Spontaneous Bacterial Peritonitis in Decompensated Liver Cirrhosis: Comparison
Please note this is a comparison between Version 1 by Chien-Hao Huang and Version 2 by Lindsay Dong.

Spontaneous bacterial peritonitis (SBP) is defined as a bacterial infection of the ascitic fluid without a surgically treatable intra-abdominal infection source. SBP is a common, severe complication in cirrhosis patients with ascites, and if left untreated, in-hospital mortality may exceed 90%. However, the incidence of SBP has been lowered to approx. 20% through early diagnosis and antibiotic therapy. There are three types of SBP. Bacterial translocation from the gastrointestinal tract is the most common source of SBP. Distinguishing SBP from secondary bacterial peritonitis is essential because the conditions require different therapeutic strategies. The standard treatment for SBP is prompt broad-spectrum antibiotic administration and should be tailored according to community-acquired SBP, healthcare-associated or nosocomial SBP infections, and local resistance profile. Albumin supplementation, especially in patients with renal impairment, is also beneficial. Selective intestinal decontamination is associated with a reduced risk of bacterial infection and mortality in the high-risk group.

  • spontaneous bacterial peritonitis
  • liver cirrhosis
  • culture-negative neutrophilic ascites
  • monomicrobial non-neutrocytic bacterascites
  • bacterial translocation
  • ascites fluid
  • Gram-negative bacilli
  • Gram-positive cocci
  • antibiotic prophylaxis

1. Introduction

Cirrhotic patients have an altered defense against bacteria associated with reduced bacterial clearance [1]. This immune defect facilitates bacterial translocation induced by increased intestinal permeability and gut bacterial overgrowth [2]. Therefore, bacterial infection is either present on admission or develops during hospitalization in about 30% of patients with cirrhosis [3], and the most common form of these infections is spontaneous bacterial peritonitis (SBP) [3].
SBP is a severe complication in cirrhosis patients with ascites [4]. Ascites is mainly transudative fluid with poor opsonic activity, which provides a favorable environment for growth of bacteria. The prevalence of SBP is 1.5–3.5% among outpatients and 10–30% among hospitalized patients [5]. When first reported, in-hospital mortality from an episode of SBP exceeded 90%; however, this rate has been lowered to approximately 20% through early diagnosis and prompt antibiotic therapy [6].
SBP is diagnosed upon positive ascites culture and/or absolute neutrophil count (polymorphonuclear cell or PMN) within ascites fluid (AF) of ≧250 cells/mm3 [7][8][7,8]. Diagnosis is distinct from secondary peritonitis and hence is made in the absence of an intra-abdominal source of infection or other causes of an elevated ascites neutrophil count, such as hemorrhage, pancreatitis, peritoneal tuberculosis, and carcinomatosis [7], or an evident intra-abdominal, surgically treatable source [9][10][9,10].
There are three types of SBP (Table 1): (1) classic SBP; polymorphonuclear cell (PMN, also referred to as neutrophils) count in ascitic fluid is ≥250 cells/mm3 and positive ascites culture; (2) culture-negative neutrophilic ascites (CNNA), ascites with a PMN count of ≥250 cells/mm3 but with negative ascitic fluid culture; (3) monomicrobial non-neutrocytic bacterascites (MNB), PMN not elevated in ascites, but culture is positive.
Table 1.
 Three types of SBP.
Ascites Fluid Classic SBP CNNA 1 MNB 2
PMN count (cells/mm3) ≥250 ≥250 <250
Ascites culture positive negative positive
1 CNNA: culture-negative neutrophilic ascites; 2 MNB: monomicrobial non-neutrocytic bacterascites.

2. Pathogenesis

Mechanisms that may be involved in the pathogenesis of SBP are shown in Figure 1.
Figure 1.
 Mechanisms involved in the pathogenesis of SBP.

2.1. Gut Dysbiosis

One of the early stages in the development of SBP is the disturbance of gut flora leading to bacterial overgrowth and extra-intestinal dissemination of gut microorganisms [11][21]. Edema of the small intestine and ascending colon alters tight junction integrity and increases intestinal permeability, thus predisposing the patient to bacterial overgrowth in the presence of cirrhosis [11][21]. Altered small intestinal motility, presence of hypochlorhydria due to the use of proton pump inhibitors, and immunosuppression therapies commonly used during cirrhosis may also contribute to bacterial overgrowth.

