without any intra-abdominal, surgically treatable source of
infection [1]. In our experience, SBP is the second most common bacterial infec-
tion in patients with cirrhosis and ascites, coming after urinary tract infection
[1–4]. In unselected patients with ascites, the prevalence of SBP is 1.5–3.5 % in
outpatients [5, 6] and 10 % in inpatients [6]. Approximately half of the episodes
of SBP are present at the time of hospital admission and the rest are acquired dur-
ing hospitalization [1].
Pathogenesis of Spontaneous Bacterial Peritonitis
Bacterial translocation is the conditio sine qua non for the development of SBP
[6]. Bacterial translocation is defined as the migration of bacteria or bacterial
products from the intestinal lumen to the mesenteric lymph nodes [6]. In recent
years, studies have shown increased bacterial translocation in cirrhotic rats [6].
This ‘pathological bacterial translocation’ in cirrhosis is related to several factors,
including bacterial overgrowth, increased intestinal permeability and systemic
and local defects in host immunity [6].
Bacterial Overgrowth
Intestinal bacterial overgrowth plays a key role in bacterial translocation in cir-
rhosis and is the result, at least partly, of a decrease in small-bowel motility and
the delayed intestinal transit present in these patients [7]. It seems that auto-
nomic dysfunction, increased nitric oxide (NO) synthesis and the oxidative stress
of the mucosa are the main causes for decreased intestinal motility [7].
Intestinal Permeability
The intestinal mucosal barrier represents a physical and biological hurdle to bac-
terial translocation. Mucins, secretory mucosal immunoglobulin A antibodies,
alfa-defensins, lysozymes and the tight junctions protect the epithelium against
local and systemic bacterial invasion [8]. Cirrhotic patients were found to have
increased intestinal permeability compared to healthy controls [9]. Furthermore,
there was a significant correlation between the increased intestinal permeability,
559
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the severity of the liver disease and history of SBP [9]. Several factors increase
intestinal permeability in cirrhosis, including ultrastructural changes in the intes-
tinal mucosa, such as widening of intracellular spaces, vascular congestion,
edema of the lamina propria, fibromuscular proliferation, a decreased villous/
crypt ratio, wall thickening and tight junctions disruption [10]. Oxidative stress
of the intestinal mucosa increases lipid peroxidation and glycosylation of the
brush border membranes and mucins [11]. These changes are accompanied by
changes in bacterial flora in the gut, which have increased hydrophobicity and
adherence to the mucosa that may facilitate translocation across the mucosa. The
inflammatory pathway also appears to affect intestinal permeability. In experi-
mental cirrhosis, overproduction of tumor necrosis factor (TNF)-α and NO have
been described [6], altering the structure of the intestinal mucosa, decreasing
expression of tight junctions (zona occludens 1; ZO-1) and increasing intestinal
permeability [12].
Host Immunity in Cirrhosis
The intestinal tract is also an active immune organ. Gut-associated lymphoid tis-
sue (GALT) comprises four compartments: Peyer’s patches, lamina propria lym-
phocytes (including dendritic cells), intraepithelial lymphocytes, and mesenteric
lymph nodes. The interaction between intestinal bacteria and gut epithelium
stimulates GALT, triggering innate and acquired immune responses. Physiologic
bacterial translocation to mesenteric lymph nodes is part of the immune
response, allowing local immune stimulation without inducing systemic and local
inflammation [6]. In cirrhosis, because of local and systemic immune deficien-
cies, mesenteric lymph nodes are unable to contain bacterial infection. This
‘pathological’ bacterial translocation process is followed by bacteremia, ascitic
fluid inoculation and inflammatory response [6]. In recent years, several lines of
evidence have confirmed that a pathological bacterial translocation can occur as
a ‘continuum event’ in up to 32–42 % of patients with cirrhosis and ascites [13].
Innate Immunity in cirrhosis
Peripheral mononuclear cells are increased markedly in number and present an
over expression of Toll-like receptors (TLRs) [14] and an overproduction of TNF-
α [15]. Neutrophils showed reduced phagocytic activity, probably due to low
serum and ascitic complement levels as well as defects in Fc gamma-receptor
expression or tuftsin deficiency [16, 17].
Acquired immunity in cirrhosis
The absolute number of circulating T lymphocytes is reduced in cirrhotic
patients [18]. On the other hand, percentages of T lymphocytes, senescent CD8+
or pre-apoptotic CD4+ and CD8+ T cells are increased in cirrhotic patients com-
pared with healthy controls [18]. This is probably because prolonged antigenic
stimulation of T lymphocytes, with a significant number of effector cells impli-
cated in the antigenic response, leads to a higher probability of activation-
induced death (activation induced cell death describes the induction of cell death
in already activated T cells by restimulation of their T cell receptors) [18]. It is
possible to speculate that immunosuppression, associated classically with liver
cirrhosis, may be in part secondary to an exhausted state of the acquired immu-
nity. Recently, in experimental cirrhosis, it has been established that hyperactivity
560 S. Piano, F. Morando, and P. Angeli
XIII
of the splanchnic sympathetic nervous system impairs host defense, playing a
role in the translocation of Gram-negative bacteria [19].
Risk Factors
We will consider below three classes of predisposing factors for SBP: Genetic fac-
tors, disease-related factors, and environmental factors.
