Cirrhosis increases the risk of bacterial infections which are a leading cause of death in patients with liver disease. Bacterial infections commonly seen in cirrhosis include spontaneous bacterial peritonitis (SBP), urinary tract infections, pneumonia, and bacteremia. The pathogenesis involves bacterial translocation from the gut and impaired immune defenses in cirrhosis. Clinical features can include fever, abdominal pain, renal failure, and hepatic decompensation. Diagnosis involves identifying signs of infection and testing ascitic fluid or other body fluids by cell count, cultures, and other tests. Antibiotic prophylaxis is recommended for gastrointestinal bleeding and recurrent SBP based on increased mortality from infection in these high risk groups.

1. Bacterial Infections in
Cirrhosis
Mario U. Mondelli
Research Laboratories, Department of Infectious Diseases,
Fondazione IRCCS Policlinico San Matteo and Department of Internal
Medicine, University of Pavia, Italy.
Middle East School of Hepatology (MESH), Dubai, November 15, 2013

2. Key Concepts in Bacterial Infections
in Cirrhosis
• Cirrhosis is an independent risk factor for
infections.
• Bacterial infections are a leading cause of acute
liver failure and are associated with high
mortality in end-stage liver disease 1.
• Dysfunction of the immune defensive
mechanisms makes patients with cirrhosis prone
to the development of sepsis and SBP 2,3.
[1] Bajaj JS, et al. Gut 2012;61:1219–25. [2] Garcia-Tsao G. Gastroenterology 2001;120:726–48.
[3] Navasa M, Rodes J. Liver Int 2004;24:277–80.

3. Bacterial Infections in Cirrhosis
• Epidemiology
• Pathogenesis
• Clinical manifestations
• Diagnosis
• Prophylaxis
• Treatment

4. A Multidisciplinary Perspective on the Management of HCC
Study (publication year) Odds ratio (95% CI) % Weight
Strauss (1993) 2.96 (1.84–4.75) 16.0
Terg (1987) 5.00 (1.23–20.24) 2.2
Sharma (1987) 4.16 (1.81–9.57) 5.9
Tito (1988) 3.81 (2.14–6.78) 11.5
Wang (1991) 5.07 (2.20–11.68) 5.9
Caly (1993) 7.29 (2.62–20.22) 4.0
Toledo (1993) 6.52 (2.51–16.95) 4.6
BAC (1993) 2.40 (0.86–6.70) 4.0
Bernard (1995) 5.35 (1.62–17.60) 3.0
Wang (2000) 5.33 (1.79–15.86) 3.5
Vivas (2001) 23.00 (4.35–121.73) 1.6
Borzio (2001) 2.60 (1.35–5.00) 9.2
Yoneyama (2002) 2.79 (1.47–5.27) 9.6
de Mattos (2002) 3.50 (1.51–8.14) 5.8
Plessier (2003) 2.22 (0.40–12.29) 1.5
Cholongitas (2006) 10.11 (3.01–33.92) 2.9
Fasolato (2007) 2.12 (1.00–4.51) 7.1
Piekarska (2008) 5.78 (1.27–26.26) 1.9
Overall (95% CI) 3.76 (3.05–4.63)
Arvaniti V, et al. Gastroenterology 2010;139:1246–56
 In patients with cirrhosis, infections result in a 4-fold increase mortality
 30% of patients die within 1 month after infection
 A further 30% die by 1 year
Meta-analysis (18 studies) on the rate of deaths
in cirrhotic patients with and without infection
0.5 1 3 10
Mortality higher in non-infected Mortality higher in infected
Cirrhotic HCV Patients with Infections Carry
a High Risk of Death

5. Prevalence and Risk Factors of Bacterial
Infections in Cirrhotic Patients
• The prevalence of bacterial infections in
hospitalized cirrhotics is >30%1.
• Risk higher in CTP C than in CTP A/B or
in patients with MELD >15.
Additional risk factors:
– Alcohol abuse
– History of previous infection
– GI bleeding
[1] Fagiuoli S, et al. Dig Liver Dis 2013, in press

6. Cirrhosis Associated Immune Dysfunction
Syndrome : Role of Impaired Immune System
Bonnel AR et al Clin Gastroenterol Hepatol 2011

