Infection and Sepsis are often difficult to Diagnose 4/13/18. Procalcitonin: A Novel Biomarker of Bacterial Infection and Sepsis.

Procalcitonin: A Novel Biomarker of Bacterial Infection and Sepsis Teddie Proctor BSN, RN Senior Medical Science Liaison The world leader in serving science Disclosures I work for Thermo Fisher Scientific, Inc. I am not tied to any sales associated with the instrumentation you may be considering I am agnostic to the assay platforms My roles as a Medical Science Liaison (MSL) are to: Provide education on procalcitonin as a subject matter expert Increase the awareness of sepsis and the utility of procalcitonin in the management of sepsis Provide information and answer any questions regarding PCT and its utility regarding antimicrobial management or any other disease processes. 2 Infection Diagnosis Infection and Sepsis are often difficult to Diagnose 3 1

Current Diagnostic Tools Non-specific and poor indicators of infection Lactate - Hypoperfusion WBCs Fever/hypothermia BP - Hypotension HR - Tachypnea RR Tachycardia Blood Cultures 4 Comparison of Clinical Biomarkers Biomarker Specificity Bacterial Infection Sensitivity Inflammation Advantages Disadvantages WBC + +++ C-reactive protein (CRP) ++ ++ Lactate + + Procalcitonin (PCT) ++++ + Simple Inexpensive Inexpensive Moderately specific Inexpensive Reliable marker of perfusion Prognosis > Sepsis Specificity for bacteria Favorable kinetics Rise/half-life Correlates with severity of illness Antibiotic use Sensitivity for bacteria Non-specific for bacterial infection All inflammation & infections Disease states/drug - 596 All inflammation & Infections Slow induction (peak >24h) No correlation with severity Must be in sepsis to be elevated Very poor specificity for bacterial infection Education Instrument for Lab More expensive than WBC, CRP, and lactate 5 Reinhart K, et al. Crit Care Clin. 2006;22:503-19 Infection Spectrum 6 2

New Definition of Sepsis Sepsis- life-threatening organ dysfunction due to a dysregulated host response to infection. Organ dysfunction can be identified as an acute change in total SOFA score 2 points consequent to the infection. Patients with suspected infection who are likely to have a prolonged ICU stay or to die in the hospital can be promptly identified at the bedside with qsofa, ie, alteration in mental status, systolic blood pressure 100 mm Hg, or respiratory rate 22/min. 7 Singer M, et al.jama 2016 The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) Pathophysiology of Sepsis Sepsis Cascade Invasive Infection Foreign antigens from cell walls of bacteria, fungi, bacterial DNA, RNA from viruses etc. Cytokine Release Interleukins, interferons, tumor necrosis factor Immune Response Macrophages, neutrophils, endothelial cells, monocytes Vasodilation, capillary leak Inflammation Coagulation Fibrinolysis Inflammation Severe Sepsis/Septic Shock Multiple Organ Dysfunction Syndrome Death 8 Adapted From: Vervloet MG et al., Semin Thromb Hemost. 1998; 24(1): 33-44. Sepsis is costly and life-threatening 4600 New sepsis patients each day in the US In-Hospital mortality rate 16% Clinical diagnosis remains challenging 62% readmission within 30 days (primary sepsis) Severe sepsis accounts for $20.3 billion hospital inpatient costs The top cause of sepsis is bacterial pneumonia 9 3

Antimicrobial Use and Misuse 10 25. MMWR Vital Signs: Improving Antibiotic Use Among Hospitalized Patients. 2014;63(09):194-200 Early Action Reduces Mortality Risk Mortality risk with increasing delays in initiation of effective antimicrobial therapy 11 Kumar A, et al. Crit Care Med 2006 Jun;34(6):1589-96. What is Procalcitonin (PCT)? What is Procalcitonin 12 4

Procalcitonin a precursor to the hormone calcitonin Simple blood test specific for bacterial infection In healthy people, PCT concentration are found below 0.05ng/ml Concentrations exceeding 0.5ng/ml can be interpreted as abnormal During severe bacterial infections and sepsis, blood levels rise rapidly (up to x100k) no elevation from viral infections Is the Standard of Care for much of Europe in the management of infection and sepsis 13 PCT----Pro Hormone to Calcitonin Thyroid After P. Linscheid, Endocrinology 2003 N N-Pro Calcitonin Katacalcin 1 57 60 91 96 116 C LOW PCT values in the blood of healthy persons: 46.7 pg/ml (97.5 percentile); median = 12.7 pg/ml* 14 Morgenthaler N. et al., Clin Lab 2002, 48: 263-270 Induction and release of PCT due to bacterial infection Alternative synthesis of PCT Bacterial toxins (gram+/-) and cytokines stimulate production of PCT in all parenchymal tissues PCT is immediately released into bloodstream This process can be blocked during viral infections 15 Adapted from Christ-Crain et al. 2005 5

Highly specific induction Produced all tissue Calcitonin: Source of production in healthy people Healthy Sepsis PCT: Source of Production in Septic Patients In relevant bacterial infection, PCT is produced and released into circulation from the entire body 16 Müller B. et al., JCEM 2001 PCT Kinetics Plasma Concentration PCT 1 2 6 12 24 48 72 Time (Hours) Rapid kinetics: Rises 3h after bacterial invasion Peak: 6-24h Half-life: ~ 24h 17 Brunkhort FM et al., Intens. Care Med (1998) 24: 888-892 Dandona P. ed al., J. of Endocrineologiy and Metabolism. (1994). 79: 5 PCT: Inflammatory Biomarker Assoc with Bacterial infection Bacterial Insult Inflammation PCT Release 18 6

