Kantonsspital Aarau
Universitätsklinik der Medizinischen Fakultät Basel
Die Rolle von Procalcitonin
und anderen Biomarkern in der Sepsis ?
Beat Müller, M.D.
23 Juni 2011
Why is a critically-ill medical patient “septic”?
„Bacterial“ Sepsis
≈ 65% organism known, <50% pos BC
„Bacterial“ CAP
≈ 30% organism known, ≈ 10% pos BC
?
others
Brain
CardioVascular
Dyspnea
(AECB…)
Sepsis
33%
Pneumonia
67%
UTI
GIT
others
Müller B, Crit Care Med 2000; 28: 977-83
Christ-Crain M, AJRCCM, 06; 174: 84-93
„Patientflow“
„Common Cold“
RTI
Setting
Primary Care
Emergency Room
Pneumonia
Hospital
Sepsis
ICU
Outpatient
Diagnosis
RTI ?
Prevalence
Mortality
Bronchitis
Therapy
Antibiotics ?
Management
Prognosis ?
Inpatient
ICU
EU ≈500Mio
<<1%
≈50Mio
<1-3%
≈5Mio
5-20%
≈0.05Mio
30-70%
>100 infection and sepsis markers proposed
Why Procalcitonin?
PCT
1
1
Sensitivity
Sensitivity
CRP
IL-6
PCT + Clinical Diagnosis
Lactate
Clinical Diagnosis alone
0
0
0
1- Specificity
1
0
1- Specificity
1
Müller B, Crit Care Med (2000) 28:977-983
Harbarth S, Am J Respir Crit Care Med (2001) 164:396-402
Risk-adapted Medicine
Family Physician !
“Overruling”
(“Gatekeeper”)
(High-risk, Co-Morbidities)
Diagnosis
Respiratory
Tract Infection?
Therapy
Antibiotics ?
 side effects↑
costs↑
antibiotic resistance↑
History & Clinical Exam
“Biomarker”
(essential!)
(Grenzbereiche)
Signs &
Symptoms
Culture, Serology
Acute
Bronchitis
COPD
Exacerbation
70% of antibiotics
for 70% viral (!)
respiratory infections!
Radio
-logy
<0.1
CAP
STOP
Pneumonia Antibiotics
0.1-0.25
0.26-0.5
Stop/Start
based on
Algorithm
≥0.5
START
Antibiotic
PCT guided AB treatment
ER
LRTI
ICU
Schütz et al., Exp Rev Anti Infect 2010
Procalcitonin to reduce antibiotic use
Schütz et al., Exp Rev Anti Infect 2010
Safety of PCT guided antibiotic stewardship
SAE n=233 (17.2%)
SAE n=168 (18.1%)
Schütz P et al, JAMA 09
Schütz P et al, JAMA 09
PCT-guided AB-Therapy in ICU‘s?
Procalcitonin to reduce antibiotic use
Schütz et al., Exp Rev Anti Infect 2010
The PRORATA Study
Multicenter, ICU, Sepsis
N = 621
Antibiotic
Duration
Outcome
23% more antibiotic free days alive
Bouadma et al, Lancet 2010
Summary - Procalcitonin Guided Antibiotic Therapy
RTI
Setting
Mortality
„Common Cold“
Primary Care
Bronchitis
Emergency Room
Pneumonia
Hospital
<<1%
<1-3%
5-20%
30-70%
14%
125d
64%
0%
106d
AB-Initiation 75%
Duration 
AB exposure 75%
44%
40%
44%
40%
The less antibiotic exposure, the
less antibiotic resistance!
Sepsis
ICU
40%
Christ-Crain et al., Lancet 04
Christ-Crain et al., AJRCCM 06 & 08
Stolz et al., CHEST 07
Nobre, AJRCCM 07
Briel et al., Arch Int Med 08
Schütz et al., JAMA 09
Stolz et al., ERJ 2010
Bouadma, Lancet 2010
If PCT would be used in „real life“ for RTI...
Reduced AB-Prescription using PCT-Guidance
95%?
75%
Asia!
USA!
Latin
America!
