Spontaneous bacterial peritonitis: Recent data on incidence and treatment

Abstract

Recent studies have shown that spontaneous bacterial peritonitis (SBP) is more common than previously thought among patients admitted to the hospital with cirrhotic ascites. Other recent studies have clarified which antibiotic regimens are most successful for treatment and prevention, often shortening the duration of treatment. Still, the prognosis is poor and recurrence of SBP is common.

Full text

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 7 JULY 2004
569
IRRHOTIC PATIENTS WITH ASCITES are par-
ticularly susceptible to spontaneous bac-
terial peritonitis (SBP) due to altered gut per-
meability, suppression of the reticuloendothe-
lial system, and bacterial overgrowth. When
SBP is discovered, something must be done
quickly. Even then, the long-term outlook is
not good, and recurrence is common.
An increased willingness to perform para-
centesis to confirm SBP has led to the detec-
tion of more cases, and clinical trials have
added to our knowledge of how to prevent or
minimize recurrences. We present an overview
of the diagnosis, treatment, and prevention of
SBP.
■ WHAT IS SBP?
In 1971, Conn and Fessel described a syn-
drome of infected ascitic fluid in patients with
hepatic cirrhosis, which they named SBP.
1
SBP is by definition an infection of previously
sterile ascitic fluid, without any apparent
intra-abdominal source of infection.
2
The
infecting organisms are usually those found
among the normal intestinal flora.
■ HOW DOES SBP DEVELOP?
The pathophysiology of SBP is not completely
understood, but evidence suggests that bacte-
ria translocate from the intestinal lumen to the
systemic circulation, causing bacteremia and
subsequent colonization of the ascitic fluid (
FIG-
URE 1
).
3–6
Bacteremia from the urine or the res-
piratory tract can also lead to infection of the
ascitic fluid and SBP, and SBP may also be
iatrogenic,
7–9
such as after endoscopic treat-
ment of esophageal or gastric varices.
MANSOUR A. PARSI, MD
Department of Gastroenterology and
Hepatology, The Cleveland Clinic Foundation
ASHISH ATREJA, MD
Department of Gastroenterology and
Hepatology, The Cleveland Clinic Foundation
NIZAR N. ZEIN, MD
Department of Gastroenterology and
Hepatology, The Cleveland Clinic Foundation
Spontaneous bacterial peritonitis:
Recent data on incidence and treatment
REVIEW
■ ABSTRACT
Recent studies have shown that spontaneous bacterial
peritonitis (SBP) is more common than previously thought
among patients admitted to the hospital with cirrhotic
ascites. Other recent studies have clarified which antibiotic
regimens are most successful for treatment and prevention,
often shortening the duration of treatment. Still, the
prognosis is poor and recurrence of SBP is common.
■ KEY POINTS
More than 92% of all cases are monomicrobial. Aerobic
gram-negative bacilli (
Escherichia coli, Klebsiella
sp) are
responsible for more than two thirds of all cases.
The diagnosis is based on testing of the ascitic fluid
obtained by paracentesis. A polymorphonuclear cell count
of more than 250 cells/mm
3
of ascitic fluid is considered
diagnostic and warrants immediate antibiotic treatment.
Several studies have since confirmed the effectiveness of
cefotaxime in patients with SBP. A short course of
cefotaxime is often as effective as a long course in these
patients. Treatment with albumin, in addition to
antibiotics, has been shown to improve survival.
Antibiotic prophylaxis to prevent a recurrence of SBP is
recommended in selected patients, but with caution so as
not to promote the development of resistance.
C
This paper discusses therapies that are experimental or are not approved by the US Food and
Drug Administration for the use under discussion.
CREDIT
CME

