HPN HOSPITALIZED PNEUMONIA APPLICATION

HPN HOSPITALIZED PNEUMONIA APPLICATION Investigational Use. Not available for Sale in the United States.

Content UNYVERO HPN HOSPITALIZED PNEUMONIA APPLICATION The Unyvero HPN Pneumonia Application combines adequate detection of pathogens and antibiotic resistances to aid diagnosing pneumonia. A single test handles one patient sample analyzing 39 DNA targets and delivers reliable results within 4 hours. This approach facilitates a confident treatment decision at an earlier stage in the cycle of care. Infections and Resistances 04 05 Faster diagnostics for pneumonia 06 07 Increasing Antibiotic Resitances 08 09 IDEAL PNEUMONIA ASSAY 10 13 UNYVERO HPN HOSPITALIZED PNEUMONIA APPLICATION 14 15 A broad spectrum 16 17 established technologies in a new format 18 19 Unyvero WORKFLOW 20 21 Unyvero System And Applications 22 23 UNYVERO AT A GLANCe 24 25 2 Investigational Use. Not available for Sale in the United States. 3

Infections and Resistances INFECTIOUS DISEASES MEDICAL AND ECONOMIC BURDEN Severe acute infections and growing antibiotic resistances are a major burden for today s health care systems infections are together the number 3 cause of death. Fighting such infections would benefit from faster and more comprehensive diagnostics. The diagnosis and treatment of infections as it is today is imprecise and fraught with problems. Results from sample cultures usually take 2 days or longer. Clinicians must almost always begin treatment before results are available. In addition, antibiotic resistances compound the difficulty of therapy selection. They have risen steadily in the last several decades also due to inadequate antibiotic treatment. Clinical studies have demonstrated that adequate initial antibiotic treatment for most severe acute infections significantly improves medical outcome. In addition, appropriate and early antibiotic selection will limit the risk of increasing antibiotic resistance in the population as a whole. 4 Investigational Use. Not available for Sale in the United States. 5

Treating pneumonia patients with the right antibiotics at the right time often makes the difference between life and death. Faster diagnostics for pneumonia MEDICAL NEED IN PNEUMONIA FASTER DIAGNOSTIC TOOLS Pneumonia is a severe, life-threatening high incidence acute infection of the lower respiratory tract (LRT), which results from various causes, most commonly bacteria or viruses. It is a fast progressing disease with mortality rates up to 30% and an average hospital stay of 11 to 14 days associated with high treatment costs. The American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines distinguish the following types of pneumonia: > Community-acquired Pneumonia (CAP) is acquired in the community without a history of medical intervention. Often caused by viruses, they usually follow a mild course, however 25% of CAP need hospitalization (hcap). > Hospital-acquired (or nosocomial) Pneumonia (HAP) is a pneumonia that occurs 48 hours or more after admission and did not appear to be incubating at the time of admission. > ventilator-associated Pneumonia (VAP) is a type of HAP that develops more than 48 to 72 hours after endotracheal intubation. > Healthcare-associated Pneumonia (HCAP) is defined as pneumonia that occurs in a nonhospitalized patient with extensive healthcare contact. Studies have demonstrated, that the medical outcome of hcap and scap including VAP would certainly benefit from faster diagnostics. 6 Investigational Use. Not available for Sale in the United States. 7

Increasing Antibiotic Resitances GLOBAL CHALLENGE ANTIBIOTIC RESISTANCE > Antibiotic resistant bacteria have become an everyday occurrence and problem in hospitals across the world. > misuse of antibiotics may cause patients to become colonized or infected with antibiotic resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci (VRE) and highly-resistant Gram-negative bacilli. > The emergence, selection and spread of resistant bacteria is a threat to patient safety in hospitals because: - infections with antibiotic resistant bacteria result in increased morbidity, mortality, and length of hospital stay. - antibiotic resistance frequently leads to a delay in appropriate antibiotic therapy. - inappropriate or delayed antibiotic therapy in patients with severe infections is associated with worse patient outcomes and sometimes death. - patients who are hospitalized have a high probability of receiving an antibiotic and 50% of all antibiotic use in hospitals can be inappropriate. - misuse of antibiotics in hospitals is one of the main factors that drive the development of antibiotic resistance. 8 Investigational Use. Not available for Sale in the United States. 9

