The MALDI Biotyper An In Vitro Diagnostic System (IVD) for Identification of Bacteria and Yeasts with a Global Reach

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1 The MALDI Biotyper An In Vitro Diagnostic (IVD) for Identification of Bacteria and Yeasts with a Global Reach The MALDI Biotyper identifies microorganisms using MALDI-TOF (Matrix Assisted Laser Desorption Ionization - Time of Flight) Mass Spectrometry to measure a unique molecular fingerprint of an organism. Specifically, the MALDI Biotyper measures highly abundant proteins, such as ribosomal proteins, that are found in all microorganisms. The characteristic patterns of these highly abundant proteins (molecular fingerprints) are used to reliably and accurately identify microorganism by matching the respective pattern in a database to determine the identity of the microorganism down to the species level. With its combination of performance and utility, the MALDI Biotyper is revolutionizing the way microbial identification is performed in the clinical microbiology laboratory.

2 In 2009, after extensive and successful performance evaluation studies, the MALDI Biotyper was CE-marked according to the European Union In Vitro Diagnostic Directive 98/79/EC. The library of the covers a broad range of microorganisms including nonfermenting gram-negative bacteria, enterobacteriaceae, other gram-negative bacteria, gram-positive bacteria, and yeasts. Together with the bench-top LT/SH MALDI-TOF mass spectrometer, automated analysis software, the IVD Bacterial Test Standard (BTS), a 96-spot MALDI target, the system subsequently received clearance as a medical device in various countries throughout the world (table 1). Table 1: Countries / Regions with MALDI Biotyper Regulatory Clearance Country/Region Product Registration Date Note Germany December 2009 United Kingdom December 2010 France May 2010 Registration was done in each EU country separately before May 2011 EU (European Union) May 2011 July 2014 Turkey September 2012 Israel September 2014 Canada MALDI Biotyper July 2010 Ecuador June 2012 Colombia August 2012 Guatemala January 2013 Mexico April 2013 Argentina September 2013 Brazil July 2014 US MALDI Biotyper CA November 2013 March 2015 Gram (40 species/groups) Gram-; Gram+; Yeast (170 species/groups) Costa Rica December 2014 Japan Taiwan China Australia South Korea MALDI Biotyper July 2011 December 2011 May 2014 June 2014 July 2014 Vietnam August 2014

3 MALDI Biotyper CA In 2013, the Food and Drug Administration granted 510(k) clearance to the MALDI Biotyper CA system for identifying Gram-negative bacterial colonies cultured from human specimens. This marked the arrival of the MALDI Biotyper CA system as an in vitro diagnostic device in the U.S. market. With a subsequent clearance by the FDA of expended library containing aerobic Gram-positive, fastidious Gram-negatives, enterobacteriaceae, anaerobic bacteria and yeasts, the MALDI Biotyper CA can identify 210 species or species groups, covering in total 280 clinically relevant bacteria and yeast species, and representing more than 98% of the typical bacterial identification workflow of clinical microbiology laboratories. The multi-center clinical trials compared results generated by the MALDI Biotyper CA to 16s rdna molecular sequencing for bacteria and ITS sequencing for yeast supplemented by protein gene sequencing. Up to thirty independent isolates were tested for each organism in the clinically validate library. The data showed that 99.2% of the isolates tested have resulted in correct identifications to the genus or species level, with only 0.6% of isolates unable to be identified (table 2). Table 2: Overall Performance of the MALDI Biotyper CA in the FDA Clinical Trial (Claim 1 and 2 Combined). The excellent performance was supported by robust and easy-to-perform sample preparation methods. Direct transfer colony from a culture plate to a selected position on an MALDI target plate (US IVD 48 spot target plate) followed by overlaid MALDI matrix (US IVD HCCA portioned) could produce high confidence results for majority of samples. For those samples that high confidence identification could not be achieved by this direct transfer method (DT), an extended transfer method (edt), which is overlaying with 70% aqueous formic acid solution on smeared bacteria colony on the MALDI target before matrix application, and extraction procedure (Ext) could be performed. This tiered approach ensures an efficient and effective microorganism identification workflow for clinical microbiology laboratories (figure 1). In occasions where a clinical sample is rare and therefore not contained in the MALDI Biotyper CA library, a library containing 955 clinically non-validated organisms (CNVO) is automatically searched and could produce higher matching score value (figure 2). The CNVO matching result is intended for alerting laboratory staff around that matching organism for directional purposes. Additional testing should be conducted and these CNVO results must not be reported unless they are confirmed using alternative laboratory methods*. Correct ID Species Genus / % No ID 42 42/ % *For complete lists of organisms covered in the library, MALDI Biotyper CA library and CNVO library please send an to: MBTlibraries@bruker.com MALDI Biotyper Advantages This level of performance is the highest identification accuracy for any mass spectrometry-based bacterial and yeast identification system as of today. Highly Accurate Applicable to a Wide Range of Microorganisms Much Faster than Traditional Methods Cost Effective Robust and Easy-to-Use A True Benchtop

4 MALDI Biotyper CA Workflow Figure 1

5 Result overview Figure 2: For organism identifications reported in blue, refer to Organism Identification Hint Table section located in the reference library package insert for further information. Summary The MALDI Biotyper is cleared as an in vitro diagnostic device in different countries and regions throughout the world. Both MBT CA (in the U.S) and IVD MBT (outside of U.S) have comprehensive libraries that cover wide varieties of clinical relevant bacteria and yeast (Table 3). The MALDI Biotyper is changing how clinical microbiology being practiced by improving laboratory efficiency and patient care. MBT CA (USA) IVD MBT (outside USA) Clinically validated Clinically non validated GN 164 GP 88 YE 31 GN 424 GP 469 YE 63 GN 973 GP 1123 YE 192 (Fil. Fungi 42; Myco 41) Table 3: GN = Gram Negative; GP = Gram positive, YE = Yeasts Fil. Fungi = Filamentous Fungi*; Myco = Mycobacteria* *not part of the IVD workflow

6 Bruker Daltonics is continually improving its products and reserves the right to change specifications without notice. Bruker Daltonics , MALDI Biotyper is a registered trademark of Bruker Daltonik GmbH in the European Union and USA. Bruker Daltonik GmbH Bremen Germany Phone +49 (0) Fax +49 (0) ms.sales.bdal@bruker.com -