le infezioni nel cirrotico: aspetti clinici - gastrolearning®
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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Multicenter Italian Database, unpublished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
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