Introduction
Recently WHO has recognized sepsis as a Global Health Priority [
1]. The true burden of sepsis remains unknown. The current estimates of 30 million episodes and 6 million deaths per year come from a systematic review that extrapolated from published national or local population estimates to the global population [
2]. This estimate is based on data on hospital-treated sepsis in high-income countries and does not include statistics from the low- and middle-income countries (LMICs) where 87% of the world’s population lives. This lack of data is compounded by the fact that sepsis is treated as a “garbage code” in the Global Burden of Disease statistics, where most deaths due to sepsis are classified as being caused by the underlying infection [
3]. Sepsis is associated with a mortality rate of 25–30% and mortality due to septic shock is 50–85% [
4,
5]. Empiric antimicrobial therapy is the cornerstone of the treatment [
6]. Current guidelines recommend starting antibiotic therapy within one hour of identification of septic shock [
7]. Every hour delay is associated with a 6% rise in mortality [
8,
9]. There are no prospective data that early broad-spectrum antibiotic therapy reduces mortality in severe sepsis, but prompt initiation of antimicrobial therapy remains important for suspected infections [
10]. If the pathogen is resistant to antibiotic, early or late initiation of antibiotic therapy cannot improve the outcome. Inappropriateness of empirical antibiotic therapy can contribute to high level of mortality [
11]. The crisis emerges of antibiotic resistance for microbial pathogens [
12‐
14]. As a result, the treatment of sepsis becomes increasingly difficult. Numerous mechanisms of bacterial resistance are revealed and described in detail [
15‐
18]. At the same time, some other causes of decreased effectiveness of antibacterial therapy in sepsis are less reported.
Human innate immunity in sepsis
The pathogenesis of the sepsis syndrome is dependent on activation of the innate immune response. Innate immunity plays a direct role in the development of sepsis and is also crucial for the activation and modulation of later antigen-specific adaptive immune responses. The clinical manifestations of sepsis and the systemic inflammatory response syndrome (SIRS) can be attributed to components of the innate immune response [
19].
At present at least five lines of innate immunity defense against sepsis-causing bacteria are identified. Bacteria usually first enter host tissues. If the tissue is injured and a hemorrhage is available, infection confronts blood clot and complement as the first line of host defense; otherwise antigen-presenting cells such as monocytes/macrophages play major roles as sentinels for first line alerts or as mediators that shape the adaptive immune response [
20]. Once activated by microbial products, macrophages acquire microbicidal competence that usually leads to effective immunity [
21]. However, several bacterial pathogens, first of all, sepsis-causing bacteria, have evolved mechanisms of inhibiting macrophages and host immune response.
Bacteria enter the bloodstream when they penetrate tissue barrier. In the bloodstream erythrocytes are the main bactericidal cells [
22]. Entering the bloodstream, bacteria move with blood flow and become electrically charged because of the phenomenon of triboelectric (friction) charging. Bacterial cell wall is a negatively charged structure. The electro negativity (zeta (ζ) electrokinetic potential) of bacteria depends on bacterial physiological state whereas the triboelectric charge of bacteria is determined by the friction of bacteria with blood plasma, vessel walls and other cells. The triboelectric charge of bacteria considerably exceeds bacterial zeta potential and interacts with any nearby electric charge that is strong enough. Erythrocytes are the cells with very strong electric charge. Erythrocyte membrane properties (density, elasticity, deformability, flexibility, frictional resistance, etc.) and biconcave shape provide strong triboelectric charging during rubbing to other cells and vessel walls. The blood flow induces additional charging of erythrocytes dependent on the speed, kind (laminar, turbulent) of blood flow and blood viscosity. Triboelectrically charged erythrocyte membrane immediately attracts and fixes nearby floating bacteria. Microbial proteases and pathogen-associated molecular patterns irritate erythrocyte membrane and provoke rapid release of reactive oxygen species from hemoglobin to the surface of erythrocytes. The majority of bacteria are sensitive to oxidation and released reactive oxygen species (peroxides, superoxide, hydroxyl radical, singlet oxygen, etc.) rapidly kill bacteria on the surface of erythrocytes. As a result, bacteria are killed in the bloodstream rapidly: erythrocytes first attract and keep bacteria by electric charge, then bacteria on the surface of erythrocytes cause immediate release of oxygen from oxyhemoglobin to the surface of erythrocytes and finally released oxygen oxidizes and kills bacteria [
22,
23]. Killed bacteria lose both triboelectric charge and zeta potential and are washed from erythrocyte surface out into blood plasma. Passing the liver and the spleen, killed bacteria are caught and digested by Kuppfer cells of the liver and lymphoid tissue macrophages of the spleen [
24,
25].