PCT Levels Associated with Severity of Infection Localized Infection Low Levels of PCT 19 PCT Levels Associated with Severity of Infection Systemic Inflammation Higher Levels of PCT 20 Procalcitonin Interpretation Clinical Condition PCT (ng/ml) 100 Septic Shock Severe Sepsis 10 PCT thresholds depend on clinical situation of the patient 5 Systemic Infections (Sepsis) Local Infections 2 0.5 Normal Values 0.05 Harbarth S et al. AJRCC Med. 2001;164:396-402. Meisner M et al. Crit Care. 1999, 3:45-50. Krüger S et al. Eur Respir J. 2008;31: 349 55. 21 7

Procalcitonin Elevation: Non-Bacterial Causes Non-Bacterial Stimuli: Trauma: Multiple Trauma, Severe Burns, Major Surgery Prolonged Circulatory Failure Newborns < 72 hours: Increased PCT Value (Physiological Peak). Non-Bacterial Stimuli: Pro-inflammatory Treatment: OKT3, Injection Therapy, TNFα, IL-2, Anti-lymphocyte globulins. Certain Cancers: Medullary C-cell Cancers of the Thyroid, Pulmonary Small-cell Carcinoma, and Bronchial Carcinoma Malaria and Certain Fungal Infections 22 Meisner M, UNI-MED, Bremen 2010. Procalcitonin Usage Aid in the risk assessment of critically ill patients on their first day of intensive care unit (ICU) admission for progression to severe sepsis and septic shock. Aid in assessing the cumulative 28-day risk of all-cause mortality for patients diagnosed with severe sepsis or septic shock in the ICU or when obtained in the emergency department or other medical wards prior to ICU admission, using a change in PCT level over time. Aid in decision making on antibiotic therapy for patients with suspected or confirmed lower respiratory tract infections (LRTI) defined as community acquired pneumonia (CAP), acute bronchitis, and acute exacerbation of chronic obstructive pulmonary disease (AECOPD) in an inpatient setting or an emergency department. Aid in decision making on antibiotic discontinuation for patients with suspected or confirmed sepsis. 23 PCT Clinical Application Does the patient have a bacterial infection? How serious is the infection? Is the patient responding to therapy? 24 8

Accuracy: Sepsis vs. Non-Infectious Inflammation Sensitivity Sensitivity: 89% Specificity: 94% NPV: 90% / PPV: 94% 1 - Specificity PCT levels accurately differentiate sepsis from noninfectious inflammation PCT has been demonstrated to be the best marker for differentiating patients with sepsis from those with systemic inflammatory reaction not related to infectious cause Mueller et al. Crit Care Med. 2000; 28(4) 997-983. 25 Differential Diagnosis: Bacterial Vs. Viral 29.5 ng/ml 0.05 ng/ml 26 Cuquemelle et al. Int Care Med 2011;37:796 PCT and NPV OBJECTIVE: Evaluate the usefulness of PCT as a marker of BSI in adult patients suspected of systemic infections in the ED (n = 367) Compared PCT values to: Positive blood culture Negative blood culture Positive blood culture with contaminant 27 9

Negative Predictive Value (NPV) PCT Cutoff 0.1 ng/ml 0.1475 ng/ml 1.0 ng/ml Sensitivity 75 75 37.5 Specificity 70.6 78.9 92.8 PPV 12.8 16.9 23.1 NPV 96.3 98.2 96.3 AUC 0.72 0.79 0.65 Accuracy 70.9 78.6 89.8 28 Riedel et al. Am J Clin Pathol 2011;135:182-189 NPV and Blood Cultures 29 NPV and Blood Cultures Gram + Gram - Enterobacteria Anaerobic NFGNB Fungi NPV (%) 98.4 98.9 99.2 99.9 99.7 99.6 Cut-off Range: <0.4 to < 0.75ng/ml 30 Oussalah A. et al. Medicine. November 2015 10

BE 67 Y/O female CC: Mild mental confusion, c/o pain in neck, shoulders, upper and lower back, and other diffuse arthralgia s Medical History: Recurrent Urinary Tract Infections Hypertension Migraine headaches Depression NOS Generalized Anxiety D/O Fibromyalgia Restless leg syndrome Osteoporosis CC/Hx Chlorthalidone 25mg daily Lisinopril 10mg daily Verapamil 240mg daily Sumatriptin 50mg prn Milnacipran 50mg bid Sertraline 50mg daily Pregabalin 150mg bid Clonazepam 0.5mg prn bid Pramipexole 1mg HS Nitrofurantoin 100mg bid Hydrocodone/Acetamin 7.5mg/325mg prn q 4 hours Medications 31 BE UA collection Mini-Cath - clogged Required 4 attempts Urinalysis Nitrite positive WBC: 5 Bacteria 4+ Dark yellow Clarity: cloudy Other Lab WBC: 9.6 x 1000 PCT: 0.05ng/ml 32 BE 5 4.5 4 3.5 3 2.5 2 4.3 2.7 BP 142/82 BP 90/58 BP 98/60 STEMI + 2 Stents PCT Lactate 1.5 1 0.5 Ceftriaxone Piperazillin/Tazo + Tobramycin Fluids + Vancomcin 1.51 Troponin 0 0.05 0.05 0.05 Day 1 @ 0800 Day 2 @ 0700 Day 2 @ 1700 Day 2 @ 1800 33 11

