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Spontaneous bacterial
peritonitis (SBP)
1
SBP-Definition
Peritoneal infections are classified as primary (ie,
spontaneous), secondary (ie, related to a pathologic
process in a visceral organ), or tertiary (ie, persistent
or recurrent infection after adequate initial therapy).
 Spontaneous bacterial peritonitis is characterized by
the spontaneous infection of ascitic fluid in the
absence of an intraabdominal source of infection
(e.g. intestinal perforation, abscess).

(Genuit T., e-medicin august, 2002).
(Garcia-Tsao, Can J Gastroenterol. 2004)
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SBP-Definition
Other spontaneous infections in cirrhotic patients are
spontaneous bacterial empyema and spontaneous
bacteremia (positive blood cultures in the absence of
a source of infection). All have the same
pathogenesis and should be managed in the same
fashion.
 The most common is SBP with an incidence of
approximately 10-30%.

(Garcia-Tsao, Can J Gastroenterol. 2004)3
SBP-Aetiology
 Infection is blood-born and in 90% monmicrobial.
 The majority (70%) of the cases are caused by organisms of
the normal flora of the intestine, mainly aerobic gramnegative organisms with E. coli accounting for half the
cases.
 The next most frequent microorganisms are gram-positive
cocci, mainly Streptococcus sp (20%) with enterococcus
accounting for 5% of the cases.
 Infection with more than one organism is likely to be
associated with abdominal paracentesis or intra-abdominal
source of infection.
(Garcia-Tsao, Can J Gastroenterol. 2004
(Sheila Sherlock2002).
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SBP-Aetiology


A variety of abnormalities have been identified contributing
to infection. Gastrointestinal bleeding, Increased
colonization of the small bowel with prominent bacterial
translocation, decreased opsonin function in both blood and
ascites, impaired complement, leukocyte dysfunction,
decreased antibodies and increased immunosuppressive
cytokines, endotoxin, or tumor necrosis factor have been
found in advanced liver failure.
Invasive procedures, such as endoscopy or TIPS, the use of
indwelling venous and urinary catheters are often immediate
antecedents of infection
(Iber, American J Gastro 1999)
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SBP-Pathogenesis


As cirrhosis develops in animals, gram-negative bacteria
increase in numbers in the gut. The gut of patients with
advanced cirrhosis is more permeable to bacteria than the
normal gut and more permeable than the gut in less
advanced cirrhosis.
Once bacteria reach a critical concentration in the gut
lumen, they "spill over", and escape the gut,
"translocating" to mesenteric lymph nodes. Then they can
enter lymph, blood, and eventually ascitic fluid.
(Runyon Gut 2004)
(Cirera, J Hepatol 2001)
( Runyon J Hepatol 1994)
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SBP-Pathogenesis



Peritoneal macrophages are the first line of defence against
bacterial colonisation of ascitic fluid. SBP occurs when
macrophages fail to kill the bacteria and the second line of
defence is called in, the neutrophils.
Opsonins assist motile and fixed killers of bacteria, the
neutrophils and Kupffer cells, respectively. If the ability of
the ascitic fluid to assist macrophages and neutrophils in
killing the errant bacteria is deficient, uncontrolled growth
occurs.
The opsonic activity of the ascitic fluid is proportional to
protein concentration and SBP is more likely if ascitic fluid
protein is less than 1 g/ dl.
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SBP-Pathogenesis


Thus SBP is the result of failure of the gut to contain
bacteria and failure of the immune system to kill the
virulent bacteria once they have escaped the gut making
patients with cirrhosis vulnerable to infection by their own
gut flora.
The recent molecular evidence of bacterial translocation
shows patients with cirrhosis having bacterial DNA in
their serum and ascitic fluid, and that DNA is always
present simultaneously in both body fluids.
(Such Hepatology 2002 Francés, Gut 2004)
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SBP-Pathogenesis


Innate defenders against bacterial invasion include
macrophages, dendritic cells, and natural killer cells. These
cells synthesise proinflammatory cytokines and effector
molecules, which assist in killing bacteria. Unfortunately,
patients with advanced cirrhosis have been reported to
have defects and dysfunction in many of these systems of
protection.
To make matters worse, some of the effector molecules and
cytokines that help kill the bacteria have undesired side
effects. NO and TNF are important mediators of
vasodilation and renal failure that too often accompany
SBP.
Fiuza J Infect Dis 2000 &Such, Eur J Gastroenterol Hepatol, 2004
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SBP-Diagnosis



