Sepsis Diagnostics

Sepsis is among the most common causes of death with a mortality rate that exceeds even myocardial infarction. Further, sepsis has long-lasting health consequences that are, as of yet, unrecognized. For instance, recent studies have demonstrated that patients who survive sepsis are at risk for physical and cognitive impairment and have a significantly greater five-year mortality rate compared to similar patients without the disease. As more research on this condition continues, other negative effects may be revealed.

There are more than 1.6 million cases of sepsis per year in the U.S. with a reported mortality rate of 30 percent to 60 percent, depending on the severity of the disease state. Sepsis arises from the host response to infection, and early diagnosis, followed by prompt, appropriate treatment, improves prognosis. It has been shown that each hour of delay in the administration of the appropriate antimicrobial therapy is associated with a decrease in survival of nearly 8 percent. Notably, the case-fatality rate has been shown to be reduced by 33 to 77 percent with early administration of the appropriate antimicrobial agents.Sepsis

Whereas the symptoms of sepsis are fairly easy to identify, confirmation of the disease is more problematic as it depends on proving the presence of an infection. Unfortunately, an accurate and timely diagnosis represents a significant hurdle. Even more complicated is the identification of the cause of infection and selection of appropriate antimicrobial coverage. To treat these patients appropriately, the common practice is to rely on blood culture (BC) as the diagnostic foundation for pathogen identification. This is a problematic diagnosis and treatment strategy because blood culture itself is a slow and insensitive method, and the post-culture diagnostic techniques will never be faster or more accurate than the system on which they are based.

Today, 30 to 40 percent of all cases of severe sepsis and septic shock are culture-proven bloodstream infections (BSIs), for which there is a rapid decline in survival rates when inadequate antimicrobial therapy is administered in the first 24 hours. As a result, clinicians often resort to providing “best guess,” or empirical broad-spectrum, antimicrobial therapy, which may not be targeted and effective against the infecting agent. The challenge of empirical coverage is selecting which problem to solve. Is the issue resistant pathogens, invasive fungal (e.g. Candida) infections, minimizing consumption of more expensive third-line agents (e.g. tigecycline, daptomycin, ceftaroline) or drug toxicity issues (e.g. colistin)?

All of these problems are present when dealing with the most important sepsis pathogens because these infections raise all of these issues. Specifically, the following pathogens are infamous for treatment practices that are inappropriate and/or delayed, and, thus, have been shown to represent an independent risk for mortality: Acineotobacter, Klebsiella pneumonia, Pseudomonas aeruginosa, Enterococcus, E. Coli, Staphylococcus aureus and Candida species.

It is important to understand that sepsis is not the same as a bacterial infection. Indeed, bacteria are only part of the story — and not always the most deadly. Fungal infections, specifically Candida infections, are common, deadly and expensive to manage. It has been demonstrated that BSI caused by Candida species initiates a septic response comparable to that of sepsis caused by S. aureus, but with a much higher mortality rate.

Given the relationship between the timely and appropriate (right drug, right dose) antimicrobial coverage, the Surviving Sepsis Campaign developed evidence-based practice guidelines with the intention of standardizing sepsis care to reduce mortality. The goal of the guidelines is to ensure a rapid response to sepsis in the absence of diagnostic tools that can provide accurate results within hours of the patient’s presentation of symptoms. Currently, they recommend, in addition to hemodynamic resuscitation and source control, timely empiric combination therapy targeting likely bacterial and/or fungal pathogens.

In recognition of the role that Candida plays in severe sepsis and septic shock, the guidelines also recommend the use of fungal biomarkers, if available, to improve the timeliness of diagnosis when candidiasis is considered. Consistent with these recommendations, Kollef et al have identified the importance of source control and empiric therapy in septic patients with candidiasis. Delayed (greater than 24 hours) antifungal treatment and failure to achieve timely source control were independently associated with a greater risk of in-hospital mortality. As such, the Sepsis Guidelines attempt to balance concerns regarding delayed therapy and overuse of antimicrobials with the attendant risks of mortality, expense and resistance.

There are several barriers to the timely administration of appropriate antimicrobial therapy in sepsis. These include delayed recognition of sepsis and septic shock, unrecognized risk factors for multidrug-resistant (MDR) pathogens and lack of an etiologic (causal) diagnosis. These barriers may be overcome by updating policies to minimize delays in treatment and through the implementation of rapid, culture-independent diagnostic tests and further education of healthcare professionals.

At the present time, the Sepsis Guidelines’ recommendation regarding antimicrobial therapy continues to focus on BC-based diagnostics despite the fact that BCs are slow (24 to greater than 90 hours), and its results are negative in more than 50 percent of cases where true bacterial or fungal sepsis is believed to exist. Although BCs remain at the heart of Sepsis and BSI core guidelines, emerging alternative technologies aimed at complementing the deficiencies of BC, particularly related to improving time and, in at least one case, accuracy are now available. Examples of rapid BC-independent tests for sepsis and sepsis pathogens include biomarkers such as procalcitonin and homebrew PCR (polymerase chain reaction) platforms and the use of T2MR (T2 magnetic resonance) technology.

Procalcitonin (PCT) is a blood test that reflects the response of the host to a bacterial challenge. PCT levels are not elevated in infections due to Candida or viruses. Elevated or rising PCT levels represent the systemic response to infection, indicating that infection is developing or is outside the control of the immune system. Several measurements of PCT provide a clearer picture of the patients’ response to antibacterial treatment such that decreasing levels indicate effective treatment, and persistently elevated levels indicate possible treatment failure. Importantly, PCT does not provide an etiologic diagnosis, and PCT levels increase non-specifically in other inflammatory instances, such as trauma and surgery.

It is widely recognized that PCR has the potential to provide species-level detection and identification of sepsis pathogens with results available within 24 hours of sample receipt. However, these are not FDA-cleared technologies, and are considered homebrew applications. While not standardized, some manufacturers offer kits in Europe and elsewhere that are more controlled than lab-developed reagents.

For instance, Roche has developed the SeptiFast real-time PCR system. The SeptiFast platform allows for the detection of 19 bacterial targets, 5 Candida species and aspergillus fumigatus. SeptiFast requires DNA extraction from whole blood and employs fluorescent-based detection with melting curve analysis for species identification. The overall sensitivity of SeptiFast is 75 percent, and the specificity is 92 percent. Reported turnaround time (TAT) varies, but can be as fast as 6 hours for a single test. (PLOS ONE | 1 May 2013 | Volume 8 | Issue 5 | e62323)

T2MR is the most recent technology product to address sepsis, and the only one to provide species identification directly from a whole blood sample. T2MR employs nanotechnology and magnetic resonance for rapid and accurate species identification directly from whole blood without the need for DNA extraction or sample manipulation. To apply the technology to sepsis diagnostics, nanoparticles are coated with target-specific binding agents that cluster in the presence of a sample containing a target complementary to the probes.

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