Bacterial infections in cirrhosis

1
Bacterial infections in cirrhosis

• Dr Jean-Didier Grangé
• Hôpital Tenon, Paris, France
• AP-HP - Université Paris VI

2
Infections and cirrhosis

• More frequent complication in patients with
  cirrhosis (30 to 47 in hospitalized patients)
  (1)
• Mortality related factor 30 vs 5 - 12 (2)
• The most frequent types of infection SBP (7 -
  31), urinary (12 - 29) pulmonary infections (6
  - 21) and bacteremia (10 - 12)
• The most severe (mortality) pulmonary (30 à 41)
  and SBP (20 à 30 )

(1) Caly WR J Hepatol 199318271-2. (2) Yoneyama
K 2002371028-34.
3
Enteric bacteria
Infections and cirrhosis Pathophysiology
Bacterial overgrowth
Gut permeability
Bacteria in mesenteric lymph nodes
Systemic circulation
Urinary infections
Pulmonary infections
Dysfunction of innate defenders
Reticuloendothelial system depression
Bacteremia
SBP
4
Type of bacteria isolated in SBPChanging
epidemiology ?
Grangé JD et al. Gastroenterol Clin Biol
199822301-4.
5
Rapid diagnosis of SBP by use of reagent strips
Authors Reagent Strip N SBP Se Sp PPV NPV
Castellote Aution Sticks 228 57 96 89 74 99
Butani Multistix 90 9 89 99 89 99
Vanbiervliet Multistix 72 9 100 100 100 100
Sapey Nephur Test Multistix 245 17 88 100 94 99
Sapey Nephur Test Multistix 245 17 65 100 92 97
Thévenot Multistix 100 9 89 100 100 99
Lescano Multistix 96 12 67 100 100 95
Nousbaum Multistix (2) 2123 117 45 99 78 97
False negative 64/117
6
Diagnosis of SBP

• - Dipstick testing of ascitic fluid may improve
  early detection of SBP (great sensitivity)
• However, diagnosis must be based on the PMN count
• PMN gt 250 /mm3
• - Gram stain positive in only a few cases (lt 10
  )
• Culture into blood culture bottles positive in
  50 - 70
• Main mortality predictive factor renal
  function

Follo et al. Hepatology 1994201495-1501
7
Prognosis of SBP
8
Curative treatment of SBP
Authors Treatments N Cure Survival
Félisart 85 Tobra/ampi Cefotaxime 2g x 6 36 37 56 85 61 73
Rimola 95 Cefotaxime 2 g x 4 Cefotaxime 2g bid 71 72 77 79 69 79
Navasa 96 Ofloxacin 0.4 g x 2 PO Cefotaxime 2 g x 4 64 69 84 85 81 81
Terg 00 Ciprofloxacin IV Ciprofloxacin 2d IV then PO 40 40 76 78 77 77
Sort 99 Cefotaxime 2g x 4 Cefotaxime and albumin 63 63 94 98 71 90
Ricart 00 Amox/clavu 1g tid IV then PO Cefotaxime 1g x 4 24 24 87 83 87 79
plt0.02 p 0.01
9
Cefotaxime - plus - albumin Results
p0.002

• Cefotaxime 2g/6 h IV
• Albumin (n 63)
• 1.5 g/kg within 6 hours of enrollment
• 1 g/kg on day 3

Sort N Engl J Med 1999341403
10
Cefotaxime - plus - albumin Mortality

p0.03
p0.01
Beneficial effect if bilirubingt68 µmol/L and
creatininegt88 µmol/L
Sort N Engl J Med 1999341403
11
Decision criteria
EBM Advantages Disadvantages
cefotaxime 1 ascites PK NGB IV Enterococcus Cost
A-AC 1 ascites PK IV and PO cost PGC Hepatotoxicity PO 500 / 62.5

• Other evaluated antibiotics
• ? quinolones ciprofloxacine, ofloxacin and
  moxifloxacin
• ? ceftazidime, ceftizoxime and ceftriaxone
• ?Aminoglycosides aztreonam EBM 1

12
Summary Treatment of SBP

• SBP PMN gt 250/ mm3
• cefotaxime or amoxicillin/clavulanic acid
• Prevention of renal insufficiency? Avoid
  aminoglycosides, NSAIDs, large volume
  paracentesis? Baseline BUN elevation ? albumin
• Assess response to treatment (48 hours)
• Uncomplicated SBP oral therapy with quinolones
  or amoxicillin-clavulanic acid
• One year survival 30 to 40 Secondary
  prophylaxis Evaluation for liver
  transplantation

13
Cirrhosis and pulmonary infections

• Frequent 6 to 21 in prospective studies
• No RCT in patients with cirrhosis
• Mortality 30 to 40
• Fine Score