PCT
PARTI - study, Briel M., Arch Int Med 2008
Filippini M, Health Policy, 2006
ProREAL-Team:
Dr. W. Albrich
Dr. M. Batschwaroff
Dr. F. Dusemund
Dr. P. Schuetz
Mrs. K. Regez, RN
Mrs. U. Schild, RN
Mrs. R. Bossart, RN
Principal Investigator:
Prof. Dr. B. Müller
Study sponsor:
bioMérieux, Lyon (F)
ProREAL-Contact:
+41 79 706 3003
proreal@bluewin.ch
Co-Investigators
Switzerland
Prof. Dr. W. Zimmerli (Liestal)
PD Dr. E. Bächli (Uster)
Dr. S. Meier, S. Kraljevic (Menziken)
Dr. B. Bucher, A. Spillmann (Muri)
Prof. Dr. S. Bassetti (Olten)
Dr. R. Thomann (Solothurn)
Dr. Thomas Sigrist (Klinik Barmelweid)
Dr. Daniel Rodrigues (GP, Baden)
France
Dr. G. Beaune (Annecy)
Dr. J. Gaillat (Annecy)
Prof. Dr. P. Hausfater (Pitié Salpêtrière, Paris)
Dr. P. Banel (Beaume les Dames)
Dr. E. Carre (GP‘s association president)
Dr. P. Chatron (GP, Clermont-Ferrand)
Dr. J. Thierry (GP, Lyon)
USA
Dr. D. Amin (Clearwater, FL)
1801 patients enrolled . . . !
Good compliance is feasible in real-life conditions
and leads to shorter duration of AB therapy
72.4%
Compliance
2.3% respiratory instab
0.2% hemodynamic instab
0.2% imminent death
0.8% chronic
immunosuppression
0.7% chronic or other infection
- 6.0d
- 5.7d
- 1.7d
- 76%
- 79%
- 18%
- 6.1d
- 3.8d
- 43%
81%
0.5% complication/difficult-totreat-organism
3.9% low PCT, high clinical
severity
19.0% no predefined criteria
Over entire index presentation:
algorithm-compliance 68.2%
experience country, treatment site
Algorithm-Compliance depends
on country, treatment site, experience & diagnosis
F, ambulatory
85.1%
P=0.63
CH, ambulatory
87.6%
F, hospital
66%
P<0.0001
USA, hospital
33.5 %
P=0.06
P<0.0001
CH, hospital
74.5 %
naive
60.1 %
P<0.0001
experienced
82.5 %
diagnosis
Influenza
81.0%
CAP
63.7 %
COPD exacerbation
70.1 %
Bronchitis
0%
81.0%
20%
40%
60%
80%
100%
Compliance
Limitations of Procalcitonin
&
Reasons for „Overruling“
Limitations of PCT as a marker of infection
• Cut-off range depends on clinical setting
– PCT does not replace the doctor („pretest-probability“!)
– Co-Morbidities? Setting? Site & Extent of Infection? Assay?
• False positives & negative values occur (≈10%)
– pos: SIRS, ARDS, „cytokine storm“, malaria, newborns…
– neg: early, localised, subacute, immunocompromised,
fungal...
Procalcitonin remains low in localised infections
75 yrs old patient with Empyema
T: 38.1°C, CRP: 150 mg/L, Lc: 13.4x109
PCT: 0.19 ng/ml
Procalcitonin for antibiotic stewardship in other
sites of infections?
Meningitis
Sepsis
Endocarditis
Respiratory tract infections
UTI
Abdominal infections
e.g. Pancreatitis,
Diverticulitis
Arthritis
Osteomyelitis
Limitations of PCT as a marker of infection
• Cut-off range depends on clinical setting
– PCT does not replace the doctor („pretest-probability“!)
– Co-Morbidities? Setting? Site & Extent of Infection? Assay?
• False positives & negative values occur (≈10%)
– pos: SIRS, ARDS, „cytokine storm“, malaria, newborns…
– neg: early, localised, subacute, immunocompromised,
fungal...
• „Single“ PCT measurement is of limited value
– Course & prognosis of disease?
– Withhold antibiotic therapy?
• It cannot identify the pathogen
• Cave misuse without therapeutic impact
- only then possibly cost-effective
Is Procalcitonin testing Cost-effective?
Cost: around 24 USD per measurement
Heyland KH et al, CCM 2011
What are good Predictors of Bloodculture positivity?
