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Spontaneous Bacterial Peritonitis A disease of the gut?Therapeutic implications
Andrés Cárdenas, MD, MMScInstitut de Malalties Digestives i Metaboliques
University of BarcelonaHospital Clinic, Barcelona
OutlineOutline
• Scope of the problem
• Concepts on pathogenesis• Bacterial translocation
• Treatment options based on the above
• Scope of the problem
• Concepts on pathogenesis• Bacterial translocation
• Treatment options based on the above
Types of Bacteria Isolated from Hospitalized Cirrhotic Patients
Types of Bacteria Isolated from Hospitalized Cirrhotic Patients
00
2020
4040
6060
8080
100100Culture positiveCulture positiveGram (-) bacteriaGram (-) bacteriaGram (+) bacteriaGram (+) bacteriaBothBoth
SBPSBP UTIUTI PneumoniaPneumonia OverallOverall
%%
Fernández et al., Hepatology 2002; 35:140Fernández et al., Hepatology 2002; 35:140
TYPES OF BACTERIA ISOLATED FROM HOSPITALIZED CIRRHOTIC PATIENTS
Bacterial Translocation (BT) is the Main Mechanism Implicated in SBP
Bacterial Translocation (BT) is the Main Mechanism Implicated in SBP
• Definition: migration of viable microorganisms from the intestinal lumen to mesenteric lymph nodes (MLN) and other extraintestinal sites
• BT increases in conditions associated with a high risk of infection by gram-negative organisms (e.g. burns, trauma, hemorrhagic shock, cirrhosis)
• E. Coli, Klebsiella, enterococcispecies
• Definition: migration of viable microorganisms from the intestinal lumen to mesenteric lymph nodes (MLN) and other extraintestinal sites
• BT increases in conditions associated with a high risk of infection by gram-negative organisms (e.g. burns, trauma, hemorrhagic shock, cirrhosis)
• E. Coli, Klebsiella, enterococcispecies
BACTERIAL TRANSLOCATION (BT) IS THE MAIN MECHANISM IMPLICATED IN SPONTANEOUS BACTERIAL PERITONITIS (SBP)
E. coli
Gut as Source of Bacteria in SBP Causal Relationship
Gut as Source of Bacteria in SBP Causal Relationship
1. Organisms in SBP are of enteric origin
2. Selective intestinal decontamination (norfloxacin) decreases the development of SBP
3. Cirrhotic rats with positive ascites cultures have concurrent positive MLN cultures, often with the same organism
4. DNA typing of organisms - identity rate of 80% in 5 cases in which bacteria were isolated from both MLNs and ascites
1. Organisms in SBP are of enteric origin
2. Selective intestinal decontamination (norfloxacin) decreases the development of SBP
3. Cirrhotic rats with positive ascites cultures have concurrent positive MLN cultures, often with the same organism
4. DNA typing of organisms - identity rate of 80% in 5 cases in which bacteria were isolated from both MLNs and ascites
Garcia-Tsao G. Gastroenterology 2001; 120:314Llovet et al., J Hepatol 1998; 28:307-313Garcia-Tsao G. Gastroenterology 2001; 120:314Llovet et al., J Hepatol 1998; 28:307-313
In Experimental Cirrhosis, Bacterial Translocation Increases with Severity of Cirrhosis
In Experimental Cirrhosis, Bacterial Translocation Increases with Severity of Cirrhosis
%with positive MLN
bacteriological culture
%with positive MLN
bacteriological culture
6060
2020
00
4040
0/90/9
5/95/9
Cirrhosis,no ascitesCirrhosis,no ascites
Cirrhosiswith ascitesCirrhosis
with ascites
0/120/12
NormalNormal
Garcia-Tsao et al., Gastroenterology 1995; 108:1835Garcia-Tsao et al., Gastroenterology 1995; 108:1835
IN EXPERIMENTAL CIRRHOSIS, BACTERIAL TRANSLOCATION (BT) INCREASES WITH SEVERITY OF CIRRHOSIS
