Tools and instruments available in the clinical microbiology labs are constantly evolving with an objective to decrease the overall time taken to obtain the results, enhance ease of sample processing, and increase sample turnaround time.
In recent years there has been a drastic increase in the antibiotic resistance among bacterial pathogens and this is considered as one of the biggest threats to global health in the current era. Antibiotic resistance, worldwide, leads to 700,000 deaths each year and it is predicted that the number is expected to grow to 10 million deaths annually by 2050, unless stringent actions are taken to curb misuse and overuse of antibiotics. In India, the growing burden of infectious diseases is amongst the highest worldwide. Although antibiotic-resistant bacterial infections can occur in the community, most deaths due to resistance are seen among inpatient healthcare settings such as hospitals and nursing homes. The current technologies used in clinical microbiology to identify the bacterial agent and profile antimicrobial susceptibility are time-consuming and frequently expensive. As a result, physicians prescribe empirical antimicrobial therapies. This scenario is often the cause of therapeutic failures, leading to higher mortality rates and healthcare costs, as well as the emergence and spread of antibiotic resistant bacteria. As such, new technologies for rapid identification of the pathogen and antimicrobial susceptibility testing (AST) are needed.
Timeliness and accuracy in the diagnosis of microbial infections are associated with decreased mortality and reduced length of hospitalization, especially for severe, life-threatening infections. Every hour of delay in administrating the targeted antibiotics to septic shock patients, decreases their chances of survival by 7.6 percent. Tools and instruments available in the clinical microbiology labs for analysis of patient samples and diagnosis are thus constantly evolving. The main motivation behind this is to decrease the overall time taken to obtain the results from the instruments, enhance the ease of sample processing, increasing the sample turnaround time with the ultimate goal of earlier patient treatment and better recovery rates. This is especially true in the case of AST, where every hour saved in obtaining the results leads to an earlier switch to targeted antibiotic therapy and has a direct influence on improving clinical outcomes. Reduction in the time to obtain AST results reduces the duration of use of broad-spectrum antibiotics, which in turn decreases the emergence of antibiotic resistance among bacteria.
With recent advancements, a number of products have been developed which can provide direct-from-sample pathogen identification, bypassing the need for isolating colonies. In addition to pathogen identification, many of these also provide information regarding presence or absence of a select set of genes known to cause antibiotic resistance. Many clinical microbiology labs possess one or more of such instruments. There are a few rapid identification systems in the market currently, which can directly use positive culture samples to determine bacterial identification, but none exist for rapid AST. Many of the traditional methods available for AST are labor intensive and slow, despite being precise in obtaining results. This has not gone unnoticed amongst the scientific community and several researchers are working on developing rapid AST diagnostics to improve clinical outcomes and reduce antibiotic resistance among microorganisms. Thus, there is now a trend toward development and use of automated diagnostic instruments which are rapid and easy-to-use.
Antimicrobial resistance (AMR) is a growing concern in India, with several government initiatives beginning to fund research and development (R&D) in this space. A high-level Inter-Ministerial Consultation on Antimicrobial Resistance was organized by the Ministry in April 2017. In August 2017, the Ministry of Health and Family Welfare (MoHFW), National Centre for Disease Control (NCDC), and World Health Organization (WHO) jointly organized a two-day National Consultation to Operationalize Action against AMR. The MoHFW is constantly engaged in activities for containment of AMR in the country. The National Action Plan on AMR (NAP-AMR) has since been adopted. Laboratories have been able to initiate a data reporting system in WHONET, the software for AMR surveillance data reporting. Labs have also been assessed for building capacity toward quality testing. However, given the cross-disciplinary and multi-faceted nature of antimicrobial resistance, it is and will likely to remain as a grand challenge for India.
bioMérieux. In September 2017, bioMérieux participated in the AMR Challenge, a Center for Disease Control and Prevention (CDC) initiative to bring government, healthcare, and industry leaders together in a year-long concentrated effort to accelerate the fight against public health threat of AMR. Accordingly, in 2018, approximately 75 percent of bioMérieux’s clinical R&D budget is dedicated to develop effective diagnostics that support the fight against AMR. Among several public–private partnerships, bioMérieux is part of COMBACTE (combatting bacterial resistance in Europe), a unique research consortium aiming at boosting research and innovation against AMR within the framework of innovative medicines initiative (IMI). Furthermore bioMérieux is leading an IVD industrial community calling for an IMI co-funded project to demonstrate the value of diagnostics to combat antimicrobial resistance by optimizing antibiotic use.