Collection of 2x2 blood cultures in 925
patients with CAP
91% negative blood cultures
(n=844)
9% positive bood cultures
(n=81)
1.00
(84% Strept. pneumoniae)
0.50
0.25
0.00
Sensitivity
0.75
Clinical predictors AUC
Age:
0.55
BD systolic:
0.63
Previous AB:
0.59
Temperature:
0.61
0.00
0.25
0.50
0.75
1-Specificity
Risk predictors
PSI:
0.55
Biomarkers
Leukocytes:
CRP:
PCT
0.57
0.67
0.83
1.00
Müller F. (in preparation)
Efficiency versus Economic Benefits
of PCT pre-screening
PCT cut off (µg/L)
Reduction in blood culture
collection (%)
Total costs (USD) *
Missed pathogens
Number needed to screen to
detect 1 pathogen
All
patients
0.1
0.25
0.5
1.0
1.5
-
12.6%
36.9%
51.5%
60.5%
67.5%
134’125 117’225 84’633
65’051
52’979
43’591
-
1.2%
3.7%
11.1%
16.0%
18.5%
11.4
9.1
6.5
5.2
4.4
3.5
*Asumming cost for 2 x 2 bottels of blood cultures of 145 USD
indirect costs are not included (i.e. nurses work)
Müller F. (in preparation)
PCT improves antibiotic exposure
Does PCT improve length of hospitalisations?
Obviously not….but why?
Medizin: Strategie vs. Realität
proADM
KSA Medizin
Bettenbelegung 95-105%
Pneumonia severity index (PSI)
[Fine NEJM 1997;336:243]
Co-Morbidität:
•
Tumor
•
Herzinsuffizienz
•
cerebrovask. Erkr.
•
Nierenerkrankung
•
Lebererkrankung
+
+
+
+
+
30
10
10
10
20
Labor & Röntgen
art. pH
< 7.35
P-Harnstoff > 11mmol/l
P-Natrium < 130 mmol/l
P-Glucose > 14 mmol/l
Hämatokrit < 30%
PaO2
<60mmHg (8 KPA)
Pleura-Erguss
Untersuchung
•
Verwirrung
•
HF > 125/min
•
AF > 30/min
•
Bdsyst < 90 mmHg
•
Temp < 35° / >40°
+
+
+
+
+
20
10
20
20
15
…….………
Punkte





< 50 Punkte
<70 Punkte
71-90 Punkte
91-130 Punkte
> 130 Punkte
PSI Klasse
-->
-->
-->
-->
-->
PSI
PSI
PSI
PSI
PSI
Klasse
Klasse
Klasse
Klasse
Klasse
I
II
III
IV
V
Gesamtpunkte….....
Mortalität
-->
-->
-->
-->
-->
.......
.......
+ 10
Alter m (in Jahren)
f (in Jahren -10)
aus Altersheim
Mortalität:
Mortalität:
Mortalität:
Mortalität:
Mortalität:
+
+
+
+
+
+
+
30
20
20
10
10
10
10
…….………
weiteres Management
0.1%
0.6%
0.9%
9.3%
27.0%
-->
-->
-->
-->
-->
Ambulantes Management erwägen
Ambulantes Management erwägen
Ambulantes Management erwägen
Hospitalisation erwägen
Hospitalisation / IPS erwägen
CAP patients are hospitalised because
of (mis)perceived medical reasons
Medical
factors
Inpatient?
SAE 5%
SAE 25%
Nursing Patients` Relatives` Organisational
factors preference preference
factors
Physicians
High risk CAP patients
(n=215)
Outpatient?
Percentage (%)
Percentage (%)
Low risk CAP patients
(n=181)
Prognostic
Risk Assessment!
Nurses
Patients
Medical
factors
Nursing Patients` Relatives` Organisational
factors preference preference
factors
Relatives
Bähni C, Meier S., Spreiter P, BMC Pulm Med 2010
Diagnostic & Prognostic Biomarkers ?
MR-proADM
Risk-adapted Medicine
Family Physician !
“Overruling”
“Overruling”
(“Gatekeeper”)
(High-risk, Co-Morbidities)
(Wish of patients & relatives)
Diagnosis
Respiratory
Tract Infection?
Therapy
Antibiotics ?
Management
Hospitalisation?
History & Clinical Exam
Procalcitonin
Prognost. Assessment
(essential!)
(Grenzbereiche)
(Scores, Biomarker, Pflege)
Signs &
Symptoms
Culture, Serology
Acute
Bronchitis
COPD
Exacerbation
Radio
-logy
<0.1
CAP
STOP
Pneumonia Antibiotics
0.1-0.25
0.26-0.5
Stop/Start
based on
Algorithm
≥0.5
START
Antibiotic
Sehr tief Tief
Outpatient
Hoch
Short stay
NLU / Rehab
Home-Nursing
OPTIMA
Sehr hoch
Hospital.
