by author ESCMID eLibrary Liver cirrhosis

Bacterial infections in specific patient populations:

an update for the infectious diseases consultant

Liver cirrhosis

Pierluigi Viale Infectious Disease Unit Teaching Hospital S. Orsola–Malpighi Bologna ItalyESCMID eLibrary

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The infectious risk in liver cirrhosis

• A CLINICAL-EPIDEMIOLOGICAL OVERVIEW

• THE PATHOGENESIS : ENDOGENOUS & EXOGENOUS RISK

• ETIOLOGIES and ANTIMICROBIAL RESISTANCE TRENDS

• MOVING TOWARD AN IMPROVED MANAGEMENT

CONTENTS

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ED Visits Related to Cirrhosis: A Retrospective Study of the NationwideEmergency Department Sample 2006 to 2011 Pant C et al, Medicine 2015; 94:e308

During the calendar years 2006 to 2011, there were an estimated total of 3,127,986 EDvisits associated with an ICD-9-CM diagnosis code of cirrhosis in 951 US hospitals. Themedian age of patients was 56 years (interquartile range (IQR) 16)

4

6

15.5

20.1

HRS

EVB

HE

INFECTION

Rates of Cirrhosis-Associated ED Visits

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Approximately 30% of cirrhotic patients admitted to thehospital have an infection or develop an infection during thehospitalization

(Fernandez J et al., Hepatology 2002)

Overall mortality of infected cirrhotic patients is 30.3% at1 month and 63% at 12 months.

(Arvaniti V et al., Gastroenterology 2010)

AN EPIDEMIOLOGICAL OVERVIEW


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Acute-on-chronic liver failure (ACLF)J Hepatol 2015;62: S131–S143

Acute-on-chronic liver failure (ACLF) is a recently recognized syndrome

characterized by acute decompensation of cirrhosis (ascites,

encephalopathy, gastrointestinal hemorrhage and/or bacterial

infections) and organ/system failure(s) (liver, kidney, brain, coagulation,

circulation and/or respiration) with extremely poor survival (28-day

mortality rate 30–40%).

Acute-on-chronic liver failure is caused by bacterial infection in32.8% of cases (Moreau R et al., Gastroenterology 2013)ESCMID eLibrary

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A short case report … FC 52 year old, HCV related cirrhosis

Last ambulatory check March, 18

Body Weight 96 kg

P.A. 130/80

R.R. 16

Mental status 0

Bilirubin 4.9 mg/dl

INR 1.45

Creatinine 0,68 mg/dl

ACLF-2 expected 90-day mortality: >50%

Hospital admission April, 3Hospital admission April 3

Body Weight 110 kg

P.A. 120/780

R.R. 24

Mental status 2

Bilirubin 13 mg/dl

INR 2.35

Creatinine 3,89 mg/dl

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SMALL INTESTINAL BACTERIAL OVERGROWTH and DYSBIOSIS

BLOOD

SPONTANEOUS BACTERIAL PERITONITIS

BLOODSTREAM INFECTION

BLOODSTREAM INFECTION

BLOOD

ASCITIC FLUID

MESENTERIC LYMPHONODES

ABNORMAL BACTERIAL TRANSLOCATION

CIRRHOSIS ASSOCIATED IMMUNE DYSFUNCTION

Jalan R et al J Hepatol. 2014;60:1310-24.

PATHOGENESIS : the endogenous riskThe infectious risk in liver cirrhosis

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PNEUMONIACR-BLOODSTREAM INFECTION

INVASIVE PROCEDURES


CAID

HIGH COLONIZATION RATE

SSTIENDOTIPSITIS

POST- SURGICAL INFECTIONS

PATHOGENESIS : the exogenous risk

DRUGS HIGH FREQUENCY

OF HOSPITAL ADMISSIONS

UTI

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Endogenous route Exogenous route

The infectious risk in liver cirrhosis The main involved microorganisms

PRIMARY BSI SBP

EnterobacteriaceaeEnterococcus spp Candida spp

PNEUMONIA

S. pneumoniaeH. influentiae

Non Fermentative Gram neg Enterobacteriaceae

SSTICR-BSI

S. AureusCoNS

POST SURGICAL INFECTIONS

S. aureus , CoNSEnterobacteriaceae

Candida spp

intense antibiotic exposure

ESLD related dysbiosis

CDAD

MDRO

ENDOTIPSITIS

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Bacterial infection in compensated viral cirrhosis impairs 5-year survival (ANRS CO12 CirVir prospective cohort) Nahon P et al, Gut, November 6, 2015

Prospective study involving 35 French centers, enrolling Child–Pugh class A patients with HCV orHBV proven cirrhosis without previous cirrhosis related complications .Overall 1672 patients were enrolled (HCV 1323, HBV 318, HCV-HBV 31), between 2006-12.