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CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 7 JULY 2004
■ A PREVALENT AND DEADLY DISEASE
Studies from the 1970s reported that the
prevalence of SBP was 5% to 10% in cirrhot-
ic patients with ascites.
10–12
Recent studies
using newer diagnostic criteria and improved
culture techniques have estimated a preva-
lence of 10% to 30% in cirrhotic patients with
ascites admitted to hospitals.
6,13,14
Factors contributing to mortality
SBP is deadly. In reports from the 1970s, the
mortality rate exceeded 90%.
15,16
Today, even
with intensive treatment, the in-hospital mor-
tality is still between 10% and 30%.
17
Factors
associated with poor outcome include several
indicators of poor liver function: eg, the devel-
opment of renal failure, hepatic encephalopa-
thy, high levels of serum bilirubin, and upper
gastrointestinal bleeding.
18–20
The development of renal impairment
after the diagnosis of SBP is probably the
strongest independent predictor of death. In a
study by Follo et al,
21
in 252 consecutive
episodes of SBP, the mortality rate was 100%
when associated with progressive renal impair-
ment, 31% when associated with steady renal
impairment, and only 7% in those without
renal impairment.
21
■ MANAGEMENT
Presentation depends on stage
The clinical presentation of SBP depends on
the stage at which the infection is diagnosed.
2
In the early stages, most patients are asympto-
matic. As the disease progresses, patients show
signs and symptoms of peritoneal infection.
Even with
intensive
treatment, in-
hospital
mortality is
10% to 30%
PERITONITIS PARSI AND COLLEAGUES
Proposed pathophysiology of SBP
Other sources
(skin, urine, respiratory tract)
Enteric bacteria
Altered gut permeability
Bacterial overgrowth
Bacterial translocation
Portal vein
Mesenteric lymph nodes
Reticuloendothelial system
depression
Systemic circulation
Leukocyte dysfunction
Bacteremia
Bacterial infection of ascitic fluid
Altered ascitic fluid defenses
Spontaneous bacterial peritonitis
FIGURE 1. Altered gut permeability and bacterial overgrowth in cirrhotic patients lead to
translocation of intestinal bacteria to the systemic circulation and bacteremia. Seeding of
bacteria to the ascitic fluid leads to spontaneous bacterial peritonitis. Leukocyte dysfunction
and decreased ascitic fluid defense mechanisms facilitate this process. Reprinted from
reference 2, with permission from Elsevier.

Fever is the most common presenting
symptom and is present in as many as two
thirds of patients at the time of diagnosis.
Approximately half of patients present with
abdominal pain or altered mental status, and
about one third present with diarrhea or para-
lytic ileus. Hypotension or hypothermia is
found in fewer than 20% of patients.
22
Because the presentation depends on the
stage of the disease, and because the signs and
symptoms are nonspecific, the diagnosis relies
on laboratory and microbiological tests.
Currently, paracentesis with laboratory testing
of the ascitic fluid is the only way to confirm
or rule out SBP in patients with cirrhosis.
Diagnostic paracentesis should therefore be
performed in:
• Any patient with new-onset ascites,
including patients with congestive heart fail-
ure or Budd-Chiari syndrome
• Any cirrhotic patient with ascites who
develops symptoms such as unexplained
encephalopathy or renal failure
• Any patient with stable cirrhosis and
ascites whose condition deteriorates sudden-
ly.
17,23
If SBP is suspected in a patient with clin-
ically undetectable ascites, ultrasonography is
indicated to identify the ascites and to per-
form guided paracentesis.
Cell counts in ascitic fluid
A polymorphonuclear cell count of more than
250/mm
3
in ascitic fluid is currently consid-
ered diagnostic of SBP and warrants the
prompt start of antibiotic treatment.
24
In
patients with hemorrhagic ascites or in those
with traumatic paracentesis, an adjustment of
the cell count should be made to account for
the presence of blood in the ascitic fluid. This
is done by subtracting one polymorphonuclear
cell for every 250 red blood cells in the ascitic
fluid.
24
For instance, if the red blood cell
count in the ascitic fluid is 50,000/mm
3
and
the polymorphonuclear cell count is 350/mm
3
,
the adjusted polymorphonuclear cell count
will be 150/mm
3
.
Culturing ascitic fluid
The ascitic fluid obtained from paracentesis
should also be sent for Gram-staining and cul-
ture. Studies have shown that bedside inocu-
lation of the ascitic fluid into blood culture
bottles significantly increases the detection
rate for the responsible microorganism.
25–27
Compared with conventional culturing tech-
niques, bedside inoculation also provides
quicker identification of the culprit organ-
isms.
25
Optimal sensitivity is achieved when
at least 10 mL of ascitic fluid is inoculated
into the blood culture bottles.
25
The sensitiv-
ity of this culture technique decreases sharply
when lower volumes of ascitic fluid are used.
In patients with SBP, studies based on
quantitative cultures of ascitic fluid have
shown a median bacterial concentration of
one organism (one bacterium) per milliliter of
ascitic fluid.
25
This low concentration
explains the low sensitivity of conventional
culture techniques for detection of the respon-
sible microorganism, and it explains the low
sensitivity of Gram-staining for SBP (approx-
imately 10%).
Bacteria isolated from the ascitic fluid in
patients with SBP are usually those of the nor-
mal intestinal flora. More than 92% of all
cases of SBP are monomicrobial, with aerobic
gram-negative bacilli being responsible for
more than two thirds of all cases. Escherichia
coli accounts for nearly half of these cases, fol-
lowed by Klebsiella species and other gram-
negative bacteria. Almost 25% of cases are
caused by gram-positive organisms, with strep-
tococcal species being the most common.
SBP is only rarely caused by anaerobic
organisms or by more than one type of bacte-
ria, so their presence in ascitic fluid should
raise suspicion of bacterial peritonitis due to
some other cause.
23
In these cases, evaluation
for perforation of the gut or other hollow
organs is indicated. Imaging with upright
abdominal radiography, abdominal computed
tomography, or water-soluble gut contrast
studies may help in determining the diagnosis.
In some of these cases, surgical intervention
may be necessary and life-saving.
■ TREATMENT
Starting empiric antibiotic therapy immedi-
ately improves survival in SBP,
28
although the
mortality rate is still about 10% to 30%, and
those who survive are at high risk of a recur-
rence.
23
Empiric antibiotic treatment
24
should
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The only way to
confirm SBP is
by paracentesis
with lab testing