ICU
Outcome prediction in CAP
42
24
p = ns
20
ProCT (ng/ml)
Temperatur
Temperature
(°C)
41
40
39
38
16
12
8
4
37
0
36
I1
II2
3
4
III
IV
PSI Klasse
class
PSI
500
Mortalität
p =0%
ns
1
5
V
35
Leukozten
300
200
100
3
4
5
40
30%
400
2
PSI class
Leucocyte count (x109)
Protein
C-reaktives
CRP (mg/L)
p <0.001
p = ns
30
25
20
15
10
5
0
I1
II2
3
4
III
IV
PSIKlasse
class
PSI
V5
0
I1
II2
3
4
5
III
IV
V
PSIKlasse
class Christ-Crain et al., Crit Care 06
PSI
Stress hormones to predict severity of
pneumonia
200
p < 0.001
p < 0.001
Cortisol (nmol/L)
Copeptin (pmol/L)
240
200
160
120
80
150
100
50
40
0
I
II
III
IV
PSI Klasse
V
0
I
II
III
IV
PSI Klasse
V
Mortalität
0%
30%
0%
30%
Christ-Crain et al., Eur J Clin Invest 07
Christ-Crain et al., Am J Respir Crit Care Med 07
Cortisol predicts Mortality in CAP
3500
120
P<0.001
P=0.001
110
Free cortisol (nmol/L)
Total cortisol (nmol/L)
3000
2500
2000
1500
100
90
80
70
60
1000
50
1.00
Survivors
Survivors
Non-Survivors
Non-Survivors
n=85
0.50
0.75
n=166
Total cortisol < 960 nmol/L
0.25
Total cortisol > 960 nmol/L
0.00
Probability of survival
P < 0.0001
0
20
40
Analysis time (days)
60
Christ-Crain M, AJRCCM 2007
Adrenomedullin in pneumonia
6
p < 0.001
ProADM (nmol/L)
5
4
3
2
1
p < 0.02
0.50
PSI:
0.75
ProADM:
0.76
Combined: 0.78
0.00
0.25
Sensitivity
0.75
1.00
0
250
0.00
0.25
0.50
1-Specificity
0.75
1.00
Adrenomedullin
NH2-
QKL
QG
DNV AP
V
A
K
L
Q G Y -C
F
Y
T
P
D
R
H
R
N
K
R
C
S K IS
Q
S
Q
N
D
T
F
S M
I
T
GCR G
YQ F
F
O
NH2
Adrenomedullin
The CALC Gene Family
I'
II'
III'
IV'
V'
VI'
I'
II'
III'
IV'
V'
VI'
CT/PCT
CGRP I
CGRP II
I
II
II'
III'
VI'
Amylin
ADM
I'
V'
IV'
V'
- One of the most potent vasodilating agents
- Bactericidal activity
- Increased in sepsis, higher in non-survivors than survivors
Prognostic Biomarkers in LRTI
Prediction of Mortality & SAE
(PSI & CURB65: validated only for mortality in CAP)
 Biomarkers predict both outcomes in CAP & LRTI
ProHOSP, LRTI n=1359
ProADM improves the prognostic posttest
accuracy of the PSI Score to predict mortality
Pre-test
Probability
CAP PSI I-III
~ 1%
CAP overall
~ 7%
CAP PSI IV-V
~ 20%
ProADM < 1.8 nM LR- 0.28
ProADM > 1.8 nM LR+ 2.9
LR
Post-test
Probability
40 %
ICU ?
20 %
3%
0.2 %
Outpatient ?
