Infections In Cirrhotic patients. Dr Abid Suddle Institute of Liver Studies King s College Hospital

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1 Infections In Cirrhotic patients Dr Abid Suddle Institute of Liver Studies King s College Hospital

2 Infection in cirrhotic patients Leading cause morbidity/mortality Common: 30-40% of hospitalised cirrhotic patients vs 5-7% general population 50% mortality rate increase in patients with sepsis Decompensation of Liver function Bleeding, Jaundice, Ascites/ HRS, Encephalopathy Increased frequency of extra-hepatic organ failure & requirement for organ support Acute on Chronic Liver Failure Increased susceptibility to secondary infections Bajaj et al; Hepatology 12 14; Karvellas et al; Crit Care Med 10 ; Moreau et al, Gastro 13

3 Infections in cirrhosis 1.Frequency 1. Hospitalised cirrhotic patients % 2. Hospitalised cirrhotic patients with GI bleeding - 45% 3. vs. hospitalised patients overall 5-7% 2.Sites of first infections 1. SBP % 2. UTI % 3. Pneumonia 8-15% 4. Skin and soft tissue 3.Pathogens 1. Gram-negative (E. coli, Klebsiella spp) 2. Gram-positive (Streptococcus pneumonia, Staphyloccocus aureus) 3. Other bacterial- pseudomonas, enetrococci 4. Fungi- increased mortality 5. MDRO Tandon, Sem Liver Disease, 2008 Borzio et al., Dig Liver Dis, 2001 Moreau et al; Gastro 13 Baja et al, Hepatology 12 Moreau et al, Gastro 13 Fernández J et al., Hepatology 02 Karvellas et al; Crit Care Med 10 Bonnel et al., Clin Gastro Hepatol 11 Baja et al; Hepatology 12

4 Epidemiology, predictors and outcomes of multidrug-resistant bacterial infections in patients with cirrhosis across the world The intercontinental Global study investigated the epidemiology and outcome of bacterial/fungal infections in hospitalized patients with cirrhosis Methods: Demographic, clinical, microbiological and treatment data collected from 1,302 patients at 46 centres Results: The most common infections were SBP (27%), UTI (22%) and pneumonia (19%) The global prevalence of multidrug-resistant (MDR) bacteria* was 34% Patient location (%) and global MDR bacteria prevalence Independent risk factors for MDR infections OR p-value Infection in Asia Infection in India 7.94 <0.001 Infection in South America Antibiotic use in last 3 months Nosocomial infection 2.65 <0.001 Healthcare-associated infection Pneumonia 3.20 <0.001 UTI 2.48 <0.001 Skin/soft tissue infection MDR bacteria infection were associated with: Lower rate of response to empirical antibiotic treatment (40 vs. 68%; p<0.001) Higher incidence of shock (27 vs. 15%; p<0.001) New organ failures (42 vs. 31%; p=0.001) Lower rate of resolution of infection (82 vs. 72%; p=0.003) Higher in-hospital mortality (31 vs. 21%; p=0.004) Conclusions: There is a need to develop different empirical antibiotic strategies across different continents and countries. Every effort should be made to reduce the spread of MDR bacteria in cirrhosis *MDR bacteria were defined as resistant to at least one antibiotic in >2 classes Piano S, et al. ILC 2018, GS-001

5 Infection, SIRS and cirrhosis: Diagnostic difficulties 30-50% infections remain culture negative in cirrhosis SIRS in cirrhosis is atypical : Reduced baseline PMN count Elevated baseline HR (hyperdynamic circulation) Reduced baseline BP (hyperdynamic circulation) Baseline hyperventilation due to encephalopathy Blunted elevation in body temperature SIRS criteria & biomarkers (eg CRP, procalcitonin) do not definitively differentiate infectious vs non-infectious SIRS Both infectious and non-infectious SIRS associated with poorer outcomes

6 Mortality rate caused by bacterial infections in cirrhosis in the last decades p= NS Aravanti, Gastro 2010

7 Infection and AoCLF Common in AoCLF Infection precipitates AoCLF in 30-57% of cases in Europe, North and South America The major determinant of outcome Levesque E et al. J Hepatology 2012, n = 377

8 Why are Cirrhotics at increased risk of infection?

9 Infection in Cirrhotics- Approach to management Assume a sick Cirrhotic is infected until proved otherwise High index of suspicion for infection in Cirrhotics presenting with: Deterioration in liver function Bleeding Ascites: new onset/ worsening Renal failure HE Organ failures (AoCLF) Local or systemic signs of infection/ inflammation Immediate Empirical broad spectrum antibiotics after appropriate microbiological tests/ advise taken

10 Identifying those requiring early level 2/3 care qsofa (Quick SOFA) Criteria Respiratory rate 22/min Altered mentation Systolic blood pressure 100 mm Hg

11 Infections in Cirrhotics: Use broad spectrum antibiotics at the outset Prospective, randomised study Mortality lower in broad spectrum antibiotic group: 25% vs 6%, p=0.01 Merli Hepatology 2016