Pneumonia causing pathogens Pneumonia Treatment guidelines Pneumonia Assay Hcap/ hcap Hap Vap Bacteria Viruses Fungi Hap Hcap/ hcap Vap Staphylococcus aureus Streptococcus pneumoniae Chlamydophila pneumoniae Enterobacteriaceae Staphylococcus aureus Streptococcus pneumoniae Pseudomonas aeruginosa Enterobacteriaceae Staphylococcus aureus Streptococcus pneumoniae Pseudomonas aeruginosa Enterobacteriaceae e.g. Piperacillin Ceftazidime Cefepime e.g. Erythromycin Azithromycin Clarithromycin e.g. Azithromycin Clarithromycin Levofloxacin e.g. Clindamycin Augmentin Piperacillin-tazobactam 1. Coverage Detects 90% of infectious disease causing pathogens 2. Diversity Enables testing of clinically relevant, different native 3. Speed Delivers clinically relevant answers in time Klebsiella pneumoniae Klebsiella pneumoniae Klebsiella pneumoniae Ticarcillin-clavulanic acid Levofloxacin Erythromycin Ticarcillin-clavulanic acid and clinically most relevant sample types Escherichia coli Legionella pneumophila Escherichia coli Proteus spp. Enterobacter spp. Haemophilus influenzae Erythromycin Azithromycin Augmentin Moxifloxacin Cefuroxime Piperacillin-tazobactam Ampicillin-sulbactam Cefoxitin antibiotic resistances Moraxella catarrhalis Haemophilus influenzae Pneumocystis jirovecii Enterobacter spp. Serratia marcescens Legionella pneumophila Stenotrophomonas maltophilia Ciprofloxacin Cefepime Clindamycin Levofloxacin > 35 genetic markers sputum, Lavage (BAL), tracheal aspirate 4 5 h Mycoplasma pneumoniae Moraxella catarrhalis Haemophilus influenzae Acinetobacter baumannii Candida spp. > 15 genetic markers to be tested Staphylococcus aureus Streptococcus pneumoniae Chlamydophila pneumoniae Serratia marcescens Legionella pneumophila Moraxella catarrhalis Risk: Antibiotic resistance PreRequisites Pseudomonas aeruginosa Haemophilus influenza Enterobacteriaceae Stenotrophomonas maltophilia Escherichia coli Acinetobacter baumannii Klebsiella pneumoniae Pneumocystis jirovecii Proteus spp. Enterobacter spp. Mycoplasma pneumoniae Important genetic resistance markers > should work with various native samples > needs sample preparation with high DNA yield An ideal Pneumonia assay should cover 90 % have to be tested in an ideal Pneumonia assay > allows multiplex PCR of up to 100 analytes of pathogens causing hospitalized pneumonia > requires highly specific detection 10 Investigational Use. Not available for Sale in the United States. 13

UNYVERO HPN HOSPITALIZED PNEUMONIA APPLICATION PCR set-up PREREQUISITES FOR AN IDEAL SOLUTION UNYVERO HPN HOSPITALIZED PNEUMONIA APPLICATION DNA purification Multiplex PCR with array detection PNEUMONIA ASSAY: The unique Unyvero HPN HOSPITALIZED PNEUMONIA CARTRIDGE allows the detection of 39 analytes and integrates Unique solution tailored to clinical needs > COVERAGE > DNA purification, > PCR set-up, > multiplex endpoint PCR and, > amplicon detection by array hybridization. > Comprehensive, disease-oriented test panels run on an easy to operate platform, requiring neither the special infrastructure of a laboratory environment nor specially trained personnel. > DIVERSITY > SPEED Therefore, the closed Unyvero Cartridge is equipped with integrated reagent containers, a DNA purification column, eight PCR chambers and an according number of arrays. The cartridge is pre-filled with buffers for DNA cleanup, reagents and fluorescence-labeled primers for PCR amplification, respectively for array hybridization of the PCR product. > Translates a complex laboratory process into an easy to use format. The analytical process requires only addition of the unprocessed patient sample and enzymes for DNA amplification. > Generates complete diagnostic information in 4 5 hours, without any further operator interaction. 1. Unyvero T1 Sample Tube for preparation of the patient sample, pre-filled with specific lysis reagents. 2. Unyvero T1 Sample Tube Cap seals the Unyvero Sample Tube and contains proteinase K and an internal control gene for quality control. 3. Unyvero T1 Sample Transfer Tool is a pipetting aid for use with a 1 ml Luer-lock syringe. 4. Unyvero M1 Master Mix Tube with reagents for DNA amplification. 1 2 3 4 14 Investigational Use. Not available for Sale in the United States. 15