Genetic Factors
Some genes that predispose to development of SBP have been identified recently.
Presence of the nucleotide-binding oligomerization domain containing 2 (NOD2)
variants, p.R702W, p.G908R, and c.3020insC, has been shown to increase the
development of SBP 3-fold, probably by increasing intestinal permeability [20].
Monocyte chemotactic protein-1 (MCP-1) polymorphism 2518 genotype AA has
been reported to be a risk factor for development of SBP in alcoholic cirrhosis
[21]. Further studies are needed to identify additional genetic factors predispo-
sing to the development of SBP.
Severity of Liver Disease
The Model of End-stage Liver Disease (MELD) score and Child-Pugh score corre-
late directly with the onset of SBP [22]. Serum bilirubin level > 2.5 mg/dl, low
level of serum albumin, creatinine level > 1.2 mg/dl, serum sodium level
e 130 mmol/L, hepatic venous pressure gradient > 12 mmHg reflect the severity
of liver disease and represent a risk factor for the development of SBP [23, 24].
Protein ascitic levels < 1.5 g/dl and low concentrations of C3 correlate with SBP;
they probably reduce opsonization of bacteria [16, 24]. Gastrointestinal bleeding
increase the risk of SBP 4-fold [1]; a possible explanation for this finding is that
the hemorrhagic shock increases bacterial translocation and intestinal permeabil-
ity. In patients who survive an episode of SBP, the 1-year cumulative recurrence
rate is 70 % [1].
Environmental Factors
Proton pump inhibitor therapy increases bacterial colonization of the upper gas-
trointestinal tract, predisposes to bacterial overgrowth and translocation and has
been recently associated with SBP [25].
Clinical Presentations and Complications of SBP
In up to 3 % of outpatients, SBP was diagnosed by a paracentesis which was per-
formed to control ascites [5]. Inhospitalized cirrhotic patients with ascites, SBP
can also be asymptomatic [5]. More frequently, patients with SBP may have one
or more of the signs or symptoms reported in Box 1 [1].
In the general population, high serum levels of C-reactive protein (CRP) sug-
gest the presence of a bacterial infection [26]. Since CRP is an ‘acute-phase
response protein’ produced by hepatocytes, the diagnostic value of CRP measure-
Spontaneous Bacterial Peritonitis in Patients with Cirrhosis and Ascites 561
XIII
Box 1. Clinical presentation of sponta-
neous bacterial peritonitis
Signs and/or symptoms of systemic inflammation:
) hyper- hypothermia
) chills
) altered white blood cell count
) tachycardia
) tachypnea
Septic shock
Symptoms and/or signs of peritonitis:
) abdominal pain
) abdominal tenderness
) vomiting
) diarrhea
) ileus
Worsening of liver function (e.g., development of
hepatic encephalopathy):
Renal failure:
) hepatorenal syndrome
) acute tubular necrosis
) pre-renal failure
Gastrointestinal bleeding
ment may be limited in ‘infected’ patients with cirrhosis and liver failure. How-
ever, studies performed in patients with cirrhosis found significantly higher
serum CRP levels in patients with bacterial infection (including SBP) than in
those without [26]. Interestingly, increased serum procalcitonin concentrations,
another biomarker of infection, were found in patients with cirrhosis and bacte-
rial infection [26].
SBP leads frequently to a broad spectrum of complications, such as hepatore-
nal syndrome (HRS), hepatic encephalopathy, gastrointestinal bleeding and septic
shock [4]. In addition, these patients may have sepsis-induced hyperglycemia,
defective arginine-vasopressin secretion, adrenal insufficiency, or compartmental
syndrome. Development of complications contributes to the high rate mortality
of SBP [1, 4]. The most frequent complication is renal failure, which occurs in
33 % of these patients [27]. The development of renal dysfunction and type 1
HRS suggests a poor prognosis with an in-hospital mortality rate ranging from
40 %-78 % and a median survival rate from the moment of onset of 2 weeks [4,
28]. Septic shock also affects the prognosis, with a mortality rate exceeding 70 %
[4].
Diagnosis
Neutrophil Count in Ascitic Fluid
Peritoneal infection causes an inflammatory reaction resulting in an increased
number of neutrophils in ascitic fluid. The greatest sensitivity for the diagnosis of
SBP is reached with a cut-off neutrophil count of 250/mm3, although the greatest
specificity is reached with a cut-off of 500 neutrophils/mm3 [1, 3]. In patients with
hemorrhagic ascites with a fluid red blood cell (RBC) count > 10 000/mm3 (due to
562 S. Piano, F. Morando, and P. Angeli
XIII
concomitant malignancy or traumatic tap), a correction factor of 1 neutrophil per
250 RBCs has been proposed, since this is the maximum expected ratio of neutro-
phils to RBCs normally present in peripheral blood [1]. Manual counts are rec-
ommended, because they are more than the automated counts [1]. Nevertheless,
one recent study found excellent correlation between these two techniques, even
at low counts, suggesting that automated counting may replace manual counts
[29]. In contrast, the use of reagent strips cannot be recommended for the rapid
diagnosis of SBP because of their inadequate diagnostic accuracy [29].