7. Cirrhosis Associated Immune Dysfunction Syndrome:
Role of Portal Hypertension and Porto-Systemic Shunts
Bonnel AR et al Clin Gastroenterol Hepatol 2011

8. 0
25
50
75
100
SBP No SBP
Small Intestine Bacterial Overgrowth
in Cirrhotics and SBP
CS. Chang et al. Hepatology 1998 ; 28 : 1187-1190.
P <0.01
Percent

9. Factors Contributing to BacterialOvergrowth
in the Small Intestine of Cirrhotic Patients
• Reduced gastric acid secretion (role of
PPI?)
• Reduced intestinal peristalsis
• Defective mucosal immunity

10. Wiest R & Garcia Tsao G. Hepatology 2005;41:422-433
Mechanisms of Bacterial Translocation

11. Markers of Bacterial Translocation
Death of Gram-negative bacteria and
release of LPS, bactDNA, lipoproteins

12. bactDNA+
patients
bactDNA-
patients
63.4%
36.6%
E. coli
E. faecium
K. pneumoniae
S. aureus
57.7%
7.7%
7.7%
26.9%
Prevalence of Bact-DNA in Patients with
Cirrhosis and Refractory Ascites
P. Angeli et al . (AASLD 2010)

13. Bacteria Responsible for Infection in Cirrhotics
• Bacteria of intestinal origin, particularly E. coli are most
often involved in community-acquired infections.
• Methicillin-resistant S. aureus (MRSA) is an increasingly
frequent MDR pathogen.
• Patients receiving quinolone prophylaxis are at
increased risk of resistance.
• Increased resistance to quinolones and 3rd
generation cephalosporins in Enterobacteriaceae,
including E. coli and Klebsiella species.
Gustot T, et al. Hepatology 2009;50:2022–33. Rimola A, et al. J Hepatol 2000;32:142–53.
Merli M, et al. Clin Gastroenterol Hepatol 2010;8:979–85. Tandon P, Garcia-Tsao G. Sem Liver Dis 2008;28:26–42.
Fernandez J, et al. Hepatology 2012;55:1551–61.
.

14. Clinical Manifestations of Bacterial Infections
in Patients with Cirrhosis
• Most common bacterial infections:
– SBP (14-25%)
– UTI (20%)
– Pneumonia (15%)
– Bacteraemia (12%)
– Cellulitis (variable)
– Medical manoeuvres (TIPS, tracheal intubation, oesophageal balloon
tamponade, antiviral treatments)
• SBP is commonly observed in cirrhotic patients who
recovered from an episode of SBP and/or with low (<1.5 g/dl)
ascites protein concentration 1.
– Impaired renal function on admission is associated with increased
mortality 2.
Borzio M, et al. Dig Liver Dis 2001;33:41–8. Fasolato S, et al. Hepatology 2007;45:223–9.
Merli M, et al. Clin Gastroenterol Hepatol 2010;8:979–85. Tandon P, Garcia-Tsao G. Sem Liver Dis 2008;28:26–42.
Fernandez J, et al. Hepatology 2012;55:1551–61.
[1] Guarner C, et al.Gastroenterology 1999;117:414–9. [2] Barahona-Garrido J, et al. J Clin Gastroenterol 2010;44:e218–23.

15. Outcomes in Clinical Practice: CUPIC Cohort of
the French EAP – Week 16 Interim Analysis
*septicemia, septic shock, pneumopathy (2), endocarditis, bleeding
from oesophageal varices, ‡pneumopathy.
Hézode C, et al. Hepatology 2012;56(Suppl. 4):217A

16. When Infection Should Be Suspected ?
• Onset of porto-systemic encephalopathy without
obvious causes.
• Deterioration of renal function.
• Increase WBC count.
• Deterioration of liver function tests.
• Fever (differential diagnosis of FUO).

17. Diagnosis of Bacterial Infection
• Biological fluid cultures are the basic tests for
the diagnosis of bacterial infections and should
be carried out before initiation of antibiotic
therapy.
• Collection, analytical phases (direct and indirect
identification,confirmation and susceptibility test)
must be performed according to standard
operating procedures (SOP).

