Anatomy

The peritoneum is the largest and most complex serous membrane in the body. It forms a closed sac (ie, coelom) by lining the interior surfaces of the abdominal wall (anterior and lateral), by forming the boundary to the retroperitoneum (posterior), by covering the extraperitoneal structures in the pelvis (inferior), and by covering the undersurface of the diaphragm (superior). This parietal layer of the peritoneum reflects onto the abdominal visceral organs to form the visceral peritoneum. It thereby creates a potential space between the 2 layers (ie, the peritoneal cavity). The peritoneum consists of a single layer of flattened mesothelial cells over loose areolar tissue. The loose connective tissue layer contains a rich network of vascular and lymphatic capillaries, nerve endings, and immune-competent cells, particularly lymphocytes and macrophages. The peritoneal surface cells are joined by junctional complexes, thus forming a dialyzing membrane that allows passage of fluid and certain small solutes. Pinocytotic activity of the mesothelial cells and phagocytosis by macrophages allow for clearance of macromolecules. Normally, the amount of peritoneal fluid present is less than 50 mL, and only small volumes are transferred across the considerable surface area in a steady state each day. The peritoneal fluid represents a plasma ultrafiltrate, with electrolyte and solute concentrations similar to that of neighboring interstitial spaces and a protein content of less than 30 g/L, mainly albumin. In addition, peritoneal fluid contains small numbers of desquamated mesothelial cells and various numbers and morphologies of migrating immune cells (reference range is < 300 cells/ L, predominantly of mononuclear morphology). The peritoneal cavity is divided incompletely into compartments by the mesenteric attachments and secondary retroperitonealization of certain visceral organs. A large peritoneal fold, the greater omentum, extends from the greater curvature of the stomach and the inferior aspect of the proximal duodenum downward over a variable distance to fold upon itself (with fusion of the adjacent layers) and ascends back to the taenia omentalis of the transverse colon. This peritoneal fold demonstrates a slightly different microscopic anatomy, with fenestrated surface epithelium and a large number of adipocytes, lymphocytes, and macrophages, and it functions as a fat storage location and a mobile immune organ. The compartmentalization of the peritoneal cavity, in conjunction with the greater omentum, influences the localization and spread of peritoneal inflammation and infections.

Pathophysiology
In peritonitis caused by bacteria, the physiologic response is determined by several factors, including the virulence of the contaminant, the size of the inoculum, the immune status and overall health of the host (eg, as indicated by the Acute Physiology and Chronic Health Evaluation II [APACHE II] score), and elements of the local environment, such as necrotic tissue, blood, or bile.[2] Intra-abdominal sepsis from a perforated viscus (ie, secondary peritonitis or suppurative peritonitis) results from direct spillage of luminal contents into the peritoneum (eg, perforated peptic ulcer, diverticulitis, appendicitis, iatrogenic perforation). With the spillage of the contents, gram-negative and anaerobic bacteria, including common gut flora, such as Escherichia coli and Klebsiella pneumoniae, enter the peritoneal cavity. Endotoxins produced by gram-negative bacteria lead to the release of cytokines that induce cellular and humoral cascades, resulting in cellular damage, septic shock, and multiple organ dysfunction syndrome (MODS). The mechanism for bacterial inoculation of ascites has been the subject of much debate since Harold Conn first recognized it in the 1960s. Enteric organisms have traditionally been isolated from more than 90% of infected ascites fluid in spontaneous bacterial peritonitis (SBP), suggesting that the GI tract is the source of bacterial contamination. The preponderance of enteric organisms, in combination with the presence of endotoxin in ascitic fluid and blood, once favored the argument that SBP was due to direct transmural migration of bacteria from an intestinal or hollow organ lumen, a phenomenon called bacterial

translocation. However, experimental evidence suggests that direct transmural migration of microorganisms might not be the cause of SBP. An alternative proposed mechanism for bacterial inoculation of ascites suggests a hematogenous source of the infecting organism in combination with an impaired immune defense system. Nonetheless, the exact mechanism of bacterial displacement from the GI tract into ascites fluid remains the source of much debate. A host of factors contributes to the formation of peritoneal inflammation and bacterial growth in the ascitic fluid. A key predisposing factor may be the intestinal bacterial overgrowth found in people with cirrhosis, mainly attributed to decreased intestinal transit time. Intestinal bacterial overgrowth, along with impaired phagocytic function, low serum and ascites complement levels, and decreased activity of the reticuloendothelial system, contributes to an increased number of microorganisms and decreased capacity to clear them from the bloodstream, resulting in their migration into and eventual proliferation within ascites fluid. Interestingly, adults with SBP typically have ascites, but most children with SBP do not have ascites. The reason for and mechanism behind this is the source of ongoing investigation.