PCT plus Clinical Assessment Improves Diagnostic Accuracy PCT can aid in the diagnosis and severity stratification in patients suspected of sepsis, severe sepsis, and septic shock. Clinical symptoms of other noninfectious disease conditions are often similar In multiple studies, PCT has demonstrated a high sensitivity and specificity for the differentiation of sepsis from SIRS (Systemic Inflammatory Response Syndrome) 34 Harbarth S et al. Am J Respir Crit Care Med 2001; Meisner M et al., Critical Care 1999; Krüger S. et al., Eur Respir J 2008 Disease Severity PCT (ng/ml) PCT (ng/ml) Sepsis 1000 100 10 1 0.1 0.01 SIRS Sepsis Severe Septic Sepsis Shock Organ Dysfunction p< 0.05 100 p< 0.001 p< 0.001 10 1 0.1 n=32 n=161 n=106 n=7 1-6 7-12 13-18 19-24 Categories in the SOFA Score PCT (ng/ml) Pneumonia 1000 100 10 1 0.1 0.01 0.001 0 1 2 3 4 CRB-65 Score Adapted From: Harbarth S et al. AJRCC Med. 2001;164:396-402. Meisner M et al. Crit Care. 1999, 3:45-50. Krüger S et al. Eur Respir J. 2008;31: 349 55. 35 MOSES Serial Procalcitonin Predicts Mortality in Severe Sepsis Patients: Results from the Multicenter Procalcitonin MOnitoring SEpsis Study (MOSES) Objective- To prospectively validate that the inability to decrease procalcitonin levels by more than 80% between baseline and day 4 is associated with increased 28-day all-cause mortality in a large sepsis patient population recruited across the United States. Design- Blinded, prospective multicenter observational clinical trial following an Food and Drug Administrationapproved protocol. N=646 Setting-Thirteen U.S.-based emergency departments and ICUs. 36 Scheutz, et al. (2017) 12

MOSES Serial Procalcitonin Predicts Mortality in Severe Sepsis Patients: Results from the Multicenter Procalcitonin MOnitoring SEpsis Study (MOSES) Comparing PCT values of the first 5 days showed that in the non-survivors the initial PCT was high and remained high throughout. 37 Scheutz, et al. (2017) MOSES Serial Procalcitonin Predicts Mortality in Severe Sepsis Patients: Results from the Multicenter Procalcitonin MOnitoring SEpsis Study (MOSES) Results- The 28-day all-cause mortality was two-fold higher when procalcitonin did not show a decrease of more than 80% from baseline to day 4. Among patients discharged from the ICU by day 4 who had a high baseline PCT value of greater than 2 μg/l, mortality was more than three-fold increased if PCT did not drop by more than 80% Similarly, for patients still residing in the ICU at day 4 and low baseline PCT of less than or equal to 2 μg/l, mortality was about three-fold higher if PCT did not drop by more than 80% compared with PCT that decreased by more than 80% 38 Scheutz, et al. (2017) Case Study 72 year old female presented to ED with acute abdomen. To OR for acute diverticulitis and perforation., colostomy placed Hx CRI and TTP. Post op required fluid resuscitation and Levophed. Started on steroid therapy and abx On day 4 BP is stable off Levophed, WBC elevated. PCT 8.0 Abx therapy changed for to expand coverage Day 5 PCT 23.0, pt now hypotensive, despite fluid. Abdomen WNL. Abd CT ordered and no source of infection found 12 hours later, PCT 30.0 patient now with elevated Temp and increased bandemia. To OR and abscess found near anastomosis. Cleaned and drained. Patient recovered and PCT was monitored daily and fell to <0.0 on day 10 Patient discharged home 39 39 13

Antibiotic Stewardship 40 CMS 482.42(b)(2)(i), (ii), and (iii) Meeting the Goals of the AMS Program CMS states the following goals for an ASP are met: 1. Demonstrate coordination among all components of the hospital responsible for antibiotic use and factors that lead to antimicrobial resistance, including, but not limited to, the infection prevention and control program, the QAPI program, the medical staff, nursing services, and pharmacy services 2. Document the evidence-based use of antibiotics in all departments and services of the hospital; and 3. Demonstrate improvements, including sustained improvements, in proper antibiotic use, such as through reductions in CDI and antibiotic resistance in all departments and services of the hospital 41 Antimicrobial Stewardship IDSA: The primary goal of antimicrobial stewardship is to optimize clinical outcomes while minimizing unintended consequences of antimicrobial use, including toxicity, the selection of pathogenic organisms (such as Clostridium difficile), and the emergence of resistance. Thus, the appropriate use of antimicrobials is an essential part of patient safety and deserves careful oversight and guidance. APIC: Antimicrobial stewardship is a coordinated program that promotes the appropriate use of antimicrobials (including antibiotics), improves patient outcomes, reduces microbial resistance, and decreases the spread of infections caused by multidrug-resistant organisms. 42 14

