IMPROVINGPATIENTPATHWAYS) INBACTERIALINFECTION ) · 2014. 3. 4. · Perit. Macrophage Thyroid...
Transcript of IMPROVINGPATIENTPATHWAYS) INBACTERIALINFECTION ) · 2014. 3. 4. · Perit. Macrophage Thyroid...
Detection of Sepsis and Monitoring of Treatment Efficacy using
Biomarkers
John Bagshaw, Clinical Strategic Marketing Manager, bioMerieux UK Ltd
IMPROVING PATIENT PATHWAYS IN BACTERIAL INFECTION
2014 WORKSHOP Venue:
IET, Austin Court, 80 Cambridge Street, Birmingham, B1 2NP
Date: Wednesday 26th February 2014 – 10am to 4pm
Agenda
Acknowledgement of Sources
And articles cited #IPP-BI
r = 0.75
Insanity: doing the same thing over and over again and expecting different results.”
Albrich WC, Emerg Inf Dis 04
Albert Einstein
Why do we overprescribe Antibiotics?
93% of physicians do it …
S. Levy, Massachusetts Physician Survey, 1998
Given that a high proportion of critically ill patients have the systemic inflammatory response syndrome (SIRS), the ability to accurately distinguish between SIRS and sepsis (sepsis is
defined as SIRS as a result of bacterial infection) has become one of the holy grails of medicine. It is therefore unsurprising that there has been considerable interest, debate and, sometimes, argument over the last two decades regarding the use of biomarkers to achieve this goal. Proposed sepsis biomarkers have included procalcitonin (PCT),2 various interleukins (ILs),2 eosinophil count,3 adrenomedullin (ADM) and pro-ADM,4 atrial natriuretic peptide (ANP) and pro-ANP,5 pro-vasopressin (copeptin),4 interferon-γ (IFN-γ),6 triggering receptor expressed on myeloid cells 1 (TREM-1),6 and resistin.7
Of these and others, PCT has been the most studied and, in some countries, is now being included in routine clinical practice and guideline recommendations.
J. Antimicrob. Chemother. (2011) 66 (suppl 2): ii33-ii40. doi: 10.1093/jac/dkq523 This article appears in:Managing infections in critical care Diagnostic and prognostic biomarkers of sepsis in critical care Savitri Kibe1, Kate Adams1 and Gavin Barlow1,2,*
What Biomarkers exist for Sepsis?
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PCT < 0.1 ng/mL in healthy subject’s blood Increases specifically when body is bacterially challenged Rapidly increases 2-3 hours with a peak after 6-12 hrs
Rapidly decreases with effective therapy with half-life time (~ 24 hr)
PCT Kinetics
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The likelihood for bacterial infections increases with PCT levels
.
Amino-ProCT (
ng/mL; n=651)
0.01
0.1
1
10
100
No SIRS No Infection
SIRS Sepsis Severe Sepsis
Septic Shock
Müller B, Crit Care Med 2000
„Healthy“
Small Intestine Colon
Heart
Brain Spine
Muscle Skin Fat Tissue
Control Sepsis
Spleen Lung Liver Kidney Adrenal
Pancreas Stomach
White Blood Cells Perit. Macrophage
Thyroid
Testes
Müller B, et al. J Clin Endocrinol Metab 2001
Calcitonin (CT) - Only a Hormone?
