Biomarkers in sepsis: Utility in critical care

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1 Biomarkers in sepsis: Utility in critical care Fathima Paruk, PhD Charlotte Maxeke Johannesburg Academic Hospital and University of Witwatersrand

2 Kumar A et al, Chest 2009; 136: von Gunten et al J Hosp Infect 2009; 71: Raineri E et al Am J infect Control 2008;36: Shorr AF et al Crit Care Med 2008;36: Luna CM et al Eur Resp J 2006;27: Erbay A et al J Hosp Infect 2005;59: Global crisis Antibiotic resistance Unnecessary and excessive use (60%) Inappropriate choice (21-77%) Incorrect dose Long duration of antibiotic use (50%) - Antibiotic Resistance, - Toxicity (Morbidity and Mortality) - Cost of care

3 South African perspective: Prescription practices in ICUs

4 South African perspective: Prescription practices in ICUs Infections 28% RTI 65% Abdominal 17% UGT 7% Antibiotics 74% (46% unnecessary) Inappropriate antibiotics 55%

5 % Mortality(%) associated with inappropriate antibiotic use % 28.0% 40.7% 14.3% 23.3% 10.6% APPROPRIATE INAPPROPRIATE ALL PUBLIC PRIVATE *p=0.01 Paruk et al,samj;2012

6 Diagnosis of infection (Sepsis) Clinical assessment Infection Clinical signs: HR,RR Temperature WCC Microbiology (MCCS)

7 Mortality (OR) 100 Timing Early initiation vital: confers mortality benefit Appropriate antibiotics within 1 hour: 79.9% survival Each hour delay: further 7.6% survival 80 n=2731 Septic shock >36 Time of first dose of antibiotics after the onset of shock (hours) Kumar et al. Crit Care Med 2006;34: Kumar A et al, Chest 2009; 136:

8 Diagnosis of infection (Sepsis) Biomarkers But >178 CRP PCT Investigational Presepsin Multimarker panels Evidence PCT vs CRP TNF ɑ strem-1 Protein C CRP Lactoferrin CD64 CD18 PCT Presepsin SAE

9 Biomarkers Diagnosis of sepsis Potential Utility When to stop antibiotics (Duration of therapy) Prognosis

10 Biomarker response to an infection PCT < 0.05ng/ml (undetectable):healthy PCT <0.5ng/ml: bacterial infection unlikely Meisner,2000

11 CRP vs PCT PCT Rapid response Specific CRP Lags behind Bacterial and viral

12 Evidence: Diagnosis of infections Trials 46: 39 positive PCT Meta-analysis Tang et al (2007) Uzzan et al (2006) Wacker et al (2013) 30 studies (n=3244) Area ROC curve 0.85 PCT superior to CRP -earlier Nil perfect -improved accuracy Adjunctive tools Clinical scenario Use both Use trends/kinetics (+clinical assessment) Sridharan P et al, Surgical Infect, 2013 Uzzan B et al Crit Care Med,2006 Tang B et al, Lancet Infec Dis,2006 Wacker C et al, Lancet Infect Dis, May 2013

13 Differential response Medical vs Surgical population Major Surgery - Abdominal surgery - Post Cardiac surgery - Thoracic Clec h C et al, Crit Care Med,2006 Aouifi A et al,crit Care Med, 2000

14 CRP and PCT surgery CRP PCT more useful (earlier decline) Following surgery Kinetics >10ng/mL Beyond D2 PCT increasin PCT PCT more useful (earlier decline) Following surgery - Kinetics - >10ng/mL Beyond D2 PCT increasing

15 PCT : Approach to initiate antibiotics PCT value-kinetics or Algorithm CLINICAL ASSESSMENT + < 0.05 Healthy < 0.25 infection very unlikely infection unlikely infection likely >1 infection more likely Boudama L et al, Lancet, 2010

16 PCT- elevated levels Acute falciparum malaria Invasive fungal infection Hyperthermia Inhalational injury Certain Immunoglobulin therapies Carcinoid syndrome Medullary Ca thyroid Small cell lung Ca Trauma Burns Pancreatitis

17 PCT concepts: Special populations Immunocompromised Elderly (immunesenesence) Autoimmune Solid organ transplants RRT Repeat infections Do not use Liver failure

18 Biomarkers Diagnosis of sepsis Potential Utility When to stop antibiotics (Duration of therapy) Prognosis

19 CRP and PCT severity of infection PCT: Higher values gram negative pathogens? Poor outcomes VAP (Day7>0.5ng/ml) LOS MODS Mortality Biomarkers: observations on prognosticate outcome Rau B et al, Arch surgery,2007;142: Luyt et al, AJRCCM,2004

20 When to stop antibiotics Infection source is eradicated by antimicrobial agent/surgical debridement Adjudged clinical response Problem with this approach prolonged antibiotic exposure biomarker kinetics (PCT) Robust evidence (medical)?

21 PCT guidance to stop antibiotics Clinically improving AND - PCT threshold (<0.5ng/mL) OR - 80% in PCT (kinetics)

22 ESICM Systematic review and Meta analysis 7 trials PCT guidance day reduction 95%CI-4.3to1.95 (p<0.001) Mortality unchanged Matthaiou DK et al, ICM, June 2012

23 7 trials (4 medico-surgical, 3 surgical) n=1075 Severe sepsis or septic shock 8 vs 6 Days (median) Prkno A et al, Crit Care,2013

24 Cochrane Review: RTI 14 trials (n=4221) Antibiotic exposure from 8 to 4 days (-3.7 days) No increase in mortality (5.7% vs 6.3%) Schuetz P et al, Coch Collab,2012

25 Systematic reviews and Meta analysis Most recent of 8 MA 18 studies Specific populations Soni NJ et al, J Hosp Med, Sept 2013

26 Systematic review and Meta analysis: Adult ICU Days Soni NJ et al, J Hosp Med, Sept 2013

27 Systematic review and Meta analysis : RTI Duration Issue Effect on short courses Days Soni NJ et al, J Hosp Med, Sept 2013

28 Summary PCT and CRP Both increase Adjunct to clinical assessment PCT: earlier response and improved accuracy PCT Negative predictive value Trend more important Differential response Medical vs surgical Duration Future Multiplex panels