ORIGINAL CONTRIBUTION ORIGINAL CONTRIBUTION Effect of Procalcitonin-Based Guidelines vs Standard Guidelines on Antibiotic Use in Lower Respiratory Tract Infections The ProHOSP Randomized Controlled Trial Philipp Schuetz, MD NNECESSARY ANTIBIOTIC USE importantly contributes to increasing bacterial resistance and increases medical costs antibiotic exposure and antibiotic-associated adverse effects. and the risks of drug-related adverse Trial Registration isrctn.org Identifier: ISRCTN95122877 1-3 events. The most frequent indication JAMA. 2009;302(10):1059-1066 www.jama.com for antibiotic prescriptions in the northwestern hemisphere is lower respiratory tract infections (LRTIs),which range 4 (CAP). Clinical signs and symptoms, as ity of bacterial origin in LRTI is the mearial community-acquired pneumonia An approach to estimate the probabil- in severity from self-limited acute bronchitis to severe acute exacerbation of well as commonly used laboratory markers, are unreliable in distinguishing visurement of serum procalcitonin (PCT). chronic obstructive pulmonary disease (COPD), and to life-threatening bacteral from bacterial LRTI.5-7 As many as Author Affiliations and Members of the ProHOSP 75% of patients with LRTI are treated Study Group are listed at the end of this article. Corresponding Author: Beat Mueller, MD, Department with antibiotics, despite the predominantly viral origin of their infection. 8 ofinternalmedicine,kantonsspitalaarau,tellstrasse,ch- For editorial comment see p 1115. 5001 Aarau, Switzerland (happy.mueller@unibas.ch). 2009 American Medical Association. All rights reserved. (Reprinted) JAMA, September 9, 2009 Vol 302, No. 10 1059 Downloaded From: http://jama.jamanetwork.com/ on 07/30/2014 Effect of Procalcitonin-Based Guidelines vs Standard Guidelines on Antibiotic Use in Lower Respiratory Tract Infections The ProHOSP Randomized Controlled Trial Philipp Schuetz, MD Mirjam Christ-Crain, MD Robert Thomann, MD Claudine Falconnier, MD Marcel Wolbers, PhD Isabelle Widmer, MD Stefanie Neidert, MD Thomas Fricker, MD Claudine Blum, MD Ursula Schild, RN Katharina Regez, RN Ronald Schoenenberger, MD Christoph Henzen, MD Thomas Bregenzer, MD Claus Hoess, MD Martin Krause, MD Heiner C. Bucher, MD Werner Zimmerli, MD Beat Mueller, MD for the ProHOSP Study Group NNECESSARY ANTIBIOTIC USE importantly contributes to increasing bacterial resistance and increases medical costs and the risks of drug-related adverse 1-3 events. The most frequent indication for antibiotic prescriptions in the northwestern hemisphere is lower respiratory tract infections (LRTIs),which range in severity from self-limited acute bronchitis to severe acute exacerbation of chronic obstructive pulmonary disease (COPD), and to life-threatening bacte- For editorial comment see p 1115. Context In previous smaller trials, a procalcitonin (PCT) algorithm reduced antibiotic use in patients with lower respiratory tract infections (LRTIs). Objective To examine whether a PCT algorithm can reduce antibiotic exposure without increasing the risk for serious adverse outcomes. Design, Setting, and Patients Amulticenter,noninferiority,randomizedcontrolled trial in emergency departments of 6 tertiary care hospitals in Switzerland with an open intervention of 1359 patients with mostly severe LRTIs randomized between October 2006 and March 2008. Intervention Patients were randomized to administration of antibiotics based on a PCT algorithm with predefined cutoff ranges for initiating or stopping antibiotics (PCT group) or according to standard guidelines (control group). Serum PCT was measured locally in each hospital and instructions were Web-based. Main Outcome Measures Noninferiority of the composite adverse outcomes of death, intensive care unit admission, disease-specific complications, or recurrent infection requiring antibiotic treatment within 30 days, with a predefined noninferiority boundary of 7.5%; and antibiotic exposure and adverse effects from antibiotics. Results The rate of overall adverse outcomes was similar in the PCT and control groups (15.4% [n=103] vs 18.9% [n=130]; difference, 3.5%; 95% CI, 7.6% to 0.4%). The mean duration of antibiotics exposure in the PCT vs control groups was lower in all patients (5.7 vs 8.7 days; relative change, 34.8%; 95% CI, 40.3% to 28.7%) and in the subgroups of patients with community-acquired pneumonia (n=925, 7.2 vs 10.7 days; 32.4%; 95% CI, 37.6% to 26.9%), exacerbation of chronic obstructive pulmonary disease (n=228, 2.5 vs 5.1 days; 50.4%; 95% CI, 64.0% to 34.0%), and acute bronchitis (n=151, 1.0 vs 2.8 days; 65.0%; 95% CI, 84.7% to 37.5%). Antibiotic-associated adverse effects were less frequent in the PCT group (19.8% [n=133] vs 28.1% [n=193]; difference, 8.2%; 95% CI, 12.7% to 3.7%). Conclusion In patients with LRTIs, a strategy of PCT guidance compared with standard guidelines resulted in similar rates of adverse outcomes, as well as lower rates of antibiotic exposure and antibiotic-associated adverse effects. Trial Registration isrctn.org Identifier: ISRCTN95122877 JAMA. 2009;302(10):1059-1066 rial community-acquired pneumonia 4 (CAP). Clinical signs and symptoms, as well as commonly used laboratory markers, are unreliable in distinguishing viral from bacterial LRTI.5-7 As many as 75% of patients with LRTI are treated with antibiotics, despite the predominantly viral origin of their infection. 