Fagan. NEJM 1975; 293: 257
Hospitalization - more than „just“ medicine
The 4 „C“
Community
Control
„Patient & Relatives“
„Hospital Management“
Cure
Care
„Doctors“
„Nurses“
Adapted from Glouberman S, Health Care Mgmt Rev 2001
Risk-adapted Patient-Management
Observationphase = Recommendation; Interventionphase = Implementation
Assessment of medical, nursing & social Risik and
need for patient education (empowerment)
(with Scores and/or Biomarkers)
Biomarker
eg proADM
RISIK
<0.75
0.75-1.5
1.5
>2.5
Low
Intermediate
High
Very high
Advice
Outpatient
Advice
• Home-nurse
• Nurse led Unit
(NLU)
• Short Inpatient
Advice
Inpatient
Advice
ICU
„Overruling“
- Medical factors: C(U)RB65 Score, (PSI, GOLD), schwere medizinische Co-Morbidität
- Nursing factors: Barthel Index, Rowland Score
- Social factors: Fear, Denial, Opposition, Lack of care at home
Follow-up assessment of triage & Rehab-Potential
Patients with LRTI  250 / yr
Currently (Apr
Independent of
- Medical assessment
250
- Nursing / functional assessment
- Preference of patient & relatives
→ Avalilability of Beds problematic / erratic
Outpatient
Home-nursing
care
ÜbergangsPost-acute
pflege
Nursing
2010)
250
Nurse-led Unit
(NLU)
Traditional
Hospital (KSA)
OPTIMA (Oct 10 – May 11)
250
150
10
Outpatient
30
Home-nursing
care
30
Post-acute
Care
30
Nurse-led Unit
(NLU)
KSA
«Kosten – Effizienz»
oder - Defizienz
in der Medizin ?
“OPTIMAL” ??
Conclusions
 Diagnosis of bacterial RTI & Antibiotic Guidance
- 11 (!) RCTs from 5 independent groups established Procalcitonin as
novel „gold standard“ biomarker for antibiotic guidance in RTI & sepsis.
 Prognosis & Hospital Management
- Substantial medical & socio-economic impact
- State-of-the-art clinical scores (PSI, CURB-65, CRB-65) NOT validated
for non-pneumonia RTI & non-fatal SAEs relevant for hospitalisation
- Biomarkers complement & improve the discriminatory ability of
these risk scores for mortality & clinical relevant SAEs
(death, ICU-admission, complications)
 Interdisciplinary Approach needed
- Medical (“fear”), nursing, social & community-related factors
- Collaboration between institutions & creation of incentives
(government, hospital, nursing home, “out-of-hospital” care)
Our health care resources are limited !
Thus, they need to be allocated to high-risk patients !!
DANKE
für Ihre Aufmerksamkeit
Limitations of PCT as a marker of infection
• Cut-off range depends on clinical setting
– PCT does not replace the doctor („pretest-probability“!)
– Co-Morbidities? Setting? Site & Extent of Infection? Assay?
• False positives & negative values occur (≈10%)
– pos: SIRS, ARDS, „cytokine storm“, malaria, newborns…
– neg: early, localised, subacute, immunocompromised,
fungal...
• „Single“ PCT measurement is of limited value
– Course & prognosis of disease?
– Withhold antibiotic therapy?
• It cannot identify the pathogen
• Cave misuse without therapeutic impact
- only then probably cost-effective
• Not for Escalation (broader) Antibiotic therapy
High / increasing PCT  Bad Sepsis-outcome
 ESCALATION of Antibiotic Therapy?
(do you believe that not
enough antibiotics
are the problem
in septic shock & MOF?)
Jensen JU, Crit Care Med 06; 34:2596-602
High / increasing PCT  Bad Sepsis-outcome
 ESCALATION of Antibiotic Therapy?
PASS trial
Patients: 1200 in ICU
Intervention: If PCT >1ng/ml or
increasing then
- (re)-sampling & imaging
- «blind» broadening of AB
1° Endpoint: Reduction in
mortality?
Power: ARR 7.5% mortality
2° Endpoint: ressource use
BUT: escalation of measures
defined by the protocol
! Problem: What was tested?
Effectiveness of PCT and/or of
broadening of AB therapy?
Jensen JU, Crit Care Med 06; 34:2596-602
ESCALATION of Antibiosis in worsening ICU-Pat.?
The PASS Study
Setting: ICU = (understandable) high baseline use of antibiotic therapy
Patients: 1200, Danish ICU, high quality of care
Admitted for failure of respiration > haemodynamic > «infection»
Intervention: If PCT >1ng/ml or increasing then
- (re)-sampling & imaging recommended
- guideline-based «blind» broadening of «empirical» therapy
Research Questions:
1° Endpoint: Does it help to give even more/broader antibiotic therapy?
Power: ARR 7.5% mortality (no sepsis study ever reached that goal!)
2° Endpoint: Will you use more ressources?
Of course you will (escalation of measures is defined by the protocol)
-What
was tested?
