The global sepsis infection rate is estimated at 15 to 19 million cases per year, with the fatality rate from septic shock as high as 50%. As current pharmacological agents are losing efficacy due to multi-drug resistance, new drugs and combinations are required to reduce the global sepsis burden.
Sepsis and septic shock:
The Third International Consensus Definitions specify sepsis as a systemic, harmful host response to infection leading to severe acute organ failure. In other words, sepsis is the body’s intense reaction to an infection. Sepsis is life-threatening, and without timely and proper treatment, it can rapidly evolve into tissue damage, organ dysfunction, and death. It affects the lungs (pneumonia), kidneys (urinary tract infection), skin, and gut.
Septic shock is as a subset of sepsis whereby the organ failure or tissue damage in response to an infection leads to precariously low blood pressure and retardation in cellular metabolism. Typically, a systolic blood pressure (SBP) under 90 mmHg, mean arterial pressure (MAP) under 70 mmHg, or an SBP decrease of greater than 40 mmHg is considered to be a symptom of septic shock.
Because anyone can be infected and any infection can lead to sepsis and septic shock, it is considered a major healthcare problem. Sepsis affects millions of people around the world each year, killing one in four, and increasing in incidence. In the US alone, sepsis and septic shock accounted for more than 5.2% of total hospital costs in 2011, which works out to over $20 billion. Elderly patients in particular are more likely to be vulnerable to sepsis due to respiratory or urinary tract infections — pneumonia being the single most common cause of sepsis in the aging population.
Cause:
Infections leading to sepsis are usually bacterial, but can also be fungal or viral. The gram-positive staphylococcal bacteria are responsible for more than 50% of cases of sepsis. Other commonly implicated bacteria include S. pyogenes, E. coli, P. aeruginosa, and Klebsiella species. Sepsis infection is more prevalent in patients after surgery. This is because urinary tract infections are more common after surgery, due to the use of catheters, and these infections can lead to sepsis. In addition, an incision is an opening into the body through which infection can begin. For these reasons, a majority of sepsis infections, ironically, occur frequently in hospitals.
Complicated symptoms:
Most individuals developing sepsis are entirely oblivious of their starting infection, which later develops into sepsis. It is for this reason that sepsis is considered to be very dangerous. With a “regular” infection, the body reacts to the danger by containing the infection at the source. Management with antibiotics is typically the first step of treatment to help the body fight the infection. However, when left untreated, often because of patients’ lack awareness or overlooking the symptoms, or if the body is incapable of stopping the infection at the source, it can spread to organs, including blood, which causes sepsis.
Antibiotics regimen:
Early recognition of infection and treatment prevents incidences of sepsis. Antibiotics are prescribed for sepsis treatment. Several factors influence the most suitable choice for the starting antibiotic program. These factors include local activity of bacterial response to antibiotics, whether the infection is thought to be a hospital or community-acquired infection, and which organ systems are infected. The recommended antibiotics for sepsis in the market are vancomycin, teicoplanin, macrolide, or fluoroquinolone. They are combined with vasopressors that elevate blood pressure or glucocorticoids for septic shock.
However, certain bacteria like P. aeruginosa, A. baumannii, and S. aureus can develop multiple drug resistance to antibiotics, rendering treatments ineffective. Therefore, new therapeutic approaches are required to improve the outcome of patients with severe sepsis and septic shock.
Potential new treatment: Vitamin C and additives
Experimental studies have demonstrated that both vitamin C and hydrocortisone have various and combined beneficial treatment effects in sepsis. Both drugs curb nuclear factor NF-κB activation, down-regulate the production of pro-inflammatory mediators, increase tight junctions between endothelial and epithelial cells, and protect endothelial function and micro-circulatory flow.
In a recent preclinical investigation, thiamine was added to vitamin C and hydrocortisone to create a combination that reduced organ injury, including acute kidney failure, and decreased the death rate of 47 ICU patients with severe sepsis and septic shock by 31%. The explanation as to why the “cocktail” of intravenous vitamin C, hydrocortisone, and thiamine seemed to have a noticeable consequence on the incidence of sepsis as compared to the other therapeutic agents which have been assessed in previous sepsis-related trials is likely related to the multiple and overlapping effects of all three molecules as compared to drugs which target a single molecule or pathway.
What’s next?
The authors report that, while the sample size is low, due to the nature and safe combination of hydrocortisone, vitamin C, and thiamine, the cocktail treatment strategy can be applied to a large patient population for stage I clinical trials. This is important because the present study was not a large and randomized control trial. It was a before-and-after study, which can have biases, and completed at a single location. The work did not evaluate the optimal dosing strategy of the mixture drugs. Therefore, multiple trials are underway to confirm the benefit, to eliminate unexpected effects as was seen in previous sepsis trials using promising drugs, and to determine the optimal dose and treatment duration, whether intermittent (high peak concentrations) or continuous dosing performs better in arresting incidents of sepsis.
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