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.