Ascitic Fluid Culture
Ascitic fluid should be inoculated at the bedside using blood culture bottles that
include aerobic and anaerobic media [1]. The minimum amount of ascitic fluid
inoculated in each bottle is 10 ml [1]. Despite the use of sensitive methods, ascites
culture is negative in 60 % of patients with clinical manifestations suggestive of
SBP and increased ascites neutrophils [1, 2]. Gram-negative bacteria used to be
responsible for nearly 80 % of SBP cases, with Escherichia coli and Klebsiella
pneumonia accounting for most. Aerobic Gram-positive bacteria, mostly Strepto-
coccus viridians, Staphylococcus aureus and Enterococcus spp, were isolated in
approximately 20 % of cases [1, 2]. Recent epidemiological data, however, suggest
a similar proportion between Gram-negative and Gram-positive bacteria, proba-
bly because of use of norfloxacin prophylaxis and more invasive procedures [2].
A recent study has shown that 30 % of isolated Gram-negative bacteria are
resistant to quinolones and 30 % are resistant to trimethoprim-sulfamethoxazole.
Furthermore, seventy percent of quinolone-resistant Gram-negative bacteria are
also resistant to trimethoprim-sulfamethoxazole [2]. The incidence of SBP due to
quinolone-resistant Gram-negative bacteria is higher in patients on norfloxacin
therapy than in patients ‘naı̈ve’ for this treatment. In contrast, the rate of cepha-
losporin-resistant Gram-negative bacteria was low in patients with SBP whether
or not they were receiving norfloxacin prophylaxis [2]. Finally, the epidemiology
of SBP in patients with cirrhosis is changing quickly in nosocomial SBP. Currently
there is already a strong difference between community-acquired SBP, in which
Gram-negative bacteria are still predominant, and nosocomial SBP, in which
Gram-positives are now predominant [2]. Likewise, the rate of cephalosporin-
resistant Gram-negative bacteria as well as cephalosporin-resistant Gram-positive
bacteria, is higher in nosocomial SBP when compared to community-acquired
SBP [30, 31].
Types of Diagnosis
Patients with an ascitic fluid neutrophil count & 250 cells/mm3 and positive cul-
tures are defined as patients with culture positive SBP. Patients with an ascitic
fluid neutrophil count & 250 cells/mm3 and negative culture have ‘culture negative
neutrocytic ascites’ [1], but their clinical presentation is similar to that of patients
with culture positive SBP [1]. Moreover, as both groups of patients have signifi-
cant morbidity and mortality, they should be treated in a similar way.
Some patients have ‘bacterascites’ in which cultures are positive but there is a
normal ascitic neutrophil count (< 250/mm3) [1]. In some of these patients, bac-
terascites is the result of secondary bacterial colonization of ascites from a con-
comitant extraperitoneal infection (e.g., pneumonia or urinary tract infection).
Spontaneous Bacterial Peritonitis in Patients with Cirrhosis and Ascites 563
XIII
Table 1. Management of bacterascites
PMN count Treatment
< 250/mm3 and a second
ascitic fluid culture positive
Antibiotic treatment appears to be the most judicious option
(further investigation necessary for this recommendation)
< 250/mm3 and symptoms/signs
of an extraperitoneal infection
(pulmonary, urinary tract infection)
Antibiotic treatment according to the in vitro susceptibility of
bacteria isolated in ascites (it is likely that this bacterium is
also responsible for the extraperitoneal infection)
< 250/mm3 and second
ascitic fluid culture negative
No further action is required
These patients usually have general and extra-peritoneal symptoms and signs of
infection. In other patients, ‘bacterascites’ is due to the spontaneous colonization
of ascites, and they can either be clinically asymptomatic or have abdominal pain
and/or fever. Whereas in some patients, particularly in those who are asymptom-
atic, bacterascites represents a transient and spontaneously reversible coloniza-
tion of ascites, in other patients, especially if symptomatic, bacterascites is the
first step in the development of SBP [1]. In patients with bacterascites who have
symptoms or signs of infection, antibiotic therapy should be administered imme-
diately according to the antibiogram [1]. In other cases, a repeat paracentesis for
neutrophil count and culture is recommended first. The subsequent management
of bacterascites is reported in Table 1.
Differential Diagnosis
The vast majority of cirrhotic patients with ascites and peritoneal infection have
SBP. However, a small group of patients have bacterial peritonitis secondary to
perforation or acute inflammation of intra-abdominal organs, abdominalwall
infections or previous abdominal surgical procedures [32]. With the exception of
peritonitis secondary to the two latter conditions, in which the precise nature of
peritoneal infection is obvious, the differential diagnosis between spontaneous
(primary) and secondary peritonitis can be difficult [32]. The differentiation is
important because secondary peritonitis usually does not resolve unless patients
are treated surgically. Conversely, surgical therapy may be accompanied by signif-
icant deterioration in the clinical status of cirrhotic patients with SBP [32].
Secondary peritonitis should be suspected when at least one of the following
features is present [33]:
) reduction in ascitic fluid neutrophil count of less than 25 % (or even an
increase) of the pretreatment value after two days of antibiotic treatment in
follow-up paracenteses performed during therapy.
) More than one organism isolated from ascites, strongly suggestive of perfo-
rated bowel (particularly when the growth of anaerobic bacteria or fungi is
observed).