2.2. Bacterial Translocation

Another important step following bacterial overgrowth is the translocation of enteric bacteria to extraintestinal sites, such as the mesenteric lymph nodes (MLN), which drain lymph from the gut [11][21]. Bacterial translocation (BT) has been defined as culture-positive MLN [12][22] and is culture-negative in healthy experimental animals without cirrhosis [12][22] but culture pathogenic bacteria in 78.1% of animals with cirrhosis and ascites [11][21]. The fact that SBP is monomicrobial implies that there are “filters” between polymicrobial intestinal sources and the ascitic fluid [11][21]. The first filter is the gut mucosa itself, and the second filter is the MLN [11][21]. If these MLN fail to sequester and destroy the bacteria, the pathogens can move from the mesenteric lymphatic system to systemic circulation and then percolate through the liver and extravasate across Glisson’s capsule to enter the ascitic fluid [13][23].

2.3. Impaired Host Defense System

Conversely, the host defense system also plays an important role in SBP pathogenesis. Once a microorganism enters the ascitic fluid, a battle ensues between the invading bacteria and the host’s immune system. Peritoneal macrophages are the first line of defense in the peritoneal cavity [14][15][26,27]. If these phagocytes fail to eradicate the invading microorganism, the complement system is activated, and cytokines are released [16][28]. Polymorphonuclear leukocytes (PMNs) then enter the peritoneum to eliminate the foreign bacteria. However, cirrhotic patients are known to have impairment in neutrophil and reticuloendothelial function [17][18][29,30]. In addition, many cirrhotic patients with ascites have a complement or opsonin deficiency [19][31]. The opsonic activity of ascitic fluid parallels the ascitic fluid total protein concentration [20][32]. Since opsonins are required by phagocytic cells to eliminate the offending microorganisms, cirrhotic patients with an ascitic fluid protein concentration of less than or equal to (≦) 1 g/dL are 10-times more likely to develop SBP during hospitalization than those with a protein concentration greater than (>) 1 g/dL [19][31].

3. Bacteriology

Bacterial translocation (BT) from the GI tract is the most common source of SBP. However, especially in nosocomial SBP, other sources, such as transient bacteremia due to invasive procedures, can also lead to SBP [21][33]. The bacteriology of SBP can be classified into Gram-negative bacilli, Gram-positive cocci, multidrug-resistant microorganisms, and anaerobes by bacterial spectrum, and classified into community acquired (CA), healthcare-associated (HCA), and nosocomial (hospital-acquired) infections by facilities. Two thirds (66.7%) of SBP cases are caused by Gram-negative bacilli (GNB) from BT, almost exclusively Enterobacteriaceae, and occur independently from the site of acquisition [3][22][3,19]Escherichia coli (E. coli) is the most frequently isolated pathogen (46–70%) [3][23][3,34], followed by Streptococcus pneumoniae (18–19%) and Klebsiella (9–13%) [22][23][19,34].  On the other hand, Gram-positive organisms accounted for less than one third (33.3%) of SBP and were predominated by Streptococcus (60%) and Staphylococcus aureus (40%) [22][24][19,35]. The emergence of multidrug-resistant (MDR) microorganisms, such as extended-spectrum β-lactamase (ESBL)-producing GNB and enterococci [25][40], fluroquinolone-resistant (QR) GNB [26][41], cefoxitin/methicillin-resistant Staphylococcus aureus (MRSA) [27][11], vancomycin-resistant enterococcus (VRE), and other resistant microorganisms [25][40] have altered prior conceptions toward SBP bacteriology and treatment [28][42].  Although gut floras are responsible for the majority of SBP cases, anaerobes appear to be rare, presumably due to the high oxygen content of the intestinal wall and AF, as well as because of the relative inability of anaerobes to translocate across the intestinal mucosa [29][30][46,47].

4. Diagnosis

Spontaneous bacterial peritonitis (SBP) should be suspected in patients with cirrhosis who develop signs or symptoms, such as fever (69%), abdominal pain (59%), altered mental status (54%), abdominal tenderness (49%), diarrhea (32%), ileus (30%), hypotension/shock (21%), or hypothermia (17%) [29][46]. However, 10% of cases show no signs or symptoms, partly because a large volume of ascites prevents contact of the visceral and parietal peritoneal surfaces to elicit the spinal reflux that cause abdominal rigidity [29][46].

