Spontaneous bacterial peritonitis overview

# Overview
Spontaneous bacterial peritonitis (SBP) is a form of peritonitis that occurs in most of the patients with advanced cirrhosis, in 10-30% of hospitalized patients with ascites and in various other clinical settings, such as nephrotic syndrome, heart failure, tuberculous infection, continuous ambulatory peritoneal dialysis for chronic renal failure.  SBP is diagnosed with a positive bacterial culture for a single organism and an AF ( ascitic fluid) : polymorphonuclear (PMN) cell count of > 250/mm3, in the absence of a surgically treatable intra-abdominal source of infection. More than 60% of SBP episodes are caused by enteric gram-negative organisms such as Escherichia coli and Kleibsella. Selective intestinal decontamination (SID) with fluorinated quinolones suppresses the gram-negative intestinal flora and is known to reduce the incidence of SBP. SBP results due to the inability of the gut to contain bacteria and failure of the immune system to eradicate the organisms once they have escaped into the blood stream. Clinical signs and symptoms are non specific and indistinguishable from secondary peritonitis. Ascitic fluid analysis is helpful in differentiating SBP from secondary peritonitis. Because of the lack of specificity and sensitivity of clinical signs and symptoms, cirrhotic patients with unexplained deterioration should undergo a diagnostic paracentesis. Once diagnosed, patients with SBP should receive prompt empiric antibiotic treatment ( Cephalosporins) without waiting for the ascitic fluid culture. Failure of prompt initiation of antibiotics results in  significant and potentially fatal deterioration in the clinical status of the patient. Patients who survive an episode of SBP are at high risk of recurrence. Patients with cirrhosis and ascites developing abdominal pain and/or temperature >100F are more prone to have SBP and should receive empiric antibiotic treatment. Early detection and treatment improve outcome and prevent complications such as shock and renal failure.
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# Historical Perspective
Kerr and colleagues (1963) described 11 episodes of ascitic fluid infection in 9 cirrhotic patients while Harold O.Conn , M.D, a world-renowned hepatologist (1964) introduced the term spontaneous bacterial peritonitis for the first time in English literature. Later in the history, SBP was studied extensively by many renowned researchers and health care professionals as this condition was seen among many patients with cirrhosis, which has lead to the thorough understanding and recognition of SBP.

# Classification
Spontaneous bacterial peritonitis is one of the variants of ascitic fluid infections.. Classification of ascitic fluid infections is based on neutrophil count and culture report.. Asymptomatic bacterascites is usually the transient residence of bacteria in ascitic fluid without clinical features of peritonitis or increased ascitic fluid polymorphonuclear cells.. SBP is also classified based on the routes of infection and the clinical setting as follows Health care-associated, Nosocomial, Community acquired, Multi-drug resistant, Recurrent.

# Pathophysiology
Spontaneous bacterial peritonitis is thought to result from a combination of factors related to cirrhosis and ascites such as: altered microbial flora, hypo-motility of the intestine, intestinal bacterial overgrowth, increased intestinal mucosal permeability, bacterial translocation to lymph nodes. Presence of ascites is an important risk factor for the development of bacterial translocation. In healthy individuals, bacteria that colonize lymph nodes are killed by local immune defenses. However, in the setting of cirrhosis, an acquired state of immunodeficiency there is: malfunctioning of the reticulo-endothelial and neutrophilic system, reduced cellular and humoral bactericidal function which favor the spread of bacteria to the blood stream.
- Alterations in the systemic immune response: Bacteremia in a healthy host results in rapid coating of the bacteria by IgG/complement components which help in engulfing and killing of the bacteria by circulating neutrophils. But in cirrhosis, several abnormalities have been described which lead to defective clearance of the bacteria include : decreased serum levels of complement components (C3, C4), impaired chemotaxis, poor function and phagocytic activity of neutrophils, decreased function of Fc-gamma-receptors in macrophages.
- Reticuloendothelial system phagocytic activity: The stationary macrophages, such as the Kupffer cells of the liver, assist the circulating neutrophils in the extraction and killing of particulate matter (e.g., bacteria) from the systemic circulation. In Cirrhosis, there is hepatic reticuloendothelial system (RES) dysfunction and  kupffer cells are decreased in number with impaired function along with the malfunctioning of the neutrophilic system. Patients with the most severe dysfunction of RES are at highest risk of bacteremia and concomitant shortened survival, due to sepsis. The presence of intrahepatic and extra hepatic porto-systemic shunts as a consequence of portal hypertension, prevent circulating bacteria from encountering kupffer cells. The final consequence of these abnormalities is the prolongation of bacteremia and eventual seeding of other sites, including ascitic fluid. 
- Ascitic fluid defense mechanisms, decreased local AF opsonic activity: The presence of bacteria in ascitic fluid does not guarantee infection will develop, as ascitic fluid is capable of humoral self-defense due to the effectiveness of the complement system and patients with adequate activity of this vital bactericidal system do not develop AF bacterial infections. In patients with ascitic fluid C3 < 1g/dl and a protein level < 1g/dl are at an increased predisposition to SBP. The complement levels may be deficient because of increased consumption of these components or because of impaired synthesis, resulting in colonization of AF by bacteria. The decreased antimicrobial ability and can eventually lead to the development of infection bacteremia/ endotoxemia leading to activation of cytokine cascade. NO and TNF are important mediators of the further vasodilation and renal failure that often accompany SBP.