Becton, Dickinson and Company. In April 2018, BD introduced several new informatics and automation solutions for clinical laboratories, which may play a critical role in the fight against infectious diseases and antimicrobial resistance. The company announced its plan for the commercial availability of BD Synapsys microbiology informatics solution, which provides laboratories with secure connectivity across instruments and locations. The new easy-to-use, browser-based application will help streamline workflows, automate manual processes, and facilitate on-demand actionable insights. Together these capabilities will enable laboratories to improve productivity, simplify compliance, and ultimately get results to clinicians more efficiently.
In September 2017, BD had launched the first automated phenotypic test to detect and classify carbapenemase-producing organisms (CPO). Available as part of the BD Phoenix automated microbiology system in Europe, the new BD Phoenix CPO detect test helps hospitals identify and contain infections caused by CPO, while potentially combating an increase in antimicrobial resistance. Fully integrated within BD Phoenix panels, Phoenix CPO detect test enables laboratories to offer a more comprehensive antimicrobial susceptibility test profile while improving laboratory process efficiency.
Beckman Coulter Diagnostics. In August 2018, Beckman Coulter announced the commercialization of its DxM MicroScan WalkAway system, a diagnostic solution for bacterial identification and antibiotic susceptibility testing (AST) for microbiology laboratories. The DxM MicroScan WalkAway system uses direct minimum inhibitory concentrations (MIC) for detection of antimicrobial resistance, offering greater confidence in results through gold-standard accuracy and the broadest breadth of first-time reporting. Building upon 40 years of trusted MicroScan technology, the DxM MicroScan WalkAway system supports microbiology laboratories that seek to optimize patient care, while reducing the risks, costs, and operational burden of emerging antimicrobial resistance.
Thermo Fisher Scientific. In July 2018, Thermo Fisher Scientific introduced new compounds for AST, delafloxacin and meropenem/vaborbactam. The antimicrobial delafloxacin, and the combination of meropenem and vaborbactam are available on FDA-cleared microbroth dilution susceptibility plates. Delafloxacin is available for testing select fastidious and non-fastidious Gram positive and non-fastidious Gram negative organisms, including MRSA, MSSA, and E. coli, while meropenem/vaborbactam is available for select Gram negative, non-fastidious isolates. The Thermo Scientific Sensititre ID/AST system is the first to offer delafloxacin and meropenem/vaborbactam on IVD-labeled, microbroth dilution susceptibility plates.
In July 2017, B·R·A·H·M·S GmbH, a part of Thermo Fisher Scientific, received 510(k) clearance from the US FDA for expanded use of the B·R·A·H·M·S PCT sensitive KRYPTOR assay. The assay helps hospital clinicians decide whether to initiate antibiotic therapy in patients with suspected or confirmed lower respiratory tract infections (LRTI) and when to safely discontinue antibiotics in patients with LRTI and sepsis. The clearance provides clinicians in emergency departments, intensive care, and other hospital units with an effective tool for antibiotic stewardship, identified by the CDC as a key strategy for addressing the problem of antibiotic resistance.
Bruker Corporation. In September 2017, Bruker closed the acquisition of Merlin Diagnostika GmbH. Merlin has in-depth expertise in products, services, and consulting in the fields of antibiotic resistance testing (ART) and AST. Merlin’s technology and product portfolio for human and veterinary antibiotic resistance and specialty susceptibility testing further expands Bruker´s microbiology business, which is based on rapid, broad-based microbial identification using Bruker’s market-leading MALDI Biotyper (MBT) platform for proteomic fingerprinting.
In June 2017, Bruker introduced major innovations for strain typing, hospital hygiene, and infection control. The novel, bench-top IR Biotyper system for microbial strain typing is based on Fourier-Transform Infrared (FTIR) spectroscopy technology, and complements Bruker’s world-leading MBT mass spectrometry (MS) platform for fast microbial identification from cultures using protein fingerprinting. The IR Biotyper system can be used as a stand-alone for routine hospital hygiene and infection control, as it is capable of providing results on dozens of hygiene samples overnight, or it can be combined in a workflow with parallel microbial species identification by the MBT. Due to its fast time-to-result (TTR), excellent strain differentiation performance, low cost per sample, ease of use, robustness, and throughput, the IR Biotyper can perfectly complement next-generation sequencing (NGS) strain-typing results, which typically require more time, training, and infrastructure in core labs.
