Spontaneous bacterial peritonitis overview

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Shivani Chaparala M.B.B.S [2]

Overview

Spontaneous bacterial peritonitis (SBP) is a form of peritonitis that occurs almost exclusively in patients with advanced cirrhosis as a manifestation of severe derangement of hepatic function. It occurs in 10-30% of hospitalized patients with ascites. SBP has also been described to occur in various other clinical settings, such as nephrotic syndrome or heart failure, tuberculous infection, continuous ambulatory peritoneal dialysis for chronic renal failure. SBP has been 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 like Escherichia coli. Selective Intestinal Decontamination ( SID ) with fluorinated quinolones, to suppress the gram-negative intestinal flora has been known to reduce the incidence of SBP.SBP is a result of culmination of the inability of the gut to contain bacteria and failure of the immune system to eradicate the organisms once they have escaped. Clinical signs and symptoms do not distinguish secondary from spontaneous peritonitis. AF analysis is helpful in differentiating SBP from secondary peritonitis which is a surgically treatable source of infection. The symptoms observed most frequently are Fever and abdominal pain. Because of this lack of specificity and sensitivity of clinical signs and symptoms, instances of unexplained deterioration in patients with cirrhosis should lead to a diagnostic paracentesis. Once diagnosed, patients with SBP should receive prompt empiric antibiotic treatment ( Cephalosporins) without waiting for the AF culture results because a delay in antibiotic treatment may result in a significant and potentially fatal deterioration in the clinical status of the patient. Prompt diagnosis and treatment maximize survival among patients with AF infections. Those patients who survive an episode of SBP are at high risk of recurrence. Patients with newly developed abdominal pain and/or temperature >100F are more prone to progress to SBP and therefore should receive empiric antibiotic treatment as stated for SBP. Currently, there are essentially no deaths as a result of SBP, provided it is detected and treated before the development of shock or renal failure, which are the most frequent complications of this disease.

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 appears to be 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 by IgG and/or Complement components and then engulfing and killing by circulating neutrophils. But in cirrhosis, as stated above several abnormalities have been described including : 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, 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 have the 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 AF.
• Ascitic fluid defense mechanisms:
  • Decreased local AF opsonic activity: The arrival of bacteria to the AF does not guarantee that infection will develop. Cirrhotic AF is capable of humoral self-defense, mainly on the basis of effectiveness of the complement system, patients with adequate activity of this vital bactericidal system usually do not develop AF bacterial infections, patients with AF C3 < 1g/dl and a protein level < 1g/dl have an increased predisposition to SBP, the complement levels may be deficient because of increased consumption of these components or because of impaired synthesis, if the complement levels are adequate to effectively kill the bacteria, infection will not develop, if complement levels are consumed and depleted, killing may be ineffective, frequent colonization of AF by bacteria decreases its antimicrobial ability and can eventually lead to the development of infection bacteremia/ endotoxemia leads to activation of cytokine cascade and some of these effector molecules and cytokines that help kill the bacteria have undesired side effects. NO and TNF are important mediators of the further vasodilation and renal failure that too often accompany SBP. Iatrogenic and treatment related factors like PPI, and increased use of invasive procedures and catheters in patients with Cirrhosis and ascites. Other compelling factors like malnutrition and alcohol drinking also predispose to SBP.

Causes

Spontaneous bacterial peritonitis is often 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 sp in 20% cases with enterococcus accounting for 5% of the cases. Staphylococcus aureus and Streptococcus salivarius are less frequent causes. Poly-microbial infection is mostly because of Iatrogenic cause (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 in whom a diseased liver and altered portal circulation result in a 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 has typically been described 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.In patients with ascites both sexes are affected equally.

Risk Factors

Common risk factors in cirrhotic patients with ascites include: Low protein level in ascitic fluid (<1 g/dL), Upper GI bleeding, Low complement concentration (complement 3) in ascitic fluid, Renal failure, Elevated serum bilirubin level (>4 mg/dL), Use of Proton pump inhibitors (PPI) in cirrhotic patients pose an increased risk, Child-Pugh stage C, MELD≥22.

Screening

There is no definitive screening test for spontaneous bacterial peritonitis. According to European Journal of Gastroenterology & Hematology a positive Multistix8SG rapid urine screening test result in ascitic fluid in cirrhotic patients with ascites appears to be an indication for antibiotic treatment. 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

Natural History

Spontaneous bacterial peritonitis (SBP) is the most frequent and severe infectious complication in patients with cirrhosis and ascites, composing one-third of all bacterial infections and is more common than urinary tract infections and pneumonia in this population. SBP is a potentially fatal yet reversible cause of deterioration in patients with advanced cirrhosis. SBP usually occurs at the time of greatest ascites volume, but can be present in settings where the fluid is clinically undetectable. SBP in the absence of ascites is extremely unlikely. The symptoms of Spontaneous bacterial peritonitis (SBP) usually develop in the age group 41–50 years, with a mean of 49 years and start with symptoms such as Fever, abdominal pain, mental status changes, ileus and worsening of pre-existing ascites. The symptoms of SBP typically develop on exposure to various risk factors in patients with decompensated liver disease. All patients with cirrhosis and ascites with worsening clinical appearance and gastrointestinal bleeding should undergo diagnostic paracentesis to rule out SBP. Empirical antibiotic therapy is recommended after paracentesis if suspicion for infection exists. Without treatment, the patient will develop symptoms of renal failure and shock which will eventually lead to death of the patient. Delaying treatment until the culture results are available are also known to result in death of the patient from overwhelming sepsis. Prophylaxis is safe and should be limited to high-risk settings. Mortality rates in SBP have declined dramatically in the recent years, largely due to earlier detection and improved therapy. Survivors of a prior episode of SBP are at increased risk for recurrence.. Approximately half of all deaths in patients with SBP occur after resolution of the infection and are from gastrointestinal hemorrhage or liver or renal failure. The presence of renal insufficiency is the strongest independent prognostic indicator.

