Sepsis guidelines and diagnostics: Current impact and future outlook

Sepsis, caused by the body’s uncontrolled immune response to an infection, is a very complex and challenging disease state for clinicians to manage. Sepsis is the leading cause of death in U.S. hospitals, the most expensive cause of hospitalization, and the leading cause of readmission, costing the U.S. healthcare system more than $25 billion annually.^1,2 Optimal management of septic patients requires timely action by the full spectrum of healthcare providers, from the nurses and clinicians who initially diagnose a patient with the signs and symptoms of sepsis to the laboratorians who provide critical diagnostic results that help clinicians optimize antimicrobial therapy.

Significant strides have been made during the past decade in the recognition, diagnosis, and management of sepsis. While these advances have improved outcomes, the burden of this disease remains large. Researchers and diagnostic manufacturers in the U.S. and abroad are actively tackling sepsis to provide better clinical practice guidelines and diagnostic solutions to combat this devastating disease state.

The need for speed

The common thread connecting all initiatives for improving care for septic patients is the inverse relationship between time to optimal treatment and patient outcome. Kumar et al. noted that for each hour the patient is withheld appropriate therapy after initiation of hypotension related to sepsis, the patient’s mortality rate increases by 7.6 percent.³ Clinicians, nurses, and other healthcare providers who interact with patients are being asked increasingly to focus on ruling out sepsis versus ruling in sepsis because of the time sensitivity associated with initiating and optimizing care for these patients.

The most widely noted clinical guidelines for sepsis are the Surviving Sepsis Campaign’s International Guidelines for Management of Severe Sepsis and Septic Shock. The “3-Hour Bundle” described in these guidelines as a best practice places an emphasis on healthcare providers taking quick action with septic patients, requiring measurement of lactate levels, obtaining blood cultures prior to administration of antibiotics, administration of broad-spectrum antibiotics, and administration of 30 ml/kg crystalloid for hypotension or lactate ≥ 4 mmol/L, all within three hours of the first interaction with a potentially septic patient.⁴ Leisman et al. demonstrated in a prospective, multisite, observational study that strict compliance with an aggressive three-hour sepsis bundle led to a statistically significant reduction in mortality and mean hospital costs across three independent cohorts.⁵

Additional efforts tied to earlier recognition of septic patients are also coming in the form of software-driven solutions that monitor vital signs and health records to assist clinicians in identifying septic patients earlier. Balamuth et al. showed that a vital sign-based electronic sepsis alert plus clinician review of electronic sepsis alert-negative patients improved emergency department sepsis detection rates from 83 percent to 96 percent.⁶ Whether guideline- or software-driven, the recent shift in focus of clinicians and nurses to place a much larger emphasis on the early recognition and initiation of care for septic patients is making a substantial impact on improving patient outcomes.

Rapid testing

As with the clinical management guidelines and software alert solutions for sepsis, diagnostics targeted at improving care for septic patients are focused on reducing the time necessary to generate clinically actionable results. The diagnostic application with some of the greatest technological advances and overall positive impact on care for septic patients over the past decade is rapid blood culture diagnostics. The first generation of rapid blood culture tests cleared by the U.S. Food and Drug Administration have been molecular-based, using various detection methodologies including peptide nucleic acid fluorescent in situ hybridization, real-time polymerase chain reaction (PCR), nested PCR, and direct microarray hybridization. Instead of relying on the growth necessary for phenotypic diagnostic methods, these methods can identify the causative pathogen and associated genetic antibiotic resistance markers within one to four hours of a blood culture bottle ringing positive versus 24 to 48 hours with conventional culture-based phenotypic methods.

