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Kantonsspital Aarau
Universitätsklinik der Medizinischen Fakultät Basel
Die Rolle von Procalcitoninund anderen Biomarkern in der Sepsis ?
Beat Müller, M.D.
23 Juni 2011
Why is a critically-ill medical patient “septic”?
Müller B, Crit Care Med 2000; 28: 977-83 Christ-Crain M, AJRCCM, 06; 174: 84-93
Sepsis33%
others
Cardio-Vascular
Brain
Dyspnea(AECB…)
Pneumonia67%
UTIGIT
others
?„Bacterial“ Sepsis ≈ 65% organism known, <50% pos BC„Bacterial“ CAP ≈ 30% organism known, ≈ 10% pos BC
Therapy Antibiotics ?
Management Prognosis ?
Diagnosis RTI ?
„Patientflow“
Outpatient
Inpatient
ICU
„Common Cold“ Bronchitis Pneumonia Sepsis
Mortality <<1% <1-3% 5-20% 30-70%
RTI
Prevalence EU ≈500Mio ≈5Mio ≈50Mio ≈0.05Mio
Emergency Room HospitalPrimary Care ICUSetting
>100 infection and sepsis markers proposed
Why Procalcitonin?
Müller B, Crit Care Med (2000) 28:977-983
1- Specificity1- Specificity
Sen
siti
vity
Sen
siti
vity
00 1
11
00
PCT
Lactate
CRPCRP
IL-6IL-6
00 11
Sen
siti
vity
Sen
siti
vity
11
00
PCT + Clinical Diagnosis
Clinical Diagnosis alone
Harbarth S, Am J Respir Crit Care Med (2001) 164:396-402
Diagnosis Respiratory
Tract Infection?
History & Clinical Exam(essential!)
Family Physician ! (“Gatekeeper”)
Risk-adapted Medicine
Therapy Antibiotics ?
“Biomarker”(Grenzbereiche)
“Overruling”(High-risk, Co-Morbidities)
Signs & Symptoms
Radio-logyCulture, Serology
COPDExacerbation
CAPPneumonia
Acute Bronchitis
<0.1 0.26-0.5 ≥0.50.1-0.25
Stop/Start based onAlgorithm
STOPAntibiotics
STARTAntibiotic
70% of antibiotics for 70% viral (!)
respiratory infections!
side effects↑costs↑antibiotic resistance↑
PCT guided AB treatment
Schütz et al., Exp Rev Anti Infect 2010
ERLRTI
ICU
Schütz et al., Exp Rev Anti Infect 2010
Procalcitonin to reduce antibiotic use
Safety of PCT guided antibiotic stewardship
Schütz P et al, JAMA 09
SAE n=168 (18.1%)SAE n=233 (17.2%)
Schütz P et al, JAMA 09
PCT-guided AB-Therapy in ICU‘s?
Schütz et al., Exp Rev Anti Infect 2010
Procalcitonin to reduce antibiotic use
The PRORATA Study
Multicenter, ICU, SepsisN = 621
23% more antibiotic free days alive
AntibioticDuration
Outcome
Bouadma et al, Lancet 2010
„Common Cold“ Bronchitis Pneumonia Sepsis
Mortality <<1% <1-3% 5-20% 30-70%
RTI
Summary - Procalcitonin Guided Antibiotic Therapy
Emergency Room Hospital
AB-Initiation Duration
40% 14% 125d
75%
Primary Care ICUSetting
0% 106d
Christ-Crain et al., Lancet 04Christ-Crain et al., AJRCCM 06 & 08
Stolz et al., CHEST 07Nobre, AJRCCM 07
Briel et al., Arch Int Med 08Schütz et al., JAMA 09
Stolz et al., ERJ 2010Bouadma, Lancet 2010
44%
AB exposure 40%75% 44% 64% 40%
The less antibiotic exposure, the less antibiotic resistance!
