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Spontaneous bacterial peritonitis:recent guidelines and beyondR
Wiest,1 A Krag,2 A Gerbes3
INTRODUCTIONSpontaneous bacterial peritonitis (SBP) is the
mostfrequent and life-threatening infection in patientswith liver
cirrhosis requiring prompt recognitionand treatment. It is defined
by the presence of >250polymorphonuclear cells (PMN)/mm3 in
ascites inthe absence of an intra-abdominal source of infec-tion or
malignancy. In this review we discuss thecurrent opinions reflected
by recent guidelines(American Association for the Study of
LiverDiseases, European Association for the Study of theLiver,
Deutsche Gesellschaft für Verdauungs-
undStoffwechselkrankheiten),1e4 with particular focuson
controversial issues as well as open questionsthat need to be
addressed in the future. First,diagnostic criteria and tools
available for rapid andaccurate diagnosis are reviewed. Second,
sinceprophylaxis is of crucial relevance when trying toimprove
survival, we discuss who should betreated, when, how and for how
long to preventepisodes of SBP. Identification of risk factors
andindividualisation of timing and selection ofprophylactic
measures are the key to successwithout major development of
resistant bacteria.Finally, effective therapy is essential since
treat-ment failure is associated with poor outcome. Sincethe
emergence and spread of drug-resistant bacteriahas accelerated,
criteria for the choice of antibioticregimen in the individual
patient are pivotal foroptimising therapy.
EPIDEMIOLOGY AND PROGNOSIS OF SBPSBP is the most frequent
bacterial infection incirrhosis, accounting for 10e30% of all
reportedbacterial infections in hospitalised patients.5e7
Inoutpatients without symptoms the prevalence islow (3.5%8 or
lower9 10), but the prevalenceincreases in the nosocomial setting,
ranging from8% to 36%.11 12 Bacterascites, defined as
positiveculture results but no increase in the PMN count inthe
ascitic fluid, occurs with a prevalence of 2e3%in outpatients8e10
and in up to 11% in hospitalisedpatients.11 13 In-hospital
mortality for the firstepisode of SBP ranges from 10% to 50%,
dependingon various risk factors.7 14e18 One-year mortalityafter a
first episode of SBP has been reported to be31% and 93%.8 17 19e21
In fact, the occurrence ofSBP or other severe bacterial infections
markedlyworsens the prognosis in patients with cirrhosisand it has
been proposed that a new prognosticstage of cirrhosis not reflected
in current stagingsystems should be defined, the so-called
‘criticallyill cirrhotic’.22 Patients at this late stage have to
beevaluated for the possibility of liver trans-plantation.
Predictive factors reported for a poor
prognosis in various cohorts of patients with SBPare summarised
in figure 1 and include age,16 20
Child score,18 20 23 intensive care,16 18 nosocomialorigin,18 24
hepatic encephalopathy,25 elevatedserum creatinine and bilirubin,26
lack of infectionresolution/need to escalate treatment and
culturepositivity27e29 as well as the presence of bacter-aemia30
and CARD15/NOD2 variants as a geneticrisk factor.31 It is important
to stress in this contextthat the only factors that are modifiable
in thisscenario are timely diagnosis and effective
first-linetreatment.
Bacterial translocation (BT) and pathophysiologyBacterial
translocation (BT) is the most commoncause of SBP.32 33 However,
particularly in nosoco-mial SBP, other sources such as transient
bacter-aemia due to invasive procedures can lead to SBP.Limited BT
to mesenteric lymph nodes (MLN) isa physiological phenomenon,
whereas any increasein the rate and severity of BT may be
deleteriousfor the patient and thus should be termed ‘patho-logical
BT’. Only a few intestinal bacteria areable to translocate into
MLN, including Escherichiacoli, Klebsiella pneumoniae and other
Enter-obacteriaceae.34 Interestingly, these species mostfrequently
cause SBP, and DNA sequencing studiesreveal genotypic identity of
bacteria in MLN andascites in the vast majority of cases.35 36
Thissuggests that pathological BT is the underlyingcause and source
of SBP in cirrhosis and supportsthe view that the route of
pathological BT leadingto SBP is largely lymphatic. Three factors
have beenimplicated in the development of pathological BTin liver
cirrhosis32: (1) alterations in gut microbiota;(2) increased
intestinal permeability; and (3)impaired immunity.
MicrobiotaLiver cirrhosis is associated with distinct changes
infaecal microbial composition37 38 including anincreased
prevalence of potentially pathogenicbacteria such as
Enterobacteriaceae. Moreover,small intestinal bacterial overgrowth
(SIBO),defined as >105 colony forming units/ml jejunalaspirate
and/or colonic-type species, is frequentlypresent in advanced
stages of liver cirrhosis andhas been linked with pathological BT,
SBP andendotoxinaemia.39e41 In cirrhosis, factorspromoting these
changes may include deficienciesin paneth cell defensins,41a
reduced intestinalmotility, decreased pancreatobiliary secretions
andportal-hypertensive enteropathy. In experimentalcirrhosis, in
the absence of SIBO, BT occurs rarely(0e11%) and at rates
comparable to healthy
1Department for visceral surgeryand medicine, UniversityHospital
Bern, Switzerland2Department ofGastroenterology, HvidovreUniversity
Hospital,Copenhagen, Denmark3Klinikum of the University ofMunich,
Munich, Germany
Correspondence toProfessor Dr Reiner Wiest,Department for
visceral surgeryand medicine, UniversityHospital Bern, 3010
Bern,Switzerland;[email protected]
Published Online First6 December 2011
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conditions. However, BT does not occur in up tohalf of the
animals with SIBO and, thus, SIBO isnecessary but not sufficient
for BT to occur.
Intestinal permeabilityCirrhosis is associated with structural
and func-tional alterations in the intestinal mucosa thatincrease
permeability to bacteria and bacterialproducts. In particular,
changes in enterocytemitochondrial function and increased
oxidativestress of the intestinal mucosa have beenidentified.42
43
Host defenceFor translocation to become clinically
significantdthat is, for it to lead to SBP or bacteraemiadafailure
of local and systemic immune defencesappears to be the most
important prerequisite (seebelow).
Local ascitic-peritoneal host defence in peritonitisThe
peritoneal cavity probably has the most severelack of host defence
compared with othercompartments in decompensated cirrhosis. In
fact,ascites per se may be considered a risk factor for
thedevelopment of peritonitis. In healthy conditions,peritoneal
host defence mechanisms are very effi-cient and intraperitoneal
injection of variousnumbers of single organisms does not cause
peri-tonitis unless adjuvant substances or ascites arepresent.44 In
cirrhosis, deficiencies in local defencemechanisms against
bacteria, including dysfunc-tion of cellular and humoral immunity,
limitperitoneal bacterial clearance.Since the absolute number of
PMN per mm3
ascitic fluid defines SBP, the mechanisms ofchemotaxis mediating
PMN influx into the perito-neal cavity are important. The degree of
PMN
migration and accumulation in the peritonealcavity combating
invading bacteria depends ona number of factors. Resident
macrophages are thefirst to phagocytose bacteria, they further help
toattract PMN by release of chemotactic factors andactivate
complement. For instance, monocytechemotactic protein 1 is one of
the most potentchemokines, and a functional polymorphism hasbeen
proposed as a risk factor for SBP in alcoholiccirrhosis.45 A
chemotactic gradient is necessary toachieve appropriate neutrophil
recruitment into theperitoneal cavity. In fact, PMN
chemoattractantssuch as zymosan are very effective in preventingthe
death of animals with E coli-induced peritonitiswhen administered
locally but not systemically.46
Unfortunately, little is known about the influx,efflux and
kinetics of neutrophils in ascitic fluid incirrhosis and its
dependency on type, extent andduration of bacterial stimulus as
well as hostfactors.Besides influx of PMN, bacterial clearance
is
determined by the overall killing capacity which isdependent on
opsonisation, burst activity andinflammatory response. A marked
reduction inopsonic and bactericidial activity is well-known
incirrhosis. In particular, low C3 levels in cirrhoticascites
correlate strongly with opsonic activity47
and have been shown to predispose to SBP.48
However, the total protein content aslo mirrorsopsonic activity
and has been shown to be predic-tive of the development of SBP.49
At a protein levelof >1.5 g/dl ascitic fluid, the incidence
rates of SBPhave been consistently reported to be lower than1%. In
contrast, at protein levels
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chemotactic, opsonic, phagocytic and killingcapacity.58 59
Furthermore, genetic variants influ-encing host defence mechanisms
such as CARD15/NOD231 60 and TLR261 have been reported to
beassociated with an enhanced probability ofacquiring SBP. TLR2
polymorphisms and NOD2variants seem to represent supplementary
riskfactors since the simultaneous presence of bothunfavourable
polymorphisms markedly increasesthe risk of SBP.61 This underlines
the knowninteraction of NOD2 and TLRs, in particular themodulation
of TLR2-dependent cytokine responsesby NOD2.62
Medication can also affect the chances of devel-oping SBP. The
use of proton pump inhibitors (PPI)has been proposed to facilitate
SIBO and thus tocontribute to pathological BT. In fact,
retrospectivecaseecontrol studies reveal a potential
associationbetween the use of PPI and development ofSBP.63 64
Considering the frequently inadequateoveruse of PPI in patients
with cirrhosis, wetherefore recommend restricting their use to
indi-cations of proven benefit. In contrast,
non-selectiveb-blockers (NSBB) may prevent SBP.65 66 It istempting
to speculate that this benefit relates to animprovement in
chemotaxis, proinflammatorycytokine release and killing capacity
reported forb-adrenergic antagonists in various
experimentalsettings.67 68 Since the sympathetic nervous
systemaffects PMN chemotaxis, the question arises as tohow
treatment with NSBB affects the validity ofdiagnosing SBP based on
PMN count in the asciticfluid.