14

Patients characteristics Patients characteristics Patients characteristics Patients characteristics Laboratory findings Laboratory findings
Males Age Age Age PH lt 7,35 30
Females Age 10 Age 10 Age 10 BUN 10.7 mmol/L 20
Nursing home resident 10 10 10 Na lt 130 mEq/L 20
Comorbid illnesses Comorbid illnesses Comorbid illnesses Comorbid illnesses Glucose 13.9 mmol/L 10
Neoplastic disease Neoplastic disease Neoplastic disease 30 Hematocrit lt 30 10
Liver disease Liver disease Liver disease 20 P02 lt 60 mm Hg 10
Congestive heart failure Congestive heart failure Congestive heart failure 10 pleural effusion 10
Cerebrovascular disease Cerebrovascular disease Cerebrovascular disease 10
Renal disease Renal disease Renal disease 10 Fine Score
Physical examination findings Physical examination findings Physical examination findings Physical examination findings II 70 points Mortality 0.6 0.7 III 71-90 Mortality 0.9 2.8 IV 91-130 Mortality 8.2 9.3 V gt 131 Mortality 27 - 31 II 70 points Mortality 0.6 0.7 III 71-90 Mortality 0.9 2.8 IV 91-130 Mortality 8.2 9.3 V gt 131 Mortality 27 - 31
Altered mental status Altered mental status 20 20 II 70 points Mortality 0.6 0.7 III 71-90 Mortality 0.9 2.8 IV 91-130 Mortality 8.2 9.3 V gt 131 Mortality 27 - 31 II 70 points Mortality 0.6 0.7 III 71-90 Mortality 0.9 2.8 IV 91-130 Mortality 8.2 9.3 V gt 131 Mortality 27 - 31
Respiratory rate 30/min. Respiratory rate 30/min. 20 20 II 70 points Mortality 0.6 0.7 III 71-90 Mortality 0.9 2.8 IV 91-130 Mortality 8.2 9.3 V gt 131 Mortality 27 - 31 II 70 points Mortality 0.6 0.7 III 71-90 Mortality 0.9 2.8 IV 91-130 Mortality 8.2 9.3 V gt 131 Mortality 27 - 31
Systolic BP lt 90 mm Hg Systolic BP lt 90 mm Hg 20 20 II 70 points Mortality 0.6 0.7 III 71-90 Mortality 0.9 2.8 IV 91-130 Mortality 8.2 9.3 V gt 131 Mortality 27 - 31 II 70 points Mortality 0.6 0.7 III 71-90 Mortality 0.9 2.8 IV 91-130 Mortality 8.2 9.3 V gt 131 Mortality 27 - 31
T lt 35C ou 40C T lt 35C ou 40C 15 15 II 70 points Mortality 0.6 0.7 III 71-90 Mortality 0.9 2.8 IV 91-130 Mortality 8.2 9.3 V gt 131 Mortality 27 - 31 II 70 points Mortality 0.6 0.7 III 71-90 Mortality 0.9 2.8 IV 91-130 Mortality 8.2 9.3 V gt 131 Mortality 27 - 31
Pulse 125/min. Pulse 125/min. 10 10 II 70 points Mortality 0.6 0.7 III 71-90 Mortality 0.9 2.8 IV 91-130 Mortality 8.2 9.3 V gt 131 Mortality 27 - 31 II 70 points Mortality 0.6 0.7 III 71-90 Mortality 0.9 2.8 IV 91-130 Mortality 8.2 9.3 V gt 131 Mortality 27 - 31


15
Community-Acquired Pneumonia Treatment in
patients with cirrhosis
Patient profile Antibiotic therapy
Outpatients (no severity sign) Amoxicilline/clavu 3g PO or moxifloxacin ª 0.4 g PO
In-hospital management Ceftriaxone 1gIV ofloxacin (or erythromycin 3g or azithromycinb)
Suspected MRSA (previous hospitalization or antibiotherapy...) Ceftriaxone vancomycin (possible switch with linezolid 0.6g PO)
Severe pneumonia requiring ICU Ceftriaxone IV ofloxacin 0.4g IV (possible switch with moxifloxacin)
ª Izilox, b Zithromax, Rocephine. Zyvoxid,
Adapted from SPLF, SPILF, ANAES, AFSSAPS et ASCAP
CONSENSUS 2005
16
Treatment of infections (n96)Cefotaxime vs
amoxicilline/clavulanate
Ricard E et al. J Hepatol 200032596-602
17
Moxifloxacin vs amoxicilline/clavulanateType of
infections (4 countries, 28 centers)
Grangé et al. Hepatology 200440631A.
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Treatment of infections (n143)
Results Moxifloxacin Amoxicilline clavulanate
Clinical response on D3 ITT population 63/76 (83) 51/67 (76)
Clinical response EOT ITT population Excluding missing data Bacteriologically documented 56/76 (74) 56/70 (80) 31/40 (78) 54/67 (81) 54/67 (81) 28/35 (80)
End of follow-up response (21 31 j) ITT population 41/56 (73) 37/54 (69)
P lt 0.05
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SBP resolution (n 35)
SBP resolution w. Study drug Antibiotherapy modification SBP resolution End Of Treatment
Moxifloxacin 14/18 (78) Cefotaxime/ofloxacin A-AC ofloxacin Ceftriaxone Imipenem 17/18 (94)
Amoxicilline clavulanate 11/17 (65) Imipenem/gentamycin A-AC/ofloxacin Cefotaxime/ofloxacin Ceftriaxone Ceftriaxone Meropenem 16/17 (94)
20
Pneumonia resolution (n 21)
Moxifloxacin A-AC
Pneumonia 8/9 (89 ) 11/12 (92 )
21
Prophylaxis