8 www.jama.com An approach to estimate the probability of bacterial origin in LRTI is the measurement of serum procalcitonin (PCT). Author Affiliations and Members of the ProHOSP Study Group are listed at the end of this article. Corresponding Author: Beat Mueller, MD, Department ofinternalmedicine,kantonsspitalaarau,tellstrasse,ch- 5001 Aarau, Switzerland (happy.mueller@unibas.ch). 2009 American Medical Association. All rights reserved. (Reprinted) JAMA, September 9, 2009 Vol 302, No. 10 1059 Downloaded From: http://jama.jamanetwork.com/ on 07/30/2014 4/13/18 ProRATA: Secondary Endpoints Endpoint PCT Group (n=307) Control Group (n=314) P value Relapse (%) 20 (6.5) 16 (5.1) 0.45 Superinfection (%) 106 (34.5) 97 (30.9) 0.29 Days without MV (%) 16.2 (11.1) 16.9 (10.9) 0.47 ICU LOS, d 15.9 (16.1) 14.4 (14.1) 0.23 Hospital LOS, d 26.1 (19.3) 26.4 (18.3) 0.87 Multi-resistant bacteria 55 (17.9) 52 (16.6) 0.67 AB exposure/1,000 days 663 812 0.0001 **No significant difference between number and type of organ dysfunctions 46 Adapted from: Bouadma L, et al. Lancet 2010 Feb 6;375(9713):463-74. ProHosp JAMA 2009 (Schuetz et al) Mirjam Christ-Crain, MD Robert Thomann, MD Claudine Falconnier, MD Marcel Wolbers, PhD Isabelle Widmer, MD Stefanie Neidert, MD Thomas Fricker, MD Claudine Blum, MD Ursula Schild, RN Katharina Regez, RN Ronald Schoenenberger, MD Christoph Henzen, MD Thomas Bregenzer, MD Claus Hoess, MD Martin Krause, MD Heiner C. Bucher, MD Werner Zimmerli, MD Beat Mueller, MD for the ProHOSP Study Group U Context In previous smaller trials, a procalcitonin (PCT) algorithm reduced antibiotic use in patients with lower respiratory tract infections (LRTIs). Objective To examine whether a PCT algorithm can reduce antibiotic exposure without increasing the risk for serious adverse outcomes. Design, Setting, and Patients Amulticenter,noninferiority,randomizedcontrolled trial in emergency departments of 6 tertiary care hospitals in Switzerland with an open intervention of 1359 patients with mostly severe LRTIs randomized between October 2006 and March 2008. Intervention Patients were randomized to administration of antibiotics based on a PCT algorithm with predefined cutoff ranges for initiating or stopping antibiotics (PCT group) or according to standard guidelines (control group). Serum PCT was measured locally in each hospital and instructions were Web-based. Main Outcome Measures Noninferiority of the composite adverse outcomes of death, intensive care unit admission, disease-specific complications, or recurrent infection requiring antibiotic treatment within 30 days, with a predefined noninferiority boundary of 7.5%; and antibiotic exposure and adverse effects from antibiotics. Results The rate of overall adverse outcomes was similar in the PCT and control groups (15.4% [n=103] vs 18.9% [n=130]; difference, 3.5%; 95% CI, 7.6% to 0.4%). The mean duration of antibiotics exposure in the PCT vs control groups was lower in all patients (5.7 vs 8.7 days; relative change, 34.8%; 95% CI, 40.3% to 28.7%) and in the subgroups of patients with community-acquired pneumonia (n=925, 7.2 vs 10.7 days; 32.4%; 95% CI, 37.6% to 26.9%), exacerbation of chronic obstructive pulmonary disease (n=228, 2.5 vs 5.1 days; 50.4%; 95% CI, 64.0% to 34.0%), and acute bronchitis (n=151, 1.0 vs 2.8 days; 65.0%; 95% CI, 84.7% to 37.5%). Antibiotic-associated adverse effects were less frequent in the PCT group (19.8% [n=133] vs 28.1% [n=193]; difference, 8.2%; 95% CI, 12.7% to 3.7%). Conclusion In patients with LRTIs, a strategy of PCT guidance compared with standard guidelines resulted in similar rates of adverse outcomes, as well as lower rates of 47 Summary of Results PCT guided algorithm in patients presenting to the ED with LRTI, compared to conventional guided practices resulted in: Similar rates of adverse outcomes (non-inferiority) Mean antibiotic exposure was significantly lower CAP 32.4% reduction U AECOPD 50.4% reduction Acute bronchitis 65.0% reduction Antibiotic-associated adverse effects were significantly lower Schütz et al., JAMA.2009;302(10):1059-66. 48 16