If PCT would be used in „real life“ for RTI...
Filippini M, Health Policy, 2006
PARTI - study, Briel M., Arch Int Med 2008
75%
95%?
Asia!USA!LatinAmerica!
Reduced AB-Prescription using PCT-Guidance
PCT
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
Co-InvestigatorsSwitzerland
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)
FranceDr. 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)
USADr. D. Amin (Clearwater, FL)
1801 patients enrolled . . . !
Good compliance is feasible in real-life conditions
Over entire index presentation: algorithm-compliance 68.2%
Compliance
respiratory instab
hemodynamic instab
imminent death
chronicimmunosuppression
chronic or other infection
complication/difficult-to-treat-organism low PCT, high clinicalseverity
no predefined criteria
81%
72.4% 2.3% 0.2% 0.2% 0.8% 0.7% 0.5% 3.9%
19.0%
- 3.8d
- 43%
- 6.1d- 1.7d
- 18%
- 5.7d
- 79%
- 6.0d
- 76%
and leads to shorter duration of AB therapy
Algorithm-Compliance depends on country, treatment site, experience & diagnosis
0% 20% 40% 60% 80% 100%
Bronchitis
COPD exacerbation
CAP
Influenza
experienced
naive
CH, hospital
USA, hospital
F, hospital
CH, ambulatory
F, ambulatory
dia
gn
osi
sex
per
ien
ceco
un
try,
tre
atm
ent
sit
e
Compliance
81.0%
70.1%
63.7%
81.0%
82.5%
60.1%
P<0.0001
74.5%
66%
33.5% P=0.06
P<0.0001
P<0.0001
P=0.63
87.6%
85.1%
Limitations of Procalcitonin
&
Reasons for „Overruling“
• 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...
Limitations of PCT as a marker of infection
Procalcitonin remains low in localised infections
75 yrs old patient with EmpyemaT: 38.1°C, CRP: 150 mg/L, Lc: 13.4x109
PCT: 0.19 ng/ml
UTI
Meningitis Sepsis
Procalcitonin for antibiotic stewardship in other sites of infections?
Arthritis
Endocarditis
Abdominal infections e.g. Pancreatitis,
Diverticulitis
Respiratory tract infections
Osteomyelitis
• Cut-off range depends on clinical setting– PCT does not replace the doctor („pretest-probability“!)– Co-Morbidities? Setting? Site & Extent of Infection? Assay?
• „Single“ PCT measurement is of limited value– Course & prognosis of disease?– Withhold antibiotic therapy?
• False positives & negative values occur (≈10%)– pos: SIRS, ARDS, „cytokine storm“, malaria, newborns…– neg: early, localised, subacute, immunocompromised,
fungal...
• It cannot identify the pathogen
• Cave misuse without therapeutic impact- only then possibly cost-effective
Limitations of PCT as a marker of infection
Is Procalcitonin testing Cost-effective?
Heyland KH et al, CCM 2011
Cost: around 24 USD per measurement
Collection of 2x2 blood cultures in 925 patients with CAP
9% positive bood cultures (n=81)
91% negative blood cultures (n=844)
What are good Predictors of Bloodculture positivity?0
.00
0.2
50
.50
0.7
51
.00
Se
ns
itiv
ity
0.00 0.25 0.50 0.75 1.001-Specificity
Age: 0.55
Temperature: 0.61
BD systolic: 0.63
PSI: 0.55
Previous AB: 0.59
CRP: 0.67Leukocytes: 0.57
PCT 0.83
Clinical predictors
Risk predictors
Biomarkers
AUC
Müller F. (in preparation)
(84% Strept. pneumoniae)
Efficiency versus Economic Benefitsof PCT pre-screening
All patients 0.1 0.25 0.5 1.0 1.5
Reduction in blood culture collection (%) - 12.6% 36.9% 51.5% 60.5% 67.5%
Total costs (USD) * 134’125 117’225 84’633 65’051 52’979 43’591
Missed pathogens - 1.2% 3.7% 11.1% 16.0% 18.5%
Number needed to screen to detect 1 pathogen 11.4 9.1 6.5 5.2 4.4 3.5
PCT cut off (µg/L)
Müller F. (in preparation)
*Asumming cost for 2 x 2 bottels of blood cultures of 145 USD indirect costs are not included (i.e. nurses work)
PCT improves antibiotic exposureDoes PCT improve length of
hospitalisations?