In January 2017, Bruker acquired InVivo Biotech Services GmbH, a molecular biology contract manufacturing organization (CMO), and a leading provider of monoclonal antibodies and recombinant proteins. InVivo Biotech provides a complete range of biotech services, from cloning, screening, and recombinant expression of antigens to the generation of hybridoma cell lines, and from characterization of antibodies to final production of the developed monoclonal antibodies. This major addition in expertise and infrastructure for consumables development, validation, and production will also support Bruker´s strategy of expanding its microbiology assay menu for the MBT platform. Examples include Sepsityper IVD-CE assays for the fast identification of bacteria from positive blood cultures, RUO assays for selective testing of antibiotic resistance with the MBT-STAR assay family, and work-in-progress syndromic panels for the MBT as a multiplex PCR reader.
The global clinical microbiology market is expected to reach USD 4.95 billion by 2023 from USD 3.63 billion in 2018, growing at a CAGR of 6.4 percent, predicts MarketsandMarkets. Technological advancements in the field of infectious disease diagnostics, rising incidence, and prevalence of infectious diseases and growing outbreak of epidemics, and increased funding and public–private investments for the development of novel products for infectious disease diagnosis are major factors driving growth of the clinical microbiology market. Other factors leading to market growth include rapid growth in geriatric population and increasing number of clinical researches. Furthermore, improving healthcare infrastructure across emerging countries, and demand for advanced molecular diagnostic products are creating new opportunities for the market. However, reimbursement concerns and unfavorable regulatory scenario restrain market growth.
According to the American Cancer Society, around 1,688,780 new cases of cancer were diagnosed in the United States of America in 2017. High prevalence of diseases where clinical tests are used as one of the major diagnostic tools is expected to augment market growth in future. Sudden outbreaks of Ebola, Zika, and other contagious pathogens are also contributing to rising prevalence of infectious diseases. As per an article published in the Journal of Clinical Microbiology, there is a shortage of trained and skilled professionals in medical and microbiological laboratories for processing and interpreting samples and specimens. Lack of trained graduates and training programs is an issue particularly in developing countries, where demand for skilled professionals is rapidly increasing. However, entry of automated systems in the market is going to replace manually-operated conventional platforms in future, thereby reducing the impact of lack of skilled professionals.
The laboratory instruments products segment is expected to command the largest share of the market in 2018 due to factors such as continuous technological advancements and the focus on laboratory automation (coupled with the integration of robotics with conventional microbiology instruments). However, the reagents product segment is expected to grow at a higher rate from 2018 to 2023. The growth of the reagents segment can be attributed to the high prevalence of infectious diseases across major markets, growing trend of reagent rental agreements along with instrument sales, and the increasing number of life science researches in the field of pathogen-specific reagents. The market is witnessing rising investments in R&D. Almost all analytical and therapeutic research projects demand reagents and chemicals, thereby driving penetration of reagents.
The respiratory disease segment is estimated to account for the largest share of the global clinical microbiology market owing to the large patient population suffering from respiratory diseases, rising prevalence of target respiratory diseases (including TB, asthma, COPD, and bronchitis) across developing countries, and increasing number of epidemic outbreaks of respiratory infections. Increasing levels of air pollution with growing industrialization is further resulting in rapid escalation in prevalence of respiratory diseases. Also, among all infections, respiratory diseases spread rapidly owing to easy transfer of contagious pathogens. Prevalence of infectious diseases is high in developed as well as developing countries.
Geographically, North America is expected to account for the largest share of the global clinical microbiology market in 2018 due to easy accessibility and high adoption of advanced diagnostic techniques, technological advancements in microbial testing techniques, rising geriatric population, and growing public–private funding to support microbiology-based research in the region. However, Asia-Pacific is expected to be the fastest growing region. Factors such as the growing number of hospitals and clinical diagnostic laboratories in developing APAC countries; expanding research capabilities for the development of innovative and affordable clinical microbiology testing procedures across India, China, and Japan; and the rising incidence and prevalence of infectious diseases in the region are driving the market. The booming medical tourism industry is further expected to spur the demand for microbial diagnostic and monitoring tests in Asian countries. Moreover, availability of skilled labor at affordable cost and advanced manufacturing infrastructure are resulting in manufacturing facilities of major pharmaceutical and medical device makers shifting to Asia. This is boosting regional market expansion.
