Infezioni batteriche nel cirrotico

Giovanni Battista GaetaChair of Infectious DiseasesViral Hepatitis Unit – Second University of Naples

•69-year-old woman

•Liver transplantation in 1991 for HCV related cirrhosis

•HCV reinfection of the graft and cirrhosis

•First episode of decompensation (ascites) in January 2012

• Type II Diabetes Mellitus treated with Insulin

•Chronic Renal Insufficiency (Cr Clearance ~ 40 mL/m)

• Hypertension treated with calcium antagonists

Clinical case history

On Admission (Dec, 9, 2012)•Body temperature 37.5 °C

•Hypotension (100/60 mmHg)

•Tachycardia (90 b/min)

• Mild jaundice

•Moderate Ascites

•Edema of lower extremities

•Grade II Encephalopathy

•Mild elevation of body temperature

• Mild diarrhea

•Nausea

•Asthenia

• Oliguria

•Confusion and Sleepiness

December 20122 days prior to admission

(Including patients who acquire hospital infection)

20-50% of cirrhotics admitted to hospitalhave an infection

Infections in cirrhotics: dimension

Fernandez, Hepatology 2002; Arvaniti, Gastroenterology 2010; Fernandez, Hepatology 2012

Diagnosi di infezione battericaDiagnosi di infezione battericain cirrotici al ricoveroin cirrotici al ricovero

Diagnosi di infezione battericaDiagnosi di infezione battericain cirrotici al ricoveroin cirrotici al ricovero

%

Urinary tract 26.1

SBP 23.9

Bacteremia 18.5

Pneumonia 16.3

Soft tissue 4.3

Other 10.9

N : 536

Multicenter Italian Database, unpublished

%

Urinary tract 41

Ascites 23

Bacteremia 21

Pneumonia 17

Soft tissue -

Other -

Pazienti con cirrosi: 404 ricoveri in 361 pazienti

Borzio et al, 2001

Arvaniti V. et al. Gastroenterology 2010 ; 139 : 1246-1256

Risk of death in patients with and without infection(in studies reporting complete information on mortality)

Arvaniti V. et al. Gastroenterology 2010 ; 139 : 1246-1256

Parameter N° of studies N° of pataients Median Mortality

Total mortality 178 11.987 38 %

- 1 mo 51 2449 30.3%

- 3 mo 27 1439 44 %

- 12 mo 40 2154 63 %

1978-1999 total mortality 89 4890 47.4 %

- 1 mo 21 737 37.3 %

- 3 mo 18 578 43 %

- 12 mo 25 758 69.7%

2000-2009 total mortality 89 7132 32.3%

- 1 mo 29 1621 26 %

- 3 mo 9 681 44%

- 12 mo 14 634 60%

Mortality of patients with cirrhosis after infection

Martin-Llahi. M. et al. Gastroenterology 2010

Three-month probability of survival of patients with cirrhosis according to the cause of renal failure

WBC 8400/ µL

Neutrophilis 5300/ µL

HGB 10.8 g/dL

Platelets 129000 µL

PT (INR) 1.1

Albumin 2.8 g/dL

Tot. Protein 7.0 g/dL

AST 37 U/L

ALT 27 U/L

Tot. Bilirubin 3.5 mg/dL

Alk Phos 523 U/L

LDH 456 U/L

Creatinine 2.5 mg/dL

Cr clearance 20.6 mL/min

Lipase 28 U/L

GGT 121 U/L

Uric Acid 10.3 mg/dL

Cholinesterase 3876 U/L

Glucose 172 mg/dL

Alpha fetoprotein

0.7 ng/mL

CRP 6 mg/dL

ESR (1h) 46 mm

Sodium 128 mEq/L

Potassium 5.0 mEq/L

Procalcitonin 3.0 ng/mL

Main laboratory data

Diuresis 600 ml/24h

Natriuria 38.7 mEq/24h

Cloruria 31.5 mEq/24h

Kaliuria 25.0 mEq /24h

Microalbuminuria (106 mg/24h)

>35 Leukocytes x field

10 RBC x field

Urinalysis

• Cultures of blood, urine, ascites

• Neutrophil count in ascites

• Chest Xray

•Abdominal US

Microbiological and Image

The flow chart of antibiotic treatmentThe flow chart of antibiotic treatment

Infection considered

Microbiological investigations

Empirical treatment

Response-based tx

POS (50%) NEG (50%)