CalcitoninCys
GlyAsn
Ser
Leu
Thr Cys Met Leu Gly Thr Tyr Thr Gln Asp Phe Asn Lys Phe His Thr Phe Pro Gln Thr Ala Ile GlyVal
Gly
Ala
Pro
SerArg Lys Ser Arg Pro Ser Asp Leu Ser Gly Glu Arg Glu Gln Glu Gln Glu Leu Glu Ser Ala
Lys
Met
ValGln
TyrAspGlnValLeuAlaAlaLeuLeuLeuArgAlaGluAspGluSerLeuThrAlaProAspAlaProSer SerGlu
LeuAla
Ser Arg Phe Pro Ala
GlyLysLysArgAspMetSerSerAspLeuGluArgAspHisArgProHisValSerMetProGlnAsnAla
AsnCOOH-
Aminoprocalcitonin
CCP-I (Katacalcin)
- NH2
SHSH
114Calcitonin
Infection ProCT
Small Bowel Colon Heart
Brain Spine
Muscle Skin Fat Tissue
Control Sepsis
Spleen Lung Liver Kidney Adrenal
Pancreas Stomach
White Blood Cells Perit. Macrophages
Thyroid
Testis
„Hormokines“ Hormones Expressed Like Cytokines
CalcitoninCys
GlyAsn
Ser
Leu
Thr Cys Met Leu Gly Thr Tyr Thr Gln Asp Phe Asn Lys Phe His Thr Phe Pro Gln Thr Ala Ile GlyVal
Gly
Ala
Pro
SerArg Lys Ser Arg Pro Ser Asp Leu Ser Gly Glu Arg Glu Gln Glu Gln Glu Leu Glu Ser Ala
Lys
Met
ValGln
TyrAspGlnValLeuAlaAlaLeuLeuLeuArgAlaGluAspGluSerLeuThrAlaProAspAlaProSer SerGlu
LeuAla
Ser Arg Phe Pro Ala
GlyLysLysArgAspMetSerSerAspLeuGluArgAspHisArgProHisValSerMetProGlnAsnAla
AsnCOOH-
Aminoprocalcitonin
CCP-I (Katacalcin)
- NH2
SHSH
114
Müller B, et al. J Clin Endocrinol Metab 2001
ALL Other Organs
Golgi apparatus
Thyroidal C-cells
CT
Thyroidal C-cell
CT-mRNA
Golgi apparatus
ProCT
endocrine
Bacterial Infection
(e.g.Endotoxin)
IL-1β TNFα
Infla
mm
ator
y H
ost R
espo
nse
CT
Regulated Secretion (cAMP, Mg, Gastrin)
ProCT
CT-mRNA Constitutive Secretion
ProCT
"hormokine"
viral Infection
IFNγ
Linscheid P, et al Crit Care Med 04; 32: 1715-21 Endocrinology 03; 144: 5578-84 & 05; 146: 2699-708
Diagnose a bacterial infection - determine likelihood for its presence - improve clinical assessment
Prognostic Assessment in Infections - consider its course
Theragostic Use: Antibiotic Stewardship - complement current guideline
As a doctor, what can you do with PCT?
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NO antibiotics ! no antibiotics Antibiotics YES ! Antibiotics yes
Control PCT after 6-24 hours Initial antibiotics can be considered „Overruling“: - Respiratory or hemodynamic instability - Life-threatening comorbidity - Need for ICU admission - PCT < 0.1 µg/l: CAP with PSI V or CURB >3, COPD with GOLD IV - PCT < 0.25 µg/l: CAP with PSI >IV or CURB >2, COPD with GOLD > III - Localised infection (abscess, empyema) - Compromised host defense (e.g. immuno-
suppression other than corticosteroids) - Concomitant infection in need of antibiotics
Bacterial etiology very unlikely
Bacterial etiology unlikely
Bacterial etiology likely
Bacterial etiology Very likely
Procalcitonin (PCT) algorithm for stewardship of antibiotic therapy in patients with LRTI
Consider the course of PCT
If antibiotics are initiated: - Repeated measurement of PCT on days 3, 5, 7 - Stop antibiotics using the same cut offs above - If initial PCT levels are >10 µg/l, then
stop when 80-90% decrease of peak PCT - If initial PCT remains high, consider treatment
failure (e.g. resistant strain, empyema, ARDS) - Outpatients: duration of antibiotics according to the
last PCT result: - >0.25-0.5 µg/l: 3 days - >0.5 - 1.0 µg/l: 5 days - >1.0 µg/l: 7 days
PCT guided AB Treatment in the ER
Schuetz P et al, BMC HSR 07
< 0.1 µg/l 0.1 - 0.25 µg/l >0.5 µg/l >0.25 – 0.5 µg/l
Study Setting Research question
ProRESP ED Reduction of antibiotic prescription in ED patients with respiratory tract infections?
ProCAP In hospital Reduction of antibiotic exposure in patients with pneumonia?
ProCOLD COPD Reduction of antibiotic exposure in COPD exacerbation patients over 6 month?
PARTI Outpatients Safety & reduction of antibiotic exposure in outpatients with Respiratory infections?
ProSEP ICU Reduction of antibiotic exposure in septic patients in the intensive care unit (ICU) ?
ProHOSP Multicenter Safety & reduction of antibiotic exposure in a multicenter setting and patients with respiratory infections?
n=
243
302
226
458
79
1359
Procalcitonin: What is the Evidence?
The ProResp-Study Antibiotic Use in LRTI 83% → 44%
0
20
40
60
80
100
CAP Bronchitis AECB Asthma Others
Standard group PCT group
Ant
ibio
tic p
resc
riptio
ns (%
)
p = 0.03 p = 0.003 p < 0.001 p < 0.001 p = 0.003
Christ-Crain M et al, Lancet 04
ProRESP ED Reduction of antibiotic prescription in ED patients with respiratory tract infections?
ProCAP In hospital Reduction of antibiotic exposure in patients with pneumonia?
ProCOLD COPD Reduction of antibiotic exposure in COPD exacerbation patients over 6 month?