12 Spontaneous bacterial peritonitis When first described mortality 90%; currently 20% Prevalence in Outpatients %; 10% in Inpatients 50% infections acquired during hospitalisation Diagnosis based on diagnostic paracentesis Neutrophil count 250mm 3 Spontaneous bacterial empyema: rare, high mortality

13 SBP: Symptoms/ Clinical context Local symptoms/ signs of peritonitis Signs of systemic inflammation Deterioration in Liver function Renal Failure GI bleeding Can be Asymptomatic: High index of suspicion All hospitalised patients with ascites should have diagnostic paracentesis

14 Empirical Treatment of SBP (or SBE) Bernardi Jhep 2015 SBP Community acquired Hospital acquired Nosocomial 3 rd generation cephalosporin or piperacillintazobactam Area dependent: Like nosocomial if high incidence of MDRO or sepsis MICRO ADVICE Carbapenem alone or plus daptomycin Vanocomycin or linezolid if high prevalence of gram pos MDRO or sepsis

15 Management of SBP: Albumin reduces mortality and progression to HRS CIRCULATORY SUPPORT WITH I.V. ALBUMIN IN PATIENTS WITH SBP- EFFECT ON HRS DEVELOPMENT AND HOSPITAL MORTALITY Cefotaxime (n=63) Cefotaxime + albumin (n=63) Resolution of infection 57 (93%) 59 (98%) HRS Hospital mortality 20 (32%) 17 (27%) 6 (10%)* 6 (10%)* Most effective if bili > 68 and Cr> 88 Albumin: - 1.5g/kg day 1-1g/kg day 3 * p<0.001 Sort et al., N Engl J Med 1999

16 Patients surviving SBP Recurrence at one year 70% Survival at one year 35-50% Survival at two years 25-30% Evaluate for transplant if appropriate

17 SBP: Secondary prophylaxis Gines et al Hepatology 1990 Patients surviving SBP, randomised to receive: Norfloxacin 400mg od 40 patients Placebo 40 patients 1 year of follow up: Probability of SBP 20% Norfloxacin 68% Placebo p=0.0063?continue prophylaxis to LT or death (most do)?what to do if there is an indication for Rifaximin Ciprofloxacin: high incidence of quinolone resistance/ C. Diff

18 SBP: primary prophylaxis Norfloxacin 400mg od Child Score 9 Bilirubin 3mg/ dl Either renal impairment or Na Ascitic fluid <15g/dl Discontinue if clinical condition improves and ascites resolves

19 Other infections: UTI Bernardi Jhep 2015 UTI Community acquired Hospital acquired Nosocomial NO SEPSIS: Ciprofloxacin or septrin SEPSIS: 3 rd generation cephalosporin or piperacillintazobactam Area dependent: Like nosocomial if high incidence of MDRO or sepsis MICRO ADVICE NO SEPSIS: Fosfomycin or nitrofurantoin SEPSIS: Meropenem or teichoplanin or vancomycin

20 Other infections: pneumonia Bernardi Jhep 2015 Pneumonia Community acquired Hospital acquired Nosocomial Piperacillintazobactam or cephalosporin + macrolide or levofloxacin or moxifoxacin Area dependent: Like nosocomial if high incidence of MDRO or sepsis MICRO ADVICE Ceftazidime or meropenem + levofloxacin +/- glycopeptides or linezolid

21 Albumin in infections other than SBP -No evidence for routine use Thevenot et al, J Hep 2016

22 Adherence to EASL antibiotic treatment recommendations improves the outcomes of patients with cirrhosis and bacterial infections Assessment of the clinical impact of adherence to EASL recommendations on antibiotic treatment* among patients in the ICA Global Study Methods: Demographic, clinical, microbiological and treatment data were collected from 1,302 patients Results: Antibiotic treatment was adherent to EASL recommendations for 61% of patients Adherence was poorer in pneumonia (27% vs. 71%; p<0.001) and nosocomial infection (54% vs. 64%; p=0.002) Bacteria isolated in Asian centres had lower susceptibility to recommended antibiotics (58% vs. 80%; p<0.001), mainly due to MDR bacteria (51 vs. 28%; p<0.001) Conclusions: Adherence to EASL recommendations was associated with better outcomes in patients with cirrhosis and bacterial infections Different strategies should be developed in countries with high MDR bacteria prevalence *Treatment was considered adherent if 1 recommended antibiotic/combination was administered; To administered antibiotic; Adjusted for age, ACLF, quick SOFA and MELD-Na score Piano S, et al. ILC 2018, PS-080 Weaker than recommended antibiotic regimens were associated with reduced antimicrobial susceptibility Weaker than recommended antibiotic regimens were associated with higher risks New organ failures Septic shock In-hospital mortality Favours lack of adherence Favours adherence OR 1.50 p=0.010 OR 0.51 p=0.044 OR 1.47 p=

23 Fungal infection in Cirrhotics Alexopoulou J Hep 2015

24 Summary Infection is a leading cause for morbidity and mortality in Cirrhotic patients Principles of management include High index of suspicion: assume infection Early use of broad spectrum antibiotics Full supportive management Early identification of those requiring ICU Increasing importance/ significance of MDRO