ORIGINAL CONTRIBUTION Effect of Procalcitonin-Based Guidelines vs Standard Guidelines on Antibiotic Use in Lower Respiratory Tract Infections The ProHOSP Randomized Controlled Trial Philipp Schuetz, MD Mirjam Christ-Crain, MD Robert Thomann, MD Claudine Falconnier, MD Marcel Wolbers, PhD Isabelle Widmer, MD Stefanie Neidert, MD Thomas Fricker, MD Claudine Blum, MD Ursula Schild, RN Katharina Regez, RN Ronald Schoenenberger, MD Christoph Henzen, MD Thomas Bregenzer, MD Claus Hoess, MD Martin Krause, MD Heiner C. Bucher, MD Werner Zimmerli, MD Beat Mueller, MD for the ProHOSP Study Group NNECESSARY ANTIBIOTIC USE importantly contributes to increasing bacterial resistance and increases medical costs and the risks of drug-related adverse 1-3 events. The most frequent indication for antibiotic prescriptions in the northwestern hemisphere is lower respiratory tract infections (LRTIs),which range in severity from self-limited acute bronchitis to severe acute exacerbation of chronic obstructive pulmonary disease (COPD), and to life-threatening bacte- For editorial comment see p 1115. Context In previous smaller trials, a procalcitonin (PCT) algorithm reduced antibiotic use in patients with lower respiratory tract infections (LRTIs). Objective To examine whether a PCT algorithm can reduce antibiotic exposure without increasing the risk for serious adverse outcomes. Design, Setting, and Patients Amulticenter,noninferiority,randomizedcontrolled trial in emergency departments of 6 tertiary care hospitals in Switzerland with an open intervention of 1359 patients with mostly severe LRTIs randomized between October 2006 and March 2008. Intervention Patients were randomized to administration of antibiotics based on a PCT algorithm with predefined cutoff ranges for initiating or stopping antibiotics (PCT group) or according to standard guidelines (control group). Serum PCT was measured locally in each hospital and instructions were Web-based. Main Outcome Measures Noninferiority of the composite adverse outcomes of death, intensive care unit admission, disease-specific complications, or recurrent infection requiring antibiotic treatment within 30 days, with a predefined noninferiority boundary of 7.5%; and antibiotic exposure and adverse effects from antibiotics. Results The rate of overall adverse outcomes was similar in the PCT and control groups (15.4% [n=103] vs 18.9% [n=130]; difference, 3.5%; 95% CI, 7.6% to 0.4%). The mean duration of antibiotics exposure in the PCT vs control groups was lower in all patients (5.7 vs 8.7 days; relative change, 34.8%; 95% CI, 40.3% to 28.7%) and in the subgroups of patients with community-acquired pneumonia (n=925, 7.2 vs 10.7 days; 32.4%; 95% CI, 37.6% to 26.9%), exacerbation of chronic obstructive pulmonary disease (n=228, 2.5 vs 5.1 days; 50.4%; 95% CI, 64.0% to 34.0%), and acute bronchitis (n=151, 1.0 vs 2.8 days; 65.0%; 95% CI, 84.7% to 37.5%). Antibiotic-associated adverse effects were less frequent in the PCT group (19.8% [n=133] vs 28.1% [n=193]; difference, 8.2%; 95% CI, 12.7% to 3.7%). Conclusion In patients with LRTIs, a strategy of PCT guidance compared with standard guidelines resulted in similar rates of adverse outcomes, as well as lower rates of antibiotic exposure and antibiotic-associated adverse effects. Trial Registration isrctn.org Identifier: ISRCTN95122877 JAMA. 2009;302(10):1059-1066 rial community-acquired pneumonia 4 (CAP). Clinical signs and symptoms, as well as commonly used laboratory markers, are unreliable in distinguishing viral from bacterial LRTI.5-7 As many as 75% of patients with LRTI are treated with antibiotics, despite the predominantly viral origin of their infection. 8 www.jama.com An approach to estimate the probability of bacterial origin in LRTI is the measurement of serum procalcitonin (PCT). Author Affiliations and Members of the ProHOSP Study Group are listed at the end of this article. Corresponding Author: Beat Mueller, MD, Department ofinternalmedicine,kantonsspitalaarau,tellstrasse,ch- 5001 Aarau, Switzerland (happy.mueller@unibas.ch). 2009 American Medical Association. All rights reserved. (Reprinted) JAMA, September 9, 2009 Vol 302, No. 10 1059 Downloaded From: http://jama.jamanetwork.com/ on 07/30/2014 ORIGINAL CONTRIBUTION Effect of Procalcitonin-Based Guidelines vs Standard Guidelines on Antibiotic Use in Lower Respiratory Tract Infections The ProHOSP Randomized Controlled Trial Philipp Schuetz, MD Mirjam Christ-Crain, MD Robert Thomann, MD Claudine Falconnier, MD Marcel Wolbers, PhD Isabelle Widmer, MD Stefanie Neidert, MD Thomas Fricker, MD Claudine Blum, MD Ursula Schild, RN Katharina Regez, RN Ronald Schoenenberger, MD Christoph Henzen, MD Thomas Bregenzer, MD Claus Hoess, MD Martin Krause, MD Heiner C. Bucher, MD Werner Zimmerli, MD Beat Mueller, MD for the ProHOSP Study Group NNECESSARY ANTIBIOTIC USE importantly contributes to increasing bacterial resistance and increases medical costs and the risks of drug-related adverse 1-3 events. The most frequent indication for antibiotic prescriptions in the northwestern hemisphere is lower respiratory tract infections (LRTIs),which range in severity from self-limited acute bronchitis to severe acute exacerbation of chronic obstructive pulmonary disease (COPD), and to life-threatening bacte- For editorial comment see p 1115. Context In previous smaller trials, a procalcitonin (PCT) algorithm reduced antibiotic use in patients with lower respiratory tract infections (LRTIs). Objective To examine whether a PCT algorithm can reduce antibiotic exposure without increasing the risk for serious adverse outcomes. Design, Setting, and Patients Amulticenter,noninferiority,randomizedcontrolled trial in emergency departments of 6 tertiary care hospitals in Switzerland with an open intervention of 1359 patients with mostly severe LRTIs randomized between October 2006 and March 2008. Intervention Patients were randomized to administration of antibiotics based on a PCT algorithm with predefined cutoff ranges for initiating or stopping antibiotics (PCT group) or according to standard guidelines (control group). Serum PCT was measured locally in each hospital and instructions were Web-based. Main Outcome Measures Noninferiority of the composite adverse outcomes of death, intensive care unit admission, disease-specific complications, or recurrent infection requiring antibiotic treatment within 30 days, with a predefined noninferiority boundary of 7.5%; and antibiotic exposure and adverse effects from antibiotics. Results The rate of overall adverse outcomes was similar in the PCT and control groups (15.4% [n=103] vs 18.9% [n=130]; difference, 3.5%; 95% CI, 7.6% to 0.4%). The mean duration of antibiotics exposure in the PCT vs control groups was lower in all patients (5.7 vs 8.7 days; relative change, 34.8%; 95% CI, 40.3% to 28.7%) and in the subgroups of patients with community-acquired pneumonia (n=925, 7.2 vs 10.7 days; 32.4%; 95% CI, 37.6% to 26.9%), exacerbation of chronic obstructive pulmonary disease (n=228, 2.5 vs 5.1 days; 50.4%; 95% CI, 64.0% to 34.0%), and acute bronchitis (n=151, 1.0 vs 2.8 days; 65.0%; 95% CI, 84.7% to 37.5%). Antibiotic-associated adverse effects were less frequent in the PCT group (19.8% [n=133] vs 28.1% [n=193]; difference, 8.2%; 95% CI, 12.7% to 3.7%). Conclusion In patients with LRTIs, a strategy of PCT guidance compared with standard guidelines resulted in similar rates of adverse outcomes, as well as lower rates of antibiotic exposure and antibiotic-associated adverse effects. Trial Registration isrctn.org Identifier: ISRCTN95122877 JAMA. 2009;302(10):1059-1066 rial community-acquired pneumonia 4 (CAP). Clinical signs and symptoms, as well as commonly used laboratory markers, are unreliable in distinguishing viral from bacterial LRTI.5-7 As many as 75% of patients with LRTI are treated with antibiotics, despite the predominantly viral origin of their infection. 8 www.jama.com An approach to estimate the probability of bacterial origin in LRTI is the measurement of serum procalcitonin (PCT). Author Affiliations and Members of the ProHOSP Study Group are listed at the end of this article. Corresponding Author: Beat Mueller, MD, Department ofinternalmedicine,kantonsspitalaarau,tellstrasse,ch- 5001 Aarau, Switzerland (happy.mueller@unibas.ch). 2009 American Medical Association. All rights reserved. (Reprinted) JAMA, September 9, 2009 Vol 302, No. 10 1059 Downloaded From: http://jama.jamanetwork.com/ on 07/30/2014 4/13/18 ProHosp Reduction of Abx exposure in subgroups of patients: CAP Þ 32.4% reduction, AECOPD Þ 50.4% reduction, Acute bronchitis Þ 65.0% reduction U 49 Schuetz P et al. J Am Med Assoc. 2009;302(10):1059-66. ProHosp Composite of Overall Adverse Outcome (30 days) Death (any cause) All cause ICU Admissions Disease Specific Complications Recurrence/ Readmission PCT (n=671) Control (n=688) Risk Difference 15.4% 18.9% -3.5% 5.1% 4.8% 0.3% 6.4% 8.7% -2.3% 2.5% 2.0% 0.5% 3.7% 6.5% -2.8% U 50 Schuetz P et al. J Am Med Assoc. 2009;302(10):1059-66. Stop Antibiotics on PCT Guidance Study (SAPS) Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients: a randomized, controlled, open-label trial Stop Antiobiotics on PCT Guidance Study (SAPS) 51 de Jong et al. Lancet Infect Dis. February 29, 2016 17