DIAGNOSIS OF SBPSymptoms and signs are frequently absent
inpatients with SBP,69 so a diagnostic paracentesisshould be
performed in all patients with ascitesadmitted to hospital
regardless of whether or notthere is clinical suspicion. Diagnosis
should beprompt and treatment must not be delayed untilthe
microbiology results are available. Thus, in allthe available
guidelines, diagnosis is based on a fixeddefined cut-off PMN count
in the ascitic fluid.1e4 Inpatients with haemorrhagic ascites (ie,
red bloodcell count >10 000/mm3), subtraction of one PMNper 250
red blood cells should be made to adjust forthe presence of blood
in ascites. Owing to the shortlifespan of PMN, their ascitic count
is independentof diuretics and/or other modulations of
ascitesvolume. In contrast, lymphocytes which havea long lifespan
increase in concentration duringdiuresis.70 Moreover, differential
diagnoses ofpredominant lymphocytosis in ascitic fluid
includetuberculous peritonitis, neoplasms, congestiveheart failure,
pancreatitis and myxedema, but notusually SBP. PMN are therefore
used to define SBP,and the greatest sensitivity is reached at a
cut-offvalue of 250 PMN/mm3, although the best speci-ficity has
been reported with a cut-off of 500 PMN/mm3.71e74 However, since it
is important not tomiss a case of SBP, the most sensitive cut-off
valueis used. Nonetheless, this upper limit has been setquite
arbitrarily since it was tested in the setting of
culture-positive peritonitis. Thus, the range ofPMN in truly
non-infected ascitesdthat is, theascitic PMN count that is
clinically relevant forthe patientdis not known. Moreover, SBP
causedby Gram-positive cocci has been reportedfrequently to have a
PMN count below thethreshold of 250/mm3.75 Interestingly,
bactDNAfrom Gram-negative bacteria in ascitic fluid isassociated
with a higher ascitic PMN count thanbactDNA from Gram-positive
bacteria,76 under-scoring the differences in stimulatory capacity
forPMN migration depending on the type of bacteria.
Microscopy versus automated cell counterAscitic PMN cell counts
can be determined eitherby a traditional haematological method
usinga light microscope and a manual counting chamberor by
automated cell counters.77e79 Currentguidelines either do not state
specifically themethod to be used2 4 or recommend microscopy asthe
preferred method.1 However, microscopic eval-uation is
labour-intensive, time-consuming and hashigh intraoperator and
interoperator variability. Incontrast, automated cell counters, if
available, areeasily accessible in emergencies and provide
resultswithin minutes at low cost. Their use hasrecently been
validated in patients with cirrhoticascites,77 79 revealing
sufficient sensitivity fordetection of SBP, and thus should be
recommended.However, it is important to stress that not
allautomated cell counters fulfil the quality criteria.These
include sufficient functional sensitivity, testprecision and
accuracy, particularly for automatedleucocyte counts in ascites
even with low cellconcentrations (eg, XE-5000 (Sysmex,
Mundelein,IL, USA), Advia 120 (Erlangen, Germany), IrisiQ200
(Chatsworth, CA, USA), CellDyn-4000(Wiesbaden, Germany)).None of
the recent guidelines recommends the
use of reagent test strips to assess leucocyte esteraseactivity
of activated PMNs for the diagnosis of SBPowing to unacceptable
rates of false negativeresults.80 However, most of the strips used
to datehave been developed for urinary tract infectionswith a
threshold of >50 PMN/mm3.81 Recently,a reagent strip test has
been calibrated for asciticfluid with a cut-off of 250 PMN/mm3.82
Validityscores achievable were reported to be 100% sensi-tivity and
100% negative predictive value.However, this needs to be confirmed
in largemulticentre trials and, furthermore, the test wasnot
interpretable in bloody, chylous or biliousascitic fluid.
Bacterial DNA detection and culture techniquesDetection of
bacterial DNA (bactDNA) usingvarious approaches has recently been
proposed inthe ascitic fluid of patients with cirrhosis.83e85
Theadvantage of such a system would be the imme-diate
identification of the causative bacteria, thusenabling more
accurately targeted antibiotic treat-ment. BactDNA is found in the
ascitic fluid ofabout 40% of patients with cirrhosis, being
derivedmainly from Gram-negative bacteria.84 85 However,
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detection of bactDNA in ascites or serum was notassociated with
an enhanced incidence of SBP anddoes not appear to predict the
development ofbacterial infections.86
Culture techniquesGram staining of peritoneal fluid is rarely
helpful87
and is not recommended. In contrast, culture is therecommended
procedure. Although only a fewspecies and genera are found to cause
SBP, morethan 70 different microbial species have beenisolated from
the ascitic fluid of patients withbacteriologically-confirmed
SBP.88 Classical culturetechniques fail to grow bacteria in up to
65% ofneutrocytic ascites. Bedside inoculation of ascitesinto blood
culture bottles has been shown toincrease the sensitivity to nearly
80%.89e91 In thisregard, non-radiometric (eg, colorimetric
BacTec)systems in particular have improved the time todiagnosis
since they are faster than conventionalblood culture bottles.89
Handling processes influ-ence culture results and delay in
transport increasesfalse negative results.92 Separate and
simultaneousblood cultures should be collected since 30e58% ofSBP
cases are associated with bacteraemia.30 93
Other markers of inflammation and secondaryperitonitisOther
markers found to be indicative of SBP includeascitic pH, lactate
dehydrogenase, lactate (andcorresponding arterialeascitic
gradients), but noneof these is sufficiently predictive or
discriminativeand may be increased in malignancy-relatedascites.72
74 94 95 Proteins such as granulocyteelastase96 and lactoferrin97
released by PMN uponactivation have likewise been shown to
beincreased in SBP. Lactoferrin was reported to giverates of
sensitivity and specificity of 95.5% and97%, respectively, using a
cut-off value of 242 ng/ml and to decrease to below the cut-off
value inpatients responding to treatment.97 However,because of the
small number of SBP cases in thisinvestigation, confirmation is
required in multi-centre trials including assessment of its
accuracy inhaemorrhagic and coexisting malignant
ascites.Differentiation of SBP from secondary peritonitis
due to perforation or inflammation of an intra-abdominal organ
is clinically very relevant as theassociated mortality is
exceedingly high.98 In fact,all patients with perforated secondary
peritonitisnot undergoing timely surgery have been reportedto die
during hospitalisation and, thus, delayeddiagnostic investigation
is fatal. However, theproposed criteria to suspect secondary
peritonitis(eg, inadequate response to therapy, multipleorganisms)1
3 are identified too late and thereforerapid and accurate
‘chemical’ parameters availableat the time of paracentesis are
needed. Parametersproposed by Runyon et al are neutrocytic
asciteswith at least two of the following three criteria:ascitic
fluid total protein >1 g/dl (in contrast toSBP), glucose 225
mU/ml.99 The sensitivity of these criteria can be less
than 68%98 99 and thus can be optimised. In addi-tion, Wu et al
reported that ascitic fluid with eitheralkaline phosphatase >240
U/l or carcinoem-bryonic antigen >5 ng/ml in 80% of cases
reflectsperitonitis of secondary origin.100 Although no dataare
available on the diagnostic accuracy of thecombined criteria (ie,
those of either Wu et al or
Runyon et al), they are likely to improve sensitivityand should
be tested prospectively. In themeantime, we strongly recommend
performing anabdominal CT scan as soon as any of these featuresare
present.101
TREATMENT OF SBPTreatment has to be started immediately
afterdiagnosis of SBP and therefore is empirical sinceculture
results are not available at this time point.The strain of bacteria
causing SBP mainly dependson the site of acquisition. However, none
of theinternational guidelines to date differentiates
Box 1
Key messages established unequivocally< Clinical judgement
does not rule out SBP and
thus a diagnostic paracentesis should beperformed in all
patients with cirrhosis andascites at hospital admission and/or in
case ofgastrointestinal bleeding, shock signs of inflam-mation,
worsening of liver/renal function orhepatic encephalopathy.
< SBP is defined by >250 PMN/mm3 andbacterascites by
positive culture results ofascitic fluid in the absence of PMN
>250/mm3.
< Ascitic fluid culture is important to guideantibiotic
therapy and should be performed inall patients before starting
antibiotic treatmentby inoculation of ascites into blood
culturebottles at the patient’s bedside.
Controversial but proposed< PMN count in ascitic fluid can be
determined
either by microscope OR appropriate automatedcell counters.
Reagent strips currently cannot berecommended for rapid diagnosis
of SBP butascites-calibrated sticks may become available.
< Bacterial DNA is not useful in detecting orpredicting the
occurrence of SBP.
Questions to be addressed in the future< Are there potential
differences in the detection
of SBP dependent on the use of b-blockers andthe type of
causative bacteria (Gram-positive vsGram-negative)?
< Is the fixed cut-off PMN count used for definingSBP the
best choice, or is the chemotacticcapacity of each individual
patient relevant?
< Which parameters are sufficiently sensitive toguide rapid
imaging for detection of secondaryperitonitis?
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between nosocomial and community-acquired SBPwith regard to the
type of antibiotic regimen to use.This may be deleterious since
nosocomial infectionsare associated with high rates of bacterial
multi-resistance and mortality (J G Acevedo, personalcommunication,
2009).24 102 Patients with cirrhosisare also at increased risk of
healthcare-associatedinfections,103 but studies are needed to
determinethe associated risk for multiresistant bacteriacausing
SBP.
Community-acquired SBP: complicated anduncomplicated
casesHistorically, Gram-negative bacteriadalmostexclusively
Enterobacteriaceaedhave been isolatedin the overwhelming majority
of SBP cases. Morerecently, several studies have found an
increasingrate of infections with Gram-positive bacteria
andresistant microorganisms (J G Acevedo, personalcommunication,
2009).24 29 102 However, inpatients with no previous
hospitalisation and noprior antibiotic treatment, the causative
bacteriastill usually belong to the easily treatable
Enter-obacteriaceae family of bacteria. Several antibioticshave
been recommended for the initial treatment ofSBP in these cases
including cefotaxime or otherthird-generation cephalosporins,
amoxicillin-clav-ulanic acid or quinolones. Although earlier
trialshave shown comparable efficacy of
intravenousamoxicillin/clavulanic acid (1/0.2 g every 8 h)
andintravenous cefotaxime in the treatment of SBP,recent increases
in resistance to aminopenicillin/b-lactamase inhibitors104 may
limit their useful-ness. In patients presenting without
complicatingfactors that may worsen therapeutic efficacy,
oraltreatment with quinolones appears sufficient incountries with a
relatively low rate of quinolone-resistant strains of E coli.
