CLINICAL ISSUES SEP SIS
Sepsis guidelines and diagnostics:
Current impact and future outlook
By Scott Powell, MS
S
epsis, caused by the body’s uncontrolled immune re-
sponse 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 Op-
timal 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 manufactur-
ers 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, obtain-
ing blood cultures prior to administration of antibiotics, admin-
istration 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 signifi-
cant 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 per-
cent.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.
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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 Admin-
istration 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 re-
lying on the growth necessary for phenotypic diagnostic meth-
ods, 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 antimi-
crobial stewardship efforts by reducing the amount of unneces-
sary 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 or-
ganisms.7-10 The next generation of FDA-cleared rapid diagnos-
tics for bloodstream infections include rapid susceptibility ap-
plications, 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 di-
agnostics that are performed on whole blood. While limitations
still exist for each of these rapid diagnostic methods and no so-
lution 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 in-
fection may provide a faster and more accurate way for clini-
cians 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 di-
agnostic 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 per-
cent during the first four days after the onset of severe sepsis or
continued on page 32
7/14/2017 11:18:51 AM
 CLINICAL ISSUES SEP SIS
continued from page 30
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 mark-
ers 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 re-
sulted 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 guide-
line 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 con-
ditions 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.
4. Rhodes A, Evans LA, Alhazzani W, et al. Surviving Sepsis Campaign.
International guidelines for management of sepsis and septic shock: 2016. Crit Care
Med. 2017;45(3):486– 552.
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5. Leisman DE, Doerfler ME, Ward MF, et al. Survival benefit and cost savings from
compliance with a simplified 3-hour sepsis bundle in a series of prospective, multisite,
observational cohorts. Crit Care Med. 2017;45(3):395-406.
6. Balamuth F, Alpern ER, Abaddessa MK, et al.. Improving recognition of pediatric
severe sepsis in the emergency department: contributions of a vital sign-based
electronic alert and bedside clinician identification. Annals of Emergency Medicine.
http://dx.doi.org/10.1016/j.annemergmed.2017.03.019.
7. Rivard KR, Athans V, Lam SW, et al. Impact of antimicrobial stewardship and rapid
microarray testing on patients with gram-negative bacteremia. Euro J Clin Microbiol &
Infect Dis. doi: 10.1007/s10096-017-3008-6.
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 identi-
fication of the causative pathogen and
associated genetic resistance markers
for gram-positive and gram-negative
bloodstream infections.
NEW!
7/14/2017 11:19:17 AM
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