Complications

• Complications that can develop as a result of SBP are:
  • Rapidly progressive impairment in systemic hemodynamics, leading to severe renal and hepatic failure.
  • Aggravation of portal hypertension.
  • Gastrointestinal bleeding.
  • Ileus.
  • Shock, Sepsis.
  • Encephalopathy, and
  • Death.

• Complications that can develop as a result of the treatment of SBP are:
  • SBP resolves with antibiotics in approximately 90% of patients.
  • Failure of antibiotic therapy is usually due to resistant bacteria or secondary bacterial peritonitis.
  • Once secondary bacterial peritonitis has been excluded, antibiotics should be changed according to in vitro susceptibility of isolated organisms, or modified to alternative empiric broad spectrum agents.
  • Prolonged antibiotic prophylaxis (primary or secondary) has led to the emergence of Gram-negative bacteria resistant to quinolones and trimethoprim/sulfamethoxazole.
  • In addition, there is an increased likelihood of infections from Gram-positive bacteria in patients who have received long-term SBP prophylaxis.
  • This underlines the need to restrict the use of prophylactic antibiotics to patients with the greatest risk of SBP.

Prognosis

Spontaneous bacterial peritonitis (SBP) is the most frequent infection in patients with cirrhosis. Once SBP develops, the prognosis of cirrhosis worsens. The presence of renal insufficiency is the strongest independent prognostic indicator, but the presence of peripheral leukocytosis, older age, higher Child-Pugh score, and the presence of an ileus have also been shown to predict inpatient mortality. Patients with hospital versus community-acquired SBP also appear to have a higher mortality. It is associated with high mortality at admission and its occurrence alters the natural course with a high 1 year mortality. The median mortality during first episode of SBP has been reported to be around 30% (range 10-50%) and in such patients the median mortality at 1 year is reported to be about 66% (range 30-90%). Therefore, once a patient recovers from the 1st episode of SBP, he is advised to undergo liver transplant. However, the mortality associated with 1st episode of SBP, has reduced considerably during the last decade due to the awareness and identification of high risk cirrhotics likely to develop SBP, its early diagnosis and effective antibiotic strategy. The best predictor of survival is resolution of infection which is best influenced by effective first-line therapy since other factors such as Age, associated co-morbidities, site of acquisition of infection ( Community vs Nosocomial), severity of liver-dysfunction and genetic risk factors are not modifiable. Recurrence of SBP is high. Therefore primary and secondary prophylaxis using appropriate antibiotics is recommended. However, in such patients, recent recognition of SBP with multidrug resistant bacteria has been associated with very high mortality and they are difficult to treat due to the presence of bacteria nonresponsive to community used antibiotics.

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 (Level A1).
• Ascitic fluid cell analysis
  • The diagnosis of SBP is based on neutrophil count in ascitic fluid of >250/mm³ as determined by microscopy (Level A1).
  • 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 (Level A1).
  • Blood cultures should be performed in all patients with suspected SBP before starting antibiotic treatment (Level A1).
  • 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 (Level A1).
  • 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 (Level B1).

Diagnostic Criteria

The diagnosis of SBP was based on two of the following criteria from guidelines:
(1) abdominal pain and/or hyperthermia, and/or abdominal and rebound tenderness (excluding secondary peritonitis);
(2) ascitic fluid PMN count 250 cells/mm³
(3) 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

Patients with SBP may have one of the following:. Local symptoms and/or signs of peritonitis: abdominal pain, abdominal tenderness, vomiting, diarrhea, ileum, signs of systemic inflammation: hyper or hypothermia, chills, altered white blood cell count, tachycardia, and/or tachypnea; worsening of liver function; hepatic encephalopathy; shock; renal failure; and gastrointestinal bleeding. However, it is important to note that SBP may be asymptomatic, particularly in outpatients.

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 pain tenderness and altered mental status are the routine physical findings. Peritoneal signs are uncommonly encountered on examination. The patients are ill-appearing and are often noticed lying quietly supine, on the bed with the knees flexed and with frequent limited intercostal respirations because any motion intensifies the abdominal pain. The following local abdominal signs of peritonitis are usually classic for secondary peritonitis: Guarding of the abdominal musculature on palpation, pain produced on coughing, Tenderness on palpation or percussion, Rebound tenderness. Diminished or absent bowel sounds (Ileus), Abdominal distension- ascites with shifting dullness, Icterus are generally seen in SBP.

Laboratory Findings

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

Treatment

Medical Therapy

Empiric treatment

• Ceftriaxone 1 g IV Q12H
• Severe pencillin allergy:
  • 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 also receive Albumin (25%) 1.5 g/kg on day 1 and 1 g/kg on day 3.

Prevention

The AASLD guidelines suggest using long-term antibiotic prophylaxis in patients who have: Ascitic fluid total protein less than 1.5 g/dL and 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 prevented the development of spontaneous bacterial peritonitis and hepatorenal syndrome and improved survival at 3 months. Norfloxacin also reduced SBP recurrence rates from 68% to 20%

References

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