Possible complicatingfactors include shock, ileus,
gastrointestinalbleeding, severe hepatic encephalopathy or
renaldysfunction (serum creatinine >3 mg/dl).105
Nosocomial SBP: treatment failure, risk factors
andrecommendationsIn nosocomial SBP, use of the antibiotics
recom-mended above (third-generation
cephalosporins,amoxicillin/clavulanic acid or quinolones)
hasrecently led to disappointing and unacceptably lowrates of
resolution (J G Acevedo, personal commu-nication, 2009).29 106
Resistance to third-generationcephalosporins and quinolones has
been reported toincrease continuously and to reach levels of23e44%
and 38e50%, respectively, in some insti-tutions and countries (J G
Acevedo, personalcommunication, 2009).24 29 106 107 In addition,
theincidence of extended-spectrum b-lactamase(ESBL)-producing
bacteria as well as multiresistantGram-positive bacteria such as
Enterococcus faeciumor methicillin-resistant Staphylococcus
aureus(MRSA) causing nosocomial SBP is alarming (table1). MRSA has
been found in 24e27% of cases ofSBP, with detection of S aureus in
ascites severalyears ago.75 112 Fortunately, the numbers
aredecreasing in most European countries.113 In
contrast, the Study for Monitoring AntimicrobialResistance
Trends reported that hospital-acquiredESBL-positive E coli in any
intra-abdominal infec-tion have increased in Europe from 4.3% in
2002 to11.8% in 2008.114 115 ESBLs cause resistance tovarious types
of newer b-lactam antibioticsincluding third-generation
cephalosporins andmonobactams and, in addition, frequently
alsocarry genes encoding resistance even to other anti-biotics
including quinolones, tetracyclines andantifolates.116 ESBL
resistance genes/plasmidsrapidly spread around the world, with
foreigntravel being associated with intestinal colonisationrates as
high as 32% in Asia (and 88% specifically inIndia).117 118
Moreover, colonisation of these resis-tant organisms persists in a
large proportion ofpatients for many months117 and any
antibiotictreatment causes selective pressure, accelerating
theclinical relevance of these bacteria.119 For SBP,ESBL-positive
strains are not yet as frequent as inAsia but have been reported to
cause up to 22% ofnosocomial infections in Spain (J
Fernandez,personal communication, 2010). However, amongEuropean
countries and even among institutions inthe same country, there are
wide differences inresistance rates. For instance, for E coli
isolates,susceptibility rates of ciprofloxacin or
ampicillin/sulbactam are 90% and 65%, respectively, inEstonia but
are 52% and 32% in Turkey.114
The clinical relevance of these numbers isreflected in the
associated morbidity, healthcare-associated costs and mortality. In
a number ofindependent investigations, in-hospital mortalityand/or
30-day mortality have been shown to beincreased in nosocomial SBP
caused by multi-resistant bacteria compared with commonbacteria (J
G Acevedo, personal communication,2009).75 102 106 111 In some
series, most patientswith SBP due to multiresistant bacteria died
withinthe first 5 days after the diagnosis of SBP was madeand,
indeed, none of the patients with persistentinfection survived.29 A
meta-analysis of recentlypublished data found a four times
increased risk ofmortality associated with bacterial resistance
inSBP (figure 2). Nosocomial SBP due to ESBL strainsor to
multiresistant bacteria is often associatedwith a failure of
first-line empirical antibiotictreatment.29 102 109 Indeed, the
need for escalationof treatment associated with poor survival
ispredictive of in-hospital mortality24 29 and there-fore must be
avoided. The use of carbapenems andglycopeptides would be safest
and easiest since noresistance has so far been reported in cases of
SBP,but this is not practical and the choice of antibi-otics needs
to be stratified for parameters definingthe risk of resistant
bacteria. This includes hostfactors as well as validated knowledge
of theresistance profile of bacteria acting in the setting inwhich
the patient is diagnosed and treated.Reported independent risk
factors for bacterialmultiresistance are previous
hospitalisation(particularly within 3 months and intensive
caretreatment) and prior prophylactic or therapeuticantibiotic
treatment (figure 3).24 29 120 121 It is
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therefore suggested that, in patients with cirrhosiswho develop
nosocomial SBP and present with suchrisk factors, a more effective
first-line empiricalantibiotic therapy with a broader spectrum
shouldbe used, namely carbapenems. However, thisregimen should be
de-escalated as soon as possible ifmicrobiological results reveal
non-resistant easilytreatable causative microorganisms. This
minimisesresistance selection pressure on the carbapenemsand
underlines the paramount importance ofobtaining appropriate
microbiological cultures.Global susceptibility statistics from
intra-abdom-inal infections show that the susceptibilities
ofGram-negative isolates to the carbapenems haveremained stable
over the past years, with E coli andK pneumoniae isolates,
including ESBL-positiveisolates, being 98e100% susceptible.122
Imple-menting carbapenems as first-line treatment inpatients with
nosocomial SBP with risk factors formultiresistant bacteria can
therefore save lives. Thishas also been recommended in recent
guidelines onthe treatment of sepsis,123 aiming at rapid
initia-tion of an antibiotic regimen likely to cover allexpected
causative microorganisms. The sameshould be even more true for
patients withdecompensated cirrhosis who have an
enhancedproinflammatory response to bacterial stimuli124
and exhibit an increased susceptibility for anyvasodilatory
stimulus due to the already highlyhyperdynamic splanchnic
circulation.125
Treatment of bacterascitesIt is controversial whether
culture-positive resultsin the absence of an increased PMN count in
theascitic fluid require immediate initiation of antibi-otic
therapy. Some guidelines recommend antibi-otic treatment only in
patients with signs ofinfection or inflammation.4 Otherwise, a
follow-upparacentesis should establish whether SBP ispresent (PMN
count >250/mm3) and thus whethertreatment is indicated. However,
this is based ona single-centre observational cohort study126
andhas not been addressed prospectively. Until then wethink that
considering the lack of symptoms ina large number of cirrhotic
patients even in pres-ence of severe bacterial infection antibiotic
treat-ment should be used in case of bacterascites.
Use of albumin as adjuvant treatmentIn patients with cirrhosis
with SBP, a prospectiverandomised comparative study reported that
adju-vant administration of high-dose albumin (1.5 g/kgon day 1 and
1 g/kg on day 3) with antibiotictreatment prevented worsening of
renal functionwith a concomitant improvement in in-hospitaland
3-month survival.108 However, this regimen ismainly effective in
high-risk patients characterisedby serum bilirubin >4 mg/dl. In
addition, in unse-lected patients with SBP, even low-dose
albumin(10 g/day on days 1e3) has been shown to reducetumour
necrosis factor and interleukin 6 levels inserum and ascites and to
prevent increases in serumNOx induced by SBP.110 Therefore, future
trialsneed to determine whether other patients withTa
ble1
Dataon
bacterialresistance
inSBPandassociated
mortalityinlast
decade
Reference
Country
Num
berof
patients/num
ber
SBPepisodes
(yearwhere
stated)
Resistanceratesforantibiotics
(inculturable
bacteria)
ESBL(%
ofcultured
bacteria)
MRSA(%
ofcultured
bacteria)
Candida
spp
Mortalitywithvs
without
multiresistant
bacteria
(orresistance*/failure
first-
linetherapyy
)RR(95%
CI)
Singh
etal,2002
108
USA
42/61
25(1991e
1995)
17(1996e
2001)
Multiresistant:19%(overall)
8.3%
(1991e
1995)
38.5%(1996e
2001)
8.1%
5.4%
12%
30-day
mortality:
4/7vs
5/30,RR3.43
(1.23to
9.56)
Park
etal,2003
109
Korea
75/87(1995)
195/222(1998)
207/271(1999)
Cefotaximez
:7%
(1995)
and28%(1999)
Ciprofloxacinz
:10%(1995)
and32%
(1999)
Ampicillinz
:83%(1995)
and76%(1999)
7.9%
(1995)
9.7%
(1998)
19.8%(1999)
Not
stated
Not
stated
In-hospitalmortality:
ESBL94%vs
others
notstated
Angeloniet
al,2008
106
Italy
32/38
Cefotaxime:
44%
33%
00
Not
stated
Heo
etal,2009
110
Korea
145/157
Cefotaxime:
15.6%z
Ciprofloxacin:
20.4%z
Ampicillin:
61.1%z
11.1%
01.9%
In-hospitalmortality:
20/23vs
13/132,
RR8.83
(5.15to
15.15)y
4/6forESBLvs
29/151
forothers,
RR3.47
(1.81to
6.67)
Cheonget
al,2009
24
Korea
236/236
Third-generationcephalosporin:16.3%z
4.7%
0Not
stated
30-day
mortality:
46/61vs
69/175,
RR1.91
(1.52to
2.41)y
Umgelteret
al,2009
29
Germany
101/101
Cefotaxime:
33%
Ciprofloxacin:
45.2%Amoxicillin/
clavulanic
acid:38.6%
Multiresistant:26.8%
00
4.9%
8/17
vs1/12,RR5.65
(0.81to
39.42)*
(88.9%
with
multiresistant
bacteria;
personalcommunication)
Fernandezet
al,2011
111
Spain
100/126
Multiresistantbacteria:22%
(nosocom
ial);
3%(com
munity-acquired)
16%/2%
00
In-hospitalmortality:
17/116
vs5/10,
RR3.41
(1.60to
7.29)
PooledxRR3.87
(1.76to
8.52)
zFor
Gram-negativebacteria.
xRandom
effect
meta-analyses
performed
inReview
Manager
Version
5.1.
Copenhagen:
TheNordicCochraneCentre,
TheCochraneCollaboration,
2011.StatisticalmethodMantel-H
aenszel.
ESBL,
extended-spectrum
b-lactam
ase;
MRSA,methicillin-resistantStaphylococcusaureus;SBP,
spontanous
bacterialperitonitis.
302 Gut 2012;61:297e310. doi:10.1136/gutjnl-2011-300779
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-
cirrhosis could also benefit and to establish the doseand timing
of albumin needed to give most benefitto the individual
patient.