A diagnostic paracentesis should be performed in all patients with cirrhosis and ascites who require emergency room care or hospitalization, who demonstrate or report signs/symptoms mentioned above in the clinical presentations, or who present gastrointestinal bleeding, in order to confirm evidence of SBP [31][49]. However, low clinical suspicion for SBP does not preclude the necessity for paracentesis, since 10% of cases have no signs or symptoms [29][46]

Ascitic fluid tests should include cell count with a differential, Gram stain, culture, total protein, and albumin to calculate the serum-ascites albumin gradient (SAAG), if not already known [27][11]. When the diagnosis of cirrhosis is not definite, an ascites SAAG greater than or equal to (≧) 1.1 g/dl is ascribed to portal hypertension with approximately 97% accuracy [31][49]. Total ascitic fluid protein concentration should be measured to assess the risk of SBP since patients suffering from ascites with a total protein concentration lower than (<) 1.5 g/dL are at increased risk of SBP [7].

A diagnosis of (1) classic SBP is made if PMN count in the ascitic fluid is ≥250 cells/mm3, culture results are positive, and secondary causes of peritonitis are excluded [7][31][7,49]. A potential source of error in PMN count is hemorrhage into the ascitic fluid, such as with traumatic paracentesis, which can cause both red and white blood cells to enter the ascites. A corrected PMN count should be calculated if there are bloody ascites by subtracting one PMN from the absolute PMN count for every 250 red cells/mm3 [32][55]. Distinguishing SBP from secondary bacterial peritonitis is essential because the conditions require different therapeutic strategies. Mortality from SBP can be as high as 85% if a patient undergoes an unnecessary exploratory laparotomy [33][57], while mortality of secondary bacterial peritonitis can exceed 80% if treatment consists of antibiotics without surgical intervention [9].

5. Treatment

The standard treatment for SBP is prompt broad-spectrum antibiotic administration and albumin supplementation, especially in patients with renal impairment (RI) [34][54].

5.1. Antibiotic Therapy

If SBP is suspected, antibiotic therapy must be initiated immediately after AF and culture to reduce complications and mortality [7]. Potentially nephrotoxic antibiotics (i.e., aminoglycosides) should be avoided [35][80] since patients with SBP are highly sensitive to aminoglycosides-related nephrotoxicity and fatal renal failure is common even at sub-toxic doses [29][46]. Two decades ago, most cases of SBP were attributed to third generation cephalosporin-sensitive Enterobacteriaceae. Now, risk factors, such as repeated hospitalizations, invasive procedures, and frequent exposure to antibiotics either as prophylaxis or as treatment [3], have led to the development of infections caused by MDR microorganisms. Bacterial resistance carries a 3.87-fold relative increased risk of mortality in patients with SBP [21][33]. Particularly, nosocomial SBP has been associated with multi-drug resistance (HR = 4.43) and poor outcome (50% in-hospital mortality). One prospective study demonstrated that failure of recommended empirical antibiotic regimens can have a negative impact on mortality [36][81]. Therefore, it is important to distinguish community-acquired SBP from healthcare-associated and nosocomial SBP, as well as consider the severity of infection and local resistance profile before implementing antibiotic therapy [34][54] (Figure 2). Subsequently, de-escalation according to bacterial susceptibility based on positive culture is recommended to minimize resistance selection pressure.
Figure 2.
 Recommended antibiotic treatment strategy for SBP since 2018.

5.2. Albumin Supplement in Patients with Renal Impairment

5.3. Albumin Supplement in Patients with Renal Impairment

The administration of albumin (given 1.5 g/kg at diagnosis and 1 g/kg on day 3, maximum 100 g) is recommended in patients with SBP [37][97], especially in those with serum creatinine of >1 mg/dL, blood urea nitrogen of >30 mg/dL, or total bilirubin of >4 mg/dL [38][98]. In one meta-analysis of four RCTs (288 patients), albumin infusion prevented renal impairment and reduced mortality among patients with SBP [39][99].

