Summary of doctoral dissertation: The clinical, laboratorial features and treatment of spontaneous bacterial peritonitis in cirrhosis

This topic is researched for two goals: Description of clinical characteristics, subclinical disease Peritonitis infections spontaneously. Results of identification of bacteria and antibiotics on the isolates of bacteria. Evaluation of the results of treatment of peritonitis infection spontaneously in patients with cirrhosis.

MINISTRY OF EDUCATION

AND TRAINING DEPARTMENT OF DEFENSE

THE CLINICAL RESEARCH INSTITUTE OF MEDICINE SCIENCE 108

-  -

VU THANH TRUNG

THE CLINICAL, LABORATORIAL FEATURES AND

TREATMENT OF SPONTANEOUS BACTERIAL

PERITONITIS IN CIRRHOSIS

Subject: Gastroenterology Code: 62.72.01.43

SUMMARY OF THE THESIS

HANOI - 2019

CLINICAL RESEARCH INSTITUTE OF MEDICINE SCIENCE 108

Science instructors:

1 Prof.Dr MAI HONG BANG

2 Assoc PHAN QUOC HOAN

Reviewer 1:

Reviewer 2:

Reviewer 3:

The thesis has been defended before the Institute of Dissertation thesis

at the Institute: 14 hours on September 11, 2018

The thesis can be found at:

1 National library

2 Library of the Clinical Medicine Research Institute 108

INTRODUCTION AND AIMS

Cirrhosis is the common end-stage disease of a variety of chronic hepatitis Worldwide, cirrhosis is thought to be the leading cause of death in the 14th There are many types of infections that occur in cirrhosis and spontaneous bacterial peritonitis (SBP) is a severe and frequent complication The incidence of SBP in cirrhotic patients with ascites is hospitalized from 10% -30% The main causes of viral

hepatitis are Gram-negative bacteria, commonly known as E coli, Klebsiella sp., Enterobacter sp., And some Gram-positive bacteria:

Streptococci, Enterococci Ascites analysis plays an important role, determining the diagnosis and direction for treatment of SBP The diagnosis of SBP is based on the number of neutrophil counts (> 250 cells / mm3) or / and positive bacteriuria However, the pathogenic strains of bacterial pathogens are frequently altered, with increasing antibiotic resistance of bacterial strains, which makes treatment of SBP more difficult in patients with cirrhosis In Vietnam, there are not many studies on SBP

NEW CONTRIBUTION OF THE THESIS

The thesis has scientific and practical implications, which are related to many disciplines such as intestinal digestion, infectivity and microbiology In clinical practice, the topic describes the main features

of spontaneous abdominal infections in patients with cirrhosis of the ascites, the pathogenic strains, the antibiotic sensitivity assessment Bacteria isolates and evaluated the efficacy of the regimen starting with two antibiotics: Cefotaxime 4g / day + Ciprofloxacin 1g / day, effective treatment with antibiotics and experience

STRUCTURE OF THE THESIS

The dissertation has 121 pages, including: research introduction and objectives (2 pages), overview (36 pages), subjects and methods (25 pages), research results (27 pages) Comment (29 pages), conclusion (2 pages) The thesis has 32 tables, 12 charts, 15 images, 189 references including 9 Vietnamese documents and 180 English documents

Chapter I OVERVIEW DOCUMENT 1.1 History

Spontaneous peritonitis was first described in German medical journals in 1907 by Krencker E Subsequently, the findings on SBP were described in France by: Brule M 1939), Cachin M (1955) and Calori J (1958) However, in 1964, Harold O Conn introduced the term: spontaneous bacterial peritonitis (SBP), and this term has been used so far The concept of spontaneous peritonitis (SBP) refers to the bacterial ascites infection, but does not detect the pathway of bacteria and is capable of medical treatment

1.2 Epidemiology

In patients with cirrhosis, the mortality rate is related to bacterial complications of 30-50% Frequency of infection is 5-7% for external patients and accounts for 32-34% for internal patients and even up to 45% for patients with complications of gastrointestinal bleeding Common infections in patients with cirrhosis are: Peritonitis, autoimmune peritonitis - SBP (25% -31%), urinary tract infections - UTI (20% -25%), pneumonia (15% -21% %) sepsis- SEPSIS (12%), soft tissue infections (11%)