During a median follow-up of 43 months, 234 Bacterial Infections occurred in 171patients (5 year Cumulative Incidence: 12.9%).

Among infected patients 14.6% had septic shock.

BIs represented the third cause of death (14.1%) after liver failure and livercancer

Most BIs occurred as a first event prior to liver decompensation (n=140, 81.8%)and were community acquired (84.2%).ESCMID eLibrary

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OVERALL SURVIVAL

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Features associated with occurrence of BI according to Cox proportional hazards model

Variable OR 95% CI p

Age >50 1.72 1.10 to 2.68 0.017

Albumin <30 g/L 5.61 2.43 to 12.96 <0.001

Albumin 30-35 g/L 2.02 1.22 to 3.34 0.006

Positive viral load 2.60 1.72 to 3.92 <0.001

PPI 1.45 1.00 to 2.13 0.05


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INFECTIONS SITE

19

23

24

44

59

64

others

SSTI

SBP

GE

Pneumonia

UTI

MICROBIOLOGY (98 isolates)

56

43

% Gram POS

% Gram NEG

MDRO 31%

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Prevalence and Risk Factors of Infections by Multiresistant Bacteria in Cirrhosis:A Prospective Study Fernandez J et al, Hepatology 2012;55:1551-1561

A prospective evaluation in two series of patients with cirrhosis admitted with infection ordeveloping infection during hospitalization. The first series was studied between 2005 and2007 (507 bacterial infections in 223 patients) and the second between 2010 and 2011(162 bacterial infections in 110 patients).

2005-7 2010-11

MDR related infections 18% 33%

Enterococcus spp

MRSA

P. aeruginosa

ESBL

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EFFICACY OF CURRENTLY RECOMMENDED EMPIRICAL ANTIBIOTIC THERAPY

overall CA HCA HA

66% 83% 73% 40%

In HOSPITAL MORTALITY rates

MDR susceptible p

25% 12% .001


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Multivariate analysis. Factors indipendently associated to MDR infection

Variable HR 95% CI p

Nosocomial origin 4.43 2.29 - 8.59 <0.0001

Long-term norfloxacin prophylaxis 2.69 1.362 – 5.30 0.004

Previous use of β-lactams (90dd) 2.39 1.18 – 4.85 0.02

Recent infection by MDR pathogens (< 6 m) 2.45 1.04-5.81 0.04


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Risk factors for resistance to ceftriaxone and its impact on mortality incommunity, healthcare and nosocomial spontaneous bacterial peritonitis

Ariza X et al J Hepatol 2012; 56:825-32

Retrospective study of all spontaneous bacterial peritonitis episodes with positive blood and/orascitic culture (2001–2009): 246 episodes were analyzed in 200 patients : 34.6% community-acquired, 38.6% healthcare system-acquired and 26.8% hospital acquired.

7%

21%

41%

21%

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

Community-

acquired

Healthcare

associated

Hospital- acquired Overall

3rd Gen cephalosporines resistance among culture-positive SBP episodes

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Factors indipendently associated to 3rd gen cephalosporine resistance

Variable AOR 95%CI

Diabetes mellitus 2.52 1.18 - 5.35

Upper GI Bleeding 8.15 1.92 – 34.54

Hospital acquisition 2.54 1.19 - 5.42

Previous use of beta-lactams (90 days) 2.97 1.23 – 7.17

Risk factors for resistance to ceftriaxone and its impact on mortality incommunity, healthcare and nosocomial spontaneous bacterial peritonitis

Ariza X et al J Hepatol 2012; 56:825-32

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First-line treatment with cephalosporins in spontaneous bacterial peritonitis providespoor antibiotic coverage. Novovic S et al, Scand J Gastroenterol 2012;47:212-6

All patients with cirrhosis and a positive ascitic fluid culture, at three university hospitals inthe Copenhagen area during a 7-year period, were retrospectively analyzed

One hundred and forty cases with 187 microbiological isolates were identified.

Gram-positive cocci, n = 86 (45.9%)Enterobacteriaceae, n = 59 (31.7%)Aanaerobes, n = 14 (7.5%)Yeast, n = 12 (6.4%)

Overall antibiotic coverage 57% for cephalosporins73% for piperacillin-tazobactam72% for meropenem.

