Causative agents vary significantly depending on the region, hospital size, season, and type of unit (neonatal, transplantation, oncology, or hemodialysis units).          
It should be noted that pathogenic organisms are identified in only around 50% to 70% of cases of sepsis. Where organisms are identified, bacteria (gram-positive and gram-negative) are identified as the causative organism in approximately 90% of cases, with gram-positive bacteria and fungal infections increasing in frequency.  Since the mid-1980s, the frequency of gram-positive sepsis (mainly caused by Staphloccus aureus, coagulase-negative staphylococci, enterococci, and streptococci) has surpassed that of gram-negative sepsis (mainly caused by Enterobacteriaceae, especially Escherichia coli and Klebsiella pneumoniae, and by Pseudomonas aeruginosa).     
In the majority of cases of sepsis arising in the community, the causative organisms will be sensitive, frequently endogenous bacteria. However, it should be acknowledged that resistance patterns of organisms continue to change and can differ greatly according to region. For example, in the large multicenter European study, >50% of S aureus isolates in ICU were methicillin-resistant (MRSA).  Over the last 2 decades, vancomycin-resistant enterococci (VREs) have emerged, with >10% of enterococci being VREs.  MRSA is increasingly prevalent in the community, with community-acquired MRSA presenting as a severe pneumonia, often with cavitation, in patients with a recent coryzal illness. Recently in the UK, sepsis has overtaken venous thromboembolism as the most common direct cause of maternal death. Following pregnancy, group A streptococci are the most common causative agent. 
Studies tend to broadly concur on the relative frequencies of sources of infection.   In the SOAP study, the respiratory tract accounted for 60%; the bloodstream 20%; abdomen 26%; skin 14%; and urinary system 12%.  The Surviving Sepsis Campaign observational study of over 15,000 patients showed slightly fewer patients with respiratory sources (44.4%), and a greater frequency of urosepsis (20.8%).  However, in 20% to 30% of patients, a definite source of infection is not found. 
The leading fungal pathogen causing sepsis has been identified as Candida.  In a European point-prevalence study, fungi were isolated from 17% of ICU patients with nosocomial infection.  Fungi are more prevalent as isolates in patients with secondary or tertiary peritonitis, with Candida identified in up to 20% of patients with GI tract perforation.  Risk factors include fecal soiling of the peritoneum, recurrent GI perforation, immunosuppressive therapy for neoplasm or in post-transplant patients, and the presence of inflammatory diseases. These patients carry a high risk of mortality. 
Sepsis is a syndrome comprising an immune system-mediated collection of physiologic responses to an infectious agent. Clinical signs such as fever, tachycardia, and hypotension are common but the clinical course depends on the type and resistance profile of the infectious organism, the site and size of the infecting insult, and the genetically determined or acquired properties of the host's immune system.
Pathogen entry and survival is facilitated by tissue contamination (surgery or infection), foreign body insertion (catheters), and immune status (immunosuppression). 
The innate immune system is activated by bacterial cell wall products, such as lipopolysaccharide, binding to host receptors, including Toll-like receptors (TLRs).   These are widely found on leukocytes and macrophages, and some types are found on endothelial cells.  At least 10 TLRs have been described in humans. These have specificity for different bacterial, fungal, or viral products, and genetic polymorphisms are associated with a predisposition to shock with gram-negative organisms. 
Activation of the innate immune system results in a complex series of cellular and humoral responses, each with amplification steps: 
Pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-alpha and interleukins 1 and 6 are released, which in turn activate immune cells.
Reactive oxygen species, nitric oxide (NO), proteases, and pore-forming molecules are released, which bring about bacterial killing. NO is responsible for vasodilatation and increased capillary permeability, and has been implicated in sepsis-induced mitochondrial dysfunction. 
The complement system is activated, and mediates activation of leukocytes, attracting them to the site of infection where they can directly attack the organism (phagocytes, cytotoxic T lymphocytes), identify it for attack by others (antigen-presenting cells, B lymphocytes), "remember" it in case of future infection (memory cells, B lymphocytes), and cause the increased production and chemotaxis of more T helper cells. 
The endothelium and coagulation system:
The vascular endothelium plays a major role in the host's defense to an invading organism, but also in the development of sepsis. Activated endothelium not only allows the adhesion and migration of stimulated immune cells, but becomes porous to large molecules such as proteins, resulting in the tissue edema.
Alterations in the coagulation systems include an increase in procoagulant factors, such as plasminogen activator inhibitor type I and tissue factor, and reduced circulating levels of natural anticoagulants, including antithrombin III and activated protein C (APC), which also carry anti-inflammatory and modulatory roles.  
Inflammation and organ dysfunction:
Through vasodilatation (causing reduced systemic vascular resistance) and increased capillary permeability (causing extravasation of plasma), sepsis results in relative and absolute reductions in circulating volume.
A number of factors combine to produce multiple organ dysfunctions. Relative and absolute hypovolemia are compounded by reduced left ventricular contractility to produce hypotension. Initially, through an increased heart rate, cardiac output increases to compensate and maintain perfusion pressures, but as this compensatory mechanism becomes exhausted, hypoperfusion, and shock may result.
Impaired tissue oxygen delivery is exacerbated by pericapillary edema. This means that oxygen has to diffuse a greater distance to reach target cells. There is a reduction of capillary diameter due to mural edema and the procoagulant state results in capillary microthrombus formation.
Additional contributing factors include disordered blood flow through capillary beds, resulting from a combination of shunting of blood through collateral channels and an increase in blood viscosity secondary to loss of red cell flexibility.  As a result, organs may become hypoxic, even though gross blood flow to an organ may increase. These abnormalities may lead to lactic acidosis, cellular dysfunction, and multiorgan failure. 
Cellular energy levels fall as metabolic activity begins to exceed production. However, cell death appears to be uncommon in sepsis, implying that cells shut down as part of the systemic response. This could explain why relatively few histologic changes are found at autopsy, and the eventual rapid resolution of severe symptoms, such as complete anuria and hypotension, once the systemic inflammation resolves.