Oxidation of bacteria on the surface of erythrocytes kills the majority of bacterial species, but sepsis-causing bacteria have evolved numerous mechanisms against oxidation that provide their survival in the bloodstream. These mechanisms are highly effective and even additional saturation of arterial blood by hyperbaric oxygen does not provide killing of sepsis-causing bacteria in the bloodstream.
The next line of host defense is intravascular coagulation that may cause disseminated intravascular coagulation. In the case of host survival, phagocytosis of hematogeniously disseminated bacteria in the tissues is the last line of innate immunity defense [
24,
25].
Planktonic bacteria in the tissues
Bacterial cell exhibit two types of growth mode: planktonic cell and sessile aggregate which is known as the biofilm. Antoni van Leeuwenhoek in 1673 described planktonic microorganisms. Much of the knowledge of microbiology is based on studying free-floating bacteria.
Sepsis-causing planktonic bacteria usually rapidly proliferate in the tissues. They exhibit different stages of population development that may include: a. lag phase; b. logarithmic (exponential) phase; c. stationary phase (host defense starts to inhibit bacterial growth); d. death phase (the host defense against the pathogen if effective), capsule production and transition to biofilm growth (the host defense against the pathogen is relatively effective) or the phase of active proliferation (the host defense is overcome by the pathogen).
Planktonic bacteria in the tissues are free-living organisms: they float in the tissue liquids. They are relatively hydrophilic, their capsule (polysaccharide glycocalyx) is thin and does not interfere bacterial cell metabolic exchange with the tissue liquids. Sepsis-causing planktonic bacteria may be either single-celled (
Escherichia coli, Acinetobacter baumanii, Salmonella enterica, Shigella dysenteriae, Pseudomonas aeruginosa, Proteus mirabilis, Serratia marcescens and others) or two- and multiple-celled (
Neisseria meningitides, Klebsiella pneumonia, Streptococcus pneumonia, Staphylococcus aureus and others) organisms. The latter are not single-celled even in laboratory cultures. The majority of single-celled planktonic bacteria are motile whereas two- and multiple-celled pathogens are not motile and float passively with the liquid flow. In the bloodstream motile bacteria are more triboelectrically charged than non motile microbes. Planktonic bacteria with active metabolism, growth and proliferation are most sensitive to antimicrobials [
51].
Planktonic bacteria cause acute inflammation in the tissues. They stimulate vascular leakage and exudate production that provide aquatic media for their rapid proliferation and dissemination [
52]. Early adequate bactericidal therapy may eradicate infection. The use of bacteriostatic drugs does not clear bacterial population and may have the same results as the use of bactericidal antimicrobials in bacteriostatic doses. Combined use of bactericidal and bacteriostatic antimicrobials is often counter indicated because in the presence of a bactericidal drug that alone is capable of clearing a bacterial population, the addition of a bacteriostatic drug may result in a decrease in killing rates and an increase in the number of survived bacteria. For example, combinations of 30S protein synthesis and cell wall biosynthesis inhibitors, 50S protein synthesis and gyrase inhibitors, and cell wall biosynthesis and folic acid synthesis inhibitors show antagonism [
53]. On the other hand, the relevance of classifying antibiotics as bacteriostatic or bactericidal has been questioned due to the reliance of these categories on drug concentrations and the treated organisms [
54]. The bacteriostatic/bactericidal classification system varies across organisms and even across drug concentrations and the interactions between drugs may similarly shift [
53]. Antibiotic combination therapy remains an important option as a treatment strategy aimed at controlling the rise of resistance. At the same time, the combined use of antibacterial drugs may increase toxicity and side effects, besides, it is not always clear which drug in combination is really effective. Local microbial pattern based on site infection and pattern of antibiotics sensitivity test can be used as supporting data to optimize appropriateness of empirical antibiotics therapy in sepsis patients [
55].
