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?

#IPP-BI

  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

#IPP-BI

#IPP-BI

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?

#IPP-BI

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







243

302

226

458

79

1359


Study Setting Research question n=

#IPP-BI

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







243

302

226

458

79

1359


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


Safety of PCT Guided Antibiotic Stewardship

SAE n=168 (18.1%) SAE n=234 (17.2%)


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


The PRORATA Study – Subgroups

Antibiotic Duration

Outcome


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&center 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&center seUng? ED and hospital, mul&center 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&center 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&center 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)

#IPP-BI

29

PCT and LRTI- ProREAL new publication

#IPP-BI

30

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

#IPP-BI

 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

31

PCT and LRTI - ProREAL new publication

#IPP-BI

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.

#IPP-BI

‘Real World’ studies UK

#IPP-BI


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.

#IPP-BI


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.

#IPP-BI


#IPP-BI

improvingpatientpathways) inbacterialinfection ) · 2014. 3. 4. · perit. macrophage thyroid...

Documents