Modify tx

Community acquired the diagnosis of infection is made within 48 hours of hospitalization and the patient did not fulfill the criteria for HCA infection

Health Care Associated the diagnosis is made within 48 hours of hospitalization in patients with any of the following criteria: (1) had attended a hospital or a hemodialysis clinic, or had received intravenous chemotherapy during the 30 days before infection; or (2) were hospitalized for at least 2 days, or had undergone surgery during the 180 days before infection; or (3) had resided in a nursing home or a long-term carefacility.

Hospital Acquiredthe diagnosis of infection is made after more than 48 hours of hospital stay

Classification of bacterial infections

• Plasma expansion ( saline, albumin )

• Antibiotic therapy :

During the previous six months the patient had received :• Quinolones• 3rd generation cephalosporins given by GP for UTI and upper respiratory infection

Therapy was started with Meropenem 500mg/12h(according to creatinine clearance) and continued for 10 days

TherapyCase discussion

Systemic antibiotic exposure is a risk factor for bacterial resistance in cirrhosis

169 infectious episodes in 115 patients

70 culture positive infections 33 (47%) antibiotic resistant strains

Independent risk factors for resistance

Systemic antibiotics in the previous 30 days OR 13.5 (95% CI = 2.6 – 71.6)

Nosocomial infection OR 4.2 (95% CI = 1.4 -12.5)

Non-adsorbable antibiotics OR 0.4 (95% CI = 0.04 -2.8)

Tandon et al. Clin Gastroenterol Hepatol 2012; 10:1291-98

Prevalence of E.coli with resistance to quinolones

Norfloxacin + Norfloxacin - tot

Novella 1997 9/10 (90%) 4/11 (36%) 13/21

Campillo 1998 3/23 (13%) 8/42 (19 %) 11/65

Fernandez 2002 24/37 (65%) 39/135 (29%) 63/172

Cereto 2003 9/13 (69 %) 3/34 (31 %) 12/47

3rd generation cephalosporin susceptible

Ariza et al, J Hepatol 2012; 56 : 825–832

Incidence of 3rd-generation resistant episodes of SBP

Ariza et al, J Hepatol 2012; 56 : 825–832

Risk factors for SBP caused by a 3rd-generation cephalosporin-resistant microorganism

Community acquired 7 – 33%

Health care associated 21 – 50%

Hospital acquired 40 – 80%

Prevalence of resistant strains

Merli, 2012; Ariza 2012

Merli, Clin Gastroenterol Hepatol 2010

%

Prevalence of gram positive/gram negativebacteria

Prevalence of resistance to ESBL among E. coli isolates from bacteremias (EARSS 2005)

No data< 1%

1-5%

5-10%

10-25%

>25%

Microbiology, US and chest Xray

•Neutrophil count in ascites : 160/µl

•Ascites culture: sterile

• E.coli was isolated from blood and urine

•Chest Xray: no inflammatory images

•Abdominal US: mild ascites; no nodules

Case discussion

Quale terapia per le infezioni sostenute da ESBL+?

Cefalosporine di terza generazioneCefalosporine di terza generazione ––

CefepimeCefepime ––

FluorochinoloniFluorochinoloni +/–+/–

Piperacillina/tazobactamPiperacillina/tazobactam +/– +/–

CarbapenemiciCarbapenemici ++++++

TigeciclinaTigeciclina ++++

Colistin (for carbapenem resistance)Colistin (for carbapenem resistance)

Antibiotici Antibiotici ESBLsESBLs

Fernandez, Hepatology 2012

Risk Factors of Infections by Multiresistant Bacteria in Cirrhosis

*

**

*

Days

n/µL

T

C °

Days

mg/

dL

ANTIBIOTIC THERAPY STOPPED ON DAY 10Time course of bilirubin, creatinine, wbc, neutrophil and temperature

Days

Diuresis (ml/d) 600 1200 1650

Caratteristiche cliniche delle Caratteristiche cliniche delle infezioni batteriche nel cirroticoinfezioni batteriche nel cirrotico

Caratteristiche cliniche delle Caratteristiche cliniche delle infezioni batteriche nel cirroticoinfezioni batteriche nel cirrotico