The effectiveness of antibacterials in the bloodstream
In sepsis the effectiveness of antibacterials in the bloodstream is limited by different factors. The optimal strategies and the effectiveness of antibacterial treatment in sepsis depend on bacterial forms of sepsis-causing bacteria, types of sepsis, pathogen sensitivity to antibacterials, microbe respiration and metabolism, bacterial mechanisms to avoid or defeat host defense and others (Table
2).
Table 2
bacterial forms of sepsis-causing bacteria, types of sepsis and the optimal strategies of antibacterial treatment
Planktonic | Sepsis Severe sepsis Septic shock Fulminant sepsis | High | High | Toxins Catalase SOD, GPX, Hemolysins… | Appropriate antibacterials Toxin production inhibition Toxin binding and removal Antioxidant enzyme inhibition Inhibition of hemolysins Removal by mechanical device |
Encapsulated | Subacute sepsis Chronic sepsis Relapsing sepsis Indolent sepsis Latent sepsis Dormant sepsis | Moderate | Moderate | Capsular polysaccharides | Appropriate antibacterials Capsule production inhibition |
Biofilm | Low | Low | Biofilm polymers | Appropriate antibacterials after using antibiofilm drugs |
L-form | Very low | Very low | Entering host cells | Not available |
Planktonic bacteria cannot grow and multiply in the bloodstream because they become triboelectrically charged during move in the blood flow and friction with blood cells and vessel walls [
23]. Triboelectric charge inhibits metabolism of planktonic bacteria by blocking bacterial trans membrane exchange. As a result, bacteria cannot grow and proliferate and the effectiveness of antibacterial agents in the bloodsteam dramatically decreases. Moreover, sepsis-causing planktonic bacteria enter erythrocytes by producing hemolysins (that locally destroy erythrocyte membrane) and proliferate inside erythrocytes being protected against oxidation by synthesis of antioxidant enzymes. Planktonic bacteria inside erythrocytes are resistant against antibacterial agents because the latter poorly penetrate and accumulate inside erythrocytes.
Encapsulated bacteria and bacteria in biofilms are resistant to antibacterials, particularly, antibiotics because of low metabolism and polysaccharides that “isolate” bacteria from antibacterial agents. Being for bacteria chemical and electrical insulators, bacterial capsule decreases sensitivity to antimicrobials at least by two ways: (a) slowing down bacterial metabolism, growth and multiplication; (b) blocking the access of antimicrobials to bacterial cell. Encapsulated bacteria are resistant to high concentrations of antimicrobial drugs.
L-form bacteria (free and inside leukocytes) are resistant to wall-targeting antibiotics because of the absence of bacterial wall. Because of low metabolic rate, L-form bacteria may be insensitive or only slightly sensitive to antibacterials with other (than wall-targeting) mechanisms of action. Inside blood cells (erythrocytes, leukocytes, platelets), L-forms are resistant to high concentrations of antibacterials. Most antibacterials are not enough lipid-soluble for penetrating inside the blood cells; besides, serum proteins bind antibacterials [
77,
78].
Bacteria within biofilms are highly resistant to antimicrobial agents because of slow growing [
69], besides, biofilm exopolymers block the access of antimicrobials to bacteria [
70]. At the same time, planktonic cells that are shed from virtually all mature biofilms, are generally susceptible to antibiotics. Planktonic bacteria released from the biofilm micro-colonies may cause bacteremia and sepsis. Many of the cells that detach from biofilms growing on native heart valves (resulting in endocarditis) or vascular catheters are in the form of matrix-enclosed biofilm fragments that are very resistant to antibiotics, and they usually circulate until they “jam” in a capillary bed [
67]. Thus, the microorganisms in biofilms are difficult or impossible to treat with antimicrobial agents; detachment from the device may result in acute infection and sepsis.