) Runyon’s criteria, represented by neutrocytic ascites with at least two of three
criteria: ascitic fluid total protein > 1 g/dl (in contrast to SBP which selectively
occurs in low-protein ascites), glucose < 50 mg/dl (due to bacterial glucose
utilization), or lactate dehydrogenase (LDH) > 225 mU/ml (most likely due to
more rapid metabolic rate and disintegration of ascitic neutophils) [33].
564 S. Piano, F. Morando, and P. Angeli
XIII
These criteria seem to be very sensitive in the detection of secondary peritonitis
but their specificity is low [33].
In clinical practice, to distinguish ‘secondary peritonitis’ from SBP, patients
should undergo appropriate radiological investigation like chest x-ray and
abdominal computed tomography (CT) scan [32]. As reported in the recent study
by Soriano et al., Runyon’s criteria and/or polymicrobial ascitic fluid culture were
present in 95.6 % of the cases of secondary bacterial peritonitis, and abdominal
CT was diagnostic in 85 % of patients in whom diagnosis was confirmed by sur-
gery or autopsy [32]. It seems advisable that the diagnosis of secondary bacterial
peritonitis should be based on Runyon’s criteria and microbiological data,
together with an aggressive approach that includes prompt abdominal CT and an
early surgical evaluation.
Treatment and Prognosis
Empirical Antibiotic Treatment (Box 2)
Empirical antibiotic therapy must be initiated immediately after the diagnosis of
SBP. Several antibiotics can be used for the initial therapy of SBP: Cefotaxime or
other third-generation cephalosporins, or amoxicillin-clavulanic acid or quinolo-
nes (Table 2) [1, 28, 34–39].
) Third generation cephalosporins: In the 1980s, cefotaxime and other third
generation cephalosporins were investigated extensively for the treatment of
SBP because Gram-negative aerobic bacteria from the enterobacteriaceae and
non-enterococcal streptococcous species were the most common causative
microorganisms, and for the favorable pharmacokinetic properties of these
antibiotics (i.e., antibiotic concentration in the ascitic fluid > MIC90 of caus-
ative microrganisms) [1].
The optimal cost-effective dosage has only been investigated for cefotaxime.
In the first randomized, comparative study cefotaxime was more effective in
achieving resolution of SBP and other infections than ampicillin plus tobra-
mycin [34]. Furthermore, 10 % of patients treated with ampicillin plus tobra-
mycin developed nephrotoxicity and superinfections, whereas no patients
treated with cefotaxime showed this complication. Two other randomized,
controlled trials showed that 5-day therapy was as effective as 10-day treat-
ment and a dose of 4 g/day was comparable to a dose of 8 g/day in terms of
rate of resolution of the infection, recurrence of SBP during hospitalization,
Box 2. Empirical antibiotic treatment of spontaneous bacterial peritonitis (SBP): General rules
) Start antibiotic therapy as soon as possible
) Third generation cephalosporins or penicillin plus penicillinase inhibitor still represent the antibi-
otics of choice in community-acquired SBP.
) Consider a broader spectrum therapy in nosocomial SBP (carbapenems plus lipopeptides or gly-
cylcycline)
) Quinolones can be used in patients with community-acquired SBP if they were not receiving
prophylaxis with oral quinolones and only in countries without a high incidence of quinolone-
resistant bacterial infections
) Avoid aminoglycosides and/or other known nephrotoxic drugs
) Repeat paracentesis after 48 h to assess response to therapy
Spontaneous Bacterial Peritonitis in Patients with Cirrhosis and Ascites 565
XIII
Table 2. Main studies on antibiotic therapy for spontaneous bacterial peritonitis in cirrhosis
First Author,
year [ref]
Treatments N° of
patients
Infection
resolution (%)
In-hospital
survival (%)
Félisart, 1985
[34]
Tobramycin (1.75 mg/kg/8 h i.v.)
plus ampicillin (2 g/4 h i.v.)
vs cefotaxime (2 g/4 h i.v.)
36
37
56
85§
61
73
Runyon, 1991
[40]
Cefotaxime 5 days (2 g/8 h i.v.)
vs cefotaxime 10 days (2 g/8 h i.v.)
43
47
93
91
77
67
Gomez-Jimenez,
1993 [41]
Cefonicid (2 g/12 h i.v.)
vs ceftriaxone (2 g/24 h i.v.)
30
30
94
100
67
70
Rimola, 1995
[35]
Cefotaxime (2 g/6 h i.v.)
vs cefotaxime (2 g/12 h i.v.)
71
72
77
79
69
79
Navasa, 1996
[36]
Ofloxacin (400 mg/12 h PO)
vs cefotaxime (2 g/6 h i.v.)
64
59
84
85
81
81
Sort, 1999 [37] Cefotaxime (2 g/6 h i.v.)
vs cefotaxime (2 g/6 h i.v.) plus i.v.
albumin
63
63
94
98
71
90**
Ricart, 2000 [38] Amoxycillin/clavulanic acid (1/0.2 g/
8 h)
i.v. followed by 0.5/0.125 g/8 h PO
vs cefotaxime 1 g/6 h i.v.)