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CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 7 JULY 2004
be started once the polymorphonuclear cell
count in ascitic fluid exceeds 250/mm
3
.
Since gram-negative aerobic Enterobac-
teriaceae and non-enterococcal streptococci
are the most common organisms to cause SBP,
initial empiric antibiotic therapy should
cover these bacteria. It should also achieve
high concentrations in ascitic fluid.
Antibiotic regimens in evolution
Initially, the regimen most often used to treat
SBP was a beta-lactam such as ampicillin or
cephalotin, and an aminoglycoside such as
gentamycin or tobramycin. However, in the
first randomized comparative study of two dif-
ferent regimens for SBP, cefotaxime was supe-
rior to ampicillin plus tobramycin for resolv-
ing SBP.
29
In that study, ampicillin plus
tobramycin was also associated with nephro-
toxicity or superinfections in approximately
10% of patients. Several studies have since
confirmed the effectiveness of cefotaxime in
patients with SBP.
Duration of therapy
Ten to 14 days of intravenous (IV) antibiotics
used to be the standard treatment. A study by
Runyon and colleagues,
30
however, showed no
difference in rates of infection or hospital-
related mortality, bacteriologic cure, or recur-
rence of infection in cirrhotic patients with
SBP treated for 10 days vs those treated for 5
days with IV cefotaxime.
30
A short course of
cefotaxime is therefore as effective as a long
course in these patients.
Other IV antibiotic regimens shown to be
as effective as cefotaxime in these patients are
ceftriaxone, ceftizoxime, ceftazidime, and the
combination of amoxicillin plus clavulanic
acid.
31–38
Dosages are shown in TABLE 1.
29–34,37–39
Route of administration
Although IV therapy for SBP has been the
standard, a trial investigating the effectiveness
of oral ofloxacin found it to be as effective as
IV cefotaxime in cirrhotic patients with SBP.
39
All patients enrolled in this randomized trial
had uncomplicated SBP (exclusion criteria
included shock, ileus, gastrointestinal hemor-
rhage, profound hepatic encephalopathy, or
serum creatinine concentration > 3mg/dL).
This regimen can therefore be used in patients
with uncomplicated SBP who are in relatively
good clinical condition.
Patients receiving quinolone to prevent SBP
Currently, in patients taking quinolones to
prevent a second episode of SBP, the infection
is commonly caused by gram-positive cocci or
quinolone-resistant gram-negative bacilli.
40,41
Oral treatment with ofloxacin, which is a
quinolone antibiotic, should therefore be
avoided in such patients. IV cefotaxime or cef-
triaxone is an effective alternative.
41,42
Assessing treatment response
Paracentesis should be repeated after at least 2
days of antibiotic therapy to assess the response
to treatment.
18,24,43
A decrease in the polymor-
phonuclear cell count of less than 25% of the
In less severe
SBP, oral
ofloxacin was
as effective as
IV cefotaxime
PERITONITIS PARSI AND COLLEAGUES
Options for empiric antibiotic therapy of SBP
DRUG DOSE* ROUTE DURATION STUDY
Cefotaxime 2 g every 12 hours Intravenous (IV) 5 days 29,30
Ceftriaxone 2 g every 24 hours IV 5 days 31–34
Amoxicillin plus 1 g/0.2 g every 6–8 hours; IV; oral 2 days; 37,38
clavulanic acid 500 mg/125 mg every 8 hours 6–12 days
Ofloxacin
†
400 mg every 12 hours Oral 8 days 39
*
Dose may need to be adjusted according to renal function
†
Only in patients without complications (ie, sepsis, ileus, gastrointestinal bleeding, encephalopathy, or serum
creatinine concentration > 3 mg/dL) who have not received a quinolone prophylactically.
T ABLE 1