The Effectiveness of PCT and/ or
of guideline recommended broadening of antibiotic therapy?
-Were
the therapeutic measures taken effective? We don’t know !
- Early goal directed therapy randomized by PCT?
- PCT Immunoneutralisation ?
The ProCAP Study (N = 302)
Diagnostic accuracy for Bacteremia
100
0.5
80
0.25ug/L
1.0
ProCT
CRP
Lc
T
PSI
VAS
60
40
AUC 0.86
AUC 0.69
AUC 0.60
Only 11% pos. BC
in ‚bacterial‘ CAP
in need for AB!
20
0
0
20
40
60
100-Specificity
80
100
Delay? Sensitivity??
Gold standard ???
Müller B, BMC Inf Dis 2007
PCT as a marker of infection in UTI?
•
Prospective observational study in 30 women
with uncomplicated acute pyelonephritis
•
Measurement of PCT, CRP at inclusion, at day 4 and every
day until normalization (PCT < 0,25, CRP < 10) & at the end
of antibiotic treatment
• At inclusion:
- PCT>0.25ug/L: 37% (median 0.16)
- CRP>10 mg/L: 90% (median 96)
•
At day 5:
- PCT<0.25ug/L: 80%
- CRP<10 mg/L: 17%
•
Median days to normalization:
PCT: 5 days
CRP: 8 days
Abstract kindly provided by S.Harbarth, C. Delémont et al. SFMU & SAEM 2011
PCT as a marker of infection in UTI?
•
→ PCT: with this cutoff little help for antibiotic
discontinuation in APN due to small portion of patients
with abnormal PCT at diagnosis.
→ CRP: frequently elevated at diagnosis, but long time to
normalization
→ None of these markers useful to guide AB
treatment discontinuation in APN
Other cutoffs? Cave: PCT>0.25 ≠ CRP>10
Abstract kindly provided by S.Harbarth, C. Delémont et al, SFMU & SAEM 2011
Septic or non-septic Arthritis?
PCT as a marker of infection in localized
orthopaedic infections?
- Retrospective study comparing PCT & CRP in patients with
localised non-bacteremic orthopaedic infections
- 60 infected patients, tx with AB, surgery to cure infection
- Postoperative PCT were rarely elevated despite continued
infection; PCT not better than less expensive CRP
Uckay et al., Swiss med wkly 2010
Limitations of PCT as a marker of infection
• Cut-off range depends on clinical setting
– Co-Morbidities? Setting? Site & Extent of Infection? Assay?
– PCT does not replace the doctor („pretest-probability“!)
• False negative & positive values occur (≈10%)
– neg: very early, localised, subacute, immunocompromised,
fungal...
– pos: SIRS, ARDS, „cytokine storm“, malaria, newborns…
PCT to guide duration of AB therapy in
surgical ICU patients: a randomized controlled trial
Choice and Duration of Antibiotic therapy
110 Surgical ICU patients with suspicion of sepsis
Stopp AB if clinical signs improved and PCT <1 ng/ml
or the PCT value was >1 ng/ml, but had dropped to 25
to 35% of the initial value over three days.
Similar outcomes (SOFA & mortality)
Conclusion: Monitoring of PCT is a helpful tool for
guiding AB treatment in surgical intensive care
patients.
Hochreiter et all, CC 2009
CRP for RCTs?
• is frequently used in Europe (>> US)
- Low cost, easy availability, „historic practice“
• improves the „routine“ diagnosis of LRTI
– as compared to signs & symptoms, Temp, WBC
– severe bacterial infection is unlikely if CRP<50ug/L (SMW 06)
• has, like every biomarker, diagnostic pitfalls
– hsCRP = marker of „chronic, subtle inflammation“
 helpful for assessment of cardiovascular risk (US)
– Less wide „diagnostic range“ (CRP: 102, PCT: 105)
– more „unspecific“ increase in SIRS, trauma alone (CCM 00)
 Not prognostic in severe infections (CAP, sepsis; Crit Care 06)
– delayed increase during the course (peak 2-3d, Infection 07)
 limiting its use during the initial work-up & guidance of AB-duration
– hepatic production is largely IL-6 dependent
 falsely low levels with steroids (COPD!, J Leukoc Biol 02)
• may therefore be less safe to guide antibiotic therapy
Lots of Refs available upon request!