24
24
87
83
87
79
Terg, 2000 [39] Ciprofloxacin (200 mg/12 h i.v. for
7 days)
vs ciprofloxacin (200 mg/12 h i.v. for
2 days, followed by 500 mg/12 h PO
for 5 days)
40
40
76
78
77
77
Tuncer, 2003 [62] Ciprofloxacin (500 mg/12 h)
vs cefotaxime (2 g/8 h)
or ceftriaxone (2 g/24 h)
15
17
17
80
76
83
NA
Chen, 2005 [63] Cefotaxime (1 g/6 h)
vs amikacin (500 g/24 h)
19
18
79
61
79
72
Angeli, 2006 [28] Ceftazidime (2 g b.d./24 h i.v.),
vs “switch therapy” with ciprofloxacin
(200 mg b.d./24 h i.v., for 8 days
followed by 500 mg PO/24 h, for
8 days)
61
55
84
80
77
86
* Studies appear in chronological order; § p< 0.02 vs tobramycin plus ampicillin; ** p< 0.01 vs Cefota-
xime alone; NA=not available
and hospital mortality [35, 40]. These results suggest that the high efficacy of
cefotaxime in SBP can be maintained with short-course therapy and with doses
lower than those formerly used, with a significant cost reduction (a minimum
dose of 2 g/12 h i.v. should be administered in patients with normal renal func-
tion, with a recommended minimum duration of therapy of 5 days). There were
no significant differences in rates of SBP resolution or in hospital survival using
566 S. Piano, F. Morando, and P. Angeli
XIII
other cephalosporins, including cefonicid, ceftriaxone and ceftazidime, com-
pared to cefotaxime [28, 41].
) Penicillin plus penicillinase-inhibitors: In one clinical randomized controlled
trial, amoxicillin-clavulanic acid was reported to be as effective as cefotaxime
in the treatment of SBP, and was not associated with relevant adverse effects
[38]. Considering also the low cost of this therapy, amoxicillin plus clavula-
nic acid can be consider a valid alternative to cephalosporins.
) Quinolones: Ciprofloxacin, moxifloxacin and ofloxacin administered intrave-
nously and/or per os have been compared to cephalosporins and amoxycillin
plus clavulanic acid in clinical randomized controlled trials: the effectiveness
was comparable in terms of mortality and SBP resolution [28, 36, 39, 42]. In
one randomized controlled study, switching therapy to ciprofloxacin (intrave-
nous ciprofloxacin followed by oral ciprofloxacin) was more cost-effective
than intravenous ceftazidime in cirrhotic patients who were not on prophy-
laxis with quinolones [28]. Quinolones are a valid alternative to third genera-
tioncephalosporins or penicillin plus penicillinase inhibitor in the treatment
of SBP in patients who are not receiving prophylaxis with quinolones.
) Aminoglycosides: Aminoglycosides have only moderate efficacy, and are
associated with nephrotoxicity [34]. Because cirrhotic patients present an
increased risk of developing nephrotoxicity, potential nephrotoxic antibiotic
therapy (such as aminoglycosides) should be avoided as empirical therapy
for SBP.
Unfortunately, recent changes in the epidemiology of bacterial infections and par-
ticularly of SBP in cirrhosis have decreased the efficacy of the third generation
cephalosporins as well as that of alternative therapies such as amoxycillin-clavula-
nic acid or quinolones [30, 31]. Hospitalization before the development of SBP
seems to be associated with a high probability that the infection is sustained by
multiresistant bacteria [31]. Nosocomial SBP due to extended-spectrum beta-lac-
tamase-producing enterobacteriaceae (E. coli and Klebsiella species) or to multire-
sistant Gram-positive bacteria (Enterococcus faecium, methicillin-resistant Staphy-
lococcus aureus [MRSA]) is often associated with a failure of the first-line empiri-
cal antibiotic treatment [30, 31, 43]. In fact it has been observed recently that the
resolution of SBP in patients treated with third generation cephalosporins or
amoxycillin/clavulanic acid was significantly reduced to 30–40 % in patients with
cirrhosis and nosocomial SBP [43]. Hospital mortality and 30-day mortality have
been shown to be higher in SBP due to multiresistant bacteria than in SBP due to
common bacteria (66.7 % vs 30 %, p < 0.0025) [31]. Most patients with SBP due to
multiresistant bacteria die within the first 5 days after the diagnosis of SBP [31].
In addition, the change in antibiotic therapy after the failure of the first-line treat-
ment was associated with a poor survival [31]. These observations suggest that a
more effective first-line empirical antibiotic therapy should be planned in patients
with cirrhosis and nosocomial SBP including antibiotics with a broader spectrum,
such as carbapenems and glycopeptides or glycylcyclines. In order to establish the
best empirical antibiotic treatment of nosocomial SBP in patients with cirrhosis
further large controlled clinical studies are needed.
As far as community acquired-SBP is concerned, multiresistant bacteria were
isolated only in 3 % of patients. Thus, cefotaxime or other third-generation ceph-
alosporins, or amoxycillin-clavulanic acid can still be used for initial therapy of
Spontaneous Bacterial Peritonitis in Patients with Cirrhosis and Ascites 567
XIII
SBP in these patients. Quinolones should be used only in patients with commu-
nity-acquired SBP who are not on prophylaxis with norfloxacin at the time of
diagnosis of SBP and only in countries without a high rate of E. coli resistant to
quinolones.