Stop Antibiotics on PCT Guidance Study (SAPS) Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients a randomized, controlled, open-label trial Netherlands Multicenter Trial: 15 hospitals Patients: 1575 761 PCT group 785 Standard of care group E. De Jong et al.,, Lancet Infect Dis 2016 Published Online, February 29, 2016 52 E. De Jong et al.,, Lancet Infect Dis 2016 Published Online, February 29, 2016 Antibiotic Use by Country 53 Antibiotic Cost by Country 54 Brick A, Gorecki P, Nolan A. Ireland: Pharmaceutical Prices, Prescribing Practices and Usage of Generics in a Comparative Context. ESRI; 2013. https://www.esri.ie/pubs/rs32.pdf. Accessed September 5, 2017. 18

Study Design E. De Jong et al., Lancet Infect Dis 2016, Published Online, February 29, 2016 Study type: Prospective, multicentre, randomised, controlled, open-label intervention trial; 15 centers in the Netherlands Patients: 1575 adult critically ill patients admitted to the ICU Algorithm: Comparison of PCT guided treatment vs standard approach PCT arm: Non-binding advice to discontinue Abx if PCT concentration had decreased - by 80% or more of its peak value - or to 0 5 μg/l or lower Standard arm: Patients treated according to local antibiotic protocols 55 Results Stopping criteria Discontinue AB if PCT concentration had decreased by 80% or more of its peak value or to 0 5 μg/l or lower reached for 557 of the 761 pts in the PCT arm while in ICU Use of PCT stopping algorithm 350 300 250 200 150 100 50 0 243 AB stopped 24h after criteria were reached 297 17 AB stopped 48h after no stop of AB despite criteria were reached2 fulfilled criteria Only in 3% of patients no stop of AB 56 Results: Efficacy of guiding duration of antibiotic treatment Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients a randomized, controlled, open-label trial Median duration of treatment: 5 days (3 9) in the procalcitonin-guided group and 7 days (4 11) in the standard-of-care group (p<0 0001) AB consumption: 7.5 daily defined doses in the procalcitonin-guided group versus 9.3 daily defined doses in the standard-of-care group 19% relative reduction in AB consumption (p<0 0001) Effective approach: Significant reduction of antibiotic exposure 57 E. De Jong et al.,, Lancet Infect Dis 2016 Published Online, February 29, 2016 E. De Jong et al.,, Lancet Infect Dis 2016 Published Online, February 29, 2016 19