18. Diagnostic Work-Up in Cirrhotic Patients
with Suspected Infection
• Identification of symptoms and signs of SIRS, severe sepsis or septic
shock.
• Assessment of organ function.
• Identification of source of infection in body fluids or suspected sites.
• Diagnostic paracentesis (PMN count, protein concentration,
Gram stain, bedside cultures) strongly recommended on
admission in all patients with ascites [1-3].
• US scan if abdominal symptoms.
• Stool culture and C. difficile toxin assay if GI symptoms
• If fungal infection is suspected in immunosuppressed patients,
galactomannan in sputum or BAL and cryptococcal serum antigen
should be assayed and high-resolution CT should be considered.
[1] Runyon BA, et al. Gastroenterology 1988;95:1351–5. [2] Nguyen-Khac E, et al. Aliment PharmacolTher 2008;28:282–8.
[3] Mendler MH, et al. J Hepatol 2010;53:477–83.

19. CRP
• Historically used,
reliable marker
• Highly sensitive
PCT
• Specificity for sepsis
(Gram neg. ++)
higher than CRP
• Correlates with the
severity of clinical
symptoms
Luzzani A et al.. Crit Care Med 2003;31:1737-41

20. Where Is PCT
Expressed ?
THYROID C Cells
(calcitonin)
LIVER HYSTIOCYTES
(procalcitonin)
LEUKOCYTES (?)
(procalcitonin)

21. A Multidisciplinary Perspective on the Management of HCC
Markers for the Diagnosis of Sepsis
Muller B, et al. Crit Care Med 2000;28:977–83
Procalcitonin
1 ng/mL
C-reactive protein
100 mg/mL
Lactate
2 mmol/L
Interleukin-6
50 pg/mL
100
80
60
40
20
20 40 60 80
False positive (%)
100
Truepositive(%)
NPV
%
PPV
%
Procalcitonin 90 94
C-reactive
protein
74 75
Interleukin-6 71 74
Lactate 58 61
NPV: negative predictive value; PPV: positive predictive value

22. Prophylaxis of Bacterial
Infections in Cirrhotics

24. Role of Antibiotic Prophylaxis
• In consideration of the high risk of
resistance, the use of prophylactic antibiotics
must be rigorously restricted to patients with
the highest risk of developing SBP or other
bacterial infections.

25. When Should Antibiotic Prophylaxis Be Instituted ?
• GI bleeding:
– Prevalence of infection: 25-65%
– Immediate short-term antibiotic prophylaxis is standard of care
for patients with cirrhosis presenting with upper GI bleeding
– Choice of antibiotic based on:
• Patient features
• Local epidemiology
– I.V. 3rd generation cephalosporin usually preferred
• Secondary prophylaxis of SBP:
– Quinolones (norfloxacin) preferred
– Recurrence reduced from 68% to 20% (Gram neg 60% to 3%)
– Duration undefined
– High risk of resistance
• Primary prophylaxis of SBP?

26. Chavez-Tapia et al, Alim Pharm Ther 2011
ANTIBIOTIC PROPHYLAXIS FOR G.I. BLEEDING
META-ANALYSIS
PREVENTION OF BACTERIAL INFECTION

27. OVERALL MORTALITY
Chavez-Tapia et al, Alim Pharm Ther 2011
ANTIBIOTIC PROPHYLAXIS FOR G.I. BLEEDING
META-ANALYSIS

28. MORTALITY DUE TO BACTERIAL INFECTION
Chavez-Tapia et al, Alim Pharm Ther 2011
ANTIBIOTIC PROPHYLAXIS FOR G.I. BLEEDING
META-ANALYSIS

29. PREVENTION
OF
BACTERIAL
INFECTION
Chavez-Tapia et al, Alim Pharm Ther 2011
ANTIBIOTIC PROPHYLAXIS FOR G.I. BLEEDING
META-ANALYSIS

30. ANTIBIOTIC PROPHYLAXIS FOR G.I. BLEEDING
NORFLOXACINE vs CEFTRIAXONE
Fernandez et al, Gastroenterology 2006
SBP INFECTIONS

31. ANTIBIOTIC PROPHYLAXIS FOR G.I. BLEEDING
• Available information does not allow to establish the best
regimen for antibiotic prophylaxis.
• I.V. Ceftriaxone (1 g/day for 7 d) should be preferred
in patients with advanced cirrhosis (ascites, malnutrition,
serum bilirubin >3 mg/dl), in hospital settings with high
prevalence of quinolone-resistant bacterial infections and
in patients on quinolone prophylaxis.
• Oral norfloxacine (400 mg b.i.d. for 7 d) or an alternative
oral quinolones can be used in patients with less severe
disease.