Duration of treatment and control of treatmentsuccessAntibiotic
treatment can safely be discontinuedafter the ascites PMN count has
decreased to
-
Table2
Publishedrandom
ised
controlledtrialsincludingprimaryprophylaxisof
SBPtreatm
ent
Reference
Intervention,
controls,comparison
Patients
Follow-up
Previous
SBP
GIbleed
Ascites
protein(g/dl)
Child
class
(A/B/C/score)
Exclusion
criteria
Incidence
ofSBP
Survival
As
Ac
BO
IS
C/D
Soriano
etal,1991
136
Norfloxacin400mg/day
vsno
treatm
ent
32/31
Nodata
6%4/61
(6.6%)
All<1.5
TP:0.7160.3
Con:0.6760.3
TP:2/3/17
Con:1/14/16
Recentinfection
GIbleed
TP:0/32
(0%)
Con:7/31
(22.5%
)p<
0.05
TP:30/32
(93.7%
)Con:26/31
(83.9%
)NS
??
e+
+e
Rolachon
etal,1995
137
Ciprofloxacin750mg/week
vsplacebo
28/32
6months
11%
No
All<1.5
TP:0.9460.3
Con:1.0360.3
TP:0/17/11
Con:1/18/13
HCC
GIbleed
HE
TP:1/28
(3.6%)
Con:7/32(22%
)p<
0.05
TP:24/28
(85.7%
)Con:26/32
(81.2%
)NS
??
++
++
Non-com
pliant
(n¼3
),withdraw
alor
lost
tofollow-up
(n¼5
),overall13%
Singh
etal,1995
134
Trimethoprim-
sulfamethoxazole
double-strength13
/day
(5days/week)
vsno
treatm
ent
30/30
90days
(7e682)
22%
13%
Nodata
Nodata
Nodata
TP:1/30
(3%)
Con:7/30
(23.3%
)(8/30(27%
)for
endpoint*
p<0.05
TP:28/30
(93%
)Con:24/30
(80%
)NS
??
e?
+e
Novella
etal,1997
51
Norfloxacin400mg/day
continuous
vsnorfloxacin
400mg/dayin-hospital
56/53
43+3week
No
23/109
(>21%)
TP:1.06
0.2
Con:0.96
0.1
TP:0/29/27
Con:0/24/29
HCC
Bilirubin
>15
mg/dl
TP:1/56
(1.8%)
Con:9/53
(16.9%
)p<
0.01
TP:75%
Con:62%
NS
?+
e?
?e
Drop-out:>10%
Grange
etal,1998
138
Norfloxacin400mg/day
vsplacebo
53/54
6months
No
No
All<1.5
TP:0.9360.29
Con:1.0460.0.3
Nodata
GIbleed
HCC
SBPor
bacteraemiay
TP:1/53
(1.9%)
Con:9/54
(16.7%
)p<
0.05
TP:45/53
(84.9%
)Con:44/54
(81.5%
)NS
??
?+
++
Lost
tofollow-up
(4/53and4/54)
Drop-out:7.5%
non-compliant
(3/53and2/54),
withdraw
al(2/53),
overall14%
Alvarez
etal,2005
139
Norfloxacin400mg/day
vstrimethoprim-
sulfamethoxazole
160/800mg5days/week
32/25
3e547days
39%
No
Alsopts
with
>1.5
Norfloxacin:
0.9660.55
SMT:
1.3760.84
p<0.05
Norfloxacin:
1/10/21
SMT:
0/8/17
Antibiotic
within
2weeks
GIbleed
within
1week
HCC/m
alignancy
Norfloxacin:
3/32
(9.4%)
SMT:
4/25
(16%
)NS
Norfloxacin:
25/32(78.1%
)SMT:
20/25
(75%
)NS
++
e?
?e
Nodata
Fernandez
etal,2007
140
Norfloxacin400mg/day
vsplacebo
35/33
12months
No
3/68
(4.4%)
All<1.5
TP:0.9360.29
Con:1.0460.3
TP:9.96
1.5
Con:10.461.5
HCC,HIV
organic
renaldisease
TP:2/35
(5.7%)
Con:10/33(30.3%
)p<
0.05
TP:25/35
(71.4%
)Con:20/33
(60.6%
)NS
++
++
+?
Lost
tofollow-up
(3/35and2/33),
oneprotocol
violation,
non-
compliant
(3/35
and3/33)
Terg
etal,2008
141
Ciprofloxacin500mg/day
vsplacebo
50/50
12months
No
Nodata
All<1.5
TP:0.8460.01
Con:0.85+0.4
TP:8.36
1.3
Con:8.56
1.5
HE,
HCC/
malignancy
creatinine
>3mg/dl
platelets
<98
000
TP:2/50
(4%)
Con:7/50
(14%
)NS
TP:44/50
(80%
)Con:36/50
(72%
)p<
0.05
*SBPor
spontaneousbacteraemia.
yPrim
aryendpointisGram-negativeinfections
butno
inform
ationon
SBPalone.
As,
allocationsequence;Ac,
allocationconcealment;B,blinding;O,outcom
edata
setcomplete?;I,intentionto
treat;S,samplesize
calculation;
C/D,compliance/drop-out
rate.
Con,control;GI,gastrointestinal;HCC,hepatocellularcarcinom
a;HE,
hepatic
encephalopathy;NS,notsignificant;SBP,
spontanous
bacterialperitonitis;
SMT,
trimethoprim-sulfamethoxazole;TP,therapy.
304 Gut 2012;61:297e310. doi:10.1136/gutjnl-2011-300779
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-
a higher rate of quinolone-resistant organisms131
and, in our view, should therefore be avoided. Datasupporting
the use of trimethoprim/sulfamethox-azole are weak,132 while its
side effects are poten-tially dangerous and probably
under-reported.133
Moreover, resistance to this class of antibiotics hasincreased
to a degree that it is no longer recom-mended as the first-line
choice for the empiricaltreatment of urinary tract infections in
somecountries.134 In patients with cirrhosis withgastrointestinal
haemorrhage, quinolones are mostfrequently used and have been found
to decreasethe incidence of severe infections (SBP
and/orsepticaemia) and mortality. However, in patientswith bleeding
necessitating invasive procedures,infections are increasingly
caused by Gram-positivebacteria and intravenous delivery may be
moreappropriate than the oral route. In fact, the third-generation
cephalosporin ceftriaxone administeredintravenously has been shown
to be superior to oralnorfloxacin in patients with advanced
cirrhosis(ie, with at least two of the following: ascites,severe
malnutrition, encephalopathy or bilirubin>3 mg/dl).135
With regard to the use of antibiotics for primaryprophylaxis in
the setting of low protein ascites(
-
Nonetheless, guidelines state very cautiously thatthe long-term
use of norfloxacin can be justified4 orshould be considered in
these selected patients.1 3
However, since this trial fulfils the highest qualitycriteria
(Jadad score 5) and represents a well-definedgroup of patients, we
consider the use of norflox-acin for primary prophylaxis as a
standard of careprocedure.
Limitations in antibiotic prophylaxis andalternativesThe longer
the duration of antibiotic treatment, thegreater is the risk for
selection of resistant strainsand the lower is the chance of
reducing the inci-dence of SBP. In fact, survival advantage
usingnorfloxacin as primary prophylaxis in highlyselected patients
is most marked during the first3 months of treatment (94% vs 62%,
p¼0.003) anddecreases over time.138 145 We therefore proposethat
the use of norfloxacin for primary prophylaxisshould also be
considered in unselected patientswith low protein ascites if liver
transplantation isa realistic option within a few months.
Althoughthere are no long-term data, the same time courseof
antibiotic efficacy is likely to be present as insecondary
prophylaxis. Its use is recommended tobe continued until liver
transplantation or until thedisappearance of ascites (eg, in
alcoholics stoppingalcohol ingestion).2 3 In any other case,
antibiotictreatment guidelines support long-term use but, inour
view, improvement in liver disease should leadto interruption of
treatment.Overall, the continuous use of a single antibiotic
appears not to be the optimal solution and effortsshould be made
to seek alternatives which couldinclude antibiotic cycling. The
basic principle ofcycling antibiotics is that bacteria acquiring
resis-tance to the first course of treatment would
remainsusceptible to the second regimen, and so on. Inthis context,
future trials should test the use ofrifaximin since (a) it belongs
to a different antibi-otic class from the antibiotics tested
prospectivelyso far; (b) it exerts a broad range of
antimicrobialactivity including Gram-positive bacteria141; (c)
itappears to cause considerably less bacterial resis-tance147 148;
and (d) it acts predominantly in thesmall intestine,147e149 the
site of bacterial over-growth in cirrhosis. Finally, as has been
pointed outby others,150 151 effective non-antibiotic approachesin
reducing the incidence of SBP represent the HolyGrail.
Interestingly, a significant decrease in theincidence of
postoperative infections has beenreported in a cohort study of
patients with cirrhosistreated with propranolol and
ciprofloxacincompared with ciprofloxacin alone after laparo-scopic
surgery.152 Moreover, NSBB have beenreported to ameliorate
pathological BT in experi-mental cirrhosis.153 Finally, recent
meta-analyses ofavailable data indicate that NSBB lower the risk
ofSBP in patients with cirrhosis which may occurindependently of
the haemodynamic responseachieved.65 66 However, the use of NSBB in
patientswith refractory ascites has been suggested toworsen
prognosis154 155 and to be associated with
haemodynamic adverse effects after large-volumeparacentesis.156
Future prospective trials thereforeneed to address these questions
in detail in order toestablish the use of NSBB in the right patient
at theright time.Cisapride, a serotonin 5-HT4 receptor agonist
and intestinal prokinetic drug, has been shownto decrease SIBO
and BT in experimentalcirrhosis41 157 but was abandoned due to
cardiacside effects. Nonetheless, these encouraging resultsshould
stimulate human prospective trials investi-gating other prokinetics
such as the new highlyselective 5-HT4 receptor agonist prucalopride
whichshowed no interaction at other receptor sites.158
Other promising approaches reported to amelio-rate BT in
experimental cirrhosis include orallyadministered conjugated bile
acids, chol-ylsarcosine,159 insulin-like growth factor I)160
andanti-tumour necrosis factor.161 Probiotics have beenreported to
correct bacterial overgrowth, stabilisemucosal barrier function,
improve neutrophilfunction and decrease BT in experimental
liverfailure.162 163 In patients with cirrhosis, symbiotictreatment
significantly reduced endotoxin levelsand improved the Child-Pugh
functional class innearly 50% of cases.164 Similarly, the addition
offibre to lactobacilli decreased postoperative bacterialinfections
after liver transplantation.165 Probioticsmay even be helpful in
limiting the development ofbacterial resistance, and trials are
ongoing toinvestigate their efficacy in eradicating
carba-penem-resistant bacteria as well as the decolonisa-tion of
MRSA in carrier patients (NCT00722410/NCT00941356).
