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1 What room for biomarkers in the management of anti-infective therapy Philippe Montravers Hôpital Bichat-Claude Bernard, Pole SUPRA APHP UFR Paris Diderot, Paris 7, Paris Cité Sorbonne

2 Disclosures Speaker for Astellas, Astra Zeneca, Basilea, Cubist, MSD, Pfizer, The Medicines Company Participation to advisory boards for Astra Zeneca, Cubist, MSD, The Medicines Company, Pfizer, Tetraphase But nothing for biomarkers..

3 A brief history of biomarkers 1848, immunoglobulins and multiple myeloma 60s, alpha-fetoprotein and carcino-embryonic antigen 80s, tumour markers CA 125 and PSA Citations «PCT» Pubmed Citations «biomarkers» Pubmed

4 What biomarkers? 178 biomarkers evaluated in 3,370 studies linked to sepsis Cytokines and chemokines Cellular biomarkers Receptors biomarkers Coagulation biomarkers Biomarkers linked to injury of endothelial cells Biomarkers linked to vasodilation Biomarkers linked to organ dysfunction Acute phase response proteins And many others. Pierrakos C et al. Crit Care 2010,14:R15

5 Potential use of biomarkers in the management of infections Prediction of severity and prognosis Initiation of treatment Monitoring of clinical response Interruption of therapy Identification of complications, relapse, failure

6 Non-commercially available biomarkers Soluble triggering receptor expressed on myeloid cells-1 (strem-1) TNF IL-6 IL-8 G-CSF ICAM -1 And many others.

7 Biomarkers in the «real life» C-Reactive protein (CRP) Identifiyed in 1930 for diagnosis and follow-up But questionable Sensitivity and Specificity. Limitations: long half-life delayed response increased in case of inflammatory response (even without infection) Procalcitonin (PCT) 116 amino-acids, precursor of calcitonin, produced by thyroid C cells following an hormonal stimulation Following an inflammation trigger : PCT synthesis at high concentrations by other cells Protein of acute phase response of inflammation Plasma concentration in healthy adults < 0.05 ng/ml Bacterial infection induces an increased expression of CALC-1 gene: «more specific» PCT at H3-H4 ; T1/2 = 24-30h Unknown role in sepsis

8 Cytokines and Biomarkers in the course of infection Meisner M et al. J Lab Med 1999 Dandona P et al. J Clin Endocrinol Metab 1994 Harbarth S et al. Am J Respir Crit Care Med

9 Biomarker-based Initiation of antibiotic therapy PCT-based Initiation of antibiotic therapy

10 Some clinical diagnoses do not need any biomarkers

11 Differentiation between severe sepsis and severe inflammation Muller B et al. Crit Care Med 2000 Harbarth S et al. Am J Respir Crit Care Med 2001

12 PCT s shortcomings Main causes of increased PCT concentrations Increased concentrations Surgery, Cardiopulmonary bypass, Cardiac arrest, SIRS, malaria, Macrophagic activation syndrome, Severe renal failure False negative Early infections (< 3h) Compartimentalized infection Partially treated infection with previous AB Becker CCM 2008; 36 : 941

13 PCT and atypical bacterial infection Legionnella pneumophila 61 patients with community-acquired pneumonia due to S. pneumoniae or Legionella Lower PCT concentrations in case Legionella than S. pneumoniae Bellmann-Weiler R et al. J Clin Microbiol 2010;48: High PCT concentration = poor prognosis Bellmann-Weiler R et al. J Clin Microbiol 2010;48: Haeuptle J et al. Eur J Clin Microbiol Infect Dis 2009;28:55-60 (29 patients) De Jager CP et al. Clin Microbiol Infect 2009;15: (18 patients) Chlamydia Mycoplasma pneumoniae Good results of CRP and PCT in case of SIRS in paediatric patients Han XH et al. Zhongguo Dang Dai Er Ke Za Zhi. 2007;9: Helicobacter pylori Poor results of CRP and PCT for diagnosis and follow-up Saribas S et al. J Med Microbiol 2004;53:639-44

14 Fungal infections Candidas: Disappointing results or poorly discriminative Martini A et al. J infection 2010;60:425 Charles PE et al. Intensive Care Med 2009:35;2146 Dornbusch HJ et al. Support Care Cancer 2005;13:343 Leon C et al. Intensive Care Med 2012;38: Molds: few data but also disappointing Zeglen S et al. Transplant Proc 2011;43:3089 Dornbusch HJ et al. Support Care Cancer 2005;13:343 Beaune G et al. Infection 1998:26;168 Huber W et al. Infection 1997;25:377