PARTI Outpatients Safety & reduction of antibiotic exposure in outpatients with Respiratory infections?
ProSEP ICU Reduction of antibiotic exposure in septic patients in the intensive care unit (ICU) ?
ProHOSP Multicenter Safety & reduction of antibiotic exposure in a multicenter setting and patients with respiratory infections?
243
302
226
458
79
1359
Procalcitonin: What is the Evidence?
Study Setting Research question n=
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The ProCAP Study – Antibiotic Duration
p < 0.001
Standard group ProCT
group
2 4 6 8
10 12 13
20
Ant
ibio
tic d
urat
ion
(day
s)
15 17 19
0
10
20
30
40
50
60
70
80
90
100
AB started > 4d > 6d > 8d > 10d > 14d > 21d
Ant
ibio
tic P
resc
ripto
in (%
)
Christ-Crain M et al, Am J Respir Crit Care Med 2006
Shorter AB-Courses ⇒ Fewer Resistances!
Standard group ProCT group
ProRESP ED Reduction of antibiotic prescription in ED patients with respiratory tract infections?
ProCAP In hospital Reduction of antibiotic exposure in patients with pneumonia?
ProCOLD COPD Reduction of antibiotic exposure in COPD exacerbation patients over 6 month?
PARTI Outpatients Safety & reduction of antibiotic exposure in outpatients with Respiratory infections?
ProSEP ICU Reduction of antibiotic exposure in septic patients in the intensive care unit (ICU) ?
ProHOSP Multicenter Safety & reduction of antibiotic exposure in a multicenter setting and patients with respiratory infections?
243
302
226
458
79
1359
Procalcitonin: What is the Evidence?
Study Setting Research question n=
ProHOSP - Feasibility in a Multicenter Setting
Schuetz P, ProHOSP, n=1359, JAMA, 2009
Differential effects of PCT - Guidance Depending on type and severity of LRTI
Schuetz P, ProHOSP, n=1359, JAMA, 2009
Safety of PCT Guided Antibiotic Stewardship
SAE n=168 (18.1%) SAE n=234 (17.2%)
Schuetz P, ProHOSP, n=1359, JAMA, 2009
How about “Safety” of Control Patients ?
Risk of Drug related Adverse Events increases with duration of AB Therapy
adjusted OR: 1.08 (95%CI 1.05-1.10)
42% increase in AB side effects in ProHOSP control patients
(28.1% vs 19.8%, p<0.001)
Schuetz P, Virulence, 2009 (in press) Schuetz P, ProHOSP, n=1359, JAMA, 2009
PCT algorithm for patients with Sepsis in the Intensive Care Unit
Schuetz P, Expert Review in Infectious Disease
PROcalcitonin Reduce Antibiotic Treatments in Acutely ill Patients (PRORATA)
• Setting: Multicenter RCT in 9 different French ICUs • Intervention: comparing a conventional strategy versus a PCT-guided
strategy to start or to discontinue antibiotics, in patients with suspected community or hospital- acquired infection
• Population: 630 ICU patients with suspicion of bacterial infection, • Outcomes: Mortality and Exposition to antibiotics
Bouadma, Lancet 2010
The PRORATA Study
Multicenter, ICU, Sepsis N = 621
23% more antibiotic free days alive
Antibiotic Duration
Outcome
Bouadma, Lancet 2010
The PRORATA Study – Subgroups
Antibiotic Duration
Outcome
Bouadma, Lancet 2010
Overview of PCT Intervention studies for Antibiotic Stewardship (n=3691)
Autors Study name Research ques3on Se4ng n=
Mortality (n=) Control vs. PCT group
AB exposure Control vs. PCT
group
Rela3ve An3bio3c reduc3on
Christ-‐Crain et al,40 ProRESP Reduc&on of an&bio&c prescrip&on
for LRTI in the ED? ED, single center 243 4 vs 4 10.7 vs 4.8* 55.1%
Christ-‐Crain et al,41 ProCAP Reduc&on of an&bio&c exposure in
CAP in ED and hospital? ED and hospital, single center 302 20 vs 18 12.9 vs 5.7* 55.8%
Stolz et al,60 ProCOLD Reduc&on of an&bio&c exposure in COPD exacerba&on over 6 months?
ED, single center 208 9 vs 5 7.0 vs 3.7* 47.1%
Briel et al,56 PARTI Safety & reduc&on of an&bio&c exposure in upper and lower RTI?