Box 3
Key messages: established unequivocally< In patients with
gastrointestinal haemorrhage,
antibiotic prophylaxis is mandatory using third-generation
cephalosporins (eg, ceftriaxone) insevere liver disease or
quinolones in less severeand uncomplicated cases.
< Secondary prophylaxis is recommended afterresolution of SBP
with the strongest evidencesupporting use of norfloxacin.
Controversial but proposed< Primary prophylaxis can be
justified in patients
with low protein ascites (
-
Acknowledgements The authors thank Professor Thomas
Glueck(Hospital Trostberg, Germany) for helpful discussions,
scientificadvice and for reviewing the manuscript.
Competing interests None.
Contributors RW and AG wrote the manuscript. AK performed
thestatistical analysis and meta-analysis.
Provenance and peer review Commissioned; externally
peerreviewed.
REFERENCES1. Fernandez J, Navasa M, Planas R, et al. Primary
prophylaxis of
spontaneous bacterial peritonitis delays hepatorenal syndromeand
improves survival in cirrhosis.
Gastroenterology2007;133:818e24.
2. Grange JD, Roulot D, Pelletier G, et al. Norfloxacin
primaryprophylaxis of bacterial infections in cirrhotic patients
withascites: a double-blind randomized trial [see comments].
JHepatol 1998;29:430e6.
3. Terg R, Fassio E, Guevara M, et al. Ciprofloxacin in
primaryprophylaxis of spontaneous bacterial peritonitis: a
randomized,placebo-controlled study. J Hepatol 2008;48:774e9.
4. Runyon BA. Management of adult patients with ascites due
tocirrhosis: an update. Hepatology 2009;49:2087e107.
5. Fernandez J, Navasa M, Gomez J, et al. Bacterial infections
incirrhosis: epidemiological changes with invasive procedures
andnorfloxacin prophylaxis. Hepatology 2002;35:140e8.
6. Caly WR, Strauss E. A prospective study of bacterial
infectionsin patients with cirrhosis. J Hepatol 1993;18:353e8.
7. Pinzello G, Simonetti RG, Craxi A, et al. Spontaneous
bacterialperitonitis: a prospective investigation in
predominantlynonalcoholic cirrhotic patients. Hepatology
1983;3:545e9.
8. Evans LT, Kim WR, Poterucha JJ, et al. Spontaneous
bacterialperitonitis in asymptomatic outpatients with cirrhotic
ascites.Hepatology 2003;37:897e901.
9. Castellote J, Girbau A, Maisterra S, et al. Spontaneous
bacterialperitonitis and bacterascites prevalence in asymptomatic
cirrhoticoutpatients undergoing large-volume paracentesis.
JGastroenterol Hepatol 2008;23:256e9.
10. Jeffries MA, Stern MA, Gunaratnam NT, et al.
Unsuspectedinfection is infrequent in asymptomatic outpatients
withrefractory ascites undergoing therapeutic paracentesis. Am
JGastroenterol 1999;94:2972e6.
11. Conn HO, Fessel JM. Spontaneous bacterial peritonitis
incirrhosis: variations on a theme. Medicine
(Baltimore)1971;50:161e97.
12. Rimola A, Garcia-Tsao G, Navasa M, et al. Diagnosis,
treatmentand prophylaxis of spontaneous bacterial peritonitis: a
consensusdocument. International Ascites Club. J
Hepatol2000;32:142e53.
13. Chu CM, Chang KY, Liaw YF. Prevalence and
prognosticsignificance of bacterascites in cirrhosis with ascites.
Dig Dis Sci1995;40:561e5.
14. Follo A, Llovet JM, Navasa M, et al. Renal impairment
afterspontaneous bacterial peritonitis in cirrhosis: incidence,
clinicalcourse, predictive factors and prognosis.
Hepatology1994;20:1495e501.
15. Nobre SR, Cabral JE, Gomes JJ, et al. In-hospital mortality
inspontaneous bacterial peritonitis: a new predictive model. Eur
JGastroenterol Hepatol 2008;20:1176e81.
16. Thuluvath PJ, Morss S, Thompson R. Spontaneous
bacterialperitonitisein-hospital mortality, predictors of survival,
and healthcare costs from 1988 to 1998. Am J
Gastroenterol2001;96:1232e6.
17. Tito L, Rimola A, Gines P, et al. Recurrence of
spontaneousbacterial peritonitis in cirrhosis: frequency and
predictive factors.Hepatology 1988;8:27e31.
18. Toledo C, Salmeron JM, Rimola A, et al. Spontaneous
bacterialperitonitis in cirrhosis: predictive factors of infection
resolutionand survival in patients treated with cefotaxime.
Hepatology1993;17:251e7.
19. Andreu M, Sola R, Sitges-Serra A, et al. Risk factors
forspontaneous bacterial peritonitis in cirrhotic patients with
ascites.Gastroenterol 1993;104:1133e8.
20. Silvain C, Besson I, Ingrand P, et al. Prognosis and
long-termrecurrence of spontaneous bacterial peritonitis in
cirrhosis. JHepatol 1993;19:188e9.
21. Terg R, Levi D, Lopez P, et al. Analysis of clinical course
andprognosis of culture-positive spontaneous bacterial peritonitis
and
neutrocytic ascites. Evidence of the same disease. Dig Dis
Sci1992;37:1499e504.
22. Arvaniti V, D’Amico G, Fede G, et al. Infections in patients
withcirrhosis increase mortality four-fold and should be used
indetermining prognosis. Gastroenterology
2010;139:1246e56,1256.e1e5.
23. Altman C, Grange JD, Amiot X, et al. Survival after a
firstepisode of spontaneous bacterial peritonitis. Prognosis
ofpotential candidates for orthotopic liver transplantation.
JGastroenterol Hepatol 1995;10:47e50.
24. Cheong HS, Kang CI, Lee JA, et al. Clinical significance
andoutcome of nosocomial acquisition of spontaneous
bacterialperitonitis in patients with liver cirrhosis. Clin Infect
Dis2009;48:1230e6.
25. Almdal TP, Skinhoj P. Spontaneous bacterial peritonitis
incirrhosis. Incidence, diagnosis, and prognosis. Scand
JGastroenterol 1987;22:295e300.
26. Terg R, Gadano A, Cartier M, et al. Serum creatinine and
bilirubinpredict renal failure and mortality in patients with
spontaneousbacterial peritonitis: a retrospective study. Liver
Int2009;29:415e19.
27. Franca AV, De Souza JB, Silva CM, et al. Long-term
prognosisof cirrhosis after spontaneous bacterial peritonitis
treated withceftriaxone. J Clin Gastroenterol 2001;33:295e8.
28. Kamani L, Mumtaz K, Ahmed US, et al. Outcomes in
culturepositive and culture negative ascitic fluid infection in
patientswith viral cirrhosis: cohort study. BMC Gastroenterol
2008;8:59.
29. Umgelter A, Reindl W, Miedaner M, et al. Failure of
currentantibiotic first-line regimens and mortality in hospitalized
patientswith spontaneous bacterial peritonitis. Infection
2009;37:2e8.
30. Cho JH, Park KH, Kim SH, et al. Bacteremia is a
prognosticfactor for poor outcome in spontaneous bacterial
peritonitis.Scand J Infect Dis 2007;39:697e702.
31. Appenrodt B, Grunhage F, Gentemann MG, et al.
Nucleotide-binding oligomerization domain containing 2 (NOD2)
variants aregenetic risk factors for death and spontaneous
bacterialperitonitis in liver cirrhosis. Hepatology
2010;51:1327e33.
32. Wiest R, Garcia-Tsao G. Bacterial translocation (BT) in
cirrhosis.Hepatology 2005;41:422e33.
33. Wiest R. Role of bacterial infections for hepatorenal
syndrome.In: Gerbes A, ed. Frontiers in Gastrointestinal Research.
Aszites,Hyponatremia and heptorenal syndrome. Basel,
Switzerland:Krager, 2010.
34. Wells CL. Relationship between intestinal microecology and
thetranslocation of intestinal bacteria. Antonie Van
Leeuwenhoek1990;58:87e93.
35. Guarner C, Gonzalez-Navajas JM, Sanchez E, et al.
Thedetection of bacterial DNA in blood of rats with
CCl4-inducedcirrhosis with ascites represents episodes of
bacterialtranslocation. Hepatology 2006;44:633e9.
36. Llovet JM, Bartoli R, March F, et al. Translocated
intestinalbacteria cause spontaneous bacterial peritonitis in
cirrhoticrats: molecular epidemiologic evidence. J
Hepatol1998;28:307e13.
37. Chen Y, Yang F, Lu H, et al. Characterization of fecal
microbialcommunities in patients with liver cirrhosis.
Hepatology2011;54:562e72.
38. Yan AW, Fouts DE, Brandl J, et al. Enteric dysbiosis
associatedwith a mouse model of alcoholic liver disease.
Hepatology2011;53:96e105.
39. Bauer TM, Steinbruckner B, Brinkmann FE, et al. Small
intestinalbacterial overgrowth in patients with cirrhosis:
prevalence andrelation with spontaneous bacterial peritonitis. Am
JGastroenterol 2001;96:2962e7.
40. Guarner C, Runyon BA, Young S, et al. Intestinal
bacterialovergrowth and bacterial translocation in cirrhotic rats
withascites. J Hepatol 1997;26:1372e8.
41. Pardo A, Bartoli R, Lorenzo-Zuniga V, et al. Effect of
cisapride onintestinal bacterial overgrowth and bacterial
translocation incirrhosis. Hepatology 2000;31:858e63.
41a. Teltschik Z, Wiest R, Beisner J, et al. Intestinal
bacterialtranslocation in cirrhotic rats is related to compromised
Panethcell antimicrobial host defence. Hepatology (in press).