15 Many patients are not adequately investigated: Immunosuppressed cases Increased PCT concentrations: following anti-thymoglobulin infusion Brodska et al. Crit Care 2009;13:R37 Following anti-t cells Ab, IL2, alemtuzumab Following granulocytes transfusion Dornbusch et al. Support Care Cancer 2008;16: Liver metastases Matzaraki et al. Clin Biochem 2007;40: GVH No increased PCT concentrations no identification of infection Blijlevens et al. Clin Diagn Lab Immunol 2000;7: Increased PCT concentrations identification of infection Pihusch M et al.eur J hematol 2006;76: Doubtful Dombusch HJ et al. Support Care Cancer 2008;16:1035

16 PCT kinetics in surgical patients 26 patients Lung transplantation From D0 to D6 PCT assessed daily Desmard M et al. J Heart Lung Transplant 2015;34:189-94

17 31 patients followed prospectively including 12 patients with persisting intra-abdominal sepsis (IAS+) PCT (ng/ml) PCT kinetics in surgical patients IAS+ IAS- D0 D1 D2 D3 D4 D5 Postoperative days CRP (mg/ml) D0 D1 D2 D3 D4 D5 Postoperative days IAS+ IAS- Paugam-Burtz, Arch Surg 2007

18 PCT and renal dysfunction 276 patients who underwent major aortic surgery Infection proven in 67 patients Renal dysfunction in 75 patients With Renal dysfunction (clearance 50 ml/mn) Without Renal dysfunction (clearance 100 ml/mn) Amour et al., Crit Care Med 2008

19 Median age 86 years [IQR: 81-90] Female gender 72% Creatinin clearance (estimated) 67 ml/mn/m 2 [50-83] Biomarkers. 2012;17:477-81

20 What is the PCT value in case of prolonged antibiotic therapy? Osteitis/osteomyelitis Deep abcesses Endocarditis Mediastinitis Tuberculosis Pneumocystosis Toxoplasmosis

21 What threshold for PCT? Example : pancreatitis suspected of infection Mofidi et al. Surgery 2009;146:72

22 acute pancreatitis, respiratory tract infections meningitis sepsis Quenot JP et al. Ann Intensive Care 2013;3:21

23 Pulmonary Infections 11 randomised trials in adult patients gathering overall 4,412 cases PCT-guided strategy for initiating antibiotic therapy Similar algorithm for initiation and continuation of antibiotic therapy with a lower PCT threshold of <0.25 ng/ml to encourage physicians to withhold antibiotic prescription Limited value of 0.25 ng/ml threshold in elderly patients 8% false-positive rate Chenevier-Gobeaux C et al. Biomarkers 2012;17: Only one study in ventilator-associated pneumonia on PCT-guided strategy for initiating antibiotic therapy 141 patients = 5% of all the cases 99% received AB in the PCT-guided group and 100% in the conventional control group Bouadma et al. Lancet 2010;375: Insuffisant data to recommend initiation of antibiotic therapy based on PCT levels

24 Differentiation between viral and bacterial infection 103 cases of Influenza CAP 47% with bacterial co-infection PCT cut-off 0.8 Se: 91%, Sp 68%, NPV 91% AUC 0.90 (95% CI ) Cuquemelle E et al. Intensive Care Med 2011; 37:

25 PCT-guided strategy for initiating antibiotic therapy in ICU patients 2 randomised trials in adult patients 1,139 patients evaluated Bouadma et al. Lancet 2010;375: Layios N et al. Crit Care Med 2012;40: Insufficient data available to recommend using repeated PCT measurements and serum kinetics for the decision to initiate antibiotic therapy in ICU patients suspected of ICUacquired infection Quenot JP et al. Ann Intensive Care 2013;3:21