5.3. Discontinue NSBB in Patients with SBP

5.4. Discontinue NSBB in Patients with SBP

Given that NSBB may interfere with systemic hemodynamics, effect on outcome was examined in a retrospective study of 607 patients with cirrhosis and ascites [40][100]. Once SBP developed, patients receiving NSBB suffered lower transplant-free survival (HR = 1.58; 95% CI: 1.098–2.274). In addition, a higher proportion of patients on NSBBs suffered hepatorenal syndrome (24% vs. 11%, p = 0.027) [40][100]. Therefore, NSBB should be discontinued after a diagnosis of SBP.

5.4. Other Novel Therapeutic Strategies

5.5. Other Novel Therapeutic Strategies

The emergence of MDR bacteria may require novel therapeutic strategies that do not involve the use of antibiotics. One potential approach is human amniotic mesenchymal stromal cell (hA-MSC) treatment. One in vitro study found hA-MSCs added to ascites fluid could significantly reduce the proliferation of both bacterial strains at 24 h as well as affect M1/M2 polarization, C3a complement protein, and ficolin 3 concentrations during the course of infection in a strain-dependent manner [41][101]. Validation of an in vivo model is warranted for future hA-MSC application in treating ascites infected with carbapenem-resistant bacteria [41][101].

6. Conclusions

Spontaneous bacterial peritonitis (SBP) is a severe complication in cirrhosis patients with ascites. Clinical awareness, prompt diagnosis by exclusion of secondary bacterial peritonitis, and immediate treatment are necessary to reduce mortality and morbidity in this patient group. However, the emergence of multidrug-resistant (MDR) microorganisms have changed theour understanding of SBP bacteriology and treatment. Antibiotic therapy specific to either community-acquired or nosocomial/healthcare-acquired SBP is ideal, while liver transplantation remains the definitive treatment following SBP. Prevention of SBP recurrence by antibiotic prophylaxis while patients wait for a liver transplant is therefore an important clinical issue. The poorly absorbed antibiotic rifaximin may be effective for both primary and secondary SBP prophylaxis, but additional prospective studies are required. Further development of non-antibiotic strategies based on pathogenic mechanisms are also urgently needed. Blind studies that avoid post-randomization dropout and consider clinically relevant outcomes, such as mortality, health-related quality of life, and decompensation events, are desired for future research. There are three types of SBP. Bacterial translocation from the GI tract is the most common source of SBP. Therefore, two thirds of SBP cases were caused by Gram-negative bacilli, almost exclusively Enterobacteriaceae. Escherichia coli (E. coli) is the most frequently isolated pathogen. However, a trend of Gram-positive cocci (GPC)-associated SBP has been demonstrated in recent years, representing a changing paradigm in the known bacteriology of SBP, especially in nosocomial SBP; other sources, such as transient bacteremia due to invasive procedures, can also lead to SBP Gram-positive cocci (GPC), such as Staphylococcus, Enterococcus, as well as multi-resistant bacteria have become common pathogens and have changed the conventional approach to treatment of SBP. Healthcare-associated and nosocomial SBP infections should prompt greater vigilance and consideration for alternative antibiotic coverage. Acid suppressive and beta-adrenergic antagonist therapies are strongly associated with SBP in at-risk individuals. A diagnostic paracentesis should be performed in all patients with cirrhosis and ascites who require emergency room care or hospitalization, who demonstrate or report signs/symptoms mentioned above in the clinical presentations, or who present gastrointestinal bleeding, in order to confirm evidence of SBP. Distinguishing SBP from secondary bacterial peritonitis is essential because the conditions require different therapeutic strategies. Since SBP may be regarded as the final clinical stage of liver cirrhosis [42][63], one-year overall mortality rates range from 53.9 [43][76] to 78% [43][44][45][64,76,79]. Liver transplantation should be seriously considered for SBP survivors who are good candidates for transplantation. The standard treatment for SBP is prompt broad-spectrum antibiotic administration and should be tailored according to either CAP or hospital-acquired, or to local resistance profiles. Albumin supplementation, especially in patients with renal impairment (RI) is also beneficial. Not all patients with cirrhosis and ascites require antibiotic prophylaxis, sometimes referred to as selective intestinal decontamination (SID). SID is associated with a reduced risk of bacterial infection [46][47][48][49][37,102,103,104] and mortality.

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