Resolution of infection in SBP is associated with an improvement in symptoms
and signs [1]. For those patients who do not improve, treatment failure should be
recognized early by performing a paracentesis after 48 h of antibiotic treatment;
a reduction in ascitic fluid neutrophil count of less than 25 % of the pretreatment
value suggests failure to respond to therapy [1, 35]. This should indicate further
evaluation or modification of antibiotic treatment according to in vitro sensitivity
or on an empiric basis as previously discusses.
Intravenous Albumin in Patients with SBP
SBP and other bacterial infections may precipitate a further deterioration in cir-
culatory function, hepatic dysfunction, and can induce an impairment in renal
function [3, 4, 27, 28]. The impairment in renal function in patients with cirrho-
sis and ascites as a result of SBP, biliary tract infections or urinary tract infections
often meets the diagnostic criteria for type 1 HRS. Development of type 1 HRS is
one of the strongest predictors of mortality in SBP and is associated with 30 %
hospital mortality despite infection resolution if this complication is not pre-
vented or treated [27, 37]. In the only study assessing the effect of albumin infu-
sion on renal function and survival in SBP, 126 patients without shock were ran-
domized to receive either cefotaxime or cefotaxime with intravenous albumin
[37]. Albumin was given at a dose of 1.5 g/kg body weight within six hours of SBP
diagnosis, followed by 1 g/kg on day 3. Albumin infusion significantly decreased
the incidence of type 1 HRS (from 33 % to 10 %), and improved in-hospital mor-
tality (10 % vs 29 %) and three month mortality (22 % vs 41 %) compared with
cefotaxime alone. Patients who did not receive albumin did not receive any other
fluid support. The rationale for use of albumin is to improve the blood effective
circulating volume, which is usually reduced in SBP. Because of the reduction in
effective circulating volume, these patients developed frequently renal failure, that
represents a principal cause of death in SBP. Albumin can also bind endotoxins,
reducing pro-inflammatory cytokines and NO [44]. It is unclear whether fluid
support with crystalloids or other colloids would have produced the same results.
There is only one hemodynamic study performed in patients with SBP showing
that treatment with albumin is associated with significant improvement in circu-
latory function compared with equivalent doses of hydroxyethyl starch [45]. How-
ever, recently a pilot study reporting rates of renal impairment and mortality in
high risk patients with SBP suggested that gelanfundin 4 % given with ceftriaxone
may be a less expensive therapeutic alternative to albumin [46]. Interestingly,
albumin significantly decreased the incidence of type 1 HRS in patients with
baseline serum bilirubin & 4 mg/dl and in those with baseline serum creatinine
& 1 mg/dl [37]. More recently, Terg et al. in a retrospective review of patients with
SBP confirmed that serum bilirubin levels > 4 mg/dl and serum creatinine levels
> 1 mg/dl at the time of diagnosis represented significant risk factors for the clin-
ical outcomes of patients with SBP [47]. Finally it has been observed that treat-
ment of SBP-induced type 1 HRS with terlipressin and albumin reduced the mor-
tality rate due to the infection by almost 20 % [28].
568 S. Piano, F. Morando, and P. Angeli
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Prognosis
When SBP was initially described in medical literature, in the 1960s, prognosis
was really poor, with an in-hospital mortality of 100 % [48]. Outcome has been
considerably improved because of early diagnosis and use of effective antibiotic
therapy; however, SBP still has a high rate of mortality. Recently, a meta-analysis
of 101 studies (7062 patients) reported a median mortality of 43.7 %: 31.5 % at 1
month and 66.2 % at 12 months [49]. The median overall mortality was 49 % for
1978–1999 and 31.5 % for 2000–2009, solely due to reduced mortality at 30 days,
because no significant differences were documented at 3 months or at 1 year after
the episode of SBP [49].
Prophylaxis of SBP
Since SBP is thought to result from the translocation of enteric Gram-negative
bacteria, the ideal therapeutic agent should be safe, affordable and effective at
eliminating Gram-negative bacteria from the gut while preserving the protective
anaerobic flora (selective intestinal decontamination). Given the high cost and
inevitable risk of developing resistant organisms, the use of prophylactic antibiot-
ics must be strictly restricted to those at highest risk of SBP. In addition, alterna-
tive approaches to prophylaxis of SBP should be developed in patients who are at
risk of developing SBP. Three types of patient with cirrhosis should be considered
at high risk of developing SPB and, therefore, as candidates for a prophylactic
strategy: 1) patients with or even without ascites admitted with acute gastrointes-
tinal hemorrhage; 2) patients with ascites and low total protein content in ascitic
fluid and no prior history of SBP (primary prophylaxis); and 3) patients with
ascites anda prior history of SBP (secondary prophylaxis).