The growth in the global clinical microbiology market is influenced by the presence of major players such as bioMérieux, Danaher Corporation, Becton, Dickinson and Company, Abbott Laboratories, Bio-Rad Laboratories, F. Hoffmann-La Roche, Bruker Corporation, Hologic, Qiagen, Thermo Fisher Scientific, Cepheid, Agilent Technologies, Merck, Shimadzu Corporation, and 3M Company, among others. Product launches, mergers and acquisitions, partnerships, and joint ventures are some crucial strategies adopted by the major players to gain competitive advantage. Introduction of automated systems and innovative designs is expected to intensify the competition in the years to come.
Automation and informatics – solving various challenges faced by microbiology laboratories
Today’s microbiology labs face unprecedented challenges. They are forced to do more with less by processing rising specimen volumes due to lab consolidations, while they experience a shortage of skilled lab technicians and increasing cost pressures. Meanwhile, laboratories must adapt in an environment with evolving standards and available technologies. For example, more rigorous accreditation requirements and validation of new technologies can mean that laboratorians must spend time away from clinical work. A lack of access to data and performance analytics, can further exacerbate this challenge by preventing them from truly understanding the full scope of their resource needs so that they can continuously provide more accurate, reliable, and timely results to clinicians and physicians.
Automation and informatics are critical to help overcome these challenges. Microbiology lab automation technologies can automate time consuming, error prone, and manual tasks in order to increase lab efficiency, helping labs to provide higher quality and more accurate results faster. These technologies can free up precious labor resources so that skilled staff can be allocated to higher skilled and more technical tasks, while the lab processes a higher volume of samples. Lab automation is helping transform the microbiology lab workflow by automating plate selection, barcoding, inoculation, streaking, transportation, incubation, and imaging. Digital images allow lab technicians and microbiologists to review plates anytime, anywhere, including remote locations and offer the ability to build algorithms that can automatically provide results without human intervention.
Informatics tools also enable seamless connectivity between the laboratory information system (LIS) and other lab instruments. These tools help labs create an integrated workflow with a single user interface and provide laboratorians with access to real-time data and analytics. Cloud-based informatics systems also allow data to be aggregated across labs from the same network, helping with performance benchmarking, analysis, and standardization of protocols. Modern informatics systems also ensure that the latest data privacy and cyber security requirements are met, while providing on-demand access to information, reports, and analytics which can improve lab productivity, reduce errors, and shorten time to results.
Scientific advances are crucial in any field and more so in a healthcare setting where constant innovation can not only make life easier for its end users but also provide better compensation, lead to better patient outcomes and improved quality of life. Thus, there is a constant need to upgrade the existing technologies and develop innovative new technologies for better, safer, and faster diagnosis of diseases. Currently, there are several innovative approaches that are developed and are still under development for rapid AST aimed at faster detection times and reduced sample processing for effortless integration into a clinical lab setting.
Forward laser light scatter technology. FLLS is one of the emerging technologies for early determination of AST. This system uses a laser light source to measure the concentration of particles in the liquid samples (optical density – OD) as well as the scattered intensity in a direction near to the laser beam. The system can be used to run up to 16 samples simultaneously, with measurements done automatically every 3 minutes for accurate density change measurements. This was initially developed for urinalysis and now has been adapted to be used for AST. Using this technology, the system can obtain results in about 6 hours for fast growing microorganisms and can take up to 18 hours for slower growing organisms. The system is accurate and has potential to replace the existing microdilution systems and is not limited by the use of probes or markers.
Human robot collaboration in clinical microbiology. Collaborating robots is a latest technology for full laboratory automation. In an age of increasing workloads and diminishing resources, various tasks can be performed by robotic systems, while highly qualified laboratory professional can focus on esoteric tasks that require their experience, knowledge, and training. The new robotic system automatically manages many manual microbiology processes done at the laboratory bench, such as processing traditional fiber swabs, positive blood culture bottles, tissues, wound aspirates, and sterile body fluids. Technologists simply scan the specimen barcode, and the robot presents the precise sequence of pre-labeled plates or tubes. After the plates are manually seeded, the robot streaks the plates and places them on the conveyor track to incubators. The robot can also be used to automatically seed MALDI-TOF slides and set up AST/ID panels. Using this robot, can improve traceability and reduce transcription and transposition errors from manual processes.