• Patients with ascites who are recovering from a
  prior episode of SBP
• Those with an ascitic albumin concentration of
  les than 10g/L
• Those with gastrointestinal bleeding

22
Prevent recurrence of SBP (n 80)
Norfloxacin 400 mg QD Mean duration 6.4
months (35 vs 12 SBP)
P0.014
Ginés P et al. Hepatology 199012716-727.
23
Antibiotic prophylaxis in hospitalized patients
ascites protein lt 15 g/L (n 63)
P lt 0.005
n
P 0.05
Soriano et al. Gastroenterology 1991100477-81
24
Patients without prior SBP ascites protein lt
15g/L (n107)
n
Norfloxacin 400 mg/j Treatment duration 6months
plt0.03
Grangé et al. J Hepatol 199829430-436
25
Long-term prophylaxis in patients with ascites -
Meta-analysis

• 4 RCT, 1 meta-analysis

Control Treated p
Infection 39 7 lt 0.001
SBP 28 9 lt 0.001
Survival 73 82 lt 0.04
Bernard B et al, Digestion 199859 Suppl 254-57
26
Risks of antibiotic prophylaxis

• Selection of highly resistant Gram-negative
  pathogens and risk of emergence of enterococcus
  and methicillin-resistant Staphylococcus aureus.
  Campillo B et al. Epidemiol
  Infect 2001127443-50
• Factors of development of quinolone-resistant
  negative Gram bacilli
• Length of antibiotic prophylaxis
• Prevalence rate of quinolone resistance in care
  unit, hospital or country
• Immunosuppression (steroid therapy, HIV, cancer)
• Cereto F et al. Eur J
  Gastroenterol Hepatol 20021481-3

27
Antibiotic prophylaxis
Gastrointestinal hemorrhage

• Infection at admission 20 30 to 50 during
  hospitalization
• 5 RCT, 1 meta-analysis
• Infection 14 vs 45, plt0.001
• SBP 5 vs 13, plt0.01
• Survival D14 85 vs 76, plt0.01

Bernard B et al, Hepatology 1999291655
28
Antibiotic prophylaxis and early rebleeding

Ofloxacin 200 mg IV q 12 h for 2 d then 200 mg PO
q 12H for 5 d -prophylactic antibiotics
(n59) -on-demand (n61)
P0,01
early rebleeding
Hou MC et al Hepatology 200439746-53
29
Variceal bleeding in patients with
cirrhosisIn-hospital mortality

Carbonell N et al, Hepatology 200440652-9
30
Predictors of survivalMultivariable analysis

• Lower Child-Pugh Score
• Absence of hypovolemic shock
• Endoscopic therapy (? pharmacological therapy)
• Antibiotic prophylaxis
• Younger age

Carbonell N et al, Hepatology 200440652-9
31
Short-term prophylaxis

• Effective in the prevention of infections,
  significant improvement in survival
• Short-term prophylaxis should be considered
  standard of care in cirrhotic patients admitted
  with GI hemorrhage
• Norfloxacin 400 mg BID or ofloxacin for 7 days
• Hospitalized patients with ascites protein lt 10
  g/L- Norfloxacin 400 mg/d during
  hospitalization stay

32
Long-term prophylaxis

• Effective in the prevention of infections, risk
  of bacterial resistance
• Patients recovering from an episode of SBP
  norfloxacin 400 mg QD until disappearance of
  ascites, transplant or death
• Patients without prior SBP and ascites protein lt
  10g/L. The indication depends of individual
  infection risk, therapeutic plan and local
  bacterial ecology
• Patients without prior SBP and ascites protein gt
  10g/L.
• ? antibiotic prophylaxis is no recommended

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Norfloxacine et prokinétiques

• Prospectif
• Simple aveugle
• Contrôlée, randomisée

Sandhu BS et col. J Gastroenterol Hepatol
200520599-605
35
Norfloxacine et prokinétiques

• Facteurs pq ILA
• Albuminémie basse
• Protides ascite bas
• Cirrhose alcoolique

plt0,03
ns
Sandhu BS et col. J Gastroenterol Hepatol
200520599-605