Early diagnosis and the initiation of prompt effective
therapy have played key roles in decreasing the mortality
associated with SBP. SBP should be suspected if a patient
with known cirrhosis deteriorates.
Ascitic fluid protein less than 1 g/ dl and height serum
Bilirubin independently predict the first SBP. Patients with
variceal bleeding or previous SBP are at particular risk.
Patients may develop abdominal pain, tenderness, fever,
and systemic leucocytosis, however these features may be
absent and the diagnosis is made on the index of suspicion
with examination of the ascitic fluid.
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SBP-Diagnosis
A diagnostic paracentesis should be performed
 In any cirrhotic patient that develops compatible
symptoms and/or signs of peritonitis
 In any cirrhotic patient who develops sudden
unexplained deterioration in renal function or
hepatic encephalopathy.
 In any patient with cirrhosis and ascites admitted to
the hospital, independent of the presence or absence
of compatible symptoms and/or signs of a peritoneal
infection.
Rimola et al., Hepatology 1985
Garcia-Tsao, Can J Gastroenterol. 2004
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SBP-Diagnosis




The diagnosis is established with the finding of an ascites
polymorphonuclear count (PMN) >250/mm.
Bacterial count in the ascites is low. Direct inoculation of
routine blood culture bottles at the bedside with 10 cc of
ascitic fluid has been reported to significantly increase the
sensitivity of microbiologic studies
Culture-negative neutrocytic ascites exists when the ascitic
fluid cultures are negative yet the PMN count is >500
cells/mm
Bacterascites exists when a positive culture coexists with a
nonelevated ascites PMN count.
12
(Caly J, Hepatol 1993&Garcia-Tsao, Can J Gastroenterol. 2004)
SBP-Diagnosis
. Blood cultures are positive in 33%.
 An ascites lactate level of >25 mg/dL was found to
be 100% sensitive and specific in predicting active
SBP in a retrospective analysis.
 The combination of an ascites fluid pH of <7.35 and
PMN count of >500 cells/mm3 was 100% sensitive
and 96% specific.
 A diagnostic thoracentesis should be performed in
cirrhotic patients with new onset pleural effusion
and in patients in whom SBP/infection is suspected
but in whom there is no ascites or in whom the
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ascites PMN count is <250/mm3

SBP-Complication
The most severe complication of spontaneous
bacterial peritonitis is the hepatorenal syndrome,
which occurs in up to 30 percent of patients and
carries a high mortality rate.
 After resolution, SBP may recur, with an estimated
70 percent probability of recurrence at one year.

(Sort et al. N Engl J Med 1999 &GrangeJ et ai.,
Hepatol 1998)
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SBP-Treatment

A minimal duration of five days of parenteral, thirdgeneration cephalosporin such as cefotaxime 2 gm
every 12 h is usually effective. Intravenous
Amoxycillin-clavulanic acid is as effective as
cefotaxime. Intravenous ciprofloxacin followed by
oral treatment is also effective. These regimens are
for initial empiric therapy and antibiotic choice
should be reviewed once results of ascitic culture are
known.
(Sheila Sherlock2002).
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SBP-Treatment

A trial that investigated oral ofloxacin found it as
effective as intravenous cefotaxime in the treatment
of SBP. This trial identified a small subgroup of
patients with SBP that had an excellent prognosis
(100% SBP resolution and 100% survival) and was
characterized by having a community-acquired SBP,
no encephalopathy and a BUN <25mg/dL.
Navasa et al., Gastroenterology 1996
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SBP-Treatment

Intravenous albumin (1.5 g per kilogram of body
weight at diagnosis and 1 g per kilogram 48 hours
later) significantly lower rates of renal dysfunction
(10% vs. 33%), hospital mortality (10% vs. 29%)
and 3-month mortality (22% vs. 41%) compared to
patients that did not receive albumin. The inpatient
mortality rate of 10% is the lowest described so far
for SBP.
(Sort et al. N Engl J Med 1999 Garcia-Tsao, Can J Gastroenterol.
2004)
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SBP-Treatment
The group of patients that benefit from the addition
of albumin was characterized by having a serum
bilirubin >4mg/dL and evidence of renal impairment
at baseline (BUN >30 mg/dL and/or creatinine >1.0
mg/dL)13.
 This regimen is empirical, and no information exists
on the efficacy of lower albumin doses or other
plasma expanders.

