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