Pneumonia

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Pneumonia

INCIDENCE OF BACTERIAL INFECTIONS IN

CIRRHOSIS

Yoshida H et al (1993)*

Deschenes M et al (1999)**

Strauss E et al (1993)

Borzio M et al (2002)

* Many Child Pugh A patients

** Only hospital acquired infections

PATIENTS INFECTIONS

1140

140

170

405

15.4%

20%

47%

34%


TYPES OF BACTERIAL INFECTIONS IN CIRRHOSIS.

572 INFECTIONS DURING 507 ADMISSIONS IN 405

PATIENTS

INFECTIONS

SBP

UTI

Pneumonia

Scondary Bacteremia

Spontaneous Bacteremia

Other Infections

COMMUNITY

ACQUIRED NOSOCOMIAL TOTAL

102

70

43

---

13

122

36

41

35

45

15

50

138

111

78

45

28

172


Gut flora

Bacteria in:

-Mesenteric lymph nodes

- Abdomninal lymphatics

- Thoracic duct

Bacteremia

SBP

PATHOGENESIS OF SBP

TRANSLOCATION

IMPAIRED RES ACTIVITY

IMPAIRED ASCITIC FLUID

OPSONIC ACTIVITY


MECHANISM OF BACTERIAL

TRANSLOCATION IN CIRRHOSIS

Portal hypertension

Splanchnic arterial vasodilation

Disruption of

intestinal barrier

Increased permeability

Increased sympathetic

nervous activity

Intestinal hypomotility

and bacterial overgrowth

BACTERIAL TRANSLOCATION


SCHEMATIC DRAWING OF NORADRENERGIC INNERVATION

ON GUT-ASSOCIATED LYMPHOID TISSUE.

Felten DL, et. Al.

J.Immunology 1985


ACUTE BACTERIAL INFECTIONS

IN CIRRHOTICS ACCORDING TO THE

RES PHAGOCYTIC ACTIVITY (RES-PA)*

Urinary tract infection

SBP and/or bacteremia

Other infections

Normal RES-PA

(n=16)

6

1

2

p


ASCITIC FLUID OPSONIC ACTIVITY

A B C

A: Cirrhotic with SBP, B: Cirrhotics without SBP, C: Non cirrhotic ascites

Runyon, 1988


PROBABILITY OF DEVELOPMENT OF FIRST SBP

ACCORDING TO THE ASCITES PROTEIN CONCENTRATION

Probability

0.4

0.3

0.2

0.1

0.0


Probability

1.0

0.8

0.6

0.4

0.2

0.0

0

EFFECT OF LONG-TERM NORFLOXACIN ADMINISTRATION

IN SBP RECURRENCE IN CIRRHOSIS

TOTAL

Placebo

p=0.0063

Norfloxacin

4 8 12 16 20

Months

0

SBP CAUSED BY AEROBIC

GRAM-NEGATIVE BACTERIA

Placebo

Norfloxacin

p=0.0013

4 8 12 16 20

Months

Ginès, 1990


Recommended empirical therapy

Type of infection Type of empirical antibiotic therapy

SBP Ceftriaxone

UTI

Cellulitis

Community-acquired pneumonia

Nosocomial Pneumonia

Ceftriaxone

Ceftriaxone + Cloxacillin or Amoxicillin-

Clavulanic Acid

Ceftriaxone + Macrolide or

Clindamycin or Levofloxacin

Ceftazidime + Ciprofloxacin

SBP: Spontaneous bacterial peritonitis, UTI: Urinary tract infection


Prevalence of MR bacteria

Type of infection All infections Communityacquired

Nosocomial

SBP 10 (8%) 3 (3%) 7 (22%)

UTI 38 (40%) 13 (24%) 25 (60%)

Cellulitis 7 (11%) 4 (7%) 3 (27%)

Pneumonia 11 (25%) 2 (11%) 9 (35%)

Others 25 (15%) 6 (6%) 19 (31%)

TOTAL 91 (18%) 28 (9%) P


Efficacy of empirical therapy

Infections treated

with recommended

empirical therapy

All infections

Response to empirical therapy

Communityacquired

Nosocomial

SBP (n=107) 72 (67%) 67 (76%) 5 (26%)

UTI (n=89) 48 (54%) 36 (71%) 12 (32%)

Pneumonia (n=28) 10 (36%) 7 (64%) 3 (18%)

Cellulitis (n=54) 43 (80%) 40 (83%) 3 (50%)

Others (n=136) 97 (71%) 74 (84%) 23 (48%)