(Ginès, N Engl J Med 2004 & Garcia-Tsao,
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Gastroenterology 2001- Garcia-Tsao, Can J Gastroenterol.
2004)
SBP-Treatment
Diuretic therapy increases the total protein and
ascitic opsonic activity.
 Patients should be treated in the hospital until there
is clear evidence of improvement, specifically
resolution of symptoms/signs and a >25% decrease
in ascites PMN count in a follow-up (48-hour)
paracentesis.
 Spontaneous bacterial peritonitis is an indication to
consider hepatic transplantation, particularly if
recurrent.
Garcia-Tsao, Can J Gastroenterol. 2004

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SBP-Prognosis
In initial series published in the 1970’s, when the
entity was first described, the mortality exceeded
80%; studies in the early 1980’s revealed an SBP
mortality of 50% and in the early 1990’s, mortality
had decreased to around 40%.
 In more recent prospective studies with well-defined
criteria for the diagnosis of SBP, the mortality rate
was 20-30%

Ricart et al J Hepatol 2000 Thuluvath Am J Gastroenterol
2001& Garcia-Tsao, Can J Gastroenterol. 2004
.
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Mortality associated with SBP
100
90
80
% Mortality
70
60
50
40
30
20
10
0
1970’s
1980’s
Early
90’s
Late
90’
U.S.
‘95-’98
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SBP-Prophylaxis



SHORT-TERM PRIMARY PROPHYLAXIS
(PREVENTION OF BACTERIAL INFECTIONS
IN PATIENTS WITH GI HEMORRHAGE)
LONG-TERM SECONDARY PROPHYLAXIS
(PREVENTION OF SBP RECURRENCE).
PROPHYLAXIS IN PATIENTS WITHOUT
PRIOR SBP OR GI HEMORRHAGE?
Garcia-Tsao, Can J Gastroenterol. 2004
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SBP-Prophylaxis
1-SHORT-TERM PRIMARY PROPHYLAXIS
 A meta-analysis of five randomized controlled trials shows
that short-term antibiotic prophylaxis not only resulted in a
significant decrease in the incidence of infections (45% in
controls vs. 14% in antibiotic-treated patients), including
SBP (27% vs 8%) but was also associated with a significant
improvement in survival (from 24% in controls to 15% in
treated patients).
 The preferred antibiotic is norfloxacin 400 mg twice a day
orally for 7-day.
(Bernard; Hepatology 1999; Garcia-Tsao, Can J Gastroenterol. 23
2004 )
SBP-Prophylaxis
2-LONG-TERM SECONDARY PROPHYLAXIS


In patients with previous episodes of SBP, long-term
prophylaxis with oral norfloxacin 400 mg daily is initiated
as soon as the course of antibiotics for the acute episode of
SBP is completed and should be continued until
disappearance of ascites, death or transplantation.
There is a concern that long-term Prophylaxis will lead to
emergence of resistant bacteria
(Rimola et al., J Hepatol 2000 &
Garcia- Tsao Gastroenterology 2001).
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SBP-Prophylaxis
3- PROPHYLAXIS IN PATIENTS WITHOUT PRIOR SBP
OR GI HEMORRHAGE.
Currently, there is insufficient data to support the
use of long-term antibiotic prophylaxis in cirrhotic
patients with ascites who are not bleeding and who
have not had a previous episode of SBP.
 Patients with an ascites protein > 1.0 g/dL will not
develop SBP in a follow-up period of 2 years and
therefore do not require prophylaxis
(Garcia- Tsao Gastroenterology 2001).

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SBP-Prophylaxis



In patients with low ascites protein levels who have never
had SBP or who are not hospitalized with GI hemorrhage,
efforts should be made to identify other risk factors for SBP.
In a recent study, a bilirubin >3.2 mg/dL and a platelet count
<98,000 have been able to identify up to 55% of patients
that will develop SBP.
Results of prophylactic, placebo-controlled trials in this
group of patients will confirm that these are in fact high risk
patients and, more importantly, evaluate the efficacy of
primary prophylaxis.
(Grange; J Hepatol 1998 &Garcia-Tsao, Can J Gastroenterol.
26 2004)
SBP-Prophylaxis


Vaccination of all cirrhotic patients with polyvalent
pneumococcal vaccine is established as effective in reducing
colonization in cirrhosis.
In cirrhotic patients, same-day treatment centers should be
used instead of hospitalization; if hospitalization is
necessary, intensive care units and hospital days should be
used in a miserly manner.
(Zetterman, Semin Liver Dis 1995
Chang et al., Infect Control Hosp Epidemiol 1998)|
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In hospitals, skin cleanliness and universal
precautions to diminish patient-to-patient
colonization must be observed.
 Urinary and intravenous catheters should be
avoided whenever possible, and proven
techniques should be used to minimize
infection when these are necessary.

(Iber, American J Gastro 1999))
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Thank You
29
30
Bacterial infections
in
liver cirrhosis
31
Bacterial infections is second in frequency to bleeding
varices as a fatal complication of cirrhosis.
Prospective series describe an incidence of infections
in hospitalized patients of 15%, 20% and 47%. A
recently published series reported the presence of
bacterial infections (either at the time of admission or
during hospitalization) in 32% of cirrhotic patients.
These figures are in contrast with the hospital-cquired
infection rate in the general hospital population
reported to be between 5% and 7%.

