Leading Infectious Diseases in the IVD Market - Healthcare-Acquired Infections and Antimicrobial Resistance

Leading Infectious Diseases in the IVD Market - Healthcare-Acquired Infections and Antimicrobial Resistance

The following analysis is derived from Kalorama Information’s recently released global market research report:The Worldwide Market for Infectious Disease Diagnostic Tests. A more comprehensive report on markets for the control of hospital-acquired infections, including sterilization, disinfection, testing and treatment is also available withThe Market for Hospital-Acquired Infection Control.

This is the final post in a series of five outlining the leading infectious diseases or infectious disease groups in terms of IVD market sales. Previous posts were for women’s health and sexually transmitted pathogens,hepatitis,HIV/AIDS,andrespiratory tract infectiontests.

Healthcare-acquired infections (HAIs) are also known as hospital-acquired infections due to their common route of transmission through devices and procedures in inpatient settings. Combined with testing used to assess antimicrobial susceptibility (AST) or resistance, the HAI and antimicrobial resistance (AMR) test market represents in excess of $4 billion in sales. While the majority of lab microbiology identification and AST (ID/AST) work is performed for outpatients, HAI and AMR/AST testing are becoming increasingly intertwined as performed in hospital labs. Some of the most severe HAIs are characterized by their resistance to one or multiple drugs.

Healthcare facilities represent the front line in the battle against antimicrobial resistance, potentially the greatest threat to healthcare worldwide. Even the hundreds of thousands of death worldwide from HAIs and resistant infections would be dwarfed by the implications of a “post-antibiotic age” arising from widespread, ineffectively combated AMR. To address antimicrobial resistance originating from healthcare settings and properly steward antibiotic usage, hospitals and other healthcare institutions are relying upon the latest AMR testing platforms to eliminate ineffective antibiotic prescriptions and implement disease surveillance.

While the majority of lab microbiology identification and AST (ID/AST) work is performed for outpatients, HAI and AMR/AST testing are becoming increasingly intertwined as performed in hospital labs. Additionally, some of the most severe HAIs are characterized by single- or multidrug resistance.

Nosocomial infections (HAIs) are opportunistic and can cause critical infections in sick, weakened and immunocompromised patients. The threat is not limited to inpatient susceptibility to infection, but also the added difficulty of subsequent treatment in the case of resistant infections. Pathogens present in hospital and other healthcare settings are much more likely to have been frequently exposed to sometimes multiple antibiotics used for infection treatment, contributing to prevalent antimicrobial or antibiotic resistance (AMR). Community-acquired infections (contracted outside of healthcare settings) can also be resistant to antimicrobials, but the prevalence of AMR is significantly more concentrated with antibiotic usage and infected patients inside of hospitals. The overuse or over-prescription of antibiotics, antibiotic abuse (not completing a prescription cycle) and the use of broad-spectrum antibiotics have all contributed to AMR in both community and healthcare settings.

Healthcare-acquired infections can be classified by their route of transmission or by organism. Catheter-associated urinary tract infections (CAUTI) are among the most common HAIs and can be caused by a large of number of pathogens including Stenotrophomonas maltophilia and Pseudomonas aeruginosa. Ventilator-associated HAIs also include P. aeruginosa as well as ventilator and hospital acquired pneumonia (VAP/HAP). Central line-associated bloodstream infections (CLABSIs) can potentially be the most life-threatening due to the progression of sepsis from bloodstream infections, and have been the most targeted for prevention and control among hospitals. The remaining common route of nosocomial infection is surgical site infection and gastrointestinal infection, the latter often caused by opportunistic pathogens such as C. difficile. In addition to the pathogens mentioned above, the most common HAIs include Acinetobacter baumannii, Legionella (Legionnaires’ disease), Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), tuberculosis, vancomycin-resistant Enterococcus (VRE), carbapnem-resistant Enterobacteriaceae (CRE), E. coli, Shigella, Salmonella, Campylobacter, and Candida.

To address antimicrobial resistance originating from healthcare settings and properly steward antibiotic usage, hospitals and other healthcare institutions are relying upon the latest AMR testing platforms to eliminate ineffective antibiotic prescriptions and implement disease surveillance.

Traditional antibiotic susceptibility testing for the characterization of antimicrobial resistance may take a day to several months for results. Antimicrobial resistance, or conversely susceptibility, is determined through culturing a specimen on a plate or blood culture. Microbial colonies are then subjected to AST with qualitative disk or strip diffusion techniques that visually demonstrate the inhibition of growth around antimicrobial-dosed zones in the culture. While automated identification and AST (ID/AST) systems have accelerated the process, the turnaround time from sample to results for culture-based processes can exceed critical windows of time for intervention for severe infections and pre-sepsis. Rapid testing is becoming increasingly common in hospitals with the use of rapid immunoassays or molecular assays from blood culture samples or direct swabs from infection sites. The availability of rapid and sensitive HAI/AMR testing is a major motivation behind the decentralization of molecular testing; hospital labs can perform rapid tests to detect MRSA, C. difficile and other infections as part of triage, emergency care and inpatient care rather than relying on send-outs to reference labs.

While automated identification and AST (ID/AST) systems have accelerated the process, the turnaround time from sample to results for culture-based processes can exceed critical windows of time for intervention for severe infections and pre-sepsis.