Different types of sepsis
When an infection surpasses local tissue containment, bacteria enter the bloodstream and cause bacteremia. Local infection may be the source of systematic leakage of bacteria, bacterial components and products of damaged tissue to the bloodstream. Bacteria can enter the bloodstream as planktonic bacteria, encapsulated bacteria, biofilm fragments, L-form bacteria.
In the bloodstream the majority of planktonic free floating bacteria are killed by oxidation on the surface of erythrocytes. Sepsis does not develop as long as this mechanism is effective. Sepsis-causing bacteria usually survive oxidation on the surface of erythrocytes, enter erythrocytes and proliferate there. They produce toxins that intoxicate host, besides, they provoke abundant release of oxygen from erythrocytes that causes disseminated intravascular coagulation, general hypoxia and multiple organ failure [
24].
Encapsulated bacteria, biofilm fragments and L-forms have low metabolism and cause less aggressive infection. Exopolymer shielding (encapsulated bacteria, biofilm fragments) and the absence of bacterial wall (bacterial L-form) prevent triboelectric charging and they are not attracted and killed on the surface of erythrocytes. Encapsulated forms and biofilm fragments of exotoxin-producing bacteria produce relatively little amount of exotoxins because of low metabolic activity and insulation by exopolymers whereas endotoxin-producing bacteria may intoxicate the host after being decomposed by local macrophages in the liver and the spleen. L-form bacteria are inactive in the bloodstream. Non-planktonic forms of sepsis-causing bacteria may cause different types of sepsis (sepsis, subacute sepsis, chronic sepsis, latent sepsis, indolent sepsis, dormant sepsis etc.) [
80,
81] and initiate a broad spectrum of pathologies starting from pyelonephritis [
82], reactive arthritis [
83], type II diabetes [
84], carotid arterial plaques [
85], coronary thrombosis [
86], atherosclerosis [
87,
88] and ending with recurrent bloodstream infections [
89‐
91] and relapsing sepsis [
92]. A primary focus of infection and/or metastatic foci may become a long-term source of bacteremia resistant to antibacterial medications.
Bacteria clearing from the bloodstream by technical devices
Bacteria removal from the bloodstream by technical devices has a good perspective: it is effective in case of all bacterial species and does not need bacteria identification before the procedure. Plaktonic bacteria and biofilm fragments may be easily removed from the bloodstream whereas encapsulated bacteria, pathogens inside erythrocytes and bacterial L-forms may escape removal. The technical devices should be used as soon as sepsis is suspected and it should be done before empiric use of antibiotics because the latter may cause bacterial encapsulation and formation of L-forms. On the other hand, the devices provide removal and accumulation of removed bacteria in devices facilitating precise identification of pathogens.
Bacteria removal from the bloodstream was first performed 25 years ago [
247]. Bacteria were removed by matrix of micro-encapsulated albumin activated charcoal (ACAC). The bacteria adhered to the ACAC, but the charcoal was not bactericidal.10 years ago for removing bacterial toxins from blood in sepsis another device was patented [
248]. It includes hollow fiber that removes lipopolysaccharides (LPS) and lipoteichoic acids (LTA) from blood or plasma in an extracorporeal perfusion system.