Patients Admitted with Acute Gastrointestinal Hemorrhage
The incidence of infections is particularly high (ranging from 25 % to 65 % in
patients with advanced cirrhosis and/or severe hemorrhage [5]. In addition, bac-
terial infection in patients with variceal bleeding is associated with increased
rates of failure to control bleeding, rebleeding, and hospital mortality [50, 51]. In
this context, antibiotic prophylaxis was not only shown to prevent infection in the
setting of gastrointestinal bleeding, but was also shown to help prevent rebleeding
and to improve survival [3]. A meta-analysis of five studies performed in patients
with gastrointestinal bleeding has shown that antibiotic prophylaxis significantly
decreased both the incidence of severe infections (SBP and/or septicemia) and
mortality [51, 52]. Moreover, in a study that reported a reduction in mortality in
variceal hemorrhage from 43 % to 15 % over a 20-year period, antibiotic prophy-
laxis was independently associated with improved survival [53]. The most com-
mon approach in the prophylaxis of bacterial infections in cirrhotic patients with
gastrointestinal hemorrhage is selective intestinal decontamination with oral
norfloxacin (400 mg/12 h for 7 days) [3, 52]. Nevertheless, this approach has led
to a rapid emergence of quinolone resistance in cirrhotic patients treated with
norfloxacin to prevent SBP [54]. In 2006, Fernandez et al. showed that ceftriaxone
(1 g/day) for 7 days was more effective than oral norfloxacin (400 mg twice daily)
in the prevention of bacterial infections in patients with advanced cirrhosis and
Spontaneous Bacterial Peritonitis in Patients with Cirrhosis and Ascites 569
XIII
at least 2 of the following inclusion criteria: Ascites, severe malnutrition, enceph-
alopathy, bilirubin > 3 mg/dl, and gastrointestinal hemorrhage [55]. In particular,
the probability of developing proved or possible infections, proved infections, and
spontaneous bacteremia or spontaneous bacterial peritonitis was significantly
lower in patients receiving ceftriaxone (11 % versus 33 %, p = 0.003; 11 % versus
26 %, p = 0.03; and 2 % versus 12 %, p = 0.03, respectively) [55].
Patients with Low Total Protein Content in Ascitic Fluid and no Prior History of SBP
Cirrhotic patients with low ascitic fluid protein concentration (< 10 g/l) and/or
high serum bilirubin levels are at risk of developing a first episode of SBP [24,
56]. In a prospective study, patients with total ascitic protein < 10 g/l developed
SBP at a rate of 20 % over a one-year follow up period, while patients with total
ascites protein > 10 g/l did not develop SBP in a two-year period [24]. One open-
label randomized trial was performed comparing primary continuous prophy-
laxis with norfloxacin to inpatient-only prophylaxis in patients with cirrhosis and
ascitic fluid total protein level e 1.5 g/dl or serum bilirubin level > 2.5 mg/dl [57].
The study demonstrated a reduction in SBP in the continuous treatment group, at
the expense of development of a gut flora more resistant to norfloxacin in the
same group [57] (Table 3). In a second trial which was a randomized, placebo-
controlled study of norfloxacin (400 mg/day) for primary prophylaxis of SBP in
patients with low ascitic fluid protein levels (< 15 g/l), norfloxacin significantly
decreased the incidence of infections due to Gram-negative bacteria but had no
Table 3. Main studies on antibiotic prophylaxis of spontaneous bacterial peritonitis (SBP) in cirrhosis*
First author,
year [ref]
Type of patients Treatments N° of
patients
Incidence
of SBP
n (%)
p value
Ginès, 1990 [59] Patients with prior SBP Norfloxacin
vs placebo
40
40
5 (12)
14 (35)
0.02
Soriano, 1991
[56]
Patients with and with-
out prior SBP
Norfloxacin
vs no treatment
32
31
0 (0)
7 (22.5)
< 0.02
Singh, 1995 [61] Patients with and with-
out prior SBP
Trimethoprim-sulfa-
methoxazone
vs no treatment
30
30
1 (3)
7 (23)
–
Rolachon, 1995
[60]
Patients with and with-
out prior SBP
Ciprofloxacin
vs placebo
28
32
1 (4)
7 (22)
< 0.05
Novella, 1997
[57]
Patients without prior
SBP
Continuous norfloxacin
vs norfloxacin only
during hospitalization
56
53
1 (1.8) < 0.01
Grangé, 1998
[42]
Patients with prior SBP Norfloxacin
vs placebo
53
54
0 (0)
5 (9)
NA
Fernandez, 2007
[23]
Patients with prior SBP Norfloxacin
vs placebo
35
33
2
10
0.02
Terg, 2008 [58] Patients with prior SBP Ciprofloxacin
vs placebo
50
50
2 (4)
7 (14)
0.076
* Studies appear in chronological order; NA: not available
570 S. Piano, F. Morando, and P. Angeli
XIII
significant effect on the probability of developing SBP or survival [29, 42]. More
recently, two trials provided evidence of beneficial effects of long-term quinolone
therapy in patients at risk of SBP [23, 58]. In the first, Fernandez et al. performed
a randomized double-blind, placebo-controlled trial of norfloxacin (400 mg/day)
in patients with cirrhosis and low protein ascitic levels (< 15 g/l) with advanced
liver failure, classified as a Child-Pugh score & 9 points with serum bilirubin level
& 3 mg/dl or impaired renal function (serum creatinine level & 1.2 mg/dl, blood
urea nitrogen level & 25 mg/dl), or serum sodium level e 130 mEq/l [23]. Norflo-
xacin administration significantly reduced the 1-year probability of developing
SBP (7 % versus 61 %) and HRS (28 % versus 41 %). Norfloxacin also significantly
improved the 3-month probability of survival (94 % versus 62 %; p = 0.03 at 3
months and 60 % versus 48 %; p = 0.05 at one year). In the second, Terg et al. per-
formed a randomized, double-blind, placebo-controlled trial of ciprofloxacin
(500 mg/day) in patients with < 15 g/l of ascitic fluid proteins [58]. In the ciprof-
loxacin group, SBP occurred almost four times less frequently than in the placebo
group but the difference was not statistically significant. Nevertheless, the proba-
bility of remaining free of bacterial infections was higher in patients receiving
ciprofloxacin (80 % versus 55 %; p = 0.05), and the probability of survival at 1
year was higher in patients receiving ciprofloxacin (86 % versus 66 %; p< 0.04).