A broad spectrum COVERAGE CLINICALLY RELEVANT PATHOGENS AND ANTIBIOTIC RESISTANCES Group Gram-positive bacteria Enterobacteriaceae Non-fermenting bacteria Others / Fungi Pathogen Staphylococcus aureus Streptococcus pneumoniae Citrobacter freundii Escherichia coli Enterobacter cloacae complex Enterobacter aerogenes Proteus spp. Klebsiella pneumoniae Klebsiella oxytoca Klebsiella variicola Serratia marcescens Morganella morganii Moraxella catarrhalis Pseudomonas aeruginosa Acinetobacter baumannii complex Stenotrophomonas maltophilia Legionella pneumophila Pneumocystis jirovecii Haemophilus influenzae Mycoplasma pneumoniae In Pneumonia, the early detection of pathogens and antibiotic resistances is key to improving clinical outcome. The Unyvero System uniquely addresses the analysis of antibiotic resistance markers simultaneously with the pathogen detection. The Unyvero Hospitalized Pneumonia panel of microorganisms and resistance gene markers is designed based on feedback of clinical experts and international, as well as national treatment guidelines.* The panel is primarily designed to capture patients at risks for > pathogens causing severe, difficult to treat forms of pneumonia e.g. Pseudomonas aeruginosa, pathogens carrying antibiotic resistance and where patients may need isolation (Klebsiella spp., Acinetobacter spp.) > infections with multidrug-resistant bacteria, that might not be targeted by empiric treatment schemes. In addition, for the panel composition pathogen incidences have been taken into account, thus it includes those microorganisms showing an incidence of above 5%. The panel is completed by adding difficult to diagnose pathogens (e.g. Legionella pneumophila) with lower incidence, but with a rather high clinical impact. The Curetis Unyvero HOSPITALIZED Pneumonia panel targets the following antimicrobial classes by analyzing 19 genetic markers > ß-lactam-resistance > Macrolide-resistance > Fluoroquinolone resistance > resistance as clinically most relevant in pneumonia causing pathogens. Gene ermb meca mecc tem shv ctx-m kpc imp ndm oxa-23 oxa-24 / 40 oxa-48 oxa-58 vim sul1 gyra83 gyra87 resistance against Macrolide/Lincosamide Oxacillin Oxacillin Penicillin Penicillin 3rd generation Cephalosporins Sulfonamide Fluoroquinolone Fluoroquinolone * CDC: Prevention of Healthcare-Associated Pneumonia, Management of mdr Organisms in Healthcare Settings, American Thoracic Society: HAP, VAP, HCAP II Guideline, CAP Guideline Paul-Ehrlich-Gesellschaf: CAP-Leitlinie: Nosocomial pneumonia: prevention, diagnosis, treatment, European Respiratory Society: Lower Respiratory Tract Infections, British Society of Antimicrobial Chemotherapy: HAP Guideline, Canadian GuidelineCommittee: VAP Diagnosis and Treatment. 16 Investigational Use. Not available for Sale in the United States. 17