Automated plate assessment system. Traditional laboratory processes for the preparation and analysis of culture plates involve microbiologists manually examining each specimen and separating out those that need further attention. This can be a time-consuming process, which has implications for doctors and patients waiting on results, and consume critical resources. This is even truer in a country like ours where microbiologists are in short supply. APAS is an artificial intelligence technology for the automated imaging, image analysis, interpretation, and reporting of growth on microbiology plates after incubation. It helps to improve the diagnostic efficiency of microbiology laboratories and enables faster reporting of infectious diseases. The instrument successfully triages negative plates out of the workflow, allowing microbiologists to focus on positive plates only. In addition, the APAS facilitates significant upstream benefits in specimen processing.
Next-generation sequencing. Clinical microbiology laboratories help to lessen the burden of infectious disease by detecting and characterizing pathogens in infected patients or those pathogens circulating in the community. In this scenario, implementation of NGS can potentially assist in clinical and public health decisions by determining the causative agent of infectious disease and/or the epidemiology and evolution of various infecting pathogens in the hospital or community settings. With its multitude of benefits, NGS is becoming the gold standard in bacteriology; however, since it is not yet fully accessible (particularly in low resource settings), currently NGS is mainly used at a level of reference microbiology rather than routine.
With the rapid advances in NGS technologies and capabilities, clinical microbiologists are recognizing that the influence of NGS on the diagnostic cycle will be in the scale of a disruptive technology, potentially reducing the time from diagnosis to clinical treatment, while also reducing the requirement for wet laboratory-based analyses performed in tandem. It is particularly important in outbreak detection and monitoring the evolution and dynamics of multi-drug resistant pathogens. Consequently, NGS should become routine in the clinical microbiology laboratory. However, further studies are required to improve the workflow for NGS, by shortening the turnaround time for the library preparation and the runs on the NGS platforms, and further reducing costs.
Mass spectrometry. MS was successfully introduced as a new diagnostic gold standard method in clinical microbiology for rapid, accurate, and cost-effective microbial species identification. The introduction of matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) MS for routine identification of microbial pathogens has profoundly influenced microbiological diagnostics, and is progressively replacing biochemical identification methods. MALDI-TOF MS technology has been shown to be a suitable tool for high throughput and complete automation in clinical microbiology laboratory. Recently, a semi-quantitative MALDI-TOF MS-based method for the detection of antibiotic resistance was developed. This assay allows rapid identification and susceptibility testing of both Gram negative and Gram-positive pathogens in a single assay within approximately 3-4 hours. The assay is also applicable for AST directly from blood culture fluid with high sensitivity, specificity, and an overall accuracy rate of 95 percent.
The reliability and accuracy of MALDI-TOF MS in identification of clinically relevant bacteria and yeasts has been demonstrated by several studies showing that the performance of MALDI-TOF MS is comparable or superior to phenotypic methods currently in use in clinical microbiology laboratories, and can be further improved by database updates and analysis software upgrades. Besides microbial identification from isolated colonies, new perspectives are being explored for MALDI-TOF MS, such as identification of pathogens directly from positive blood cultures, sub-species typing, and detection of drug resistance determinants.
Subsequent developments have mainly focused on software and database improvements, making MALDI-TOF MS an increasingly robust and accurate tool for microbial identification. However, application of MALDI-TOF MS for rapid susceptibility testing or epidemiological studies is currently hampered by the lack of standardized protocols, test kits, and software tools. Furthermore, laboratory equipment is expensive and in need of costly maintenance although the operating costs are low.
The current systems in the market are considered gold standard and are highly reliable systems being used for decades in the clinical microbiology labs. However, they take a long time to obtain antibiotic susceptibility profiles for pathogens, which in turn causes delay in providing appropriate targeted treatment. Hence, research is now shifting toward developing rapid AST systems which are able to bypass the need for pure clinical isolates. These novel systems can either directly or through simple pre-processing of samples be used for direct AST determination from patient samples or positive culture samples. The systems employ novel approaches for AST determination including use of microscopy, DNA probes, and micro-cantilevers to name a few. Such novel devices will in the near future be able to replace the current gold standards, be faster and equally reliable in obtaining results. The new emerging technologies are also taking a similar path and are aimed at reducing the time taken between acquiring patient samples and reporting the susceptibility profiles for targeted treatment of patients. These technologies use innovative approaches such as microcalorimetry, impedance, and Raman spectroscopy to achieve their goals. These trends will inherently improve the turnaround times for sample processing in the labs, reduce the burden on technicians, provide rapid reporting of AST, with the ultimate goal of faster treatment of patients, reduced load on use of broad-spectrum antibiotics, and better clinical outcomes.