Primary Care, mul¢er 458 1 vs 0 6.8 vs 1.5* 77.9%
Nobre et al,43 "ProSEP" Reduc&on of an&bio&c exposure in
sepsis in the ICU? ICU , single center 79 8 vs 8 9.5 vs 6** 36.8%
Schuetz et al,47 ProHOSP Safety & feasibility in LRTI in a
mul¢er seUng? ED and hospital, mul¢er 1359 33 vs 34 8.7 vs 5.7* 34.5%
Stolz et al,57 ProVAP Reduc&on of an&bio&c exposure in VAP in different ICUs ? ICU, mul¢er 101 12 vs 8 9.5 vs 13*** 27%
Kristoffersen et al,49 1-‐PCT Reduc&on of an&bio&c exposure
for LRTI in ? ED and hospital, single center 210 1 vs 2 6.8 vs 5.1* 25.0%
Hochreiter et al,45 ProSICU Guiding an&bio&c therapy with PCT
in a surgical ICU? Surgical ICU, single center 110 14 vs 15 7.9 vs 5.9* 25.3%
Bouadma et al,44 ProRATA Reduc&on of an&bio&c exposure
for sepsis in French ICUs ? ICU , mul¢er 621 64 vs 65T 11.6 vs 14.3*** 23%
Total 3691 166 vs 159
Schuetz P, Expert Review in Infectious Disease (in press)
Pancreatitis (Canale, JCEM 75) Rau, Gut 97
Meningitis Assicot, Lancet 93 Gendrel, CID 97 Marc, Arch Pediatr 02
Sepsis Assicot, Lancet 93 Nobre V, AJRCCM 07
Toxic Shock Syndrom (Chesney, J Lab Clin Med 83)
Procalcitonin - Marker of Bacterial Infections
Acute Endocarditis Mueller C, Circulation 04
Arthritis Soderquist, Scand J Infect Dis 98 Huegle T, 2008 JCER (in press)
Respiratory Tract Infections (Christ-Crain, Lancet 04 & AJRCCM 06; Briel BMC Fam Pract 05; Stolz Chest 07)
Bloodstream Infections (Mueller B, CCM 00, Schuetz P, Infection 07)
Pyelonephritis, UTI
Subacute Endocarditis
Acutes Abdomen Diverticulitis
Empyema
Neutropenia?! (van Dissel & Nylen CID 07 Stryiewski GR, Ped Crit Care Med 05)
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PCT and LRTI- ProREAL new publication
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PCT and LRTI - ProREAL new publication
1425 patients with Low Respiratory Tract Infections were enrolled by General practitioners or Emergency physicians in 14 centers in France, Switzerland and USA
PCT measurement was recommended for all patients in accordance with the following algorithm
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PCT levels impacted decisions to INITIATE antibiotics, in real life, especially:
in patients with bronchitis and exarcerbation of COPD in experienced centers (Switzerland)
PCT algorithm compliance is higher if a bacterial etiology can be identified
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PCT and LRTI - ProREAL new publication
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J. Antimicrob. Chemother. (2011) 66 (suppl 2): ii33-ii40. doi: 10.1093/jac/dkq523 This article appears in:Managing infections in critical care
Diagnostic and prognostic biomarkers of sepsis in critical care Savitri Kibe1,
Kate Adams1 and Gavin Barlow1,2,*
• In the diagnosis and prognosis of sepsis in critically ill patients, PCT is an improvement on CRP and other traditional markers… but, based on current evidence, it lacks the necessary accuracy to be used without clinical judgement, which should retain a pivotal role in clinical decision-making. This is particularly important in patients who present early in the course of illness or have focal rather than systemic infection and in surgical patients in whom various cut-off points have been identified for different diagnose …PCT may be better employed to rule out rather than rule in systemic sepsis in the critical care environment, particularly if repeated measures are used.
• There is stronger evidence for its use as a tool to reduce antibiotic course length and it is perhaps in this role that it will prove most useful. However, the cost-effectiveness of PCT as an antibiotic stewardship tool is likely to depend on baseline antibiotic course length and its, as yet unknown, impact on antibiotic resistance. Critical care units intending to use PCT should consider these issues pre-implementation. In the future, to improve the accuracy of the diagnosis and prognosis of sepsis, the use of a combined panel of novel biomarkers and traditional markers of sepsis, reflecting different aspects of the human body's response to infection, is an attractive proposition and is worthy of further investigation.
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‘Real World’ studies UK
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‘Real World’ studies UK
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‘Real World’ studies UK
Anything that can improve diagnostic sensitivity, differentiating bacterial infection from noninfection, can help to improve the appropriate use of antibiotics. In this context PCT measurement appears to be a very effective tool.
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‘Real World’ studies UK
During the six-month evaluation period a reduction in antibiotic costs resulting from PCT-directed antibiotic decision-making of £14,450 was established. This represented 17.7% and 17% reductions in antibiotic use for MAU and ICU respectively, although this is likely to be an underestimate.
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‘Real World’ studies UK
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‘Real World’ studies UK
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