pre-treatment value indicates failure of antibi-
otic treatment.
24
In these cases, antibiotic ther-
apy should be modified on the basis of bacteri-
al susceptibility (in culture-positive SBP) or
empirically (in culture-negative cases). These
patients also require evaluation regarding the
possibility of secondary peritonitis.
Other treatments
In addition to antibiotics, treatment with
albumin has been associated with improved
survival in cirrhotic patients with SBP in a
randomized trial.
44
This trial demonstrated
that, in patients with SBP, treatment with IV
albumin plus an antibiotic reduces the inci-
dence of renal impairment (defined as more
than a 50% increase from baseline in blood
urea nitrogen or creatinine) and in-hospital
mortality. In this study, 126 patients with SBP
were randomly assigned to treatment with
cefotaxime alone or cefotaxime plus IV albu-
min, given at a dose of 1.5 g per kilogram of
body weight during the first 6 hours after ran-
domization, with the infusion repeated at a
dose of 1 g/kg 3 days later. Renal impairment
developed in 33% of patients receiving cefo-
taxime, but in only 10% of those receiving
cefotaxime plus albumin. The in-hospital
death rates were 28% and 6%, respectively,
and at 3 months the death rates were 41% and
22%, respectively.
Although the above findings need to be
confirmed in additional controlled studies,
based on the available data, it is appropriate to
give IV albumin as part of the treatment of
SBP because of the proven survival advan-
tage.
■ PROPHYLAXIS
As SBP is associated with high rates of illness
and death in cirrhotic patients, it seems rea-
sonable to consider measures to prevent it.
Since aerobic gram-negative bacteria of
intestinal origin are the most frequent cause of
SBP,
45–47
selective intestinal decontamina-
tion has been suggested as a way to prevent it
by inhibiting gram-negative flora of the gut
while preserving the remaining flora, especial-
ly anaerobic bacteria.
47
Preserving the anaer-
obic bacteria is important in maintaining
resistance against intestinal colonization,
overgrowth, and extraintestinal spread of
pathogenic bacteria.
45
However, antibiotics
should be used judiciously for this purpose, so
as not to encourage the development of resis-
tant strains.
Three specific groups of cirrhotic patients
known to benefit from SBP prophylaxis
include:
• Those with gastrointestinal bleeding
• Those with ascites who are recovering
from a prior episode of SBP
• Those with an ascitic albumin concentra-
tion of less than 1 g/dL.
Cirrhotic patients
with gastrointestinal bleeding
Bacterial infections are common in cirrhotic
patients with gastrointestinal bleeding. Up to
20% of cirrhotic patients with bleeding have a
bacterial infection upon hospital admission,
and another 50% develop a bacterial infec-
tion while hospitalized, compared with 5% to
7% in the general hospital population.
46–48
Furthermore, bacterial infections are associat-
ed with fivefold to sixfold increased in-hospi-
tal death rates for these patients.
45,49
Factors contributing to infection.
Gastrointestinal bleeding favors the develop-
ment of bacterial infections by several poten-
tial mechanisms, including an increase in bac-
terial translocation and an alteration of
intestinal permeability.
45,50
A retrospective
evaluation of risk factors for infections in
patients with cirrhosis and gastrointestinal
bleeding
48
showed a strong association with
bacterial infections such as sepsis and SBP.
These results were replicated in a prospective
study showing that gastrointestinal bleeding
was by far the most common risk factor for the
development of bacterial infections among
cirrhotic patients.
46
Studies in portal hypertensive rats have
shown that hemorrhagic shock is followed by
increased bacterial translocation to mesen-
teric lymph nodes due to changed permeabili-
ty of the intestinal mucosa. In this respect,
gastrointestinal bleeding with shock is more
likely to lead to SBP than gastrointestinal
bleeding without shock.
51–53
However, cir-
rhotic patients with gastrointestinal bleeding
without shock are still at higher risk for SBP
than cirrhotic patients without gastrointesti-
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Prophylaxis is
advised in those
with GI bleeding,
a prior episode
of SBP, or low
ascitic albumin