Some years ago, for bacteria and endotoxin removing from the blood magnetic nanoparticles (MNPs) modified with bis-Zn-DPA, a synthetic ligand that binds to bacteria, was used [
249]. Recently an external device that mimics the structure of a spleen and cleanses the blood in acute sepsis has been tested [
250]. In this device the blood is mixed with magnetic nanobeads coated with an engineered human opsonin—mannose-binding lectin (MBL). Magnets pull the opsonin-bound pathogens and toxins from the blood then the cleansed blood is returned back to the individual. Mechanical devices can remove from the bloodstream not only bacteria, but also toxins and cytokines. For example, a mechanical devices has been developed to remove a variety of cytokines, lipopolysaccharide, or C5a from plasma [
251]. A novel synthetic pyrolysed carbon monolith with controlled mesoporous domains of 2–50 nm can remove inflammatory cytokines TNF, IL-6, IL-1β and IL-8 [
252]. A cytokine adsorption device (CAD) filled with porous polymer beads efficiently depletes middle-molecular weight cytokines from a circulating solution [
253]. In septic patients continuous venovenous hemofiltration (CVVHF) combined with plasmapheresis (TPE) reduces mortality in single- and double-organ failure as high as 28% [
254].
At present mechanical removal of pathogens and their toxins from the bloodstream by mechanical devices is the most promising clinical application that rapidly may be seen in the near future. It is most effective in case of planktonic bacteria and less effective in the removing of encapsulated bacteria and bacterial L-forms.
Antimicrobial actions needed for increasing the effectiveness of antibacterial therapy in sepsis are summarized in Table
3.
Table 3
Antimicrobial actions needed for increasing of sepsis therapy effectiveness
New antibiotics | Should be able to: a. dissolve in bacterial polysaccharides (capsule, biofilm) – not available. b. kill bacteria in the condition of low metabolic activity – not available. c. penetrate erythrocyte membrane and accumulate inside erythrocytes – not available. d. overcome bacterial adaptation and resistance – not available. |
Exotoxin neutralizing compounds | Should be able to: a. cross-react with more than one exotoxin (available agents: synthetic peptide 6343 and antibody to the 6348 peptide). b. inhibit exotoxin production (available agents: synthesized α-globin chain peptides, synthetic variants of α-globin chain peptides, human defensins). c. reduce toxic shock mortality by suppressing TNF-alpha (available agent: glycerol monolaurate (GML). d. target exotoxins (available agents: recombinant monoclonal antibodies) e. neutralize the activity of superantigens (available agent: polyspecific immunoglobulin G (IVIG). |
Endotoxin neutralizing compounds | Should be able to: a. neutralize endotoxins (available agents: peptides modified by lipophilic moieties and non-peptidic molecules, particularly lipopolyamines (synthetic peptides, based on the endotoxin-binding domains of natural binding proteins such as lactoferrin, Limulus anti-LPS factor, NK-lysin, cathelicidins). b. neutralize TNF (available agent: anti-TNF antibodies). c. endotoxin removal (available: extracorporeal endotoxin removal devices or endotoxoid based vaccines). |
Bacterial capsule affecting agents | Should be able to: inhibit tyrosine phosphatase (PTP) and a protein tyrosine kinase (available agent: Fascioquinol E). |
Bacterial biofilm affecting agents | Should be able to: a. inhibit biofilm formation and motility (available agents: brominated furanones, ursine triterpenes, corosolic acid, asiatic acid, 3-indolylacetonitrile; indole). b. exhibit antimicrobial and antibiofilm properties (available agents: N-acyl homoserine lactones, cationic molecules with an excess of lysine and arginine residues, d-amino acids, monomeric trimethylsilane (TMS), 1-alkylquinolinium bromide ionic liquids). c. affect integrity of biofilms by degrading nucleic acid scaffold components of the extracellular matrix (available agents: nucleases such as DNase and RNase). d. target matrix-associated proteins (available agents: serine proteases). e. degrade poly-N-acetylglucosamine (PNAG), a major polysaccharide component of many bacterial extracellular matrices (available agent: Dispersin B). f. disperse biofilm (available agent: nitric oxide (NO). |
Agents that inhibit and neutralize hemolysins | Should be able to: a. inhibit the production of α-hemolysin (available agents: Totarol, cAMP). b. bound to lipoteichoic acids (available agent: apolipophorin (ApoLp). |
