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CalScreener® – an innovative device for Bacterial Analysis and Diagnostics through Growth and Energy-release in Real-time

Periodic Reporting for period 2 - BADGER (CalScreener® – an innovative device for Bacterial Analysis and Diagnostics through Growth and Energy-release in Real-time)

Reporting period: 2019-02-01 to 2020-07-31

Symcel is a Swedish medtech company that provides a sensitive analytical instrument, the calScreener, used for direct metabolic measurements of cells in real-time.

Antimicrobial resistance (AMR) is a serious global threat that can cause infections that are extremely difficult to treat – sometimes not even a single antimicrobial has remaining activity against multi-drug-resistant (MDR) bacteria. In 2050, it is estimated that up to 10 million people will die annually due to AMR. In severe bloodstream infections, sepsis, time is of immense importance with rapid increase in mortality for every hour left untreated together with a complicated antibiotics resistance profile. Tailoring the right treatment is complicated and conventional methods are outdated and slow. The world is running out of antibiotics, creating an immediate need for testing combinations of existing antibiotics that are more efficient than therapy with a single antibiotic. At present, there is no clinically validated solution for combination testing of antibiotics.

Symcel’s calScreener offers a unique possibility to evaluate combinations of antibiotics that could enable customized diagnostic solutions with rapid and accurate quantitative measurements. Through the BADGER project we have performed clinical validation studies of the calScreener as a rapid in-vitro diagnostic tool for antibiotic testing.

The BADGER project was designed to address the need for new clinical tools that can accurately test combinations of novel antimicrobials in a cost-efficient and rapid manner. A key objective has been to identify additive or synergistic effects of antimicrobials within a few hours and validate these tests in an in-vivo animal infection model. To precisely determine the desired treatment combinations will lead to better cures for difficult-to-treat infections. The BADGER project establishes the foundation to make the calScreener the new gold standard for rapid antimicrobial combination testing and more personalized treatments clinically.
The project has been conducted in three clinical evaluations. These have been performed with world-leading expertise in AMR at five major European hospitals in Sweden, Spain, Italy, Denmark and the Netherlands. Work has focused on four of the most important pathogens that cause sepsis and where the need for improved diagnostics is imminent; Escherichia coli, Klebsiella pneumonia, Pseudomonas aeruginosa and Acinetobacter baumannii.

Clinical study 1 was aimed to validate the accuracy of the calScreener antimicrobial susceptibility results for single antibiotics to be in concordance with the international ISO-standard (Broth microdilution; BMD) and to establish the time to the diagnostic result. This was successfully completed with high concordance with BMD and significantly faster time to answer at around 6h, enabling same day actionable results. A total of 159 isolates with known antimicrobial susceptibility was tested against 10 of the commonly used antibiotics.

Clinical Study 2 focused on combination testing and synergy identification of antibiotics against multiresistant bacteria, as well as with single agents. To evaluate and validate the in-vitro results of antibiotic combination treatments, results were compared to a sepsis animal model in which the identified synergistic/additive combinations were tested. 158 isolates were tested for single antibiotics and 107 isolates for combination therapy. The results were very encouraging, confirming the ability of the calScreener to predict within hours additive or synergistic antibiotic effects for the treatment of multiresistant infections and therefore be used as a viable tool for screening for new treatment regimens.

Clinical Study 3 included results of antibiotic combination experiments performed on a large multicentric collection of 578 MDR clinical isolates. These were tested with 290 meropenem-colistin and 288 meropenem-amikacin combinations. Overall, a relatively low percentage of isolates (8.6%) showed synergistic/additive effects with meropenem-colistin combination, while a better result was obtained with the meropenem-amikacin combination (22.5%). These results confirmed that synergy in-vitro between meropenem and colistin or amikacin was relatively rare in a large multicentric collection of MDR isolates, which suggests that synergy cannot be assumed without testing. The study also shows that antibiotic combination testing with the calScreener are highly related to checkerboard assays. Together with previous data from study 2, this underlines the importance of accurate rapid synergy testing before treatment. This shows that the calScreener can be a useful clinical tool that is easy to use and less labour intense than checkerboard. Importantly the calScreener can predict the efficacy of different combination therapies within 6 hours, while the checkerboard assay is a minimum of 18 hours.
By validating and commercializing the calScreener as a diagnostic tool, the BADGER project will make an important contribution to fighting AMR in Europe and establish customized treatments for severe infections. To this date no commercial method for combination testing exist and clinicians rely on empirical trial and error, on patients where every our left untreated rapidly increase mortality. The results from this project will help improve the diagnosis and treatment of sepsis and bring the first method to the market for combination testing of MDR bacteria.

Current state of the art for SINGLE antimicrobial testing:
The gold standard, BMD, is accurate but very slow (16-20 h). The surrogate disc diffusion method may provide results within 6 h, however it has shown a poor correlation with BMD and very difficult to use for MDR bacilli. Results are qualitative, and do not provide the important quantitative MIC-value. Both methods are labor intensive and low throughput and only allow limited possibilities for testing.

New state of the art – enabling COMBINATION testing:
The novelty of the calScreener diagnostic device lies in its unmatched sensitivity and specificity, enabling direct and label-free measurements of the metabolic activity. This provides the clinically relevant guidance for correct antibiotic treatment.

The calScreener can be used on any sample format, whether liquid or solid, greatly reducing the time to results and cost. The economic benefits of the calScreener derive from the opportunities to drastically reduce costs related to diagnosis and treatment of severe infections. Indirectly, the use of calScreener will lead to a reduced use of antibiotics and consequently to reduced socioeconomic costs of antimicrobial resistance. The societal benefits include a) shorter time to diagnosis and treatment, b) personalized approach to treating infections c) improved clinical outcomes d) significant role in combating the large healthcare problem of AMR.

With the BADGER project, we have established the foundation to take the calScreener to the clinical diagnostics market, focused on synergy identification and combination therapy.
Workflow from sample to data
The calScreener product suite
Heat flow profile for MIC determination of A.baumannii
The calPlate with titanium cups and single use insert
Clear synergistic effect upon combination of two antibiotics
Heat flow profile for MIC determination of P. aeuruginosa
Calorimetric signal converted to data