# Causes
Spontaneous bacterial peritonitis is a blood-borne infection caused by Enteric organisms in 70% of cases (Mono-microbial origin in 90% of cases). Aerobic gram-negative bacteria like Escherichia coli account for half of the cases. Gram-positive cocci Streptococcus species in 20% cases with enterococcus accounting for 5% of the cases. Staphylococcus aureus and Streptococcus salivarius are less frequent causes. Poly-microbial infection is Iatrogenic (more likely associated with abdominal paracentesis) or intra-abdominal source of infection. The cause of SBP has not been established definitively but is believed to involve hematogenous spread of organisms in a patient with a diseased liver and altered portal circulation resulting in defect in the usual filtration function. In adults, spontaneous bacterial peritonitis occurs most commonly in conjunction with cirrhosis of the liver and portal hypertension (frequently as a result of alcoholism and hepatitis).

# Differentiating Spontaneous bacterial peritonitis from Other Diseases
SBP has to be differentiated from other abdominal conditions presenting with fever and abdominal pain. It also has to be differentiated from secondary peritonitis, chemical peritonitis, peritoneal dialysis peritonitis, chronic tuberculous peritonitis.

# Epidemiology and Demographics
Spontaneous bacterial peritonitis (SBP) is a potentially life threatening complication in patients with cirrhosis and is seen in hospitalized patients. The prevalence of SBP in cirrhotic patients with ascites admitted to the hospital ranges from 10%-30%.. Studies have demonstrated a 12% incidence of spontaneous bacterial peritonitis in patients admitted with decompensated cirrhosis. 2 studies examining asymptomatic patients presenting for a therapeutic paracentesis showed a combined 2.5% incidence of spontaneous bacterial peritonitis. Overall one-year mortality rate after a first episode of SBP is 30%-93% regardless of its recurrence. The mean age of presentation of SBP was 49 years. There is no gender difference in the incidence of SBP in patients with ascites.

# Risk Factors
Common risk factors in cirrhotic patients with ascites include: Low protein level in ascitic fluid (4 mg/dL), use of Proton pump inhibitors (PPI) in cirrhotic patients, Child-Pugh stage C, Model For End-Stage Liver Disease MELD  22.

# Screening
There is no definitive screening test for spontaneous bacterial peritonitis. According to Liver International journal, it has been demonstrated that fecal calprotectin concentrations (FCCs) are significantly elevated in cirrhotic patients and are dependent on the severity of liver disease. Assessing FCCs may help to identify cirrhotic patients with hepatic encephalopathy and SBP as a significant correlation emerged between elevated fecal calprotection and these complications. However, there is insufficient evidence to recommend routine screening for SBP.

# Natural History, Complications, and Prognosis
Early diagnosis and initiating treatment is the most important factor for improving the survival and avoiding the complications of SBP. The sooner the diagnosis, the better the outcome. Mortality due to SBP remains high probably due to associated advanced liver disease.

# Diagnosis
According to the 2010 European Association for the Study of the Liver clinical practice guidelines the diagnosis of SBP is based on:
- Diagnostic paracentesis:
A diagnostic paracentesis should be carried out in all patients with cirrhosis and ascites at hospital admission to rule out SBP.
A diagnostic paracentesis should also be performed in patients with gastrointestinal bleeding, shock, fever, or other signs of systemic inflammation, gastrointestinal symptoms, as well as in patients with worsening liver and/or renal function, and hepatic encephalopathy.
- A diagnostic paracentesis should be carried out in all patients with cirrhosis and ascites at hospital admission to rule out SBP.
- A diagnostic paracentesis should also be performed in patients with gastrointestinal bleeding, shock, fever, or other signs of systemic inflammation, gastrointestinal symptoms, as well as in patients with worsening liver and/or renal function, and hepatic encephalopathy.
- Ascitic fluid cell analysis
The diagnosis of SBP is based on neutrophil count in ascitic fluid of >250/mm3 as determined by microscopy.
At present there are insufficient data to recommend the use of automated cell counters or reagent strips for the rapid diagnosis of SBP.
- The diagnosis of SBP is based on neutrophil count in ascitic fluid of >250/mm3 as determined by microscopy.
- At present there are insufficient data to recommend the use of automated cell counters or reagent strips for the rapid diagnosis of SBP.
- Ascitic fluid culture
Ascitic fluid culture is frequently negative even if performed in blood culture bottles and is not necessary for the diagnosis of SBP, but it is important to guide antibiotic therapy.
Blood cultures should be performed in all patients with suspected SBP before starting antibiotic treatment.
Some patients may have an ascitic neutrophil count less than 250/mm3 but with a positive ascitic fluid culture. This condition is known as bacterascites.
If the patient exhibits signs of systemic inflammation or infection, the patient should be treated with antibiotics.
Otherwise, the patient should undergo a second paracentesis when culture results come back positive.
Patients in whom the repeat ascitic neutrophil count is >250/mm3 should be treated for SBP, and the remaining patients (i.e., neutrophils <250/mm3) should be followed up .
- Ascitic fluid culture is frequently negative even if performed in blood culture bottles and is not necessary for the diagnosis of SBP, but it is important to guide antibiotic therapy.
- Blood cultures should be performed in all patients with suspected SBP before starting antibiotic treatment.
- Some patients may have an ascitic neutrophil count less than 250/mm3 but with a positive ascitic fluid culture. This condition is known as bacterascites.
- If the patient exhibits signs of systemic inflammation or infection, the patient should be treated with antibiotics.
- Otherwise, the patient should undergo a second paracentesis when culture results come back positive.
- Patients in whom the repeat ascitic neutrophil count is >250/mm3 should be treated for SBP, and the remaining patients (i.e., neutrophils <250/mm3) should be followed up .