Mortality rates in patients withisolates S or R to the initialantibiotic treatment at 30 daysfollow-up were 35% and 55%,respectively (p = 0.017).

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In culture positive patients,only 58.1% of the patientsreceived adequate antibiotictherapy with respect tosusceptibility of the identifiedmicroorganism.

All patients with incorrectempirical antibiotic therapywere initially treated with 3rd

gen. cephalosporins covering70.2% of non-nosocomial and56.3% of nosocomial-acquiredSBP cases.

Microbiology and resistance in first episodes of spontaneous bacterial peritonitis: implications for management and prognosis.

Friedrich K et al J Gastroenterol Hepatol 2015 Dec 17 [Epub ahead of print]

Retrospective analysis of cases occurred during the years 2007 to 2013.Of the 311 patients included, 114 had a positive ascites culture

6.50

13.80

26.10 40.60

7.20 4.00

Streptococcus spp

Staphylococcus spp

Enterococcus spp

Enterobacteriaceae

Yeasts

others

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SPONTANEOUS BACTERIAL PERITONITIS

MICROBIOLOGICAL CONSIDERATIONS

Gram staining of peritoneal fluid is rarely helpful and is not recommended.

Classical culture techniques fail to grow bacteria in up to 65% of neutrocyticascites. Bedside inoculation of ascites into blood culture bottles and providinghigh volumes of ascites to microbiologist have been shown to increase thesensitivity to nearly 80%.

Separate and simultaneous blood cultures should be collected since 30 to 58%of SBP cases are associated with bacteraemia

Detection of bactDNA in ascites or serum was not associated with anenhanced incidence of SBP and does not appear to predict the developmentof bacterial infectionsESCMID eLibrary

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Microbiology and resistance in first episodes of spontaneous bacterial peritonitis: implications for management and prognosis.

Friedrich K et al J Gastroenterol Hepatol 2015 Dec 17 [Epub ahead of print]

Features associated with death/Ltx in SBP patients

according to Cox’s proportional hazards model.

univariate analysis multivariate analysis

OR [95% CI] OR [95% CI]

Positive microbial ascites culture 2.01 [1.50-2.70] 1.49 [1.09-2.03]

SBP hospital acquired 1.02 [.75-1.39]

MELD-Score at time of SBP 1.06 [1.05-1.08] 1.05 [1.03-1.07]

ICU-contact during SBP episode 2.26 [1.68-3.05] 1.36 [.96-1.93]

Retrospective analysis of 311 cases occurred during the years 2007 to 2013

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Increasing frequency of gram-positive cocci and gram-negative MDR- bacteria in spontaneous bacterial peritonitis Alexopoulou A et al, Liver Int. 2013: 33: 975–981

To assess possible recent changes of the bacteria causing SBP in cirrhotic patients, 47 cases during a 4-year-period (2008–2011) were retrospectively recorded.

Gram positive cocci 26 casesStreptococcus spp (n = 10)Enterococcus spp (n = 9) MS Staphylococcus aureus (n = 4) CoNS (n = 3)

Gram negative bacteria 20 casesE. coli (n = 8) K. pneumoniae (n = 5) S. marcescens (n = 3)C. koseri (n = 1) Non fermenting bacilli (n = 3)

KPC Kp (n = 4)

ESBL (n = 3)

MDR P. aeruginosa (n = 2)

9 (45%) MDR

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Etiology distribution

Epidemiology and Outcomes of Bloodstream Infection In Patients with CirrhosisBartoletti M et al, J Hepatol 2014;61:51-8

All consecutive BSIs in patients with liver cirrhosis at a single institution (A 1350-bed teachinghospital) form Jan 2008 to Jun 2012 were retrospectively analyzed. BSI episodes were identifiedin 162 patients. A total of 202 isolates were identified.