42. Chiva M, Guarner C, Peralta C, et al. Intestinal mucosal
oxidativedamage and bacterial translocation in cirrhotic rats. Eur
JGastroenterol Hepatol 2003;15:145e50.
43. Ramachandran A, Prabhu R, Thomas S, et al. Intestinal
mucosalalterations in experimental cirrhosis in the rat: role of
oxygen freeradicals. Hepatology 2002;35:622e9.
44. Dunn DL, Barke RA, Ahrenholz DH, et al. The adjuvant effect
ofperitoneal fluid in experimental peritonitis. Mechanism and
clinicalimplications. Ann Surg 1984;199:37e43.
Gut 2012;61:297e310. doi:10.1136/gutjnl-2011-300779 307
Recent advances in clinical practice
group.bmj.com on November 26, 2014 - Published by
http://gut.bmj.com/Downloaded from
http://gut.bmj.com/http://group.bmj.com
-
45. Gabele E, Muhlbauer M, Paulo H, et al. Analysis of
monocytechemotactic protein-1 gene polymorphism in patients
withspontaneous bacterial peritonitis. World J
Gastroenterol2009;15:5558e62.
46. Joyce LD, Hau T, Hoffman R, et al. Evaluation of the
mechanismof zymosan-induced resistance to experimental
peritonitis.Surgery 1978;83:717e25.
47. Runyon BA, Morrissey RL, Hoefs JC, et al. Opsonic activity
ofhuman ascitic fluid: a potentially important protective
mechanismagainst spontaneous bacterial peritonitis.
Hepatology1985;5:634e7.
48. Such J, Guarner C, Enriquez J, et al. Low C3 in cirrhotic
ascitespredisposes to spontaneous bacterial peritonitis. J
Hepatol1988;6:80e4.
49. Runyon BA. Low-protein-concentration ascitic fluid
ispredisposed to spontaneous bacterial peritonitis.
Gastroenterol1986;91:1343e6.
50. Llach J, Rimola A, Navasa M, et al. Incidence and
predictivefactors of first episode of spontaneous bacterial
peritonitis incirrhosis with ascites: relevance of ascitic fluid
proteinconcentration. Hepatology 1992;16:724e7.
51. Novella M, Sola R, Soriano G, et al. Continuous versus
inpatientprophylaxis of the first episode of spontaneous
bacterialperitonitis with norfloxacin. Hepatology
1997;25:532e6.
52. Wiest R, Leidl F, Kopp A, et al. Peritoneal fluid
adipokines: readyfor prime time? Eur J Clin Invest
2009;39:219e29.
53. Guarner C, Sola R, Soriano G, et al. Risk of a first
community-acquired spontaneous bacterial peritonitis in cirrhotics
withlow ascitic fluid protein levels.
Gastroenterology1999;117:414e19.
54. Obstein KL, Campbell MS, Reddy KR, et al. Association
betweenmodel for end-stage liver disease and spontaneous
bacterialperitonitis. Am J Gastroenterol 2007;102:2732e6.
55. Riordan SM, Skinner N, Nagree A, et al. Peripheral
bloodmononuclear cell expression of toll-like receptors and
relation tocytokine levels in cirrhosis. Hepatology
2003;37:1154e64.
56. Wasmuth HE, Kunz D, Yagmur E, et al. Patients with acute
onchronic liver failure display “sepsis-like” immune paralysis.
JHepatol 2005;42:195e201.
57. Berres ML, Schnyder B, Yagmur E, et al. Longitudinal
monocytehuman leukocyte antigen-DR expression is a prognostic
marker incritically ill patients with decompensated liver
cirrhosis. Liver Int2009;29:536e43.
58. Hassner A, Kletter Y, Jedvab M, et al. Impaired
monocytefunction in liver cirrhosis. Lancet 1979;1:329e30.
59. Rajkovic IA, Williams R. Abnormalities of
neutrophilphagocytosis, intracellular killing and metabolic
activity inalcoholic cirrhosis and hepatitis. Hepatology
1986;6:252e62.
60. Bruns T, Peter J, Reuken PA, et al. NOD2 gene variants area
risk factor for culture-positive spontaneous bacterial
peritonitisand monomicrobial bacterascites in cirrhosis. Liver
Int2011:10e3231.
61. Nischalke HD, Berger C, Aldenhoff K, et al. Toll-like
receptor(TLR) 2 promotor and intron 2 polymorphisms are associated
withincreased risk for spontaneous bacterial peritonitis in
livercirrhosis. J Hepatol 2011;55:1010e16.
62. Netea MG, Ferwerda G, de Jong DJ, et al.
Nucleotide-bindingoligomerization domain-2 modulates specific TLR
pathways forthe induction of cytokine release. J Immunol
2005;174:6518e23.
63. Bajaj JS, Zadvornova Y, Heuman DM, et al. Association
ofproton pump inhibitor therapy with spontaneous
bacterialperitonitis in cirrhotic patients with ascites. Am J
Gastroenterol2009;104:1130e4.
64. Trikudanathan G, Israel J, Cappa J, et al. Association
betweenproton pump inhibitors and spontaneous bacterial peritonitis
incirrhotic patientsda systematic review and meta-analysis. Int
JClin Pract 2011;65:674e8.
65. Senzolo M, Cholongitas E, Burra P, et al. beta-Blockers
protectagainst spontaneous bacterial peritonitis in cirrhotic
patients:a meta-analysis. Liver Int 2009;29:1189e93.
66. Krag A, Wiest R, Albillos A, et al. Reduced mortality with
non-selective betablockers (NSBB) compared to banding is notrelated
to prevention of bleeding or bleeding related mortality:a
hypothesis for non-hemodynamic effects of NSBB. J
Hepatol2011;54:S72.
67. Sanders VM, Straub RH. Norepinephrine, the
beta-adrenergicreceptor, and immunity. Brain Behav Immun
2002;16:290e332.
68. Worlicek M, Knebel K, Linde HJ, et al.
Splanchnicsympathectomy prevents translocation and spreading of E
colibut not S aureus in liver cirrhosis. Gut 2010;59:1127e34.
69. Chinnock B, Afarian H, Minnigan H, et al. Physician
clinicalimpression does not rule out spontaneous bacterial
peritonitis in
patients undergoing emergency department paracentesis. AnnEmerg
Med 2008;52:268e73.
70. Hoefs JC. Increase in ascites white blood cell and
proteinconcentrations during diuresis in patients with chronic
liverdisease. Hepatology 1981;1:249e54.
71. Albillos A, Cuervas-Mons V, Millan I, et al. Ascitic
fluidpolymorphonuclear cell count and serum to ascites
albumingradient in the diagnosis of bacterial peritonitis.
Gastroenterology1990;98:134e40.
72. Garcia-Tsao G, Conn HO, Lerner E. The diagnosis of
bacterialperitonitis: comparison of pH, lactate concentration and
leukocytecount. Hepatology 1985;5:91e6.
73. Stassen WN, McCullough AJ, Bacon BR, et al.
Immediatediagnostic criteria for bacterial infection of ascitic
fluid. Evaluationof ascitic fluid polymorphonuclear leukocyte
count, pH, andlactate concentration, alone and in combination.
Gastroenterology1986;90:1247e54.
74. Yang CY, Liaw YF, Chu CM, et al. White count, pH and lactate
inascites in the diagnosis of spontaneous bacterial
peritonitis.Hepatology 1985;5:85e90.
75. Campillo B, Richardet JP, Kheo T, et al.
Nosocomialspontaneous bacterial peritonitis and bacteremia in
cirrhoticpatients: impact of isolate type on prognosis and
characteristicsof infection. Clin Infect Dis 2002;35:1e10.
76. Gonzalez-Navajas JM, Bellot P, Frances R, et al. Presence
ofbacterial-DNA in cirrhosis identifies a subgroup of patients
withmarked inflammatory response not related to endotoxin. JHepatol
2008;48:61e7.
77. Angeloni S, Nicolini G, Merli M, et al. Validation of
automatedblood cell counter for the determination of
polymorphonuclear cellcount in the ascitic fluid of cirrhotic
patients with or withoutspontaneous bacterial peritonitis. Am J
Gastroenterol2003;98:1844e8.
78. Riggio O, Angeloni S, Parente A, et al. Accuracy of
theautomated cell counters for management of spontaneousbacterial
peritonitis. World J Gastroenterol 2008;14:5689e94.
79. Cereto F, Genesca J, Segura R. Validation of automated
bloodcell counters for the diagnosis of spontaneous
bacterialperitonitis. Am J Gastroenterol 2004;99:1400.
80. Nousbaum JB, Cadranel JF, Nahon P, et al. Diagnostic
accuracyof the Multistix 8 SG reagent strip in diagnosis of
spontaneousbacterial peritonitis. Hepatology 2007;45:1275e81.
81. Hiscoke C, Yoxall H, Greig D, et al. Validation of a method
for therapid diagnosis of urinary tract infection suitable for use
in generalpractice. Br J Gen Pract 1990;40:403e5.
82. Mendler MH, Agarwal A, Trimzi M, et al. A new highly
sensitivepoint of care screen for spontaneous bacterial peritonitis
usingthe leukocyte esterase method. J Hepatol 2010;53:477e83.
83. Bruns T, Sachse S, Straube E, et al. Identification of
bacterialDNA in neutrocytic and non-neutrocytic cirrhotic ascites
bymeans of a multiplex polymerase chain reaction. Liver
Int2009;29:1206e14.
84. Frances R, Benlloch S, Zapater P, et al. A sequential study
ofserum bacterial DNA in patients with advanced cirrhosis
andascites. Hepatology 2004;39:484e91.
85. Frances R, Zapater P, Gonzalez-Navajas JM, et al.
BacterialDNA in patients with cirrhosis and noninfected ascites
mimicsthe soluble immune response established in patients
withspontaneous bacterial peritonitis. Hepatology
2008;47:978e85.
86. Zapater P, Frances R, Gonzalez-Navajas JM, et al. Serum
andascitic fluid bacterial DNA: a new independent prognostic
factorin noninfected patients with cirrhosis.
Hepatology2008;48:1924e31.
87. Chinnock B, Fox C, Hendey GW. Gram’s stain of peritoneal
fluidis rarely helpful in the evaluation of the ascites patient.