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CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 71 • NUMBER 7 JULY 2004
nal bleeding. This has been attributed to tem-
porary impairment in reticuloendothelial sys-
tem function, to breach of the mucous mem-
branes that usually function as barriers to bac-
terial entrance to the body, and also to endo-
scopic procedures in bleeding patients.
54,55
Recommended treatment. In cirrhotic
patients admitted for gastrointestinal bleed-
ing, regardless of whether they have ascites, a
7-day course of an antibiotic such as nor-
floxacin is shown to improve survival and is
thus recommended
24
(TABLE 2). In patients who
cannot take oral antibiotics, IV antibiotics
such as ciprofloxacin can be given.
Cirrhotic patients with ascites
and prior episode of SBP
In patients who have recovered from an
episode of SBP, recurrence of SBP is common,
estimated to be 43% at 6 months and 69% at
1 year.
56
Decreasing the risk of recurrence.
Selective intestinal decontamination, by
elimination of gram-negative bacilli from the
intestinal flora, has been shown to decrease
the risk of a recurrence of SBP. In a double-
blind, placebo-controlled study of oral nor-
floxacin 400 mg/day,
57
the overall probability
of recurrence was 20% in the norfloxacin
group vs 68% in the placebo group (P =
.0063). Even more significant, the chance of a
recurrence caused by gram-negative organisms
was 3% in the norfloxacin group vs 60% in
the placebo group (P = .0013).
Preventive therapy recommended.
Patients who have recovered from one or
more episodes of SBP should receive long-
term prophylaxis with antibiotics.
17,24
Antibiotic prophylaxis should continue until
the disappearance of ascites, or until trans-
plantation (
TABLE 2).
Cirrhotic patients
with low-protein ascitic fluid
A low concentration of ascitic fluid protein is
associated with an increased risk of SBP in cir-
rhotic patients with ascites.
58–60
A study of
127 cirrhotic patients with ascites
58
found five
variables associated with an increased risk of
SBP, but only an ascitic fluid protein concen-
tration less than 1 g/dL showed an indepen-
dent predictive value. Two later studies
59,60
also showed this association.
The endogenous antimicrobial activity
(opsonic activity) of human ascitic fluid has
been shown to correlate directly with the pro-
tein concentration of the ascitic fluid,
61
and
patients with deficient opsonic activity in the
ascitic fluid have been shown to be predis-
posed to SBP.
62
Recommended treatment. Prolonged use
of oral antibiotics leads to selection of resis-
tant organisms in the gut flora. Therefore,
only hospitalized patients with low-protein
Recurrence
is common:
43% at
6 months,
69% at 1 year
PERITONITIS PARSI AND COLLEAGUES
Recommended antibiotic regimens for the prevention of SBP
DRUG DOSING DURATION
In cirrhotic patients with gastrointestinal bleeding, with or without ascites
Norfloxacin 400 mg orally every 12 hours 7 days
In cirrhotic patients with ascites and prior SBP
Norfloxacin 400 mg orally every 24 hours All three regimens should be given
Ciprofloxacin 750 mg orally every week indefinitely, or until transplantation
Trimethoprim/ 160/800 mg (one DS tablet) daily, or resolution of ascites
sulfamethoxazole 5 days a week
In cirrhotic patients with an ascitic albumin concentration below 1 g/dL
Norfloxacin 400 mg orally every 24 hours All three regimens should be given
Ciprofloxacin 750 mg orally every week only during hospitalization
Trimethoprim/ 160/800 mg (one DS tablet) daily,
sulfamethoxazole 5 days a week
T ABLE 2

ascites (ascitic fluid albumin concentration of
less than 1g/dL) should undergo prophylactic
antibiotic therapy, and therapy should be dis-
continued at the time of discharge. A ran-
domized trial
63
indicated that this strategy
may be the best compromise for preventing
ascitic fluid infection without selecting resis-
tant organisms.
64
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575
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ADDRESS: Mansour A. Parsi, MD, Department of Gastroenterology and
Hepatology, A31, The Cleveland Clinic Foundation, 9500 Euclid Avenue,
Cleveland, OH 44195; e-mail parsim@ccf.org.
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PARSI AND COLLEAGUES