44

15 1411 10

Enterbacteriaceae Enterococci NF-GNB Stafilococci Candida

Preva

lenc

e (%)

7%

34%

44%

15%

pan S

ESBL

Q-R

KPC

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The ESKAPE gang

bacterial clones that:

• have acquired multiple resistance determinants (MDR/XDR phenotypes)

• retain a notable propensity for cross-transmission and spreadingplaying a relevant role in infections and in the dissemination of resistant determinants (low impact of resistance on epidemiological fitness high epidemiological risk)

• are associated to significant morbidity and mortality (low impact of resistance on clinical fitness high clinical risk)

Woodford et al - FEMS Microbiol Rev 2011ESCMID eLibrary

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MOVING TOWARD AN IMPROVED MANAGEMENT

Issues

Adequate and early prediction of infection

Risk Factors for mortality – grading of severity

Improved microbiological work-out

Empirical drugs choice

Peculiarity of PK/PD behavior of antimicrobials


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LIVER CIRRHOSIS: RISK FACTORS FOR BACTERIAL INFECTIONS

RISK FACTOR Reference

STAGE of CIRRHOSIS / BIOMARKERS

Bilirubin > 3.2 mg/dL PLT < 98000/mmc

Guarner Gastroenterology 1999Andreu M Gastroenterology 1993

protein levels in ascitic fluid <1.5 g/L Child-Turcotte-Pugh >9 MELD > 19Lymphocytes < 900/mmc

Fernandez J, Gastroenterology 2007

Ximenes RA, Am J Emerg Med, 2015

MEDICATIONS

Use of PPILong term exposure to antibiotics

O’ Leary J et al Clin Gastroenterol Hepatol 2015Nahon P et al, Gut 2015

PRECIPITATING EVENTS

Acute variceal hemorrage Bernard B, et al. Hepatology, 1999

Previous infection Fernandez J, Gastroenterology 2007 ESCMID eLibrary

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Potential tools for early detection of infection.

EASL position paper J Hepatology 2014;60:1310–24ESCMID eLibrary

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Issues







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SEVERE SEPSIS

SEPSIS

T° > 38.3 / < 36°C

pulse rate > 90 beats/minute

respiratory rate > 20 breaths/min

WBC > 12.000 / < 4.000/mmc

glycemia > 120 mg/dL

lactemia > 2 mmol/L

plasma C-reactive protein >2 SD above the normal value (0.5 mg/L)

plasma procalcitonin > 2 SD above the normal value (0.1 pg/ml)

refilling > 2 seconds

altered mental status

hypotension (systolic < 90 mmHg)

lactemia > 4 mmol/L

organ disfunction/s

hypotension despite 20-40 ml/kg 1^h

SEPSIS DEFINITION

SEPTIC SHOCK ESCMID eLibrary

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How to stratify the risk of mortality in patients with cirrhosis and bacterial infections?

LIMITATIONS of SEPSIS CRITERIA

• Low WBC and PLTs count may be due to portal hypertension and hypersplenism

• Acute Phase protein are less accurate (reduction liver synthesis)

• Hyperventilation may be present in patients with large volume of ascites or incase of hepatic encephalopathy

• Liver disease slows lactate removal

• Normal hearth rate may be the consequence of prophylaxis with beta-blockersor tachyardia can be due to hyperdynamic circulationESCMID eLibrary

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Are SIRS criteria useful for diagnosis of bacterial infections in cirrhotic patients?

Cazzaniga M et al Journal of Hepatology 2009Thabut D et al Hepatology 2007

In a signle-center studypatients with ESLDconsecutively admitted tohospital were enrolled

Only 57% patients with infection met SIRS criteria

Multicenter prospectivestudy with the aim todetermine the prognosticfactors in a population ofpatients with cirrhosis andfunctional renal failureenrolling 83 pts

56% of patients with SIRS had an infection

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CLIF SOFA define 4 groups of patients with ACLF based on number of organ failuresNO ACLF ACLF 1ACLF 2ACLF 3

Acute-on-Chronic Liver Failure Is a Distinct Syndrome That Develops in patientsWith Acute Decompensation of Cirrhosis Moreau R et al, Gastroenterology 2013 ;144:1426-37

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MELD score as prognostic index for 30-day survival

Baseline 24h 48h 72h 96hdiagnosis

Median

MELD +

/-95% C

I

Time of Assessment

10

15

20

25

30

35 Non-survivors Day 30; n=47 (29%)

Survivors Day 30; n=115 (71%)

A retrospective analysis of all consecutive BSIs in patients with liver cirrhosis at our 1350-bed teaching hospital (Jan 2008 to Jun 2012): 162 cases detected (11.7 per 10,000 patient-days)


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0 20 40 60 80 100

0

20

40

60

80

100

100-Specificity

Sen

sitivity

Variable aROC (95% CI)

MELD at BSI 0.81 (0.74-0.87)

∆ MELD at BSI 0.89 (0.83-0.94)

∆ MELD 24h 0.54 (0.45-0.62)

∆ MELD 48h 0.66 (0.56-0.76)

∆ MELD 72h 0.76 (0.66-0.86)

∆ MELD BSI

∆ MELD 72h

∆ MELD 48h

∆ MELD 24h

MELD at BSI

Comparison of aROC for MELDscore variables as a predictor of30-day survival status

Δ MELD was evaluable in 150 patients, 9±6 in NS vs. 2±3 in S, P<0.0001


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Kaplan-Meier analysis of 30-day crude mortality stratified by Δ MELD.