AnnEmerg Med 2009;54:78e82.
88. Conn HO. Unusual presentations of SBP. In: Conn HO, Rodes
J,Navasa M, eds. London: Informa Healthcare, 2000:47e74.
89. Ortiz J, Soriano G, Coll P, et al. Early microbiologic
diagnosis ofspontaneous bacterial peritonitis with BacT/ALERT. J
Hepatol1997;26:839e44.
90. Siersema PD, de Marie S, van Zeijl JH, et al. Blood
culturebottles are superior to lysis-centrifugation tubes
forbacteriological diagnosis of spontaneous bacterial peritonitis.
JClin Microbiol 1992;30:667e9.
91. Castellote J, Xiol X, Verdaguer R, et al. Comparison of
twoascitic fluid culture methods in cirrhotic patients
withspontaneous bacterial peritonitis. Am J
Gastroenterol1990;85:1605e8.
92. Klaerner HG, Eschenbach U, Kamereck K, et al. Failure of
anautomated blood culture system to detect nonfermentative
gram-negative bacteria. J Clin Microbiol 2000;38:1036e41.
308 Gut 2012;61:297e310. doi:10.1136/gutjnl-2011-300779
Recent advances in clinical practice
group.bmj.com on November 26, 2014 - Published by
http://gut.bmj.com/Downloaded from
http://gut.bmj.com/http://group.bmj.com
-
93. Pelletier G, Salmon D, Ink O, et al. Culture-negative
neutrocyticascites: a less severe variant of spontaneous bacterial
peritonitis.J Hepatol 1990;10:327e31.
94. Gerbes AL, Jungst D, Xie YN, et al. Ascitic fluid analysis
forthe differentiation of malignancy-related and
nonmalignantascites. Proposal of a diagnostic sequence.
Cancer1991;68:1808e14.
95. Wang SS, Lu CW, Chao Y, et al. Malignancy-related ascites:a
diagnostic pitfall of spontaneous bacterial peritonitis by
asciticfluid polymorphonuclear cell count. J Hepatol
1994;20:79e84.
96. Casafont F, Rivero M, Fernandez MD, et al. Granulocyte
elastasein cirrhotic patients with spontaneous bacterial
peritonitis. Dig DisSci 1999;44:1985e9.
97. Parsi MA, Saadeh SN, Zein NN, et al. Ascitic fluid
lactoferrin fordiagnosis of spontaneous bacterial peritonitis.
Gastroenterology2008;135:803e7.
98. Soriano G, Castellote J, Alvarez CE, et al. Secondary
bacterialperitonitis in cirrhosis: a retrospective study of
clinical andanalytical characteristics, diagnosis and management. J
Hepatol2009;52:39e44.
99. Runyon BA, Hoefs JC. Ascitic fluid analysis in the
differentiationof spontaneous bacterial peritonitis from
gastrointestinal tractperforation into ascitic fluid. Hepatology
1984;4:447e50.
100. Wu SS, Lin OS, Chen YY, et al. Ascitic fluid
carcinoembryonicantigen and alkaline phosphatase levels for the
differentiation ofprimary from secondary bacterial peritonitis with
intestinalperforation. J Hepatol 2001;34:215e21.
101. Wiest R, Schoelmerich J. Secondary peritonitis in
cirrhosis: “Oilin fire”. J Hepatol 2009;52:7e9.
102. Song KH, Jeon JH, Park WB, et al. Clinical outcomes
ofspontaneous bacterial peritonitis due to extended-spectrum
beta-lactamase-producing Escherichia coli and Klebsiella species:a
retrospective matched case-control study. BMC Infect
Dis2009;9:41.
103. Merli M, Lucidi C, Giannelli V, et al. Cirrhotic patients
are at riskfor health care-associated bacterial infections. Clin
GastroenterolHepatol 2010;8:979e85.
104. Kresken M, Hafner D, Schmitz FJ, et al. Resistenzsituation
beiklinisch wichtigen Infektionserregern gegenüber Antibiotika
inDeutschland und im mitteleuropäischen Raum. 2010.
http://www.p-e-g.org
105. Navasa M, Follo A, Llovet JM, et al. Randomized,
comparativestudy of oral ofloxacin versus intravenous cefotaxime
inspontaneous bacterial peritonitis [see comments].Gastroenterology
1996;111:1011e17.
106. Angeloni S, Leboffe C, Parente A, et al. Efficacy of
currentguidelines for the treatment of spontaneous
bacterialperitonitis in the clinical practice. World J
Gastroenterol2008;14:2757e62.
107. Castellote J, Ariza X, Girbau A, et al.
Antibiotic-resistantbacteria in spontanous bacterial peritonitis.
Is it time to change?J Hepatol 2010;52:S69.
108. Singh N,Wagener MM, Gayowski T. Changing epidemiology
andpredictors of mortality in patients with spontaneous
bacterialperitonitis at a liver transplant unit. Clin Microbiol
Infect2003;9:531e7.
109. Park YH, Lee HC, Song HG, et al. Recent increase in
antibiotic-resistant microorganisms in patients with spontaneous
bacterialperitonitis adversely affects the clinical outcome in
Korea. JGastroenterol Hepatol 2003;18:927e33.
110. Heo J, Seo YS, Yim HJ, et al. Clinical features and
prognosis ofspontaneous bacterial peritonitis in korean patients
with livercirrhosis: a multicenter retrospective study. Gut
Liver2009;3:197e204.
111. Campillo B, Dupeyron C, Richardet JP. Epidemiology of
hospital-acquired infections in cirrhotic patients: effect of
carriage ofmethicillin-resistant Staphylococcus aureus and
influence ofprevious antibiotic therapy and norfloxacin
prophylaxis. EpidemiolInfect 2001;127:443e50.
112. Piroth L, Pechinot A, Minello A, et al. Bacterial
epidemiology andantimicrobial resistance in ascitic fluid: a 2-year
retrospectivestudy. Scand J Infect Dis 2009;41:847e51.
113. Kock R, Becker K, Cookson B, et al.
Methicillin-resistantStaphylococcus aureus (MRSA): burden of
disease and controlchallenges in Europe. Euro Surveill
2010;15:19688.
114. Hawser SP, Bouchillon SK, Hoban DJ, et al. Incidence
andantimicrobial susceptibility of Escherichia coli and
Klebsiellapneumoniae with extended-spectrum beta-lactamases
incommunity- and hospital-associated intra-abdominal infections
inEurope: results of the 2008 Study for Monitoring
AntimicrobialResistance Trends (SMART). Antimicrob Agents
Chemother2010;54:3043e6.
115. Coque TM, Baquero F, Canton R. Increasing prevalence of
ESBL-producing Enterobacteriaceae in Europe. Euro
Surveill2008;13:19044.
116. Pitout JD, Laupland KB. Extended-spectrum
beta-lactamase-producing Enterobacteriaceae: an emerging
public-healthconcern. Lancet Infect Dis 2008;8:159e66.
117. Tangden T, Cars O, Melhus A, et al. Foreign travel is a
major riskfactor for colonization with Escherichia coli producing
CTX-M-typeextended-spectrum beta-lactamases: a prospective study
withSwedish volunteers. Antimicrob Agents
Chemother2010;54:3564e8.
118. Walsh TR, Weeks J, Livermore DM, et al. Dissemination
ofNDM-1 positive bacteria in the New Delhi environment and
itsimplications for human health: an environmental point
prevalencestudy. Lancet Infect Dis 2011;11:355e62.
119. World Health Organisation. Combat Drug Resistance: No
ActionToday Means No Cure Tomorrow. World Health Day 2011,
2011.http://www.who.int/mediacentre/multimedia/podcasts/en/
120. Rodriguez-Bano J, Picon E, Gijon P, et al. Risk factors
andprognosis of nosocomial bloodstream infections caused
byextended-spectrum-beta-lactamase-producing Escherichia coli.J
Clin Microbiol 2010;48:1726e31.
121. Rodriguez-Bano J, Picon E, Gijon P, et al.
Community-onsetbacteremia due to extended-spectrum
beta-lactamase-producingEscherichia coli: risk factors and
prognosis. Clin Infect Dis2010;50:40e8.
122. Hoban DJ, Bouchillon SK, Hawser SP, et al. Susceptibility
ofgram-negative pathogens isolated from patients withcomplicated
intra-abdominal infections in the United States,2007e2008: results
of the Study for Monitoring AntimicrobialResistance Trends (SMART).
Antimicrob Agents Chemother2010;54:3031e4.
123. Capp R, Chang Y, Brown DF. Effective Antibiotic
TreatmentPrescribed by Emergency Physicians in Patients Admitted to
theIntensive Care Unit with Severe Sepsis or Septic Shock: Where
isthe Gap? J Emerg Med. Published Online First: 1 March 2011.PMID:
21371846.
124. Deviere J, Content J, Denys C, et al. Excessive in vitro
bacteriallipopolysaccharide-induced production on monokines in
cirrhosis.Hepatology 1990;11:628e34.
125. Wiest R, Das S, Cadelina G, et al. Bacterial translocation
incirrhotic rats stimulates eNOS-derived NO production and
impairsmesenteric vascular contractility. J Clin Invest
1999;104:1223e33.
126. Runyon BA. Monomicrobial nonneutrocytic bacterascites:a
variant of spontaneous bacterial peritonitis.
Hepatology1990;12:710e15.
127. Runyon BA, McHutchison JG, Antillon MR, et al.
Short-courseversus long-course antibiotic treatment of spontaneous
bacterialperitonitis. A randomized controlled study of 100
patients.Gastroenterology 1991;100:1737e42.
128. Runyon BA, Hoefs JC. Spontaneous vs secondary
bacterialperitonitis. Differentiation by response of ascitic fluid
neutrophilcount to antimicrobial therapy. Arch Intern
Med1986;146:1563e5.
129. Fong TL, Akriviadis EA, Runyon BA, et al. Polymorphonuclear
cellcount response and duration of antibiotic therapy in
spontaneousbacterial peritonitis. Hepatology 1989;9:423e6.
130. Gines P, Rimola A, Planas R, et al. Norfloxacin
preventsspontaneous bacterial peritonitis recurrence in cirrhosis:
results ofa double-blind, placebo- controlled trial.