One of the most proactive IVD companies in the AMR and HAI testing space is Cepheid. The company developed a highly popular molecular platform, the GeneXpert, with a small footprint and integrated design for easier and more flexible operation among hospitals, developing world healthcare systems, and even reference labs. Additional rapid molecular platforms for AMR and HAI testing are available from companies such as Biofire Diagnostics (bioMérieux), Becton, Dickinson & Co.  (BD), QIAGEN, and Nanosphere. The assays run on these companies’ rapid molecular platforms can be syndromic panels or otherwise multiplex for several pathogens able to be detected from a sample type such as a blood culture (e.g. FilmArray BCID, Nanosphere Blood Culture Tests). Multiplex detection of pathogens on such assays can also be accompanied by the detection of one or several genes for AMR (e.g. mecA - methicillin resistance; vanA/B - vancoymycin resistance). Otherwise, AMR/HAI tests may target one pathogen commonly harboring resistance and its known resistance genes (e.g. BD MAX assays, Cepheid Xpert assays, Seegene Seeplex ACE assays, Roche cobas and LightCycler MRSA assays).

The availability of rapid and sensitive HAI/AMR testing is a major motivation behind the decentralization of molecular testing; hospital labs can perform rapid tests to detect MRSA, C. difficile and other infections as part of triage, emergency care and inpatient care rather than relying on send-outs to reference labs.

Common molecular amplification assays (e.g. PCR, isothermal) can significantly shorten the time to results for AMR characterization and pathogen detection, either through shorter detection times from cultures or rapid results from non-cultured samples. Other molecular assay forms enable even greater multiplexing or use more flexible probes to capture genomic data insights into resistance or pathogen virulence. Microarrays are available from the IVD industry on a more limited basis than PCR and other molecular amplification assays, but provide more specific characterization of AMR. Examples include Akonni Biosystems MDR-TB and MRSA microarrays (research use only [RUO]), Veredus Laboratories’ MDR-TB microarray (RUO), AutoGenomics’ MDR-TB microarray for the INFINITI analyzer platform (RUO), and CapitalBio Corporation’s TB resistance assay (CE-IVD, China [SFDA]).

Among the leaders in the NGS space for clinical infectious disease testing and antimicrobial resistance surveillance is BioInnovation Solutions (formerly Pathogenica). The company’s CE-IVD-marked HAI BioDetection Kit is multiplexed for the 12 most common nosocomial infections and 15 drug-resistance genes. The kit uses hundreds of probes to amplify loci of interest. Amplicons are compiled in a library and subsequently sequenced and analyzed by means of a bioinformatics package. Sequencing results are referenced against databases for species, strains, substrains, and resistance genes.

Approved for clinical diagnostic use in Europe, the HAI BioDetection Kit is an excellent representative of the dual and unique value of clinical sequencing. The kit not only informs individual patient treatment, it also serves as a tool for disease control and surveillance in a healthcare setting. The detailed results provided by the sequencing kit enable outbreak tracking through the identification of bacterial clones or distinct strains and substrains.

Standardized sequencing assays for clinical infectious disease testing are available from only a couple of other diagnostics companies. Abbott Molecular offers its CE-IVD HBV sequencing assay for the determination of hepatitis B virus genotype and drug resistance prior to antiviral therapy. Singapore’s Vela Diagnostics has developed Sentosa NGS, a genotyping assay for hepatitis C. It is currently only a RUO platform that integrates with a number of Vela components. It is intended for viral genotyping from plasma or serum. Vela also offers Sentosa assays for oncology that already have CE-IVD marking. Siemens has marketed TRUGENE and VERSANT genotyping assays for the assessment of HIV, HBV and HCV susceptibility to antivirals prior to therapy.

However, the majority of NGS assays are available only as laboratory-developed tests or testing services that do not require premarket approval or other clearance processes for clinical use otherwise required of test kits.

Automated ID/AST systems have been widely adopted as more rapid, accurate and high throughput options for microbiology laboratories. The systems are widely available from microbiology diagnostics leaders and can provide faster results regarding antimicrobial susceptibility than manual methods that expose cultured isolates to various dilutions or concentrations of antimicrobials or qualitative disk or strip diffusion techniques that visually demonstrate the inhibition of growth around antimicrobial-dosed areas. Automated AST usually relies upon more sensitive (and therefore less time-demanding) detection methods such as turbidimetric detection and digital imaging. bioMérieux’s VITEK 2 system uses self-contained disposable test cards with multiple configurations of antimicrobials. Culture medium is introduced to the miniature antimicrobial wells on the card and microbial growth is determined through turbidimetry or the scattering of light across cell populations in the well. Most automated ID/AST systems use turbidimetry or the measurement of optical density in wells with the addition of colorimetric or fluorometric reagents to interpret the results of microdilution AST. Results are available in several hours or overnight.

Automated AST usually relies upon more sensitive (and therefore less time-demanding) detection methods such as turbidimetric detection and digital imaging… Results are available in several hours or overnight.

Mass spectrometry (MS) is appealing for AMR/HAI testing with its complex yet open, data-rich results that may reveal the unique fingerprints of nosocomial strains or antimicrobial resistance. Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) MS is most often used in clinical MS applications including microbiology. Cell surface proteins corresponding to drug resistance are identifiable by the mass/charge (m/z) ratio of fragments vaporized and ionized off of the MALDI plate. Stable isotope labeled amino acids (SILAC) may be used in microbial cultures to indicate microbial growth or more thoroughly characterize resistance. Another MS-based method for AST involves the detection of beta-lactamase hydrolysis by resistant bacteria; fragments of the hydrolyzed antibiotic are in relatively higher abundance in the mass spectra of analyzed resistant bacteria.