Obviously not….but why?
Medizin: Strategie vs. Realität
proADM KSA Medizin Bettenbelegung 95-105%
Pneumonia severity index (PSI)
< 50 Punkte --> PSI Klasse I --> Mortalität: 0.1% --> Ambulantes Management erwägen <70 Punkte --> PSI Klasse II --> Mortalität: 0.6% --> Ambulantes Management erwägen 71-90 Punkte --> PSI Klasse III --> Mortalität: 0.9% --> Ambulantes Management erwägen 91-130 Punkte --> PSI Klasse IV --> Mortalität: 9.3% --> Hospitalisation erwägen > 130 Punkte --> PSI Klasse V --> Mortalität: 27.0% --> Hospitalisation / IPS erwägen
[Fine NEJM 1997;336:243]
Co-Morbidität: Tumor Herzinsuffizienz cerebrovask. Erkr. Nierenerkrankung Lebererkrankung
Untersuchung Verwirrung HF > 125/min AF > 30/min Bdsyst < 90 mmHg Temp < 35° / >40°
Alter m (in Jahren) f (in Jahren -10)aus Altersheim+ 30
+ 10+ 10+ 10+ 20
+ 20+ 10+ 20+ 20+ 15
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
+ 30+ 20+ 20+ 10+ 10+ 10+ 10
.......
.......+ 10
Gesamtpunkte…..... …….……… …….………
Punkte PSI Klasse Mortalität weiteres Management
CAP patients are hospitalised because
of (mis)perceived medical reasons
Medical factors
Nursing factors
Patients` preference
Relatives` preference
Organisational factors
Per
cen
tag
e (%
)
Medical factors
Nursing factors
Patients` preference
Relatives` preference
Organisational factors
Per
cen
tag
e (%
)
Low risk CAP patients (n=181)
High risk CAP patients (n=215)
Physicians Nurses Patients Relatives
Prognostic Risk Assessment!
Outpatient?SAE 5%
Inpatient?SAE 25%
Bähni C, Meier S., Spreiter P, BMC Pulm Med 2010
MR-proADM
Diagnostic & Prognostic Biomarkers ?
Diagnosis Respiratory
Tract Infection?
History & Clinical Exam(essential!)
Family Physician ! (“Gatekeeper”)
Risk-adapted Medicine
Therapy Antibiotics ?
Procalcitonin(Grenzbereiche)
“Overruling”(High-risk, Co-Morbidities)
Signs & Symptoms
Radio-logyCulture, Serology
COPDExacerbation
CAPPneumonia
Acute Bronchitis
<0.1 0.26-0.5 ≥0.50.1-0.25
Stop/Start based onAlgorithm
STOPAntibiotics
STARTAntibiotic
Management Hospitalisation?