Submucosal edema & inflammationLow albumin, high bilirubin
In Humans, Bacterial Translocation Increases with Severity of Cirrhosis
%with positive MLN
bacteriological culture
MLN isolated at liver transplantation
%with positive MLN
bacteriological culture
MLN isolated at liver transplantation
CirrhosisNo AscitesCirrhosis
No Ascites
3/543/54
5/255/25
4/134/13
CirrhosisAscites
CirrhosisAscites
Child BChild BChild AChild A Child CChild C
1/291/29
3/373/37
4040
3030
2020
1010
00
Cirera et al., J Hepatol 2001: 34:32-37Cirera et al., J Hepatol 2001: 34:32-37
IN HUMANS, BACTERIAL TRANSLOCATION INCREASES WITH SEVERITY OF CIRRHOSISIN HUMANS, BACTERIAL TRANSLOCATION INCREASES WITH SEVERITY OF CIRRHOSIS
n=79
MECHANISMS OF BACTERIAL TRANSLOCATION (BT)
Intestinal Bacterial OvergrowthHypomotility-Delayed transit timeOveractive SNS / NOPortal HTN, oxidative stress
Intestinal Bacterial OvergrowthHypomotility-Delayed transit timeOveractive SNS / NOPortal HTN, oxidative stress
Enhanced Intestinal PermeabilityMucosal Hypoxia, inflammationATP depletion, NO, LPS, TNF
Enhanced Intestinal PermeabilityMucosal Hypoxia, inflammationATP depletion, NO, LPS, TNF
Impaired ImmunityLocal: Impaired chemotaxis, migration, phagocytic function, Systemic: deficient RES.
Impaired ImmunityLocal: Impaired chemotaxis, migration, phagocytic function, Systemic: deficient RES.
Mechanisms of Bacterial TranslocationMechanisms of Bacterial Translocation
Anaerobic bacteria
Anaerobic bacteria
Aerobic bacteriaAerobic bacteria
EnterocytesEnterocytes
Lamina propriaLamina propria
Garcia-Tsao et al., AGA-GTP 2006
>
Bacteria in mesenteric lymph nodes
Bacterial Overgrowth
IncreasedPermeability
Decreased Transit time Impaired RES activity and systemic
clearance
BacteremiaUrinary tract Infection
Respiratoryinfection
Reduced ascitic fluid antimicrobial activity
Nonentericbacteria
GUT FLORADecreased immunity
Ascites colonization
SPONTANEOUS BACTERIAL PERITONITIS
ADVANCED CIRRHOSIS
AntibioticsAntibioticsBacterial translocation
- Increased cytokine production
- Infections due to bacteria from intestinal origin(spontaneous bacterial peritonitis, sepsis)
- Impairment of circulatory / renal function- Increased nitric oxide production
Possible Consequences of BacterialTranslocation In Cirrhosis
Wiest et al., J Clin Invest 1999
BACTERIAL TRANSLOCATION CYTOKINE AND NITRIC OXIDE PRODUCTION
Control LC, BT- LC, BT+
TNFα in lymphnodes (pg/mL)
80
60
40
140
120
100
*
TNFα in plasma(pg/mL)
20
10
0
50
40
30
*
Nitric oxide inplasma (10-3M)
20
10
0
40
30
*
*
p<0.05 p<0.05p<0.05
LC: cirrhosis BT: bacterial translocation
CIRRHOSIS
Bacterial translocation to lymph nodes
Portal hypertension
BACTERIAL TRANSLOCATION, SBPAND CIRCULATORY / RENAL FUNCTION
Increased NO & cytokine production
Impairment of circulatory function(arterial vasodilation)
Reduction of effective arterial blood volume
Activation of vasoconstrictor systems
SELECTIVEINTESTINALDECONTAMINATION
Improvement
HEPATORENAL SYNDROME
Rasaratnam et al., Ann Intern Med 2003
CIRCULATORY FUNCTION IN CIRRHOSISNorfloxacin 400 mg bid (n=14) vs placebo (n=14)
Mean arterial pressure (mmHg) Systemic vascular resistance (units)
Therapy 4 weeks Therapy 4 weeks
SELECTIVE DECONTAMINATION IN CIRRHOSISEFFECT ON RENAL FUNCTION AND SURVIVAL
Fernandez J, et al. Gastroenterology 2007
serum creatinine > 1.2mg/dL, protein levels in ascitic fluid of less than 15 g/L, Child-Pugh score >9, dilutional hyponatremia (serum sodium < 130mEq/L).