Agents that inhibie antioxidantenzymes | Should be able to: a. inhibit superoxide dismutase (available agents: the manganese and zinc binding protein calprotectin (CP). b. inhibit catalase – not available. c. inhibit glutathione peroxidase – not available. |
Agents of “Biological antibacterial weapon” | Bacteriophage therapy Therapy by Bdellovibrio like organisms Saccharomyces therapy |
Technical devices for bacteria clearing from the bloodstream | Should be able to: a. remove bacteria and their toxins (available technologies: micro-encapsulated albumin activated charcoal (ACAC), magnetic nanoparticles (MNPs) modified with bis-Zn-DPA, bacteria binding synthetic ligands, magnetic nanobeads coated with an engineered human opsonin—mannose-binding lectin (MBL), synthetic pyrolysed carbon monolith, venovenous hemofiltration (CVVHF) combined with plasmapheresis. |
Non-antimicrobial solutions for managing sepsis
In sepsis planktonic bacteria cause abundant release of oxygen from erythrocytes [
22,
23]. Oxygen oxidizes and inactivates plasma hormones and other biologically active substances. As a result, a severe endocrine dysregulation occurs in septic patients and so the replacement of hormones, peptides and other active substances in sepsis is indispensable. Corticosteroids were the first drugs tested in randomized controlled trials [
255‐
259], then catecholamines, anti-diuretic hormone, thyroxin, insulin, adrenocorticotropin, growth hormone, estrogens, androgens, etc. were also tested [
260‐
267]. The results of separate and combined use of hormones are controversial and the positive effect is not convincing. Hormonal replacement therapy (protocol) should include simultaneous use of a combination of hormones that takes into account their synergism and antagonism, anabolic and catabolic properties, half-life, resistance to oxidation, pharmacokinetics, pharmacodynamics, etc. The profile and proportions of most important hormones and regulatory substances for support of vital functions should be established and the replacement of all indispensable hormonal and other regulatory components should be performed. Injected components may be oxidized and inactivated so constant control of their concentrations is necessary.
Optimal route and timing of antibiotic administration in sepsis
Central venous catheters (CVC) are an integral part in medical management of sepsis, particularly, they are indispensable for antibiotic therapy. In sepsis catheters can be placed in veins in the neck (internal jugular vein), chest (subclavian vein or axillary vein), groin (femoral vein), or through veins in the arms (a PICC line, or peripherally inserted central catheters). Catheters are used to administer medication or fluids that are unable to be taken by mouth or would harm a smaller peripheral vein, obtain blood tests (specifically the “central venous oxygen saturation”), measure central venous pressure, etc. Three anatomical sites (the subclavian, jugular, or femoral vein) are commonly used to insert central venous catheters, but insertion at each site has the potential for major complications. Subclavian-vein catheterization is associated with a lower risk of bloodstream infection and symptomatic thrombosis and a higher risk of pneumothorax than jugular-vein or femoral-vein catheterization [
268].
Subclavian and internal jugular CVC have similar risks for catheter-related complications in long-term catheterization. Subclavian CVC is preferable to femoral CVC in short-term catheterization because of lower risks of catheter colonization and thrombotic complications. In short-term catheterization, femoral and internal jugular CVA routes have similar risks for catheter-related complications; internal jugular CVA routes are associated with higher risks of mechanical complications [
269].
In sepsis pathogens circulate in the bloodstream. Catheters themselves can introduce bacteria into the bloodstream. Catheter-related bloodstream infections (CRBSIs) may deteriorate the condition of patients with sepsis. Although earlier studies showed a lower risk of catheter-related bloodstream infections when the internal jugular was compared to the femoral site, recent studies show no difference in the rate of catheter-related bloodstream infections between the sites [
270]. Biofilms that harbor microorganisms are demonstrated on external and internal surfaces of the indwelling catheters within as early as 24 h after their placement [
271].
If a central line infection is suspected in a person, blood cultures are taken from both the catheter and a vein elsewhere in the body. If the culture from the central line grows bacteria much earlier (> 2 h) than the other vein site, the line is likely infected. Quantative blood culture is more accurate, but it is not widely available [
272].