Prognost. Assessment(Scores, Biomarker, Pflege)
“Overruling”(Wish of patients & relatives)
Sehr tief Hoch Sehr hochTief
Short stayNLU / Rehab Home-Nursing
Out-patient
Hospital.ICU
OPTIMA OPTIMA
Outcome prediction in CAP
1 2 3 4 5
PSI class
36
37
38
39
40
41
42
Tem
per
atu
re (
°C)
p = ns
Te
mp
era
tur
1 2 3 4 5
PSI class
0
100
200
300
400
500
CR
P (
mg
/L)
1 2 3 4 5
PSI class
0
5
10
15
20
25
30
35
40
Leu
cocy
te c
ou
nt
(x10
9)
p = ns p = ns
I II III IV V PSI Klasse
Le
uk
ozt
en
C-r
ea
kti
ve
s P
rote
in
I II III IV V PSI Klasse Christ-Crain et al., Crit Care 06
I II III IV V PSI Klasse
Mortalität 0% 30%
1 2 3 4 5
PSI class
0
4
8
12
16
20
24
Pro
CT
(n
g/m
l)
p <0.001
0% 30%
p < 0.001
I II III IV V PSI Klasse
Stress hormones to predict severity of pneumonia
Christ-Crain et al., Eur J Clin Invest 07
Co
pep
tin
(p
mo
l/L
)
Mortalität
0% 30% 0% 30%
Christ-Crain et al., Am J Respir Crit Care Med 07
0
40
80
120
160
200
240
0
50
100
150
200
I II III IV V PSI Klasse
Co
rtis
ol
(nm
ol/
L)
p < 0.001
Cortisol predicts Mortality in CAP
1000
1500
2000
2500
3000
3500
Tota
l c
ort
iso
l (n
mo
l/L
)50
60
70
80
90
100
110
120
Fre
e c
ort
iso
l (n
mo
l/L
)
Survivors Non-Survivors Survivors Non-Survivors
P<0.001 P=0.001
Christ-Crain M, AJRCCM 2007
0.00
0.25
0.50
0.75
1.00
0 20 40 60
Total cortisol < 960 nmol/L
Total cortisol > 960 nmol/L
Analysis time (days)
Pro
bab
ility
of
surv
ival
P < 0.0001
n=166
n=85
Adrenomedullin in pneumonia
0
1
2
3
4
5
6
Pro
AD
M (
nm
ol/L
)
p < 0.001
250
0.00
0.25
0.50
0.75
1.00
Se
nsi
tivity
0.00 0.25 0.50 0.75 1.001-Specificity
Combined: 0.78
ProADM: 0.76
PSI: 0.75
p < 0.02
Adrenomedullin
CGRP ICT/PCT
ADM
Amylin
The CALC Gene Family
I II V'
II' III'I' IV' V' VI'
CGRP IIII' III'I' IV' V' VI'
II' III'I' IV' V' VI'
- One of the most potent vasodilating agents- Bactericidal activity- Increased in sepsis, higher in non-survivors than survivors
YRQS M
N
NH2- NFQ G
LRSFG C R F
GT
TC
VQ K L
AHQIYQ F
T
D
DK
K D N V APRS K I
SP Q G Y
O
NH2
-C
Adrenomedullin
Prognostic Biomarkers in LRTI Prediction of Mortality & SAE
ProHOSP, LRTI n=1359
(PSI & CURB65: validated only for mortality in CAP)
Biomarkers predict both outcomes in CAP & LRTI
ProADM improves the prognostic posttest accuracy of the PSI Score to predict mortality
Fagan. NEJM 1975; 293: 257
20 %
3 %
40 %
0.2 %
CAP PSI IV-V ~ 20%
CAP PSI I-III ~ 1%
CAP overall ~ 7%
Pre-testProbability
Post-testProbability
LR
Outpatient ?
ICU ?