32. SBP
• SBP is a bacterial infection of ascitic fluid without any
intraabdominal surgically treatable source of infection.
• Prevalence of SBP is 1.5-3.5% in outpatients and about
10% in hospitalized patients.
• Diagnosis of SBP is based on ascites PMN count 250/ L.
• PMN counts 250/ L excludes SBP (in patients with
haemorragic ascites substract 1 PMN per 250 RBC).
• A diagnosis of SBP solely on the basis of clinical symptoms
is not acceptable.
• Severe renal failure is common in patients with SBP and is
associated with poor outcome.
• Mortality is still about 20%.
A. Rimola, et al. J. Hepatol. 2000 ; 32 : 142-153.

33. Patients at High Risk of Developing SBP
1. Patients with acute gastrointestinal
haemorrhage.
2. Patients with low total protein content in
ascitic fluid and no prior history of SBP
(primary prophylaxis).
3. Patients with a previous history of SBP
(secondary prophylaxis)

34. Fever 50-75%
Abdominal pain 27-72%
Chills 16-29%
Nausea and vomiting 8-21 %
Diarrhea up to 32%
Ileus up to 30%
Shock up to 21%
Encephalopathy up to 50%
Renal failure up to 34 %
Asymptomatic up to 13 %
Symptoms of SBP
3.5% of pts. with refractory or recurrent ascites may be asymtomatic
TA. Sheer, et al. Dig. Dis. 2005 ; 23 : 39-46 2003 ; 98 : 1844-1848.

35. • Renal failure 29 25.0
 Onset of renal failure 10 8.6
 Impairment of pre-existing renal failure 20 17.2
 Type 1 HRS 19 16.4
Cirrhotic patients with ascites and SBP (n=116)
Prevalence of Renal Failure Precipitated by SBP
P. Angeli, et al. Aliment. Pharmacol. Ther. 2006 ; 23 : 75-84.
n ° %

36. Sensitivity and Specificity of a Multistix Reagent
Strip c/o≥ 2 in Ascitic Fluid in the Diagnosis of SBP
Author
N° of
patients
Sensitivity
(%)
Specificity
(%)
Delaunay-Tardy K,
2003
50 60 98
Campillo B, 2006 116 45.7 98
Kim DK, 2005 257 100 99
Butani RC, 2004 75 83 99
Ribero TC, 2007 82 71 99
E. Nguyen-Khac et al. Alim. Pharmacol. Ther. 2008 ; 28 : 282-288.

37. Patients with Prior SBP
• Recurrence rate at 1 year is 70% 1.
• Probability of survival:
– 1 yr 30–50%
– 2 yrs 25–30%
[1] Garcia-Tsao G. Gastroenterology 2001;120:726–748.

38. Secondary SBP Prophylaxis
• Long-term antiobiotic prophylaxis is recommended in all
patients with prior SBP.
• Administration of norfloxacin 400 mg/day (or other
quinolones) is the first-choice regimen 1.
• Prophylactic therapy should be instituted after the
completion of antibiotic therapy for acute SBP, but its
duration is unknown.
• The efficacy of prophylaxis with oral quinolones in
patients with SBP caused by Gram-pos bacteria or by
quinolone-resistant Gram-neg bacteria is questionable
[1] Ginès P, et al. Hepatology 1990;12:716–724.