TOTAL (n=414) 271 (65%) 224 (78%) P


Recommended empirical antibiotic in patients

at risk of nosocomial multiresitant infections*

Type of infection Type of empirical antibiotic therapy

Spontaneous bacterial peritonitis Meropenem + teicoplanin

Urinary infections

Cellulitis

Nosocomial pneumonia

Spontaneous bacteremia

*Risk factors: recent exposition to quinolones

or β-lactams or current/recent hospitalization

Meropenem + teicoplanin

Meropenem + teicoplanin

Meropenem + ciprofloxacin**

Meropenem + teicoplanin

**: Add linezolid if recent mechanical

ventilation


Creatinine (mg/dL)

ACUTE ON CHRONIC LIVER FAILURE (A-CLIF)

6

5

4

3

2

1

0

Type-2 HRS Type-1 HRS

Therapeutic

paracentesis

Cefotaxime

-6 -4 -2 0 1 2 3

Months Weeks

Encephalopathy

Jaundice


EVOLUTION OF TNFα AND IL-6 PLASMA LEVELS

SBP

Non Liver patients with sepsis

Non infected cirrhotics

Baudouin et al 1993


CARDIOVASCULAR HEMODYNAMICS

IN 12 PATIENTS DEVELOPING TYPE-1 HRS*

Baseline Type-1 HRS p

MAP (mmHg) 84±2.6 70±2.3


MECHANISM OF ACUTE ON CHRONIC LIVER FAILURE IN SBP

Severe Circulatory

Dysfunction

Acute Impairment of

Cardiovascular Function

Extrahepatic organ failure (ACLF)

Intense Inflammatory

Response


PRIMARY PROPHYLAXIS WITH NORFLOXACIN IN

PATIENTS AT HIGH RISK OF SBP AND TYPE-1 HRS

Inclusion criteria:

Risk factors of SBP

- ascitic fluid protein 9 and bilirubin >3 mg/dL

Risk factors of type-1 HRS

- serum creatinine >1.2 mg/dL or serum

sodium


Probability of spontaneous

bacterial peritonitis

1.0

0.8

0.6

0.4

0.2

0.0

0

PRIMARY PROPHYLAXIS OF SBP

p=0.0007

Placebo (n=33)

Norfloxacin (n=35)

100 200 300

400

Days

SBP: 12 patients; Type-1 HRS associated to SBP: no patient

Fernandez et al. (Gastroenterology, 2007)


0.6

0.4

0.2

Probability of type-1 HRS

p=0.02

PRIMARY PROPHYLAXIS OF SBP:

PROBABILITY OF HRS AND SURVIVAL

Placebo (n=33)

Norfloxacin (n=35)

Probability of survival

p=0.05

Norfloxacin (n=35)

Placebo (n=33)

0.0

0 100 200 300

0.4

0 100 200 300

Days

Days

1.0

0.8

0.6

Fernandez et al. (Gastroenterology, 2007)


CEFOTAXIME vs

CEFOTAXIME + ALBUMIN IN SBP

DESIGN OF THE TRIAL

Cefotaxime 2 g/8 h

126 patients with SBP

Cefotaxime 2 g/8 h

+ I.V. Albumin

1st day: 1.5 g/Kg b.wt.

3rd day: 1 g /Kg b.wt.

(n=63) (n=63)

Sort et al., N Engl J Med 1999


PRA (ng/mL.h)

EFFECT OF TREATMENT ON CIRCULATORY FUNCTION

9

8

7

6

5

4

3

2

1

0

*p


CIRCULATORY SUPPORT WITH I.V. ALBUMIN

IN PATIENTS WITH SBP. EFFECT ON HRS

DEVELOPMENT AND HOSPITAL MORTALITY

Resolution of infection

HRS

Hospital mortality

Cefotaxime

(n=63)

20 (32%)

17 (27%)

Cefotaxime +

Albumin (n=63)

57 (93%) 59 (98%)

*p


CONCLUSIONS

1. Infections are frequent in cirrhosis. Epidemiology has

changed markedly in the last few years

2. The traditional recommended empirical antibiotic therapy

is not effective in a high proportion of patients.

3. Acute on chronic liver failure (ACLF), a multiorgan failure

or circulatory origin, is the most frequent cause of death

in patients with cirrhosis and SBP.

4.Primary selective intestinal decontamination with

norfloxacin in patients with advanced liver failure and

circulatory support with albumin at the time SBP

diagnosis are effective in preventing ACLF.

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