The problem of antimicrobial resistance and the use of a clinical decision score and point-of-care testing biomarkers, such as CRP and PSP,
to help solve this problem.
Introduction
Infectious diseases are a public health issue
around the world, with bacterial, viral, parasitic, or fungal-related diseases responsible for
26% of mortality worldwide, and the remaining 74% attributed to non-communicable
diseases (cardiovascular diseases, cancers,
diabetes, trauma, etc.) (WHO 2018). The
COVID-19 pandemic highlighted the high
mortality of infectious diseases, with 5.94
million deaths in two years and nearly 18.2
million deaths worldwide (as measured
by excess mortality) (COVID-19 Excess
Mortality Collaborators 2022).
Among infectious diseases, sepsis is a
major public health threat, responsible for
11 million deaths yearly (Rudd et al. 2020).
Sepsis and septic shock are also the leading
cause of death among children worldwide
(Rhodes et al. 2017). Bacterial infections
and sepsis can be effectively treated with
antibiotics. However, the overuse of broad-spectrum antibiotics has led to bacterial
antimicrobial resistance (AMR). Today, AMR
is another major public health problem, with
an estimated 4.95 million deaths associated
with bacterial AMR in 2019 (Antibiotic
Resistance Collaborators 2022). Sepsis and
AMR together are responsible for more than
12.3 million deaths each year. The WHO
has declared AMR one of the top ten global
public health threats (WHO 2021).
Hospital Acquired Infections or Healthcare
Associated Infections (HAIs) occur in 7-8%
of hospitalised patients in Europe and 56%
of patients in the ICU (Vincent et al. 2017).
The main causes of nosocomial infections
include bacterial AMR, lack of adherence to
infection control and prevention procedures.
Bacterial infections can be complicated by
sepsis and septic shock (Singer et al. 2017).
In developing countries, the incidence of
sepsis and septic shock is much higher
than in high-income countries (Rudd et al.
2020). In addition, the administration of
antibiotics is broad spectrum and leads to
AMR (WHO 2011; Flandrin 2019; WHO
2020). For example, in India, the incidence
rate of sepsis is the second highest in South
Asia after Afghanistan (WHO 2011; Belagere
2020), and the incidence of nosocomial
infection represents 11-60% (Choudhuri
et al. 2017) of hospitalised patients. India
also leads the world in human antibiotic
use (Van Boeckel et al. 2014).
While the incidence of sepsis is higher in
developing countries, the mortality rate is nearly
20-25% in developed countries. Sepsis-related
costs in U.S. hospitals surpass US$24 billion
annually, making it the most expensive disease
to manage (Torio and Moore 2016). Mortality
from sepsis increases by about 8% per hour of
delayed appropriate administration of antibiotics (Kumar et al. 2006). Hence, sepsis and
septic shock can be prevented if diagnosed and
treated early with appropriate treatment, in
particular, antibiotics.
Sepsis and Antimicrobial Resistance
The 2021 Surviving Sepsis Campaign (SSC)
guidelines recommend starting antibiotics
as soon as possible (ideally <45-60 minutes
of recognition) (Evans et al. 2021). The
determination of procalcitonin (PCT),
with a specificity of 79% and sensitivity of
77% (Wacker et al. 2013), is not recommended because it has not demonstrated
significant benefit for the patient. However,
in a medical survey with 40 Swiss intensive care physicians, 92.3% test C-reactive
protein (CRP), 84.6% PCT, 100% lactate
and 89.7% leucocytes in case of suspicion
of sepsis (Ventura 2021). Only 35.9% use
the Sepsis-3 definition alone, while 34.2%
calculate the qSOFA and 44.7% the SOFA.
These data suggest that, in current practice,
biomarkers are used more than scores. In
addition to CRP and PCT, many biomarkers
have been studied; however, none of them
are included in the guidelines for early
diagnosis of infection or sepsis because of
the lack of consistent data.
There is a need to develop and optimise
tools to manage sepsis and decrease the
unnecessary use of antibiotics and the spread
of AMR. Developing new antibiotics and
searching for accurate solutions for early
diagnosis of sepsis are also a priority. One
possible solution could be using biomarkers
combined with clinical decision support
algorithms. The positive predictive value of
biomarkers/algorithms could allow judicious
and timely initiation of antibiotics, while
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164
negative predictive values could indicate
that antibiotics need not be administered.