To prevent infection, stringent cleaning of the catheter insertion site is advised. Povidone-iodine solution is often used for such cleaning, but chlorhexidine is twice as effective as iodine [
273]. Routine replacement of lines makes no difference in preventing infection [
274]. Recommendations regarding risk reduction for infection of CVCs, include antibiotic lock therapy - a method for sterilizing the catheter lumen that involves instilling high concentrations of antibiotics into the catheter lumen for extended periods of time. Results from in vitro studies demonstrate stability of antibiotics while maintaining high concentrations for prolonged periods of time. In vivo studies show antibiotic lock technique as an effective and safe option for both prevention and treatment of CRBSIs [
275]. Recently, non-antibiotic antimicrobial catheter lock solutions also are used [
276].
Sepsis starts when infection enters the bloodstream and overcomes the host mechanisms of blood clearing from bacteria. The most common primary sites of infection include the lungs, urinary tract, abdominal organs, and pelvis. Early source identification is important if sepsis is to be treated adequately. Empiric antimicrobial therapy is the cornerstone of the treatment [
6]. Before giving antibiotics, blood cultures should be taken. Blood culture provides information regarding the infection and bacteria sensitivity to antibiotics. Revealing the source of infection is necessary for targeting of antibiotics. The primary site of infection may be the source of constant bacteremia during the course of sepsis. The blood culture may help to choose appropriate antibiotics and de-escalate from broad spectrum to narrow spectrum antimicrobials. Although blood cultures are the gold standard in identifying infections, other interventions may be also needed.
Current guidelines recommend starting antibiotic therapy in sepsis as early as possible and within one hour of identification of septic shock [
7]. The Surviving Sepsis Campaign (SSC) published their initial clinical practice guidelines (CPG) for the management of severe sepsis and septic shock in 2004 [
8]. Updated versions were published in 2008 [
277], 2012 [
11] and most recently in 2016 [
278] and 2018 [
279]. The Surviving Sepsis Campaign bundle is the core of the Campaign
’s quality improvement efforts. Applying the sepsis bundle simplifies the complex processes of the care of patients with sepsis. The “sepsis bundle” has been central to the implementation of the Surviving Sepsis Campaign from the first publication of its evidence-based guidelines in 2004 through subsequent editions. Тhe bundle elements were designed to be updated as indicated by new evidence and have evolved accordingly. Updates to clinical management guidelines precede the updates to the sepsis bundles. The first sepsis bundle published in 2004 included a “Sepsis Resuscitation Bundle” to be completed “as soon as possible” within the first 6 h of presentation and a “Sepsis Management Bundle” to be completed “as soon as possible” within the first 24 h [
8]. These initial bundles were revised in 2012 and changed to a “3-h bundle” and “6
-h bundle,” with similar elements but an effort to perform the interventions within a shorter time period [
11]. These 3- and 6-h bundles were further revised in 2015 with the elimination of central venous pressure (CVP) and S
CVO
2 measurement. Driven by the release of the International Guidelines for Management of Sepsis and Septic Shock: 2016 (guideline summary), a new bundle update was published in 2018 titled “The Surviving Sepsis Campaign Bundle: 2018 Update.” [
279]. The most important change in this new revision of the SSC bundles is that the 3-h and 6-h bundles have been combined into a single “hour-1 bundle” with the explicit intention of beginning resuscitation and management immediately. The Hour-1 bundle should be viewed as a quality improvement opportunity moving toward an ideal state. For critically ill patients with sepsis or septic shock, time is of the essence. Although the starting time for the Hour-1 bundle is recognition of sepsis, both sepsis and septic shock should be viewed as medical emergencies requiring rapid diagnosis and immediate intervention [
279]. The Hour-1 bundle encourages clinicians to act as quickly as possible to obtain blood cultures, administer broad spectrum antibiotics, start appropriate fluid resuscitation, measure lactate, and begin vasopressors if clinically indicated. Ideally these interventions would all begin in the first hour from sepsis recognition but may not necessarily be completed in the first hour. Minimizing the time to treatment acknowledges the urgency that exists for patients with sepsis and septic shock. The new “Hour-One Bundle” includes 5 steps which are recommended to begin immediately upon presentation in all patients with clinical elements suspicious for sepsis or septic shock (Table
4).