Fibrinolysis
Alterations in fibrinolysis (through increased plasminogen activator inhibitor activity) and the production of fibrin exudates have an important role in peritonitis. The production of fibrin exudates is an important part of the host defense, but large numbers of bacteria may be sequestered within the fibrin matrix. This may retard systemic dissemination of intraperitoneal infection and may decrease early mortality rates from sepsis, but it also is integral to the development of residual infection and abscess formation. As the fibrin matrix matures, the bacteria within are protected from host clearance mechanisms. Whether fibrin ultimately results in containment or persistent infection may depend on the degree of peritoneal bacterial contamination. In animal studies of mixed bacterial peritonitis that examined the effects of systemic defibrinogenation and those of abdominal fibrin therapy, heavy peritoneal contamination uniformly led to severe peritonitis with early death (< 48 h) because of overwhelming sepsis.

Bacterial load
Bacterial load and the nature of the pathogen also play important roles. Some studies suggest that the number of bacteria present at the onset of abdominal infections is much higher than originally believed (approximately 2 108 CFU/mL, much higher than the 5 105 CFU/mL inocula routinely used for in vitro susceptibility testing). This bacterial load may overwhelm the local host defense.

Bacterial virulence
Bacterial virulence factors[3] that interfere with phagocytosis and with neutrophil-mediated bacterial killing mediate the persistence of infections and abscess formation. Among these virulence factors are capsule formation, facultative anaerobic growth, adhesion capabilities, and succinic acid production. Synergy between certain bacterial and fungal organisms may also play an important role in impairing the host's defense. One such synergy may exist between Bacteroides fragilis and gram-negative bacteria, particularly E coli (see the image below) ,where co-inoculation significantly increases bacterial proliferation and abscess formation.

Gram-negative Escherichia coli.

Enterococci
Enterococci may be important in enhancing the severity and persistence of peritoneal infections. In animal models of peritonitis with E coli and B fragilis, the systemic manifestations of the peritoneal infection and bacteremia rates were increased, as were bacterial concentrations in the peritoneal fluid and rate of abscess formation. Nevertheless, the role of Enterococcus organisms in uncomplicated intraabdominal infections remains unclear. Antibiotics that lack specific activity against Enterococcus are often used successfully in the therapy of peritonitis, and the organism is not often recovered as a blood-borne pathogen in intra-abdominal sepsis.

Fungi
The role of fungi in the formation of intra-abdominal abscesses is not fully understood. Some authors suggest that bacteria and fungi exist as nonsynergistic parallel infections with incomplete competition, allowing the survival of all organisms. In this setting, treatment of the bacterial infection alone may lead to an overgrowth of fungi, which may contribute to increased morbidity.

Abscess formation
Abscess formation occurs when the host defense is unable to eliminate the infecting agent and attempts to control the spread of this agent by compartmentalization. This process is aided by a combination of factors that share a common feature, ie, impairment of phagocytotic killing. Most animal and human studies suggest that abscess formation occurs only in the presence of abscess-potentiating agents. Although the nature and spectrum of these factors have not been studied exhaustively, certain fiber analogues (eg, bran) and the contents of autoclaved stool have been identified as abscess-potentiating agents. In animal models, these factors inhibit opsonization and phagocytotic killing by interference with complement activation.

Cytokines
The role of cytokines in mediation of the body's immune response and their role in the development of the systemic inflammatory response syndrome (SIRS) and multiple organ failure (MOF) have been a major focus of research over the past decade. Comparatively few data exist about the magnitude of the intraperitoneal/abscess cytokine response and implications for the host. Existing data suggest that bacterial peritonitis is associated with an immense intraperitoneal compartmentalized cytokine response. Higher levels of certain cytokines (ie, tumor necrosis factor-alpha [TNF-alpha], interleukin [IL]-6) have been associated with worse outcomes, as well as secondary (uncontrolled) activation of the systemic inflammatory cascade.