39. Fernandez et al, Gastroenterology 2007
PRIMARY PROPHYLAXIS
NORFLOXACIN 400 mg/day

41. Bacterial Resistance
• Quinolones: 30%
• Co-Trimoxazole: 30%. 70% of quinolone-
resistant Gram - are also resistant to TMX
• No efficacy against Gram + cocci and
anaerobes

42. Primary SBP Prophylaxis
• Cirrhotic patients with low ascitic fluid protein concentration
( 15 g/L) and/or high serum bilirubin are at risk of developing
a first episode of SBP 1,2.
• Clinical trials assessing the beneficial effect of norfloxacin
prophylaxis in patients at risk of a first episode of SBP
showed reduced incidence of Gram- bacterial infections, with
reduced incidence of SBP and a favourable impact on survival
and/or occurrence of HRS 3-6.
• In patients with moderate liver disease, ascites protein
concentration 15 g/L, and without prior history of SBP, the
efficacy of quinolones in preventing SBP or improving survival
is not clearly established.
[1] Runyon BA. Gastroenterology 1986;91:1343–6. [2] Garcia-Tsao G. Gastroenterology 2001;120:726–48.
[3] Novella M, et al. Hepa-tology 1997;25:532–6. [4] Grange JD, et al. J Hepatol 1998;29:430–6.
[5] Fernandez J, et al. Gastroenterology 2007;133:818–24. [6] Terg R, et al. J Hepatol 2008;48:774–9.

43. PROPHYLAXIS OF BACTERIAL INFECTIONS
Due to the emergence of resistant bacteria with long-term
antibiotic prophylaxis, novel antibiotic regimens or alternative
approaches to prophylaxis should be developed and tailored
according the stratification of the patient risk profile and the
actual local bacterial antibiotic-resistance pattern.

44. Indicators of Selective Pressure
• Ceftazidime-resistant Enterobacteriaceae
• MRSA
• VRE
• ESBL-producing Enterobacteria
• Clostridium difficile

45. Empirical vs Targeted Therapy for
Infection in Cirrhotic Patients

46. SBP
• SBP is either community or hospital acquired and the
commonest bacterial infection in cirrhotics.
• Empirical treatment should be oriented towards SBP and
started when ascitic fluid PMN count >250/ L and/or
with positive cultures which MUST be obtained
whenever possible.
• Common pathogens include Enterobacteriaceae,
Streptococcus and Staphylococcus spp.

47. What Are the Best Options for Empirical
Treatment of SBP?
• 3rd generation cephalolosporins, such as cefotaxime 2 g
bid for 5 days is an effective option.
• P.O. or I.V. quinolones have similar efficacy as cephalosporins;
however, they should be avoided in patients receiving NFX
prophylaxis and have worst resistance profile.
• Data on quinolone-resistant and ESBL-producer strains of
Enterobacteriaceae in SBP are missing in cirrhotic patients.
• Carbapenem or tigecycline may be used with caution in case of
documented resistance.
• Combinations of drugs still active against ESBL or class C
(Beta lactamase) (AmpC)-producing enterobacteria should be
preferred.

48. Albumin in the Treatment of SBP?
• HRS occurs in approximately 30% of patients with SBP
treated with antibiotics alone, and is associated with 20%
in-hospital mortality.
• Albumin (1.5 g/kg at diagnosis and 1g/kg on day 3)
decreases the frequency of HRS (from 30 to 10%) and
reduces mortality (from 29 to 10%) [1].
[1]Sort P, et al. N Engl J Med 1999;341:403–409.

49. Summary
• Bacterial infections are highly prevalent in cirrhosis and are a
major cause of morbidity and mortality.
• Pathogenesis is complex and involves bacterial translocation
from the gut and impaired (innate) immunity.
• SBP is the most common and life-threatening bacterial
infection.
• Whenever possible treatment should be targeted on the
causative microorganism.
• Antibiotic prophylaxis is mandatory in high risk patients but
should take into consideration the increasing prevalence of
resistant bacterial strains in this setting.

50. Mortality Caused by Infection in Cirrhosis
• Overall mortality is around 38% with 30.3% of cases
occurring at 1 month and 63% at 12 months, with the
pooled odds ratio for death of infected vs uninfected of
3.75 (95% CI 2.12–4.23) 1.
• Spontaneous bacterial peritonitis (SBP) represents one
of the most common infectious complications in patients
with cirrhosis with a median mortality of 43.7% 2.
• Severe renal failure is common in patients with SBP and
is associated with poor outcome.
[1] Arvaniti V, et al.Gastroenterology 2010;139:1246–56. [2] Perdomo Coral G, et al. Can J Gastroenterol 2003;17:187–90.