Treatment and Prophylaxis of Spontaneous Bacterial Peritonitis
Treatment and Prophylaxis of Spontaneous Bacterial Peritonitis
• Third-generation cephalosporins• IV cefotaxime or ceftriaxone.
• Infuse albumin• S bili <68.4 µmol/l and • S Cr <88.4 µmol/l can be
treated without albumin
• Treat for 5 – 7 days or until disappearance of signs of infection
• Third-generation cephalosporins• IV cefotaxime or ceftriaxone.
• Infuse albumin• S bili <68.4 µmol/l and • S Cr <88.4 µmol/l can be
treated without albumin
• Treat for 5 – 7 days or until disappearance of signs of infection
• GI Bleed• Norfloxacin or IV
ceftriaxone – 1 week
• Previous SBP• Norfloxacin 400 mg
• Advanced cirrhosis / low protein in ascites (< 15 g/liter):• Norfloxacin 400 mg
• GI Bleed• Norfloxacin or IV
ceftriaxone – 1 week
• Previous SBP• Norfloxacin 400 mg
• Advanced cirrhosis / low protein in ascites (< 15 g/liter):• Norfloxacin 400 mg
Therapy Prophylaxis
Alternatives to antibiotic prophylaxis ?Antibiotic Resistance in SBP
Fernández et al. Hepatology 2002; 35:140Fernández et al. Hepatology 2002; 35:140
• High rate of infections due to quinoloneresistance (65%)
• High rate of infections due to quinoloneresistance (65%)
OPTIONS• Probiotics
• Animals/humans• Prokinetics
• Animals/ humans• Propranolol
• Animals
OPTIONS• Probiotics
• Animals/humans• Prokinetics
• Animals/ humans• Propranolol
• Animals
ProbioticsProbiotics
• Microorganisms that have beneficial properties for the host
• How they work?• Suppression of growth or epithelial
binding/invasion by pathogenic bacteria • Improvement of intestinal barrier function • Modulation of the immune system
• Use in cirrhosis - limited
• Microorganisms that have beneficial properties for the host
• How they work?• Suppression of growth or epithelial
binding/invasion by pathogenic bacteria • Improvement of intestinal barrier function • Modulation of the immune system
• Use in cirrhosis - limited
Prevented BTLactobacillus & vitamin C + glutamate
CCL4 cirrhosisChiva - 2002
Did not prevent BTlactobacillusPortal vein ligatedWiest -2003
Did not prevent BTlactobacillusCCL4 cirrhosisBauer - 2002
CommentProbioticModelAuthor - year
Use of Probiotics in Bacterial TranslocationUse of Probiotics in Bacterial Translocation
Decreased post-op bacterial infections
Living lactobacillus & planarum
Liver transplantationRayes - 2002
Improved liver testsVSL #3 lactobacillusCirrhosis Loguercio -2005
Reduced counts of gut flora, blood ammonia & MHE
Probiotics and fermentable fiber
Cirrhosis / minimal hepatic encephalopathy
Liu - 2004
CommentProbioticPatientsAuthor - year
Prokinetics- CisaprideCombination RX decreases the incidence of SBP
Prokinetics- CisaprideCombination RX decreases the incidence of SBP
n= 46
n= 48p= 0.026
Bimaljit , et al. J Gastroenterol Hepatol 2005; 20:599-605Pardo A, et al. Hepatology 2000;31:858-863Bimaljit , et al. J Gastroenterol Hepatol 2005; 20:599-605Pardo A, et al. Hepatology 2000;31:858-863
Problem – pulled from market
0
20
40
60
80
100
SIBO BT
Propranolol
Placebo
PROPRANOLOL Effects on intestinal bacterial overgrowth
and BT in cirrhotic rats
%
p<0.05
Pérez-Paramo et al. Hepatology 2000
p< 0.05
Is Spontaneous Bacterial Peritonitis A disease of the gut?
Probably yes.
Intestinal factors seem to play a major role in the pathogenesis of SBP, however we need better proof
that modulation of intestinal permeability, motility and bacterial overgrowth have a role in the management of
patients with cirrhosis and SBP.
ACKNOWLEDGEMENTS
Mentors:BarcelonaPere Gines Vicente Arroyo
Boston:Nezam AfdhalSimon RobsonSanjiv Chopra
ColleaguesJ. Bosch R. BatallerM. GuevaraJ. UrizM. MartinC. TerraM. CurryJ. Gonzalez