SAPS: Mortality: 28 days and 1 year Efficacy and safety of procalcitonin guidance in reducing the duration of antibiotic treatment in critically ill patients a randomized, controlled, open-label trial At 28 days: PCT Guided group = 20% Standard-of-care = 25% (absolute difference 5 4%, p=0 0122) According to the intention-to-treat analysis: PCT-guided group = 20% Standard-of-care = 27% (absolute difference 6 6%, p=0 0154) 1-year mortality: PCT guided group = 36% Standard-of-care group = 43% (absolute difference 7 4%, p=0 0188) 58 E. De Jong et al.,, Lancet Infect Dis 2016 Published Online, February 29, 2016 PCT Algorithms N= 4,467 Primary Outcome: Safety (non-inferiority) Secondary Outcome: Overall AB Exposure PI/Year Diagnosis Total No. Mortality, Control vs. PCT Group, # Dead/Total (%) AB Use, Control vs. PCT Relative Reduction, % Key Findings Briel (2008) URI/LRTI 458 1/226 (0.4) vs. 0/232 (0) PRIMARY CARE SETTING Prescription 97 vs. 25% Duration (mean): 7.1 vs. 6.2d Prescription: -74 Duration: -13 Reduction of AB without additional days of restricted activity Burkhardt (2010) URI/LRTI 550 0/275 (0) vs. 0/275 (0) Prescription 36.7% vs. 21.5 Duration (mean): 7.7 vs. 7.8d Prescription: -42 Duration: -1 Reduction of AB without causing health impairment Christ-Crain (2004) CAP, AECOPD, bronchitis 243 4/119 (3.4) vs. 4/124(3.2) ED SETTING Prescription 83 vs. 25% Duration (mean): 12.8vs. 10.9d Prescription: -47 Duration: -15 Reduction of AB prescriptions CAP, AECOPD, Prescription 99 vs 85% Prescription: -14 Christ-Crain (2006) bronchitis 302 20/151 (13.2) vs. 18/151 (11.9) Duration (mean): 12.9 vs. 5.8d Duration: -55 Stolz (2007) AECOPD 280 9/106 (8.5) vs. 5/102 (4.9) Prescription: 72 vs 40% Prescription: -44 Reduction of initiation and duration of AB without adverse outcomes Reduced AB exposure w/o adverse outcomes Long (2009) CAP, AECOPD, bronchitis 127 0/64 vs. 0/63 (0) Prescription 97 vs 86% Duration (median) 10 vs. 6d Prescription: -11 Duration: -40 Reduction of AB use and shorter duration Kristofferesen (2009) LRTI 210 1/107 (0.9) vs. 2/103 (1.9) Prescription 79 vs 85% Duration 6.8 vs. 5.1d Prescription: 8 Duration: -25 Shorter AB duration Schuetz (2009) CAP, AECOPD, bronchitis 1359 33/688 (4.8) vs. 34/671 (5.1) Prescription 87.7 vs. 75.4% Duration (median): 8.7 vs 5.7d Prescription: -14 Duration: -34 Non-inferiority for clinical outcomes and decreased AB use Postop septic INPATIENT AND ICU SETTING Svoboda (2007) shock 72 13/34 (38.3) vs. 10/28 (26.3) NA NA Nobre (2008) Sepsis 79 12/40 (30) vs. 8/39 (20.5) Duration (median): 9.5 vs. 6d Duration: -37 Trend to decrease in SOFA and ventilator/icu days Reduction in AB duration and ICU LOS w/o AEs Stolz (2009) VAP 101 12/50 (24) vs. 8/51 (15.7) AB free days alive: 9.5 vs. 13 Duration (median) 15 vs. 10d AB-free days alive: 27 Decreased AB use w/o increasing Duration: -33 mortality rate Hochreiter (2009) Postop patients w/ infection 110 14/53 (26.4) vs. 15/56 (26.3) Duration (mean): 7.9 vs. 5.9d Duration: -25 Reduction in AB duration and ICU LOS w/o AEs Schroeder (2009) Postop severe sepsis 27 3/13 (23.1) vs. 3/14 (21.4) Duration (mean): 8.3 vs. 6.6d Duration: -20 Shorter AB duration Bouadma (2010) Sepsis 621 64/314 (20.4) vs. 65/307 (21.2) AB free days alive: 11.6 vs. 14.3 Duration (mean) 9.9 vs. 6.6d AB-free days alive: 19 Reduction in AB use w/o increase in Duration: -33 mortality rate 59 Adapted from: Arch Intern Med. 2011;171(15):1322-1331. doi:10.1001/archinternmed.2011.318. Five Rivers Medical Center Outcomes Comparison: Control Vs. Procalcitonin 4 years Pre (n=985) and Post Procalcitonin (n=1167) implementation with one year for education between patient groups 42% Reduction in Antimicrobial Days of Therapy 51.5% Reduction in Mortality Due to Infectious Diseases 37.3% Reduction in 30-day Readmissions 60% Reduction in C. difficile Infections 41.3% Reduction in Adverse Drug Events Days of Therapy/Patient Pre: 16.43 DOT Post: 9.52 DOT Mortality due to Infectious Diseases Pre:6.9% Post: 2.8% 30-Day Readmission for Infection Pre: 18% Post: 9.5% C. difficile Rate Pre: 2.5% Post: 0.9% Adverse Drug Events Pre: 16.2% Post: 8.1% P < 0.0001 P< 0.001 P < 0.001 P 0.002 P <0.001 60 20

JW 56 Y/O male, construction worker Asthma since childhood 1.5 PPD smoker CC: SOB, productive cough, malaise, fever, duration of 12-14 days Azithromycin Z-Pak Benazepril 20 mg daily Nebivolol 5 mg daily Citalopram 20 mg daily Furosemide 80 mg daily Omeprazole 20 mg daily Prednisone 5 mg daily Mometasone 220 mcg daily Albuterol MDI prn q 4 hours for SOB/wheezing CC/Hx/Presentation Temp 99.8 BP 145/86 Pulse 90 RR 20 Pulse Ox 92% on RA WBC 14.7 x 1000 Bands 6 Lactate 1.3mmol/L Chest film and auscultation: early bilateral pneumonia Stop azithromycin Start levofloxacin 750mg daily Labs/X-Ray/Plan 61 JW Day 1 (22 hours) Temp 101.8 BP 138/82 RR 22 WBC 22.4 x 1000 Bands 10 PCT 36 ng/ml Lactate 2.1 mmol/l Day 2 Temp 103.6 BP 106/62 RR 26 WBC 28.8 Bands 12 Lactate 5.6 mmol/l PCT 86 ng/ml Blood gases 62 JW Day 2 continued Increase fluids DC Levofloxacin Start Vancomycin Start Meropenem CPAP > Ventilator Sputum Gram stain: coagulase positive/gram-positive cocci in clusters 1 st blood culture Gram stain: coagulase positive/ gram-positive cocci in clusters Nasal culture plate: MRSA Day 2 PM PCT 72 ng/ml 63 21

JW Day 3 Temp 101.2 BP 120/68 WBC 23.3 x 1000 Bands 10 Lactate 2.2mmol/L BP 120/68 PCT 46 ng/ml Sputum: MRSA Blood Cx: MRSA 64 JW Summary 100 JW Biomarker Trend 90 80 70 86 72 60 50 40 30 20 10 0 46 36 28.8 27.2 22 23.3 22.4 15 14.7 18.2 14.5 10.9 12.8 12.7 11.8 2.1 5.6 2.2 4.9 2.4 1.3 Admission Day 1 Day 2 Day 2.5 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 PCT WBC Lactate 65 Questions TEDDIE PROCTOR BSN, RN Senior Medical Science Liaison Thermo Fisher Scientific, Inc. teddie.proctor@thermofisher.com 832-289-3926 66 22