26 PCT-guided initiation of therapy In summary Bouadma et al. Lancet 2010;375:463-74

27 Biomarkers for discontinuing antibiotic therapy? Only assessed with PCT

28 Dellinger RP et al. Crit Care Med 2013; 41:

29 A large heterogeneity 14 studies have evaluated a biomarker-based strategy clinical impact discontinuation of antibiotic therapy 9 studies focusing on discontinuation of antibiotic therapy 4 studies in a pre-hospital management or emergency room 2291 pulmonary infections 5 studies in Intensive Care Unit 758 sepsis 101 ventilator associated pneumonia Stolz D et al. Eur Respir 2009;34: Quenot JP et al. Ann Intensive Care 2013;3:21

30 A large heterogeneity Conventional approach PCT-driven management

31 Key role of the algorithm in the decision-making process for stopping antibiotics Bouadma et al. Lancet 2010;375: Stolz D et al. Eur Respir 2009;34:

32 Effect of PCT guidance and severity of the cases Low severity (primary care, bronchitis, COPD) High severity (ICU, CAP, VAP) Schuetz P et al. Clin Infect Dis. 2012;55:651-62

33 Meta-analyses PCT-guided therapy in sepsis and septic shock Prkno et al. Critical Care 2013, 17:R291 Other meta-analyses on PCT-based algorithms in reducing antibiotic use and the duration of antibiotic exposure Kopterides et al, Crit Care Med 2010;38: Heyland et al, Crit Care Med 2011; 39: Schuetz et al, Arch Intern Med 2011;171: Wilke et al, Eur J Med Res 2011;16:

34 Two recent trials with negative results Importance of the thresholds for interpretation of the PCT results Jensen JU et al. Crit Care Med 2011;39:2048 Shehabi Y et al. Am J Respir Crit Care Med 2014; 190:

35 Escalation based on PCT levels? 9 university hospitals Denmark, , MICU-SICU Inclusion : all adult pt > 18year old ICU expected stay > 24h randomised cases «standard care» (596) vs «ATB-PCT alert guided» (604) Daily PCT measurement Alert-PCT : procalcitonin 1.0 ng/ml that was not decreasing at least 10% from the previous day. Every alert-pct expand spectrum of therapy administered (always covering at least the spectrum of previous antibiotic therapy) APACHE II : 18, surgical patients : 40 % Respiratory failure: 70% Circulatory failure: 43% Vasopressors: 53%, Mechanical ventilation: 67%,Renal RT: 14% Severe sepsis /Shock: 38%, no infection : 17% Jensen JU et al. Crit Care Med 2011;39:2048

36 Escalation based on PCT levels? Similar death rates in both 2 groups (31.5% PCT vs 32% control) duration of AB therapy : 6 [IQR3-11] vs 4 [3-10] Same delay for adequate AB therapy number of microbiological samples 7874 vs 6641 duration of mechanical ventilaton (+4,9%) p< duration of ICU stay: 6 [3-12] vs [3-11] p=.,004 Jensen JU et al. Crit Care Med 2011;39:2048

37 Escalation based on PCT levels? Jensen JU et al. Crit Care Med 2011;39:2048

38 Observance of the PCT protocols Poor observance of clinical algorithms (ProRATA : 53% of non observance) Bouadma et al. Lancet 2010;375: The observance of algorithms is lower in the ICU setting The observance decreases with increasing severity of illness Bouadma et al. Lancet 2010;375: Schuetz P et al. Clin Infect Dis 2012, 55:

39 An algorithm based on PCT levels on day 1 (reference value) then at day 2 3 In clinical practice and every 48 h until antibiotic therapy is stopped. In non-immunocompromised patients treated for respiratory tract infection as outpatients or hospitalised in regular wards, the following stopping rule can be used: discontinuation of antibiotic therapy if the PCT level at day 3 is lower than 0.25 ng/ml or has decreased by >80-90% relative to the maximal value initially recorded whether or not microbiological documentation has been obtained. Quenot JP et al. Ann Intensive Care 2013;3:21

40 In clinical practice For patients hospitalised in ICU, including immunocompromised patients (but not neutropenic patients or bone marrow transplant recipients), the decision rule can be suggested for nonbacteraemic patients with a known site of infection (whether or not microbiological documentation is obtained): stopping antibiotics if the PCT level at day 3 is <0.5 ng/ml or has decreased by >80% relative to the highest level recorded during this episode. In bacteraemic patients, a minimal duration of therapy of 5 days is recommended. Quenot JP et al. Ann Intensive Care 2013;3:21

41 Cost effectiveness in the ICU setting Cost <20 euros per measurements (12 euros in France) Heyland DK et al. Crit Care Med :1792-9