Hepatology1990;12:716e24.
131. Terg R, Llano K, Cobas SM, et al. Effects of oral
ciprofloxacin onaerobic gram-negative fecal flora in patients with
cirrhosis:results of short- and long-term administration, with
daily andweekly dosages. J Hepatol 1998;29:437e42.
132. Singh N, Gayowski T, Yu VL, et al.
Trimethoprim-sulfamethoxazole for the prevention of spontaneous
bacterialperitonitis in cirrhosis: a randomized trial. Ann Intern
Med1995;122:595e8.
133. Nunnari G, Celesia BM, Bellissimo F, et al.
Trimethoprim-sulfamethoxazole-associated severe hypoglycaemia: a
sulfonylurea-like effect. Eur Rev Med Pharmacol Sci
2010;14:1015e18.
134. Wagenlehner FM, Schmiemann G, Hoyme U, et al. [National
S3guideline on uncomplicated urinary tract
infection:recommendations for treatment and management
ofuncomplicated community-acquired bacterial urinary
tractinfections in adult patients] (In German). Urologe
A2011;50:153e69.
135. Fernandez J, Ruiz d A, Gomez C, et al. Norfloxacin
vsceftriaxone in the prophylaxis of infections in patients
withadvanced cirrhosis and hemorrhage.
Gastroenterology2006;131:1049e56.
Gut 2012;61:297e310. doi:10.1136/gutjnl-2011-300779 309
Recent advances in clinical practice
group.bmj.com on November 26, 2014 - Published by
http://gut.bmj.com/Downloaded from
http://gut.bmj.com/http://group.bmj.com
-
136. Saab S, Hernandez JC, Chi AC, et al. Oral antibiotic
prophylaxisreduces spontaneous bacterial peritonitis occurrence
andimproves short-term survival in cirrhosis: a meta-analysis. Am
JGastroenterol 2009;104:993e1001.
137. Loomba R, Wesley R, Bain A, et al. Role of fluoroquinolones
inthe primary prophylaxis of spontaneous bacterial
peritonitis:meta-analysis. Clin Gastroenterol Hepatol
2009;7:487e93.
138. Runyon BA. A pill a day can improve survival in patients
withadvanced cirrhosis. Gastroenterology 2007;133:1029e31.
139. Soriano G, Guarner C, Teixido M, et al. Selective
intestinaldecontamination prevents spontaneous bacterial
peritonitis.Gastroenterology 1991;100:477e81.
140. Terg R, Fassio E, Guevara M, et al. Ciprofloxacin in
primaryprophylaxis of spontaneous bacterial peritonitis: a
randomized,placebo-controlled study. J Hepatol 2008;48:774e9.
141. Koo HL, Dupont HL. Rifaximin: a unique
gastrointestinal-selectiveantibiotic for enteric diseases. Curr
Opin Gastroenterol2010;26:17e25.
142. Alvarez RF, Mattos AA, Correa EB, et al.
Trimethoprim-sulfamethoxazole versus norfloxacin in the prophylaxis
ofspontaneous bacterial peritonitis in cirrhosis. Arq
Gastroenterol2005;42:256e62.
143. Rolachon A, Cordier L, Bacq Y, et al. Ciprofloxacin
andlong-term prevention of spontaneous bacterial
peritonitis:results of a prospective controlled trial.
Hepatology1995;22:1171e4.
144. Krag A, Wiest R, Gluud LL. Fluoroquinolones in the
primaryprophylaxis of spontaneous bacterial peritonitis. Am
JGastroenterol 2010;105:1444e5.
145. Fernandez J, Navasa M, Planas R, et al. Primary prophylaxis
ofspontaneous bacterial peritonitis delays hepatorenal syndromeand
improves survival in cirrhosis.
Gastroenterology2007;133:818e24.
146. Grange JD, Roulot D, Pelletier G, et al. Norfloxacin
primaryprophylaxis of bacterial infections in cirrhotic patients
withascites: a double-blind randomized trial [see comments].
JHepatol 1998;29:430e6.
147. Dupont HL, Jiang ZD, Okhuysen PC, et al. A randomized,
double-blind, placebo-controlled trial of rifaximin to prevent
travelers’diarrhea. Ann Intern Med 2005;142:805e12.
148. Dupont HL, Jiang ZD. Influence of rifaximin treatment on
thesusceptibility of intestinal Gram-negative flora and
enterococci.Clin Microbiol Infect 2004;10:1009e11.
149. Darkoh C, Lichtenberger LM, Ajami N, et al. Bile acids
improvethe antimicrobial effect of rifaximin. Antimicrob Agents
Chemother2010;54:3618e24.
150. Garcia-Tsao G. Bacterial infections in cirrhosis: treatment
andprophylaxis. J Hepatol 2005;42(Suppl 1):S85e92.
151. Riordan SM, Williams R. The intestinal flora and
bacterialinfection in cirrhosis. J Hepatol 2006;45:744e57.
152. Chelarescu O, Chelarescu D, Ticovenau E, et al.
Propranololadministration on post surgical infections in cirrhotic
patients.J.Hepatol 2003;38:A173, (Abstract).
153. Perez-Paramo M, Munoz J, Albillos A, et al. Effect
ofpropranolol on the factors promoting bacterial translocation
incirrhotic rats with ascites. Hepatology 2000;31:43e8.
154. Serste T, Melot C, Francoz C, et al. Deleterious effects of
beta-blockers on survival in patients with cirrhosis and
refractoryascites. Hepatology 2010;52:1017e22.
155. Angeli P. beta-Blockers and refractory ascites in
cirrhosis: themessage of a team of true scientists. J Hepatol
2011;55:743e4.
156. Serste T, Francoz C, Durand F, et al. Beta-blockers
causeparacentesis-induced circulatory dysfunction in patients
withcirrhosis and refractory ascites: a cross-over study. J
Hepatol2011;55:794e9.
157. Zhang SC, Wang W, Ren WY, et al. Effect of cisapride
onintestinal bacterial and endotoxin translocation in cirrhosis.
WorldJ Gastroenterol 2003;9:534e8.
158. Tack J, van Outryve M, Beyens G, et al. Prucalopride
(Resolor) inthe treatment of severe chronic constipation in
patientsdissatisfied with laxatives. Gut 2009;58:357e65.
159. Lorenzo-Zuniga V, Bartoli R, Planas R, et al. Oral bile
acidsreduce bacterial overgrowth, bacterial translocation,
andendotoxemia in cirrhotic rats. Hepatology 2003;37:551e7.
160. Lorenzo-Zuniga V, Rodriguez-Ortigosa CM, Bartoli R, et
al.Insulin-like growth factor-I improves intestinal barrier
function incirrhotic rats. Gut 2006;55:1306e52.
161. Frances R, Chiva M, Sanchez E, et al. Bacterial
translocation isdownregulated by anti-TNF-alpha monoclonal
antibodyadministration in rats with cirrhosis and ascites. J
Hepatol2007;46:797e803.
162. Adawi D, Kasrawi FB, Molin G, et al. Effect of
lactobacillussupplementation with and without arginine on liver
damage andbacterial translocation in an acute liver injury model in
the rat.Hepatology 1997;25:642e7.
163. Wang XD, Soltesz V, Molin G, et al. The role of oral
administrationof oatmeal fermented by Lactobacillus reuteri R2LC on
bacterialtranslocation after acute liver failure induced by
subtotal liverresection in the rat. Scand J Gastroenterol
1995;30:180e5.
164. Liu Q, Duan ZP, Ha DK, et al. Synbiotic modulation of gut
flora:effect on minimal hepatic encephalopathy in patients
withcirrhosis. Hepatology 2004;39:1441e9.
165. Rayes N, Seehofer D, Theruvath T, et al. Supply of pre-
andprobiotics reduces bacterial infection rates after
livertransplantationea randomized, double-blind trial. Am J
Transplant2005;5:125e30.
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in situ hybridisation, the authors foundbacteria deeply
infiltrating the appendix.Fusobacteria (mainly Fusobacterium
nucle-atum/necrophorum) were specific componentsof epithelial and
submucosal infiltrates in62% of patients and were not found
invarious controls. The presence of Fusobac-teria correlated
positively with the severityof appendicitis. Conversely, main
faecalmicrobiota including Faecalibacterium praus-nitzii groups
were significantly decreasedwith an inverse relationship with
theseverity of the disease.1
Altogether, these observations point to thepresence of a local
appendiceal dysbiosiswith more bacteria with inflammatoryproperties
and fewer bacteria with anti-inflammatory properties associated
withacute appendicitis. The genus Fusobacteriumis characterised by
high proteolytic activityand comprises different distinct species.
Themost frequently encountered is F nucleatum,which is frequent in
the oral sphere andimplicated in periodontitis. F necrophorum hasa
high pathogenic potential and is implicatedin life-threatening
infections such asLemierre’s syndrome. In cattle, it is found
infootrot disease and is also frequent in liverabscesses. The third
important species is Fvarium. All species are part of the
normalintestinal microflora. By contrast, F praus-nitzii, which
showed decreased numbers inappendicitis, is a bacterium with
anti-inflammatory properties. Its numbers arealso reduced in
patients with inflammatorybowel disease and it is associated
withpostoperative recurrence of Crohn’s disease.2
Over 30 studies have now analysed theassociation between
appendectomy andulcerative colitis (UC) and the majority ofthe
studies support a highly significantinverse relationship.3 It is
also well estab-lished that the protective effect of appen-dectomy
depends on the inflammatoryconditions (appendicitis or
lymphadenitis)that were the indication for appendectomyrather than
on appendectomy itself.4 Theavailable data regarding whether or
notappendectomy performed after the onset ofUC can modulate its
clinical course arey stilllimited and conflicting and
properlycontrolled trials are needed.5 Despite accu-mulating
clinical evidence, the mechanismlinking appendicitis, appendectomy
and UCremains elusive.
Interestingly, a link between Fusobacteriaand UC has been
reported in several studies.In 2002, F varium was reported to be
presentin the colonic mucosa of a high proportion(84%) of UC
patients.6 Using immunoblot-ting with a F varium antigen Minami et
alfound positive signals with sera from 45(40.2%) of 112 UC
patients versus 20(15.6%) of 128 healthy controls (p