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Issues







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Adjusted HR 0.37 (0.20-0.70)

P =0.002

Adequate antibiotic therapy

within 24 hours (n=100)

Inadequate antibiotic therapy

within 24 hours (n=62)

0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

0.90

1.00

Surv

ival P

robabili

ty

0 5 10 15 20 25 30

Days after positive blood culture

Impact of inadequate antimicrobial therapy in the first 24 hours on survival


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Clinical features and impact of empirical therapy in cirrhotic adults with community-onset bacteremia. Hsieh C et al ,Am J Emerg Med. 2015;33:222-8

246 bacteremic episodes in cirrhotic patients

* Delayed: after 72 h from BSI

symptoms onset

*

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An Empirical Broad Spectrum Antibiotic Therapy in Health-Care–AssociatedInfections Improves Survival in Patients With Cirrhosis: A Randomized Trial

Merli M et al Hepatology , 2015 Nov 3.

In-hospital mortality showed a substantial reduction

in the broad spectrum versus standard group (6% vs. 25%; P<0.01)

Ninety-four patients with HCA infections were randomized to receive :1-standard treatment or 2-broad spectrum antibiotic treatment

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The Empirical Antibiotic Treatment of Nosocomial Spontaneous BacterialPeritonitis: Results of a Randomized, Controlled Clinical Trial

Piano S et al, Hepatology 2016;63:1299-1309

Patients with cirrhosis and nosocomial SBP were randomized to receive meropenem (1g/8 hours) plus daptomycin (6 mg/kg/day) or ceftazidime (2 g/8 hours). The primaryoutcome was the efficacy of treatment defined by the resolution of SBP after 7days of treatment. Thirty-two patients were randomized and 31 were analyzed.

resolution rates

Combo 86.7 %

Mono 25.0 % P < 0.001

Probability of 90-day TFS according to efficacy of first line treatmentESCMID eLibrary

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Issues







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Ensuring a prompt and appropriate empirical antimicrobialtreatment is essential in every severe infection

On the whole, pharmacokinetic variability is one of the

major contributors to therapeutic failure: therefore to

guarantee a correct exposure to antibiotics, timely

administration of the right dose at the right schedule,

according to the pathophysiological and immunological

status of the patient, is required.

Ensuring a prompt and appropriate empirical antimicrobialtreatment is mandatory in every infection occurring in Liver CirrhosisESCMID eLibrary

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Altered protein binding• Hypoproteinemia (albumin, α-acid glycoprotein)

• Elevated binding competitors (bilirubin)

• Increased Vd

Altered distribution• Increased extracellular fluid (edema, ascites)

• Increased Vd → low serum conc. → prolonged clearance

• Unpredictable serum levels

Altered renal function• GFR < 60 mL/min despite normal SeCr

• Cockcroft-Gault estimation 2-3x higher than actual GFR

• Impaired creatinine production

Impact of liver cirrhosis on antimicrobial PK/PD behavior

Given the unpredictable

drug exposure, TDM

might play a pivotal role

for individualizing doses,

both in lowering exposure-

dependent toxicity and in

ensuring an optimal drug

exposure, especially when

MDR pathogens are

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Avoid third generation cephalosporines and fluoroquinolones as empirical therapy, atleast in healthcare-associated and hospital acquired infections

Use a BL/BLI in setting with low-intermediate prevalence of ESBL producing strainsor for less severe infections (when you have the opportunity to graduate them)

Start with a carbapenem in settings with high prevalence of ESBL producing strainsattempting to de-escalate as soon as culture results become available or clinicalstability is reached

Provide anti-MR cocci drugs in pts with suspected device related infections and SBP

If time-dependent drugs (e.g., b-lactams) are administered, provide a loading doseand continuous or extended infusion;

Assess, whenever possible, drug exposure by TDM.

remarks for empirical antimicrobial treatment

Bartoletti M et al. Virulence 2016 Feb 11:0. [Epub ahead of print]ESCMID eLibrary

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Alma Mater Studiorum University of Bologna – The Library

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