Table 4
Surviving sepsis campaign hour-1 bundle of care elements
• Measure lactate levela • Obtain blood cultures before administering antibiotics. • Administer broad-spectrum antibiotics. • Begin rapid administration of 30 ml/kg crystalloid for hypotension or lactate level ≥ 4 mmol/L. • Apply vasopressors if hypotensive during or after fluid resuscitation to maintain MAP ≥65 mmHg. |
Questions about the use of triage time in the emergency department as “time zero” for starting the clock to score compliance with the elements of the Surviving Sepsis Campaign (SSC) bundles have been raised since the bundles’ 2005 introduction as a performance improvement tool. “Time zero” is the time of presentation to triage in the emergency department or if presentation occurs in a different setting (outpatient, nursing home, intensive care unit, hospital floor). “Time zero” would be the first documentation in the chart with the elements of sepsis [
279]. It is understood that the interventions may not be completed within the hour
. At the same time in sepsis every hour delay is associated with a 6% rise in mortality [
8,
9]. There are no prospective data that early broad-spectrum antibiotic therapy reduces mortality in severe sepsis, but prompt initiation of antimicrobial therapy remains important for suspected infections [
10]. If the pathogen is resistant to antibiotic, early or late initiation of antibiotic therapy cannot improve the outcome. Inappropriateness of empirical antibiotic therapy can contribute to high level of mortality [
11]. The 2016 guidelines recommend administering empiric broad-spectrum antimicrobials that cover all likely pathogens [
278]. The initial empiric antibiotic regimen for patients in septic shock should include at least two antibiotics from different classes (combination therapy) directed toward the most likely pathogens. Treatment should be narrowed once the pathogen and its antimicrobial sensitivities are ascertained or when the patient demonstrates clinical improvement. With respect to antibiotic duration, combination therapy in patients with septic shock should be de-escalated to monotherapy within a few days if clinical improvement or with evidence of infection resolution [
278]. Total treatment duration should be 7–10 days for infections with sepsis or septic shock; however, some patients may warrant a prolonged course if they respond slowly to treatment, do not have source control, have bacteremia with
Staphylococcus aureus or have immunological deficiencies or fungal/viral infections [
278].
Conclusion
Bacteria cause sepsis being in different forms: planktonic, encapsulated, L-form and biofilm fragments. Antibacterial therapy is most effective when infection is in the tissues. If infection enters the bloodstream and starts to occupy erythrocytes, the effectiveness of antibacterial therapy dramatically decreases. So the most effective approach to sepsis treatment is prevention of bacteremia. Sublethal effect of antibacterial drugs in the tissues may provoke bacterial encapsulation, biofilm growth, switching to L-form. Early detection of infection in the tissues and selection of appropriate antibacterial medication in adequate doses is of great importance. Inhibition of the production of bacterial antioxidant enzymes (catalase, superoxide dismutase, glutathione peroxidase) may increase the effectiveness of phagocytosis in the tissues and oxycytosis in the bloodstream. Inactivation of bacterial hemolysins may prevent bacterial penetration through erythrocyte membranes and forming of infection reservoir inside erythrocytes. Acceleration of bacterial respiration may increase the effectiveness of bactericidal drugs. Dispersion of bacterial exopolymers is indispensible in antibacterial therapy of infection caused by encapsulated bacteria and biofilm. Inhibition, inactivation or binding of bacterial LPS and SAgs is necessary for preventing of host intoxication and decreasing of infection virulence.
Sepsis therapy should include the use of antibacterial medications, modulation of bacterial respiration, inhibition of bacterial antioxidant enzymes and hemolysins, neutralization of exo- and endotoxins, dispersion of bacterial capsule and biofilm, increasing of host tolerance to bacterial products, facilitation of host bactericidal mechanisms, support of host vital functions and restore of homeostasis.