Several research projects are already under
way. For example, a point-of-care testing
(POCT) solution using CRP and PCT has
been integrated into algorithms. The e-POCT
solution is an innovative electronic algorithm
using host biomarker POCTs, including
CPR and PCT. It could potentially improve
clinical outcomes among children with
febrile illnesses while reducing the use of
antibiotics through improved identification
and better targeting of children in need of
antibiotics (Keitel et al. 2017).
Pancreatic Stone Protein
Another possible diagnostic tool could be
a solution based on clinical algorithms and
the use of biomarkers with the combination of CRP and a new early biomarker of
sepsis, the Pancreatic Stone Protein (PSP).
Two literature reviews (Eggimann et al.
2019; Fidalgo et al. 2022) suggest that PSP
could be an innovative tool for the detection of pre-symptomatic sepsis. PSP is a 16
kDa C-type lectin protein produced mostly
by the pancreas and the intestine. PSP is
measured in less than 10 minutes, from a
drop of capillary or venous whole blood,
at the point-of-care (POC) by an innovative nanofluidic technology (abioSCOPE,
Abionic, Epalinges, Switzerland) CE certified since January 2020. PSP can be used to
diagnose sepsis even in severe inflammatory
states, such as in trauma patients (Keel et
al. 2009; Klein et al. 2020a), postoperative
patients (Klein et al. 2020a; Klein et al.
2015), severely burned patients (Klein et
al. 2020b), and in acute respiratory distress
syndrome (ARDS) after inhalation (Klein
et al. 2020c).
A meta-analysis shows that PSP is more
sensitive and specific than CRP and PCT
for the diagnosis of infection. The combination of CRP with PSP further enhances
its accuracy with higher sensitivity and
specificity for discriminating infection
from non-infection (Prazak et al. 2021).
PSP increases early, nearly 48-72 hours
before manifestation of clinical suspicion
of nosocomial sepsis, organ dysregulated
response onset and elevation of CRP and PCT.
Findings from a study conclude that "while
the diagnostic accuracy of PSP, CRP and PCT
for sepsis were similar in this cohort, serial
PSP measurement demonstrated an increase
of this marker the days preceding the onset
of signs necessary to clinical diagnose sepsis"
(Pugin et al. 2021). The kinetics of PSP
allow early diagnosis of nosocomial sepsis,
even before manifestation of clinical signs
and symptoms. Daily measurement of this
biomarker is, therefore, routinely proposed
in the ICU (Pugin et al. 2021). The CRP/
PSP combination is also more specific and
sensitive than CRP, PCT, and PSP alone for
diagnosing sepsis. Moreover, CRP and PSP
dosages are accessible from a drop of blood
in less than 10 minutes at the POC.
Conclusion
Overall, it is evident that there is a need
for better tools to guide the initiation of
antibiotics in managing sepsis. These tools
can also lead to the appropriate use of
antibiotics and help decrease the burden of
AMR. Using PSP in combination with other
biomarkers (CRP) can provide a useful and
practical approach in patients presenting
with sepsis with a major impact on AMR.
Moreover, integrating this combination of
biomarkers (CRP/PSP) with a clinical decision support algorithm could represent an
innovative solution to help overcome the
challenges related to sepsis and AMR. The
savings for public health would also be major,
and an estimated 1 million lives could be
saved by 2030 (Ventura 2020). Hence, the
use of a clinical decision score and POCT
biomarkers, such as CRP and PSP, can help
solve several major health problems: sepsis,
AMR, and nosocomial infections.
Key Points
- Sepsis is a major public health threat
and responsible for 11 million deaths
annually.
- Antimicrobial resistance (AMR) is
another major public health problem,
with an estimated 4.95 million deaths
associated with bacterial AMR in 2019.
- The WHO has declared AMR one of the
top ten global public health threats
facing humanity.
- The 2021 Surviving Sepsis Campaign
(SSC) guidelines recommend starting
antibiotics as soon as possible, ideally
within one hour of recognition.
- There is a need to develop and optimise
tools to manage sepsis and decrease
the unnecessary use of antibiotics
and the spread of AMR.
- The use of biomarkers such as
pancreatic stone protein (PSP), a
new biomarker shown to detect presymptomatic sepsis up to 72 hours
before the current standard of care,
could be used in combination with
clinical decision support algorithms
as a possible solution to improve the
diagnosis of sepsis and ultimately
help overcome the global challenges
related to sepsis and AMR.
Disclaimer
Point-of-View articles are the sole opinion of the author(s) and they are part of the ICU Management & Practice Corporate Engagement or Educational Community Programme.
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