About 75% of cases of cirrhosis in cirrhotic patients are negative bacteria, such as Escherichia coli, Klebsiellaspp, Enterobacterspp, P aeruginosa, Vibrio spp, Aeromonas spp While

Gram-Gram positive accounts for 20.2% and anaerobic species accounts for 3.2% Recently, the prevalence of gram-positive bacterial infections has been on the rise, according to a study by Marco Fiore et al

+ Changes in anatomic structure and portal vein pressure

+ Immune disorders: site and system

_ Excessive growth of bacteria

+ Movement path of bacteria:

+ Lymphatic drainage

+ Blood sugar

+ The way of smuggling

Factors supporting the movement of bacteria:

Environment, nutrition, metabolism, stress, drug use PPIs

1.4 Clinical presentations

The main clinical symptoms of SBP include:

- Symptoms of total or local peritonitis

- infection syndrome

- Impaired liver function syndrome

- Hepatic encephalopathy (HE)

- Kidney

- Hepatic renal syndrome (HRS)

- Shock

- Gastrointestinal bleeding

In particular, asymptomatic SBP, about 1.5% -3.5%

1.5 Diagnostic tests for SBP

1.5.1 Microbiologic testings

Today, screening facilities use aseptic culture in blood culture bottles on bacterial culture systems and automatic bacteriostatic identification This method has been shown to have a higher positive rate of implantation than conventional implantation

1.5.2 Methods of counting the polymorphonuclearneutrophilic leukocyte (PMN)

The method of counting PMN cells in ascites is crucial to the diagnosis of SBP Multi-core counting methods used include:

The classic method of counting white blood cells by Giemsa staining and microscopic counts is subjective and time consuming

The automatic / semi-automatic hematopoieticcounting method has the advantage of fast and accurate and indicates the

percentage of white blood cells in ascites, which makes it easy to calculate the white blood cell count accurately PMN = total white blood cell x% Neutrophil The SBP is diagnosed valid when the number of PMN cells> 250 / μL Automatic blood counting methods have been shown to have a sensitivity and specificity of 94% and 100%, respectively Negative predictive value is 99.1%, positive predictive value is 100%

Urine reagent strip testings (Multistix 8SG urine test) The scientific

basis of this method is to detect indirectly leukocyte esterase-leukocyte esterase cells secreted by these cells Enzyme esterase activates the color indicator on the test and performs colorimetry on the machine This

method is qualitative, semi-quantitative Although the method of urine testing yielded rapid results at bedside, there was no consensus in the early diagnosis of SBP, for reasons of low sensitivity and false negative rates high, especially in cases where SBP has white blood cell count in low ascites

Measurement of Lactoferrin/ Calprotectin in ascites.Lactoferrin

/ Calprotectinis a protein that binds calcium and zinc, which is secreted

by multiplexed white blood cells and proportional to the number of these cells This method gives sensitivity and specificity of 95.4% and 85.2%, respectively However, this method has some limitations: Difficult to diagnose in cases of SBP have decreased number of white blood cells multipliers and cases secondary inflammation

1.5.3 Diagnosis of SBP is based on bacterial DNA present in ascites

Today, with molecular techniques, bacterial DNA can be detected

in the blood or in ascites DNA extraction - Real-time polymerase chain reaction (DNA sequencing) - DNA sequencing With this technique, small amounts of bacterial DNA, if present in ascites, will be detected Therefore, it is possible to diagnose VMBNKTP at early stage or in case of previous SBP using antibiotic prophylaxis, which results in negative culture However, this is a new technique and there are many limitations to overcome such as: The rate of homology between culture and DNA sequencing is not high (50%), negative bacteria DNA accounts for about half of cases of VMBNKTP negative culture; There

is a lack of standard methods and primers, so many strains of bacteria have not been identified; No antibiotic evaluation; Secondary inflammation status was not evaluated

1.6 Diagnosis

- Definitive diagnosis: SBP is based on the guidelines of the

International Asiatic Society: The number of PMN in ascites> 250 cells / mm3 and / or bacteriostatic ascites results in positive culture

- Differential diagnosis:

+ Secondary peritonitis

+ Septicemia

+ Fungal peritonitis

1.7 Treatment

Treatment principle

- Complete treatment

- Early treatment

- Select good antibiotics

- Co-ordinate with antibiotics

1.7.1 Use antibiotics according to antibiotic maps

This is a method of selecting antibiotics sensitive to pathogenic bacteria in a scientifically and economically reasonable way Even when antibiotics are well-defined, antibiotics should be combined to increase the likelihood of bactericidal activity and to reduce resistance

to antibiotics (antibiotics should not be used alone) The combination of antibiotics follows the principle of antibiotic combination among groups: for example: Cephalosporin group TH3 + fluoroquinolone group TH2; but select antibiotics sensitive in that group

1.7.2 Use of empirical antibiotics (EAT)

The use of empiric antibiotic therapy (EAT) is a method used for treatment prior to antibiotic therapy and / or for implantation negative bacteria This method is indicated as soon as the diagnosis of SBP is determined (cell count> 250 cells / mm3) without waiting for bacteriologic results Experimental antibiotic treatment is based on the results of research on epidemiology and pathogenesis of SBP; the susceptibility or antibiotic resistance of bacterial species in previous studies

The European Consensus Guide and the guidelines of the International Ascetic Society recommend that the use of the 3rd generation Cephalosporin Group be the top choice for the treatment of SBP (Cefotaxime, Ceftriaxone, Cefoperazole) The recommended standard dose for cefotaxime is 2g every 8 hours (6g / 24 hours) In cases where patients are not suitable for Cephalosporin, antibiotics such

as amoxicillin-clavulanate are used instead Antibiotic therapy should

be used with Cephalosporin TH3 and fluoroquinolone

1.7.3 Use of antibiotics in combination with albumin therapy

Numerous studies have demonstrated that treatment of cefotaxime with cefotaxime combined with albumin (1.5 g / kg for the first 6 hours

of diagnosis, followed by 1 g / kg for the next 3 days) versus treatment

by cefotaxime alone, it was shown that the patients treated with combination therapy had a 10% reduction compared with 33%, p = 0.002 and a lower mortality rate (10% vs 29% , p = 0.01) during

hospital stay; and follow-up 3 months after discharge (22% with 41%, p

Antibiotic prophylaxis is indicated for patients:

Cirrhosis with ascites has gastrointestinal bleeding

Cases with ascites volume <1g / dl and total bilirubin> 3.2 mg / dL and / or platelet count <98,000 / mm3

- Cases of premenopausal period have been affected by SBP Antibiotics used in prophylaxis: Norfloxacin, Ciprofloxacin, Rifamycin, Trimethoprim-sulfamethoxazole

Chapter II OBJECTIVES AND METHODS 2.1 Research subjects

106 patients with decompensated cirrhosis with complications of

SBP,inpatient treated in gastroenterology department, Bach Mai

Hospital, from March 2010 to October 2016

2.1.1 Criteria for selecting patients

Diagnosed with clinically definitive cirrhosis, there are two syndromes: hepatic impairment syndrome and portal hypertension syndrome

- There is ascites with SBP complications based on guidelines of the International Asiatic Society: The number of PMN in ascites> 250 cells / mm3 and / or bacterial ascites culture is positive result

- There has been no antibiotic treatment within the previous month

2.1.2 Criteria for exclusion of patients

- The cases of ascites are not due to cirrhosis

- Cirrhosis of the liver associated with liver cancer or other metastatic tumors in the abdomen

- Cases of secondary causes of peritonitis include: rupture of appendicitis, necrotizing cholecystitis, perforation of large intestine

- Cases of tuberculosis or HIV

- The cases of spontaneous peritonitis caused by fungus (results of culture of fungal infection positive ascites)

Peritoneal tuberculosis, acute pancreatitis with abdominal fluid

2.2 Research Methods

2.2.1 Research design

Is the method: description, cross sectional analysis, vertical tracking during the treatment

2.2.2 Study sample size

Use of convenient sample size (106 patients) during 2010-2016 2.3 Research facilities System of bacteriostatic, bacteriostatic and antimicrobial automatic: PHONIX 100 - BD - USA Siemens automatic cell counting system - Federal Republic of Germany Testing machines, modern imaging equipment are routinely used at Bach Mai Hospital

2.4 Research steps and research indicators

- Patient selection:

Patients with cirrhosis of the ascites hospitalized for clinical examination, routine clinical (hematological, biochemical,

immunological .), asymptomatic asymptomaticasymptomaticasymptomatic and implant count Ascites fluid by blood culture bottles Patients with a prenatal number> 250 cells / mm3 and no history of antibiotics during the preceding month, and no exclusion criteria, were selected for the study

Patients with cirrhosis of the ascites hospitalized for clinical examination, routine clinical (hematological, biochemical,

asymptomaticasymptomaticasymptomatic and implant count Ascites fluid by blood culture bottles Patients with a prenatal number> 250 cells / mm3 and no history of antibiotics during the preceding month, and no exclusion criteria, were selected for the study

- Initiate treatment with 2 antibiotics: Cefotaxime 4g / day + Ciprofloxacin 1g / day for the study group for 3 days (before the results

of antibiotic culture and antibiotic) Evaluate the clinical symptoms and re-test the hematological and biochemical parameters after 3 days of treatment

Evaluation after antibiotic culture and antibiotic: Evaluate the parameters: rate of bacterial culture, structure of bacteria, evaluation of susceptibility of some major antibiotics Isolated strains of bacteria Evaluate the rate of multidrug resistant bacteria

- Evaluation of treatment results: Patients with antibiotic therapy results, continued treatment with antibiotics Patients with multidrug resistant antibiotics or patients with negative bacteriologic results should undergo empiric therapy based on the clinical response of the patient The treatment duration is from the beginning of antibiotic treatment to the end of treatment (the patient is removed, the patient is discharged or the patient progresses, the family is discharged)

Evaluation of factors related to treatment outcome: bacteria, hepatic nephropathy, hepatic brain syndrome, septicemia

2.4 Data analysis and processing

Statistics are processed by SPSS software 20.0 Results were statistically significant with p <0.05

Chapter 3 RESULTS

3.1 Clinical and laboratory characteristics

3.1.1 Characteristics of age and sex

Table 3 1 Mean age, sex ratio in cirrhotic patients with SBP

Comments: Average age: 52.1 ± 11.7 (28 -85), male / female

Comment: The incidence of alcoholic cirrhosis is highest in 50.9%

The prevalence of hepatitis B virus infection was 31.1%, of which, alcoholism combined with viral hepatitis was 19.8%

3.1.3 Main clinical features in patients with SBP

Figure 3.1 General clinical characteristics of the study group

Comment: Common symptoms in SBP are: Fever 85.8%; abdominal

pain 82.1%; 68.9% diarrhea

3.1.4 Child-Pugh classification

Figure 3.2.Cirrhosis level according to Child-Pugh classification

Comment: Child-Pugh C has 68.9%, Child-Pugh B 31.1%

GI bleeding edema legs diarrhea abdomen pain fever

3.1.5 Hematological and biochemical findings in cirrhotic patients with SBP

Table 3.3 Mean values of hematology and biochemistry

White blood

cells

(G / L)

11,95 ± 8,06 (1,38- 40,83)

Ure

(mmol/l) 11,58 ± 12,33 Platelet

(G / L)

102,26 ± 69,91 (11,0-361)

Creatinin

(μmol/l)

133,98 ± 112,88

Prothrombin

(%)

37,22 ± 14,21 (13,5-86)

Total bilirubin

(μmol / l)

171,80 ± 180,35

GOT (U/l) 143,52 ±

179,64 Protein (g/l) 70,45 ± 6,52

GPT (U/l) 61,73 ± 66,38 Albumin (g/l) 22,07 ± 4,16

Comment

+ Most white blood cells increase above normal levels

+ Proportion of Prothrombin is very low: 37.22 ± 14.21 (%) + High blood bilirubin: 171.80 ± 180.35

+ Average serum albumin concentration is very low: 22.07 ± 4.16 (g / l)

3.2 Ascites test in patients with SBP

3.2.1 Cellular and biochemical characteristics of ascites

Table 3.4 Cellular and biochemical characteristics of ascites

(G/L)

Protein fluid (g/l) 2,4 19,8 11,34 4,80

Comment: Average index of white blood cell ascites: 9,982

± 10.04 (0.29-52.10) G / L The rate of increase of the Steering Committee (79.0%) Elevated ascites protein content: 11.34 ± 4.8 g / l

3.2.2 Results of ascites culture in patients with SBP

106 cases of cirrhosis with SBP were ascites culture by BATEC 9500 machine system obtained the following results: