Infezioni batteriche nel cirroticoGiovanni Battista GaetaChair of Infectious DiseasesViral Hepatitis Unit – Second Univers...
Clinical case history•69-year-old woman•Liver transplantation in 1991 for HCV related cirrhosis•HCV reinfection of the gra...
On Admission (Dec, 9, 2012)•Body temperature    37.5 °C•Hypotension (100/60 mmHg)•Tachycardia (90 b/min)• Mild jaundice•Mo...
December 2012      2 days prior to admission•Mild elevation of body temperature• Mild diarrhea•Nausea•Asthenia• Oliguria•C...
Infections in cirrhotics: dimension   20-50% of cirrhotics admitted to hospital   have an infection (Including patients wh...
Diagnosi di infezione batterica                  in cirrotici al ricovero                                             Pazi...
Risk of death in patients with and without infection(in studies reporting complete information on mortality)              ...
Mortality of patients with cirrhosis after infectionParameter                   N° of studies   N° of pataients   Median M...
Three-month probability of survival of patients with  cirrhosis according to the cause of renal failure                   ...
Main laboratory dataWBC              8400/ µL      Lipase           28 U/LNeutrophilis     5300/ µL      GGT              ...
UrinalysisDiuresis 600 ml/24hNatriuria 38.7 mEq/24hCloruria 31.5 mEq/24hKaliuria 25.0 mEq /24hMicroalbuminuria (106 mg/24h...
Microbiological and Image • Cultures of blood, urine, ascites • Neutrophil count in ascites • Chest Xray •Abdominal US
The flow chart of antibiotic treatment Infection considered                   Microbiological investigationsEmpirical trea...
Classification of bacterial infectionsCommunity acquiredthe diagnosis of infection is made within 48 hours of hospitalizat...
Case discussion                           Therapy  • Plasma expansion ( saline, albumin )  • Antibiotic therapy :  During ...
Systemic antibiotic exposure is a risk factor     for bacterial resistance in cirrhosis169 infectious episodes in 115 pati...
Prevalence of E.coli with resistance          to quinolones                   Norfloxacin +     Norfloxacin -     totNovel...
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                      Ariza et al,...
Prevalence of resistant strainsCommunity acquired          7 – 33%Health care associated      21 – 50%Hospital acquired   ...
Prevalence of gram positive/gram negative                 bacteria   %                        Merli, Clin Gastroenterol He...
Prevalence of resistance to ESBL among E. coli isolates from                 bacteremias (EARSS 2005)      No data       <...
Case discussion    Microbiology, US and chest Xray  •Neutrophil count in ascites : 160/µl  •Ascites culture: sterile  • E....
Quale terapia per le infezioni sostenute da                ESBL+? Antibiotici                          ESBLs Cefalosporine...
Risk Factors of Infections by Multiresistant Bacteria in                        Cirrhosis                                 ...
ANTIBIOTIC THERAPY STOPPED ON DAY 10Time course of bilirubin, creatinine, wbc, neutrophil and temperature   n/µL          ...
Caratteristiche cliniche delle       Caratteristiche cliniche delle     infezioni batteriche nel cirrotico     infezioni b...
SIRS criteria: less diagnostic accuracy in cirrhosis ?        SIRS criteria                                               ...
Il paziente con cirrosi è immunocompromesso                  Bonnel, Clinical Gastroenterol Hepatol 2011
Mechanisms of bacterial (and their products)              translocation                          Portal hypertension      ...
“Tempesta citochinica” provocata     da prodotti batterici                        From: Wong, Gut 2006
Plasma levels of TNFα in patients with cirrhosis             with and without SBP                        (pg/ml)          ...
Bacterial translocation becomes clinically significant    when it produces SBP, bacteremia, post-surgical    infectionsBac...
SBP –     A chronic inflammatory disease with flares?  bacterial translocation                              bacterial prod...
Acute-on-chronic Liver Failure    Patients’ features at enrollement       R. Moreau et al. (Canonic study) Gastroenterolog...
Renal failure in cirrhosisLeucocyte count in patients with and without ACLF           ________ Patients with no prior deco...
C reactive protein values in patients with and without ACLF    * = p < 0.01 versus No ACLF                                ...
Mechanisms for sepsis-induced organ failure                                                          microorganism-associa...
Summary & ConclusionsBacterial infection is one of the most frequent cause ofdecompensation and death in cirrhosisImmune d...