These tests, in combination with antimicrobial stewardship team efforts, have been shown to reduce time to identification of the causative pathogen by as much as 72 hours, reduce time to optimal antibiotics by as much as 36 hours, improve antimicrobial stewardship efforts by reducing the amount of unnecessary antibiotics prescribed, reduce both hospital and intensive care unit patient length of stay by one to ten days, and improve infection control efforts to minimize the spread of resistant organisms.^7-10 The next generation of FDA-cleared rapid diagnostics for bloodstream infections include rapid susceptibility applications, which reduce the time from positive blood culture to identification and susceptibility results for select organisms by around 36 hours, matrix-assisted laser desorption/ionization time-of-flight (MALDF-TOF) for cultured isolated and direct-from-specimen testing, and culture-independent molecular diagnostics that are performed on whole blood. While limitations still exist for each of these rapid diagnostic methods and no solution to date can serve as a full replacement for conventional blood culture and susceptibility, these diagnostics are driving positive outcomes for septic patients and are quickly becoming the standard of care.

An alternative approach to pathogen identification using rapid molecular or phenotypic methods for sepsis diagnosis is the characterization of the host’s response to an infection. The host’s protein biomarker or gene expression response to an infection may provide a faster and more accurate way for clinicians to quickly discriminate between bacterial and viral causes of infection and between patients with systemic inflammatory response syndrome (SIRS) and patients with sepsis. This could greatly improve the ability to prescribe appropriate antibiotics and better manage patients while waiting for confirmatory diagnostic results for pathogen identification, resistance marker detection, and/or susceptibility results.

Procalcitonin (PCT) is probably the most widely known and utilized biomarker; however, its performance and utility are not fully understood. In a recent multi-center study, Schuetz et al. demonstrated the potential utility of PCT by showing that patients with a decrease in PCT levels of no more than 80 percent during the first four days after the onset of severe sepsis or septic shock had a mortality rate twice as high as those patients whose PCT levels decreased more than 80 percent.¹¹ The FDA recently cleared another host response diagnostic application, an RNA-based blood test targeting four molecular blood markers from the patient’s immune system to differentiate sepsis from SIRS. The amount of published research in the area of host response for sepsis is rapidly growing. The results from this work could potentially lead to diagnostics that become a part of routine clinical practice and drastically improve the level of information clinicians have to better care for septic patients.

Recent advances in the care for septic patients have all resulted from guidelines and technologies that reduce the time necessary to recognize, diagnose, and treat these patients. The next wave of solutions in this space will continue with this theme. While the burden of sepsis remains large, the improved outcomes and reduced healthcare costs driven by recent guideline and technological advances are very encouraging and lend hope that the next wave of innovations will have further positive impact.

REFERENCES

1. Liu V, Escobar GJ, Greene JD, et al. Hospital deaths in patients with sepsis from 2 independent cohorts. JAMA. 2014;312(1):90-92.
2. Torio CM, Andrews RM. National inpatient hospital costs: the most expensive conditions by payer: HCUP Statistical Brief #160. 2013. Agency for Healthcare Research and Quality, Rockville, MD. http://www.hcup-us.ahrq.gov/reports/statbriefs/sb160.pdf.
3. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34(6):1589–1596.
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8. Walker T, Dumadag S, Lee JC, et al. Clinical impact of laboratory implementation of Verigene BC-GN microarray-based assay for detection of gram-negative bacteria in positive blood cultures. J Clin Microbiol. 2016;54(7):1789–1796.
9. Box MJ, Sullivan EL, Ortwine KN, et al. Outcomes of rapid identification for gram-positive bacteremia in combination with antibiotic stewardship at a community-based hospital system. Pharmacotherapy. 2015;35(3):269–276.
10. Felsenstein S, Bender JM, Sposto R, et al. Impact of a rapid blood culture assay for gram-positive identification and detection of resistance markers in a pediatric hospital. Archives of Pathology & Laboratory Medicine 2016;140:267–275.
11. Scheutz P, Birkhahn R, Sherwin R, et al. Serial procalcitonin predicts mortality in severe sepsis patients: results from the multicenter procalcitonin monitoring sepsis (MOSES) study. Crit Care Med. 2017;45(5):781–789.

Scott Powell, MS, serves as Global Product Manager for Luminex Corporation’s VERIGENE Gram-Positive (BC-GP) and Gram-Negative (BC-GN) Blood Culture Tests for the rapid identification of the causative pathogen and associated genetic resistance markers for gram-positive and gram-negative bloodstream infections.