## Diagnostic Criteria
The diagnosis of SBP is based on two of the following criteria from guidelines:
- Abdominal pain and/or hyperthermia, and/or abdominal and rebound tenderness (excluding secondary peritonitis);
- Ascitic fluid PMN count 250 cells/mm3
- Positive ascitic fluid bacterial culture.
- In the case of a traumatic paracentesis, with the entry of blood into the ascitic fluid (typically ascitic red cells greater than 10,000 cells/mm3) the PMN count should be corrected by subtracting one PMN for every 250 red cells/mm3 from the absolute PMN count.

## History and Symptoms
80-90% of patients with spontaneous bacterial peritonitis are symptomatic, in many cases the presentation is subtle. Spontaneous bacterial peritonitis may be present in 1020% of patients hospitalized with chronic liver disease, sometimes in the absence of any suggestive symptoms or signs. Patients with SBP most often present with: abdominal pain, fever, altered mental status (hepatic encphalopathy).

## Physical Examination
The clinical examination findings in spontaneous bacterial peritonitis are usually unpredictable, so there should be a low threshold to consider SBP in any patient with cirrhosis. Fever, acute abdominal and altered mental status are the physical findings. Physical examination typically demonstrates signs of chronic liver disease with ascites. Abdominal tenderness is present in less than 50% of patients, and its presence suggests other processes.

## Laboratory Findings
Early Diagnostic paracentesis (< 72hrs) is recommended in all cirrhotic patients with ascites. Paracentesis reveals an ascitic fluid with a total white cell count of up to 500 cells/mcL with a high polymorphonuclear (PMN) cell count (250/mm3 more). Ascitic fluid analysis and culture should be performed before initiating antibiotic therapy by bedside inoculation of ascitIc fluid  10 mL into blood culture bottles. Ascitic fluid analysis is the gold standard for the confirmation of the diagnosis of spontaneous bacterial peritonitis.

# Treatment

## Medical Therapy

### Empiric treatment
- Ceftriaxone 1 g IV Q12H started as soon as possible after suspecting SBP.
- Severe pencillin allergy:
Moxifloxacin 400 mg IV/PO Q24H.
- Moxifloxacin 400 mg IV/PO Q24H.
- Renal dysfunction:
Patients with serum.creatinine > 1 mg/dl, BUN >30 mg/dl or total bilirubin >4 mg/dl should receive albumin(infusion25%) 1.5 g/kg on day 1 and 1 g/kg on day 3. including the standard antibiotic therapy.
- Patients with serum.creatinine > 1 mg/dl, BUN >30 mg/dl or total bilirubin >4 mg/dl should receive albumin(infusion25%) 1.5 g/kg on day 1 and 1 g/kg on day 3. including the standard antibiotic therapy.

## Prevention
The AASLD guidelines suggest using long term antibiotic prophylaxis in patients with: Ascitic fluid total protein less than 1.5 g/dL and with at least one of the following: Serum creatinine greater than or equal to 1.2 mg/dL, Blood urea nitrogen greater than or equal to 25 mg/dL, serum sodium less than or equal to 130 mEq/L, or Child-Turcotte-Pugh greater than or equal to 9 points (with bilirubin greater than or equal to 3 mg/dL). Daily oral norfloxacin in patients with more advanced liver disease has shown to  prevent the development of spontaneous bacterial peritonitis and hepatorenal syndrome and improved survival rates at 3 months. Norfloxacin also reduced SBP recurrence rates from 68% to 20%.

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