Le infezioni nel cirrotico: aspetti clinici - Gastrolearning®
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Le infezioni nel cirrotico: aspetti clinici - Gastrolearning®

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Le infezioni nel cirrotico: aspetti clinici - Prof. G. Gaeta (Università Napoli Federico II)

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Le infezioni nel cirrotico: aspetti clinici - Gastrolearning®

  1. 1. Infezioni batteriche nel cirroticoGiovanni Battista GaetaChair of Infectious DiseasesViral Hepatitis Unit – Second University of Naples
  2. 2. Clinical case history•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
  3. 3. 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
  4. 4. December 2012 2 days prior to admission•Mild elevation of body temperature• Mild diarrhea•Nausea•Asthenia• Oliguria•Confusion and Sleepiness
  5. 5. Infections in cirrhotics: dimension 20-50% of cirrhotics admitted to hospital have an infection (Including patients who acquire hospital infection)Fernandez, Hepatology 2002; Arvaniti, Gastroenterology 2010; Fernandez, Hepatology 2012
  6. 6. Diagnosi di infezione batterica in cirrotici al ricovero Pazienti con cirrosi: N : 536 404 ricoveri in 361 pazienti % % Urinary tract 26.1 Urinary tract 41 SBP 23.9 Ascites 23 Bacteremia 18.5 Pneumonia 16.3 Bacteremia 21 Soft tissue 4.3 Pneumonia 17 Other 10.9 Soft tissue -Multicenter Italian Database, unpublished Borzio et al, 2001
  7. 7. 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
  8. 8. Mortality of patients with cirrhosis after infectionParameter N° of studies N° of pataients Median MortalityTotal 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% Arvaniti V. et al. Gastroenterology 2010 ; 139 : 1246-1256
  9. 9. Three-month probability of survival of patients with cirrhosis according to the cause of renal failure Martin-Llahi. M. et al. Gastroenterology 2010
  10. 10. Main laboratory dataWBC 8400/ µL Lipase 28 U/LNeutrophilis 5300/ µL GGT 121 U/LHGB 10.8 g/dL Uric Acid 10.3 mg/dLPlatelets 129000 µL Cholinesterase 3876 U/LPT (INR) 1.1 Glucose 172 mg/dLAlbumin 2.8 g/dL Alpha 0.7 ng/mLTot. Protein 7.0 g/dL fetoproteinAST 37 U/L CRP 6 mg/dLALT 27 U/L ESR (1h) 46 mmTot. Bilirubin 3.5 mg/dL Sodium 128 mEq/LAlk Phos 523 U/L Potassium 5.0 mEq/LLDH 456 U/L Procalcitonin 3.0 ng/mLCreatinine 2.5 mg/dLCr clearance 20.6 mL/min
  11. 11. UrinalysisDiuresis 600 ml/24hNatriuria 38.7 mEq/24hCloruria 31.5 mEq/24hKaliuria 25.0 mEq /24hMicroalbuminuria (106 mg/24h)>35 Leukocytes x field10 RBC x field
  12. 12. Microbiological and Image • Cultures of blood, urine, ascites • Neutrophil count in ascites • Chest Xray •Abdominal US
  13. 13. The flow chart of antibiotic treatment Infection considered Microbiological investigationsEmpirical treatment POS (50%) NEG (50%) Modify tx Response-based tx
  14. 14. Classification of bacterial infectionsCommunity acquiredthe diagnosis of infection is made within 48 hours of hospitalization and the patient didnot fulfill the criteria for HCA infectionHealth Care Associatedthe diagnosis is made within 48 hours of hospitalization in patients with any of thefollowing criteria: (1) had attended a hospital or a hemodialysis clinic, or had receivedintravenous chemotherapy during the 30 days before infection; or (2) were hospitalizedfor 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
  15. 15. Case discussion Therapy • 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
  16. 16. Systemic antibiotic exposure is a risk factor for bacterial resistance in cirrhosis169 infectious episodes in 115 patients 70 culture positive infections 33 (47%) antibiotic resistant strainsIndependent risk factors for resistanceSystemic 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
  17. 17. Prevalence of E.coli with resistance to quinolones Norfloxacin + Norfloxacin - totNovella 1997 9/10 (90%) 4/11 (36%) 13/21Campillo 1998 3/23 (13%) 8/42 (19 %) 11/65Fernandez 2002 24/37 (65%) 39/135 (29%) 63/172Cereto 2003 9/13 (69 %) 3/34 (31 %) 12/47 3rd generation cephalosporin susceptible
  18. 18. Incidence of 3rd-generation resistant episodes of SBP Ariza et al, J Hepatol 2012; 56 : 825–832
  19. 19. Risk factors for SBP caused by a 3rd-generation cephalosporin-resistant microorganism Ariza et al, J Hepatol 2012; 56 : 825–832