ProADM < 1.8 nM LR- 0.28ProADM > 1.8 nM LR+ 2.9
Hospitalization - more than „just“ medicineThe 4 „C“
Cure„Doctors“
Care„Nurses“
Control„Hospital Management“
Community„Patient & Relatives“
Adapted from Glouberman S, Health Care Mgmt Rev 2001
Risk-adapted Patient-ManagementObservationphase = Recommendation; Interventionphase = Implementation
Low Intermediate Very highHigh
Follow-up assessment of triage & Rehab-Potential
AdviceOutpatient
Advice• Home-nurse
• Nurse led Unit (NLU)
• Short Inpatient
AdviceICU
AdviceInpatient
Assessment of medical, nursing & social Risik and need for patient education (empowerment)
(with Scores and/or Biomarkers)
RISIK
<0.75 0.75-1.5 1.5 >2.5
„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
Biomarker eg proADM
Übergangs-
pflege
Patients with LRTI 250 / yr
250
OutpatientHome-nursing
care
Post-acute
Nursing
Nurse-led Unit
(NLU)
Traditional
Hospital (KSA)
Independent of- Medical assessment- Nursing / functional assessment- Preference of patient & relatives→ Avalilability of Beds problematic / erratic
Currently (Apr 2010)
250
Nurse-led Unit
(NLU)
150
OutpatientPost-acute
CareKSA
250
30303010
OPTIMA (Oct 10 – May 11)
Home-nursing
care
«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
• Cut-off range depends on clinical setting– PCT does not replace the doctor („pretest-probability“!)– Co-Morbidities? Setting? Site & Extent of Infection? Assay?
• „Single“ PCT measurement is of limited value– Course & prognosis of disease?– Withhold antibiotic therapy?
• False positives & negative values occur (≈10%)– pos: SIRS, ARDS, „cytokine storm“, malaria, newborns…– neg: early, localised, subacute, immunocompromised,
fungal...
• It cannot identify the pathogen
• Cave misuse without therapeutic impact- only then probably cost-effective
• Not for Escalation (broader) Antibiotic therapy
Limitations of PCT as a marker of infection
Jensen JU, Crit Care Med 06; 34:2596-602
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 trialPatients: 1200 in ICU
Intervention: If PCT >1ng/ml or increasing then
- (re)-sampling & imaging - «blind» broadening of AB1° 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?
Setting: ICU = (understandable) high baseline use of antibiotic therapy
Patients: 1200, Danish ICU, high quality of careAdmitted 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 ?
ESCALATION of Antibiosis in worsening ICU-Pat.?The PASS Study
The ProCAP Study (N = 302) Diagnostic accuracy for Bacteremia
Müller B, BMC Inf Dis 2007
ProCTCRPLcTPSIVAS
0 20 40 60 80 100
100-Specificity
100
80
60
40
20
0
Sen
sit
ivit
y
Only 11% pos. BC in ‚bacterial‘ CAPin need for AB!
Delay? Sensitivity??Gold standard ???
AUC 0.86AUC 0.69AUC 0.60
0.25ug/L0.5
1.0
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
Abstract kindly provided by S.Harbarth, C. Delémont et al. SFMU & SAEM 2011
• 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
PCT as a marker of infection in UTI?
Abstract kindly provided by S.Harbarth, C. Delémont et al, SFMU & SAEM 2011
• → 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
Septic or non-septic Arthritis?
PCT as a marker of infection in localized orthopaedic infections?
Uckay et al., Swiss med wkly 2010
- 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
• 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…
Limitations of PCT as a marker of infection
PCT to guide duration of AB therapy in surgical ICU patients: a randomized controlled trial
Hochreiter et all, CC 2009
Choice and Duration of Antibiotic therapy
110 Surgical ICU patients with suspicion of sepsisStopp 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.
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
Lisboa et al, Crit Care Med 2008
- 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
- Conclusion: Serial CRP measurements after VAP onset may help to evaluate effectiveness of AB treatment
CRP ratio (follow-up/baseline) of 0.80 = useful indicator of AB appropriateness
CRP velocity following Antibiotics
Justo et al, Eur J Int Med 2009
- 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
Cals JWL, et al, BMJ 09; 338: 1374
-42% -51% -66%
CRP for antibiotic stewardship in primary care
AB tx Control group: 31%, CRP group 37%, p=ns
139 Patients presenting to the ED with acute cough randomized to control or CRP-group control group: recommendations for chest X-ray and ABCRP group: same algorithm plus CRP testing.
Gonzales et al., J Emerg Med 2008
CRP to reduce AB in the ED?