CRP dynamics predict AB appropriateness
in VAP
- Prospective observational study in 68 patients with
suspected VAP; CRP measured on diagnosis & 96 hours
after start of AB
- Aim: to evaluate value of CRP for antibiotic response
CRP ratio (follow-up/baseline) of 0.80 =
useful indicator of AB appropriateness
- Conclusion: Serial CRP measurements after VAP onset
may help to evaluate effectiveness of AB treatment
Lisboa et al, Crit Care Med 2008
CRP velocity following Antibiotics
- Aim: to study whether CRP on admission and delta CRP
following initiation of AB provide a tool for distinguishing
CAP from COPD exacerbation
- Conclusion: CRP velocity can be used to distinguish CAP
from COPD exacerbation → Intervention studies needed
Justo et al, Eur J Int Med 2009
CRP for antibiotic stewardship in primary care
-42%
-51%
-66%
Cals JWL, et al, BMJ 09; 338: 1374
CRP to reduce AB in the ED?
139 Patients presenting to the ED with acute cough
randomized to control or CRP-group
control group: recommendations for chest X-ray and AB
CRP group: same algorithm plus CRP testing.
AB tx Control group: 31%, CRP group 37%, p=ns
Gonzales et al., J Emerg Med 2008
Biomarkers for antibiotic stewardship:
anything beyond PCT?
sTREM-1
suPAR
PCT (ug/L)
Neutrophils x109 cells/L
MIF (ug/L)
CRP (mg/L)
sTREM-1 (ug/L)
suPAR (ug/L)
Multimarker-Approach
Kofoed et al., Crit Care 2007
Multimarker-Approach
AUC‘s for detection of a
bacterial cause of inflammation:
0.50 (0.40-0.60)
0.61 (0.52-0.71)
0.63 (0.53-0.72)
0.74 (0.73-0.81)
0.72 (0.63-0.79)
0.81 (0.73-0.86)
0.84 (0.71-0.91)
0.88 (0.81-0.92)
Kofoed et al., Crit Care 2007
Combination of PCT & BPW
(biphasic transmittance waveform) from the
activated partial thromboplastin time (aPTT)
for prediction of sepsis in 200 adults admitted to ICU
Zakariah et al., Crit Care Med 2008
Combination of CRP and IL-8 to reduce AB
AB treatment in IL-8 & CRP group: 36.1%
Standard group: 49.6% p<0.001
Similar % of infections missed at initial evaluation (~ 15%)
The number of newborns who received postnatal antibiotic
therapy could be safely reduced with a diagnostic algorithm
that includes measurement of IL-8 & CRP
Franz et al., Pediatrics 2004
Conclusion
• > 100 different biomarkers for infection & sepsis proposed
• RCT‘s very limited !
• Procalcitonin: best & most frequently studied biomarker,
11 RCT‘s!
→ 35-70% reduction in antibiotic use without apparent
negative impact on patient outcome
→ Tested in primary care & hospital setting (ED, ICU)
→ limitations:
- usefulness in other infections (e.g. UTI)?
- too expensive
- false positive & negatives occur
- lacks necessary accuracy to be used without
clinical judgement
Anything beyond PCT?
• C-reactive protein:
proved to be useful for AB stewardship in primary care,
probably better marker in localised infections
→ limitations:
• rather unspecific
• delayed increase
• No RCT‘s in ER, ICU in adults!
• New biomarkers?
→ many tested in observational studies
no intervention studies available
What should we achieve by 2020?
• Test new biomarkers in intervention studies
• Combine promising markers & test in intervention studies
→ challenge to find the most cost-effective markers
& to include in daily practice
Accurate Diagnosis of Sepsis is Important
for Rapid Initiation of Antibiotics
On admission




Question
Intubated & comatose
Temperature: 38.6 °C
BP 90/55; P 113
Rales in both lungs
Really Sepsis?
Procalcitonin cut off*
<0.5ng/ml
>2.0ng/ml
Clinical Interpretation
Sepsis Very
Unlikely
Sepsis Very
Likely
Consequence for physician
Other
Diagnosis ?
Start AB
Therapy
*Guidelines from the German Sepsis Society
Monitoring PCT Gives you Important Information
about Patients’ Prognosis
Day 3 of ICU stay
 Still intubated
 Temperature subfebrile
 Need for Vasoactiva
Question
Procalcitonin
Prognosis
Decrease
No Decrease
Clinical Interpretation
Responding
Not Responding
Consequence for physician
Continue AB
Therapy
Other
Diagnosis?