Patients with Prior SBP
In patients who survive an episode of SBP, the cumulative recurrence rate at one
year is approximately 70 % [59]. Probability of survival at one year after an epi-
sode of SBP is 30–50 % and falls to 25–30 % at two years. There is only one ran-
domized, double-blind, placebo-controlled trial of oral norfloxacin (400 mg/day)
in patients who had had one episode of SBP [59]. Norfloxacin was found to
reduce the probability of recurrence of SBP from 68 % to 20 % and the probabil-
ity of SBP due to Gram-negative bacteria from 60 % to 3 % [59]. Survival benefits
could not be determined by the study as prophylactic therapy was discontinued at
6 months. Three other randomized prophylactic studies are available but they
included heterogeneous groups of patients with and without previous episodes of
SBP [56, 60, 61]. Patients with low ascites fluid protein concentrations (< 15 g/l)
were included in two of these studies, one evaluating norfloxacin and the other
ciprofloxacin [56, 60]. In the third trial, trimethoprim-sulfamethoxazole was used
[61]. The three studies showed a significant decrease in the incidence of SBP with
antibiotic prophylaxis.
Conclusion
SBP is a frequent and severe complication in patients with cirrhosis and ascites
admitted to hospital. A diagnostic paracentesis, with a polymorphonuclear leuko-
cyte count in ascites, must be performed in all patients with cirrhosis admitted to
hospital as well as in cirrhotic patients with any systemic or abdmominal evi-
dence of infection and/or a worsening of their general condition, hepatic function
or renal function. Empirical antibiotic treatment should be immediately started at
diagnosis of SBP. Third generation cephalosporins, penicillin plus penicillinase
inhibitors and quinolones are indicated in empirical therapy, taking into accountthat nosocomial SBP can be frequently sustained by bacteria resistant to first line
Spontaneous Bacterial Peritonitis in Patients with Cirrhosis and Ascites 571
XIII
therapy. Administration of albumin (at a dose of 1.5 g/kg at diagnosis of SBP, and
1 g/kg on the third day) could prevent renal damage due to severe hypovolemia in
high risk patients.
Antibiotic prophylaxis is indicated in three groups of patients with a high risk
of developing SBP. Long-term administration of norfloxacin 400 mg once a day is
recommended in patients with previous SBP and in high risk patients presenting
an ascitic fluid total protein level e 1.5 g/dl associated with advanced liver failure
(Child-Pugh score & 9 points with serum bilirubin level & 3 mg/dl and/or serum
creatinine level & 1.2 mg/dl, blood urea nitrogen level & 25 mg/dl, and/or serum
sodium level e 130 mEq/l). In patients with cirrhosis who are bleeding from the
upper gastrointestinal tract, i.v. ceftriaxone (1 g/day) for 7 days should be pre-
ferred. As a result of the optimization of their management of SBP, the short term
prognosis for patients with SBP has significantly improved. New prevention strat-
egies, focusing on intestinal permeability and bacterial overgrowth should be
performed. In future, the identification of new genes associated with the onset of
SBP could allow early identification of high risk patients. In nosocomial SBP, ran-
domized controlled trials using more broad spectrum antibiotics (such as car-
bapenems, lypopeptides or glycylcyclines) should be performed. Unfortunately,
patients who survive a SBP episode have a poor long term prognosis because of
the associated severe impairment of liver function. In these patients, the selection
program for liver transplantation must be as fast as possible.
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Spontaneous Bacterial Peritonitis in Patients with Cirrhosis and Ascites 575
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	Spontaneous Bacterial Peritonitis in Patients with Cirrhosis and Ascites
	Introduction: Definition and Epidemiology
	Pathogenesis of Spontaneous Bacterial Peritonitis
	Bacterial Overgrowth
	Intestinal Permeability
	Host Immunity in Cirrhosis
	Innate Immunity in cirrhosis
	Acquired immunity in cirrhosis
	Risk Factors
	Genetic Factors
	Severity of Liver Disease
	Environmental Factors
	Clinical Presentations and Complications of SBP
	Diagnosis
	Neutrophil Count in Ascitic Fluid
	Ascitic Fluid Culture
	Types of Diagnosis
	Differential Diagnosis
	Treatment and Prognosis
	Empirical Antibiotic Treatment (Box 2)
	Intravenous Albumin in Patients with SBP
	Prognosis
	Prophylaxis of SBP
	Patients Admitted with Acute Gastrointestinal Hemorrhage
	Patients with Low Total Protein Content in Ascitic Fluid and no Prior History of SBP
	Patients with Prior SBP
	Conclusion
	References