Biomarkers for antibiotic stewardship: anything beyond PCT?
suPAR
sTREM-1
Multimarker-ApproachN
o in
fect
ion
Bac
teria
l
Vira
lPa
rasi
tic
No
infe
ctio
nB
acte
rial
Vira
lPa
rasi
tic
No
infe
ctio
nB
acte
rial
Vira
lPa
rasi
tic
Kofoed et al., Crit Care 2007
CR
P (
mg
/L)
PC
T (
ug
/L)
Neu
tro
ph
ils
x10
9 c
ells
/L
suP
AR
(u
g/L
)
sTR
EM
-1 (
ug
/L)
MIF
(u
g/L
)
Multimarker-Approach
Kofoed et al., Crit Care 2007
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)
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
Franz et al., Pediatrics 2004
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
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
Other
Diagnosis ?
Start AB
Therapy
Accurate Diagnosis of Sepsis is Important for Rapid Initiation of Antibiotics
Really Sepsis?
<0.5ng/ml
Question
Procalcitonin cut off* >2.0ng/ml
Sepsis Very
Unlikely
Sepsis Very
LikelyClinical Interpretation
*Guidelines from the German Sepsis Society
On admission Intubated & comatoseTemperature: 38.6 °CBP 90/55; P 113Rales in both lungs
Consequence for physician
Monitoring PCT Gives you Important Information about Patients’ Prognosis
Question
Procalcitonin
Clinical Interpretation
*Guidelines from the German Sepsis Society
Day 3 of ICU stayStill intubatedTemperature subfebrileNeed for Vasoactiva
Consequence for physicianContinue AB
Therapy
Other
Diagnosis?
Prognosis
Decrease No Decrease
Responding Not Responding
Endotoxin ivEndotoxin iv
h
ug/ml
Dynamics of Biomarkers upon Infection
Pneumonia - How long to treat?
0.1
1
10
0 1 2 3 4 5 6 7 8 days on ICU
0
50
100
150
200
250
300
PCT (ng/mL)
CRP (mg/mL)
0.01"Normal" Reference range
100 T1/2 ProCT: 24h (log-linear)
J.C.E., 28yrs
Antibiotics ivAntibiotics iv
Severe Sepsis
PCT-guided Antibiotic Therapy
Sepsis
Healthy
Septic Shock
Pneumonia
ProCT (g/L)
0.1
1
10
0.01
100
0.25
0.5
2
BronchitisCOLD
Diagnosis
LU
MIt
es
t® P
CT
LIA
PC
T-Q
®
Assay?Antibiotic (AB) use?
YES!
Yes
No
NO!
ERRTI
ICUTrauma
YES
No
NO!
GPsCOPD
Christ-Crain M, Eur Resp J, 07Schuetz P, Curr Opin Crit Care, 07
YES!
Yes
No
NO! PC
T K
RY
PT
OR
® /
VID
AS
®
Time Course PCT & CRP after Heart Surgery
adapted fromSponholz C, Crit Care 06; 10:R145
CRP for antibiotic stewardship in primary care
Cals et al., Ann Fam Med 2010; 8: 124-133
- 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
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”
Schuetz P et al, Eur J of Clin Microbiology and Inf Disease, 2010
• 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
Decision of the treating physician
2%2%
Immuno-suppression
Anticipated complications
High risk patientsICU admission
Not overruled
Overruled with prespecified reason
Overruled withoutprespecified reason
Outcome and complicationsOutcome (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%)
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)
Risk factors for complications
The PRORATA Study – Subgroups
Bouadma et al, Lancet 2010
AntibioticDuration
Outcome
PCT-guided AB-Therapy in Sepsis on the ICU
Nobre V et al, AJRCCM 07
6d 10d
Shorter Antibiotic Duration
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.
2 Confessions
I received funding from vendors of biomarker assays.I never received funding from companies selling antibiotics.
So, yes, I might be biased.
