Sepsis is a major healthcare problem. There are approximately 750,000 cases of sepsis each year in the U.S. and the number is growing.
Sepsis results from complex interactions between infecting microorganisms and host immune, inflammatory, and coagulation responses. Severe sepsis is defined as sepsis with organ dysfunction. Severe sepsis with hypotension, despite adequate fluid resuscitation, is septic shock. Septic shock and multiorgan dysfunction are the most common causes of death in sepsis patients. Mortality associated with severe sepsis remains unacceptably high—20 to 50%. When shock is present, mortality is even higher—40 to 60%.
Distinguishing patients with localized infections or a systemic inflammatory response (SIRS) from those with sepsis is challenging. SIRS is not specific to sepsis and can result from other conditions such as acute pancreatitis and immunodeficiencies. This makes a quick diagnosis, difficult.
Today, blood culture and culture techniques are the gold standard for detection of infection. Physicians order cultures as soon as two or more SIRS criteria are identified. The turnaround time for culture/blood culture is lengthy, ranging from 48 to 72 hours. As a result, antimicrobial therapy administration usually begins before culture results are available.
The choice of appropriate broad-spectrum antimicrobial therapy is tricky because of the rising prevalence of resistant pathogens. Today, this choice is left up to the physician’s intuition. Patients with severe sepsis or septic shock, however, have little margin for error in what therapy they receive. Consequently, there is a huge unmet need for fast turnaround tests that enable early administration of antimicrobial therapy/antibiotics by rapid identification of infection and facilitate choice of antimicrobial therapy through rapid identification and detection of causative pathogen.
Future sepsis diagnostic options include single-analyte immunoassays and molecular identification, for which opportunities exist at both the front and back ends.
Among all single-analyte biomarkers, detection of a protein biomarker called procalcitonin (PCT) in serum holds the most promise. Serum levels of PCT have been shown to increase in patients with an infection; high values will be seen in cases of severe sepsis and septic shock.
Widespread use, however, is lacking. This is partly due to the lack of clinical trials with proper negative controls that differentiate septic from sepsis-like patients. Another difficulty lies with the riskiness of using a cut-off threshold of PCT to rule-out sepsis. Scientia’s research indicates that the possibility of false negatives is daunting and subsequent denial of antibiotic could increase the probability of mortality.
Another potential application of PCT is in therapy monitoring. PCT kinetics can be used to assess the effectiveness of treatment. If PCT levels do not begin to decline in a patient after four days of antibiotic treatment, the physician should consider changing the antibiotic regimen.
B.R.A.H.M.S. owns the IP on PCT and offers the test today along with bioMerieux. Several other immunoassay providers, including Roche Diagnostics and Siemens, have licensed PCT from B.R.A.H.M.S. and are offering it or intend to offer it on their immunoassay platforms.
Molecular identification of sepsis-causing pathogens might prove extremely helpful for rapid identification of pathogens and major antimicrobial resistance determinants. Rapid detection of hard-to-grow pathogens and antibiotic-resistant pathogens such as MRSA and VRE can significantly improve clinical outcome, enabling a narrowing of the spectrum of antibiotic coverage.
SeptiFast, a molecular sepsis test, has been launched by Roche Molecular Diagnostics in Europe. Adoption of this test has been disappointing as a result of its limited coverage of pathogens, automation issues, contamination problem, and cost.
Given the substantial barriers, many molecular diagnostic companies do not plan on taking up the daunting task of introducing a front-end molecular identification test and have resorted to the back end of identification of organisms directly in positive blood cultures instead.
The simplest of these back-end molecular identification tests is the PNA FISH (peptide nucleic acid fluorescent in situ hybridization) test. PNA FISH has the advantage of rapid hybridization kinetics and offers a sensitive way to identify S. aureus, Enterococcus faecalis, or Candida albicans in positive blood culture samples. Identification is typically done within a few hours after a positive blood culture result is obtained. PNA FISH is available today and is offered by AdvanDx.
Another emerging methodology for identification of organisms in positive blood cultures is real-time PCR. Several companies such as Cepheid (with bioMerieux) are working toward developing such a test.
Sepsis is a complex and life-threatening disease. Significant improvements in the care, management, and treatment of sepsis patients have been realized recently. While early diagnosis remains a challenge and a rapid, sensitive, and specific diagnostic test is still lacking, these new approaches open up a whole new dimension in early diagnosis of sepsis and are likely to evolve into solutions for this major unmet need.