Studies in the 1980’s showed that the most common
infections were urinary tract infections, spontaneous
bacterial peritonitis (SBP) and pneumonia, and also
showed that approximately 70-80% of infecting
organisms were gram-negative bacilli (GNB). In a
recent large series SBP was the most common
infection, followed by urinary tract infection,
pneumonia and bacteremia. The causative organisms
isolated in SBP and urinary tract infections were
mainly GNB. In contrast, the most frequent bacteria
isolated in pneumonia and bacteremias associated
with invasive procedures were gram-positive cocci.
33

Bacterial Infections in Hospitalized
Cirrhotic Patients
% 60
50
~46%
41%
40
34%
32%
30
20%
20
10
0
6%
1980’s
Deschenes
(1999)
n=140
Dupeyron
(2001)
n=589
Borzio
(2001)
n=405
Fernandez
(2002)
n=1,567
Noncirrhotics
34
150
Sources of infection in hospitalized cirrhotic
patients (n=572)
138
125
111
100
78
75
45
50
28
25
0
SBP
UTI
Pneumonia
Procedurerelated
Spontaneous
Bacteremia
35
Fernandez et al. Hepatology 2002.
CIRRHOSIS
(poor liver function)
BACTERIAL TRANSLOCATION
ANTIBIOTICS
X
TRANSIENT BACTEREMIA
PROLONGED BACTEREMIA
ASCITES COLONIZATION
SPONTANEOUS BACTERIAL PERITONITIS
36
Selective Intestinal Decontamination in the
Prevention of Infections in Cirrhosis
Setting
Rimola
Duration Untreated Treated
Non10 days
absorbable*
35%
16%
GI bleed
Norfloxacin Hospital
stay
37%
10%
6 mos
33%
7%
6 mos
17%
2%
(1992)
Gines
Infection rate
GI bleed
(1985)
Soriano
Oral
antibiotics
Prior SBP Norfloxacin
(1990)
Grange
(1998)
Low
ascites
protein
Norfloxacin
* gentamycin+vancomycin+nystatin or neomycin+colistin+nystatin37
Effect of norfloxacin prophylaxis on the type of
infections in cirrhosis
No
Norfloxacin
prophylaxis prophylaxis
(n=414)
(n=93)
p
46%
52%
ns
Quinolone
-resistant
29%
65%
0.002
TMP-SMX-resistant
44%
68%
0.02
Gram-positive
infections
46%
42%
ns
Mixed infections
8%
6%
ns
Gram-negative
infections
Fernandez et al. Hepatology 2002.
38
Prophylactic antibiotics decrease infection
and improve survival in cirrhotic patients
with GI hemorrhage
Control*
(n=270)
Antibiotic*
(n=264)
Absolute rate
difference
(95% C.I.)
Infection rate
45%
14%
- 32%
(-42 to -23)
SBP/Bacteremia
27%
8%
- 18%
(-26 to -11)
Death rate
24%
15%
- 9%
(-15 to -3)
* meta-analysis of 5 trials
39
Bernard et al. Hepatology 1999.
Probability of remaining free of recurrent variceal hemorrhage
Hou M-C et al. Hepatology 2004;39:746-753.
40
Norfloxacin significantly reduces the
recurrence of SBP
SBP CAUSED BY AEROBIC
GRAM-NEGATIVE BACTERIA
Probability of SBP recurrence
TOTAL
Placebo
Placebo
p=0.0063
p=0.0013
Norfloxacin
Norfloxacin
MONTHS
MONTHS
41
Gines et al. Hepatology 1990.
SBP – Secondary Prophylaxis
Author
(year)
Treatment
n
Dose
Gines
(1990)
Norfloxacin
40
Placebo
Bauer
(2002)
F/U
(mos)
SBP
Death
400 mg
QD
7.6
5 (12%)
7 (18%)
40
1 tab QD
5.1
14 (35%)
10 (25%)
Norfloxacin
40
400 mg
QD
6.7
6 (15%)
3 (8%)
Rufloxacin
39
400 mg
Q week
6.9
12 (31%)
5 (13%)
42
SBP - Prophylaxis
Indicated in cirrhotic patients at the greatest
risk of developing SBP:
• Hospitalized cirrhotic patients with an episode
of gastrointestinal hemorrhage (short-term)
– Norfloxacin 400 mg (or ciprofloxacin 250 mg)
p.o. BID x 7 days or
• Patients who have recovered from an
episode of SBP (long-term)
– Norfloxacin 400 mg (or ciprofloxacin 250 mg)
p.o. QD indefinitely
– Weekly quinolones not recommended
43