established technologies in a new format DIVERSITY HIGHLY SPECIFIC MULTIPLEX PCR and FAST ARRAY-BASED DETECTION Pathogen DNA Specific Amplification Specific Target Hybridization Detection and Specific Control Sample Types Sample Quality One of Curetis core competencies is the design of reliable > sputum > lavage (BAL) > tracheal aspirate > liquid > viscous > contaminated with - cells - blood bio-assays in self-contained cartridges for enabling sensitive multiplex testing. The required multiplex grade is achieved by combining the unmatched sample preparation and PCR technology with a proprietary detection array. Endpoint-PCR can deliver higher multiplex grades than most other amplification methods and in that respect holds clear advantages over e.g. real-time PCR. vim Curetis` proprietary and universal sample preparation technology prepares DNA from any native clinical sample type without losing time for preculturing. Curetis` technology efficiently extracts DNA from different microorganisms (Gram-positive and Gram-negative bacteria, fungi and other intracellular organisms) even in complex samples like highly viscous sputa or in samples contaminated with blood. Because of its universal applicability the Curetis technology can use a single protocol for sample preparation for many different sample types in any clinical application. The array has been optimized for hybridization times of a few minutes compared to standard arrays. To enhance specificity, the dissociation kinetics of the array hybridization are automatically assessed. In addition with each patient sample, an artificial gene is simultaneously processed as internal process control. The control verifies all PCR steps, as well as the array hybridization. Pneumocystis jirovecii 18 Investigational Use. Not available for Sale in the United States. 19

Unyvero Workflow Unyvero Workflow SPEED UNYVERO SOLUTION`S SIMPLIFIED WORKFLOW The intuitive simple workflow is consistent across all clinical applications and sample types, thus drastically reducing invalid tests due to operator errors. Step 1 Transfer of samples and lysis Step 2 Assembling the Unyvero Cartridge Step 3 Scanning and inserting the Unyvero Cartridge Step 4 Four to five-hour analysis process Working time ~ 60 seconds: ~ 30 seconds: ~ 20 seconds: It takes just a few minutes for subsequent analysis of the results: 1. The patient sample is transferred to the Unyvero Sample Tube, then sealed in with the Unyvero Sample Tube Cap and lysed for 30 minutes in the Unyvero Lysator. 2. After 30 minutes, the Unyvero Sample Tube can be removed from the Lysator and inserted together with the Unyvero Master Mix Tube into the corresponding Unyvero Cartridge. 3. The cartridge is now scanned and inserted into the Unyvero Analyzer. Up to two cartridges per analyzer can be analyzed simultaneously. 4. The Unyvero analysis now runs for four to five hours. The results are then displayed on the screen or can be exported as a PDF. 20 Investigational Use. Not available for Sale in the United States. 21

Unyvero System And Applications UNYVERO SYSTEM UNIVERSAL PLATFORM FEATURING MANY DIFFERENT APPLICATIONS The Unyvero Solution features a Unyvero L4 Lysator Unyvero C8 Cockpit Unyvero A50 Analyzer»sample to answers«approach and consists of: > the Unyvero L4 Lysator for sample lysis > the application specific Unyvero Cartridge > the Unyvero A50 Analyzer handling the Unyvero Cartridge > the Unyvero C8 Cockpit for intuitive user interaction > and the optional Unyvero Server Software for integration into the hospital`s information systems Unyvero Application Cartridges The Unyvero System translates a complex laboratory and the Master Mix are inserted into the cartridge, the process into an easy-to-use format. The analytical cartridge is loaded into the analyzer and processed fully process requires merely the addition of the unprocessed automatically. The Unyvero System generates complete patient sample and enzymes for DNA amplification. diagnostic information in 4 5 hours, without any further All other reagents are preloaded into a self-contained, operator interaction. contamination safe cartridge. After the patient sample 22 Investigational Use. Not available for Sale in the United States. 23

At A Glance UNyvero at a glance The Unyvero Solution > detects broad panels of pathogens and antibiotic resistances from a single sample in one run > enables testing of many clinically relevant native samples > delivers clinically relevant information in 4 5 hours, to aid an informed therapy decision as early as possible > enables point of need testing > provides high productivity through - minimizing operator time to a few minutes with full walk-away automation based on a simple and consistent workflow for any clinical application - low implementation requirements and low total cost of ownership, as no staff with molecular biology skills nor special infrastructure is needed - configurations that meet individual customer needs, satisfying any throughput demands - optimizing the routine hospital workflow by sophisticated information management 24 Investigational Use. Not available for Sale in the United States. 25

Curetis GmbH Max-Eyth-Str. 42 71088 Holzgerlingen Germany Tel.:+49 (0)7031 49195 10 Email: contact@curetis.com www.unyvero.com www.curetis.com 00124 Rev5.0 Curetis GmbH Investigational Use. Not available for Sale in the United States.