Deterioramento Deterioramento

della funzione della funzione

epaticaepatica

ItteroIttero

Creat. clearanceCreat. clearance

EncefalopatiaEncefalopatia

Deterioramento Deterioramento

della funzione della funzione

epaticaepatica

ItteroIttero

Creat. clearanceCreat. clearance

EncefalopatiaEncefalopatia

Segni e sintomi tipici di Segni e sintomi tipici di infezioneinfezione

Febbre Febbre

(assente nel 30-50%)(assente nel 30-50%)

Leucocitosi neutrofilaLeucocitosi neutrofila

(relativa!)(relativa!)

Segni e sintomi tipici di Segni e sintomi tipici di infezioneinfezione

Febbre Febbre

(assente nel 30-50%)(assente nel 30-50%)

Leucocitosi neutrofilaLeucocitosi neutrofila

(relativa!)(relativa!)

Possibile esordio grave:Possibile esordio grave: febbre, coagulopatia, coma febbre, coagulopatia, coma Cazzaniga, J Hepatol 2009; 51:475-482; Wong, Gut 2005; 54:718-25; Fasolato, Hepatology 2007; 45:223-2

• Hyperdynamic circulationleads to tachycardia

• Beta-blockers cause a reduced heart rate

• Hypersplenism decreases white blood cell count

SIRS criteria: less diagnostic accuracy in cirrhosis ?

Cazzaniga M,. J Hepatol 2009;51:475–482. Thabut D, Hepatology 2007;46:1872–1882.

SIRS criteriaIn cirrhosis

Il paziente con cirrosi è immunocompromesso

Bonnel, Clinical Gastroenterol Hepatol 2011

Mechanisms of bacterial (and their products)translocation

Portal hypertensionSplancnic vasodilation

Disruption ofintestinal barrier

Increased sympathetic nerve activity

permeabilityIntestinal hypomobility andgerm overgrow

Translocation

Transolacation is associated to increased plasma levels of cytokines(TNFα, IL-6,), MAP-K,

“Tempesta citochinica” provocata da prodotti batterici

From: Wong, Gut 2006

(pg/ml)

* = P < 0.001 vs cirrhosis without SBP

Plasma levels of TNF in patients with cirrhosis with and without SBP

*

M. Navasa et al. Hepatology 1998 ; 27 : 1227-1232.

Bacterial peptides (Porins; HSP60;) are present in the

ascites of afebrile patients with increased TNFα and IFN-

gamma concentrations

Cano et al. J Mol Med, 2010, e-Pub

Bacterial translocation becomes clinically significantwhen it produces SBP, bacteremia, post-surgicalinfections

SBP

time

SBP

bacterial translocationcytokine production

nitric oxide production

bacterial products which cause:inflammatory response

SBP – A chronic inflammatory disease with flares?

Acute-on-chronic Liver Failure

R. Moreau et al. (Canonic study) Gastroenterology 2013 (in press)

Patients’ features at enrollement

________ Patients with no prior decompensation of cirrhosis

___ _ ___ Patients with prior decompensation of cirrhosis

ACLF

NO ACLF

Leucocyte count in patients with and without ACLFRenal failure in cirrhosis

R. Moreau et al. (Canonic study) Gastroenterology 2013 (in press)

C reactive protein values in patients with and without ACLF

R. Moreau et al. (Canonic study) Gastroenterology 2013 (in press)

* *

*

**

*

* = p < 0.01 versus No ACLF

# = p < 0.05 versus No ACLF

#

microorganism-associatedmolecular patterns (MAMPs)

PRRs, pattern recognition receptors

From: Gustot et al, HEPATOLOGY 2009;50:2022-2033

Mechanisms for sepsis-induced organ failure

PAI-1, plasminogen activator inhibitorAPC, activated protein CTF, tissue factor.

Bacterial infection is one of the most frequent cause of decompensation and death in cirrhosis

Immune defects, mainly acquired but also genetic,and bacterial translocation are the main mechanismsinvolved in its pathogenesis

The prevalence of infections is likelely to be underestimated in clinical practice due to the reduced diagnostic capacity of the standard diagnostic criteria

Gram positive and MDR bacteria are increasing etiologic agents

Summary & Conclusions