  20. 20. Prevalence of resistant strainsCommunity acquired 7 – 33%Health care associated 21 – 50%Hospital acquired 40 – 80% Merli, 2012; Ariza 2012
  21. 21. Prevalence of gram positive/gram negative bacteria % Merli, Clin Gastroenterol Hepatol 2010
  22. 22. Prevalence of resistance to ESBL among E. coli isolates from bacteremias (EARSS 2005) No data < 1% 1-5% 5-10% 10-25% >25%
  23. 23. Case discussion 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
  24. 24. Quale terapia per le infezioni sostenute da ESBL+? Antibiotici ESBLs Cefalosporine di terza generazione – Cefepime – Fluorochinoloni +/– Piperacillina/tazobactam +/– Carbapenemici +++ Tigeciclina ++ Colistin (for carbapenem resistance)
  25. 25. Risk Factors of Infections by Multiresistant Bacteria in Cirrhosis * * * * Fernandez, Hepatology 2012
  26. 26. ANTIBIOTIC THERAPY STOPPED ON DAY 10Time course of bilirubin, creatinine, wbc, neutrophil and temperature n/µL TC° Days Days mg/dL Days Diuresis (ml/d) 600 1200 1650
  27. 27. Caratteristiche cliniche delle Caratteristiche cliniche delle infezioni batteriche nel cirrotico infezioni batteriche nel cirrotico Deterioramento Segni e sintomi tipici di della funzione infezione epatica Febbre Ittero (assente nel 30-50%) Creat. clearance Leucocitosi neutrofila Encefalopatia (relativa!) Possibile esordio grave: febbre, coagulopatia, comaCazzaniga, J Hepatol 2009; 51:475-482; Wong, Gut 2005; 54:718-25; Fasolato, Hepatology 2007; 45:223-2
  28. 28. SIRS criteria: less diagnostic accuracy in cirrhosis ? SIRS criteria In cirrhosis • Hyperdynamic circulation leads to tachycardia • Beta-blockers cause a reduced heart rate • Hypersplenism decreases white blood cell countCazzaniga M,. J Hepatol 2009;51:475–482. Thabut D, Hepatology 2007;46:1872–1882.
  29. 29. Il paziente con cirrosi è immunocompromesso Bonnel, Clinical Gastroenterol Hepatol 2011
  30. 30. Mechanisms of bacterial (and their products) translocation Portal hypertension Splancnic vasodilation Disruption of Increased sympathetic intestinal barrier nerve activity Intestinal hypomobility and permeability germ overgrow Translocation Transolacation is associated to increased plasma levels of cytokines (TNFα, IL-6,), MAP-K,
  31. 31. “Tempesta citochinica” provocata da prodotti batterici From: Wong, Gut 2006
  32. 32. Plasma levels of TNFα in patients with cirrhosis with and without SBP (pg/ml) * = P < 0.001 vs cirrhosis without SBP * M. Navasa et al. Hepatology 1998 ; 27 : 1227-1232.
  33. 33. Bacterial translocation becomes clinically significant when it produces SBP, bacteremia, post-surgical infectionsBacterial peptides (Porins; HSP60;) are present in theascites of afebrile patients with increased TNFα and IFN-gamma concentrations Cano et al. J Mol Med, 2010, e-Pub
  34. 34. SBP – A chronic inflammatory disease with flares? bacterial translocation bacterial products which cause: cytokine production inflammatory response nitric oxide production SBP SBP time
  35. 35. Acute-on-chronic Liver Failure Patients’ features at enrollement R. Moreau et al. (Canonic study) Gastroenterology 2013 (in press)
  36. 36. Renal failure in cirrhosisLeucocyte count in patients with and without ACLF ________ Patients with no prior decompensation of cirrhosis ___ _ ___ Patients with prior decompensation of cirrhosis ACLF NO ACLF R. Moreau et al. (Canonic study) Gastroenterology 2013 (in press)
  37. 37. C reactive protein values in patients with and without ACLF * = p < 0.01 versus No ACLF * # = p < 0.05 versus No ACLF * * * * # * R. Moreau et al. (Canonic study) Gastroenterology 2013 (in press)
  38. 38. Mechanisms for sepsis-induced organ failure microorganism-associated molecular patterns (MAMPs) PRRs, pattern recognition receptorsPAI-1, plasminogen activator inhibitorAPC, activated protein CTF, tissue factor. From: Gustot et al, HEPATOLOGY 2009;50:2022-2033
  39. 39. Summary & ConclusionsBacterial infection is one of the most frequent cause ofdecompensation and death in cirrhosisImmune defects, mainly acquired but also genetic,and bacterial translocation are the main mechanismsinvolved in its pathogenesisThe prevalence of infections is likelely to beunderestimated in clinical practice due to the reduceddiagnostic capacity of the standard diagnostic criteriaGram positive and MDR bacteria are increasingetiologic agents

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