*Guidelines from the German Sepsis Society
Dynamics of Biomarkers upon Infection
ug/ml
h
Endotoxin iv
Pneumonia - How long to treat?
PCT (ng/mL)
T1/2 ProCT:  24h
100
(log-linear)
CRP (mg/mL)
10
300
250
200
1
150
100
50
0.1
0
1
0.01
2
3
4
5
6
7
0
8 days on ICU
"Normal" Reference range
J.C.E., 28yrs
Antibiotics iv
PCT-guided Antibiotic Therapy
(mg/L)
100
Antibiotic (AB) use?
GPs
COPD
ER
RTI
ICU
Trauma
Septic Shock
10
Severe Sepsis
Sepsis
Pneumonia
Bronchitis
COLD
2
1
0.5
0.25
0.1
Assay?
YES!
YES!
Yes
YES
Yes
No
No
No
NO!
NO!
NO!
LUMItest® PCT LIA
PCT-Q®
ProCT
PCT KRYPTOR® / VIDAS ®
Diagnosis
Healthy
0.01
Christ-Crain M, Eur Resp J, 07
Schuetz P, Curr Opin Crit Care, 07
Time Course PCT & CRP after Heart Surgery
adapted from
Sponholz C, Crit Care 06; 10:R145
CRP for antibiotic stewardship in primary care
-
RCT with 258 patients of 32 GP‘s.
Randomization to usual care or CRP assistance
Primary outcome: antibiotic use after index consultation
Secondary outcomes: patient satisfaction, clinical
recovery
Cals et al., Ann Fam Med 2010; 8: 124-133
PCT guided antibiotic stewardship in “Real Life”
• Question: Is the use of PCT safe & efficient outside
controlled study conditions?
• Quality control Survey in patients with LRTI in different hospitals
• Switzerland (11 hospitals), France (3), USA (1)
• Patients with LRTI included in registry via website, where the
recommended algorithm was displayed
• 1°endpoint: AB duration within 30 days
2° endpoint: adherence to algorithm
• 1810 patients enrolled
Albrich et al, in preparation
PCT guided antibiotic stewardship in “Real Life”
• Overall compliance with algorithm on presentation 72.4%, + 8.6%
overrulings based on prespecified criteria = 81.0%
• Most important overruling criteria high clinical severity
• Antibiotic duration significantly shorter in LRTI if PCT algorithm was
followed (6.2 vs 8.4 days)
Albrich et al, in preparation
PCT guided antibiotic stewardship in “Real Life”
• Duration of antibiotic treatment was significantly lower as
compared to“pre-PCT” time & similar to PCT groups in
studies
• 18% of overrulings based on prespecified criteria
• 10% of overrulings without prespecified criteria
Overruled with
prespecified reason
Immuno-suppression
ICU admission
High risk patients
2%
2%
Anticipated complications
Overruled without
prespecified reason
Decision of the treating
physician
Not overruled
Schuetz P et al, Eur J of Clin Microbiology and Inf Disease, 2010
Outcome and complications
Outcome (in LRTI) (no.(%))
In-hospital mortality
79 (5.2%)
Need for ICU admission
159 (10.5%)
In-hospital overall complications
293 (19.3%)
30-day-mortality
109/1425 (7.6%)
30-day-recurrence rate
32/1425 (2.2%)
Risk factors for complications
30 day complications
OR
95% CI
P
CURB65
1.35
1.07-1.72
0.01
CAP (vs. bronchitis)
6.81
2.97-15.61
<0.0001
Multilobar pneumonia
5.25
1.62-17.02
0.006
History of stroke
0.25
0.08-0.77
0.015
Compliance with the algorithm was not associated with risk of complication (p=0.26)
The PRORATA Study – Subgroups
Antibiotic
Duration
Outcome
Bouadma et al, Lancet 2010
PCT-guided AB-Therapy in Sepsis on the ICU
Shorter Antibiotic Duration
6d
10d
Nobre V et al, AJRCCM 07
2 Confessions
As a clinician, I used to
diagnose bacterial
infections and
prescribe antibiotics
easily & accurately.
Now, after 20 yrs of research,
I am no longer so ignorant.
I received funding from
vendors of biomarker
assays.
I never received funding
from companies selling
antibiotics.
So, yes, I might be biased.