NEW YORK – After pandemic-related setbacks, makers of rapid pathogen identification (ID) and antimicrobial susceptibility testing (AST) systems foresee a growing crisis of drug-resistant infections moving the needle on adoption of novel diagnostic approaches.
The rapid ID/AST commercial space seemed to be on an upward trajectory pre-COVID, but faced unique challenges in the pandemic years. The case for rapid testing is stronger than ever due to increases in antimicrobial resistance (AMR), which can be tempered by new testing technologies that may provide answers in hours rather than days or weeks.
However, uptake of rapid ID/AST platforms is slowly recovering to pre-pandemic levels. Regulatory delays, a lack of large outcomes studies, insufficient funding, and the requirement that rapid technologies be used in conjunction with antimicrobial stewardship strategies continue to impact the adoption of these novel technologies.
Bacteria and fungi can be harmless — or even helpful — on many sites of the human body, but in the wrong place at the wrong time they can be fatal. Unfortunately, the antimicrobial drugs that kill bacteria and fungi also exert evolutionary pressure on these rapidly evolving organisms, quickly fostering resistance.
Humans have been battling deadly infections for millennia, finally gaining an advantage about a century ago with the development of the first antibiotics. Now, "we're losing the fight again," said Steve Lufkin, CEO of Selux, a developer of rapid AST systems.
Resistance to antimicrobials is currently considered an urgent global public health threat, according to the US Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO), as increasing resistance rates mean some of our best weapons against infection may soon become useless.
The world had been on track for 10 million AMR-related deaths per year by 2050, according to estimates published in 2016 by a UK government-funded task force, at a cumulative global cost of $100 trillion.
By 2019, antimicrobial-resistant infections were among the leading causes of death worldwide, an analysis published in The Lancet suggested, claiming nearly 5 million lives that year alone. In the US, the CDC estimated antibiotic-resistant pathogens caused 2.8 million infections in 2019, leading to 35,000 deaths.
Then, the COVID-19 pandemic happened. Although the past three years may have felt like a lifetime, 2020 was roughly 80,000 lifetimes ago for bugs that divide three times every hour. The more exposure those pathogens had to antimicrobials, the more likely resistant strains could prevail.
And that is what happened. While the most current surveillance data is not yet available, between 2019 and 2020 alone the proportion of bacterial and fungal infections in the US that were resistant to treatment increased 15 percent on average, according to a report issued by the CDC.
The CDC attributed the reversal of some of the hard-won gains of aggressive antimicrobial stewardship missions to supply chain challenges and reduced staffing during the pandemic, making it tougher to follow infection prevention and control guidance. Peaks of COVID waves also led to a jump in hospital-acquired infections and antimicrobial use for those patients who languished for months in the ICU on ventilators and catheters.
The pandemic also made it harder for public health labs to track antimicrobial resistance, with many shunting resources to COVID testing and surveillance instead. The CDC said that 21 percent fewer bacterial whole-genome sequences were submitted to the Antimicrobial Resistance Laboratory Network in 2020, for example, and data from that year is delayed or unavailable for nine out of 18 major resistance threats, such as Clostridioides difficile and drug-resistant gonorrhea.
Still, working with the data available, the CDC surmised that some pathogens and their drug-resistant strains — like tuberculosis, Shigella, and group B Strep, for example — became less prevalent in 2020 due to lockdowns, social distancing, and avoidance of hospitals by people who weren't critically ill.
Unfortunately, these reductions were offset by large increases in AMR for other infections, particularly certain fungi and Gram-negative bacteria that tend to be acquired during long hospital stays.
Leading the pack, infections with strains of Acinetobacter — a Gram-negative bacteria that causes blood, urinary tract, and pneumonia infections — that are resistant to carbapenem drugs increased 78 percent in 2020, while rates of antifungal-resistant Candida auris increased 60 percent.
Available data also show that carbapenem-resistant Enterobacterales species — a Gram-negative intestinal flora that causes urinary tract, respiratory system, and soft tissue infections — increased 35 percent in 2020, the CDC report said. Enterobacterales can also acquire resistance by producing an enzyme called extended spectrum beta-lactamase, or ESBL, which breaks down cephalosporin drugs, and these ESBL-producing Enterobacterales increased 32 percent in 2020.
The CDC also found that multidrug-resistant Pseudomonas aeruginosa, a common culprit in bloodstream and lung infections, increased 32 percent, while methicillin-resistant Staphylococcus aureus, or MRSA, infections increased 13 percent, and vancomycin-resistant Enterococcus, or VRE, increased 14 percent.
Serious COVID-19 infections also led to a high incidence of secondary infections acquired in the ICU, and many of these infections resisted treatment.
For example, a meta-analysis of 148 global studies including 362,976 hospitalized COVID-19 patients published in The Lancet Microbe estimated that nearly 61 percent of the secondary infections were resistant to antimicrobials. And, in cases where pathogens were cultured and isolated then doused with antimicrobials, nearly 38 percent of isolates were resistant. The study also noted that the odds of an isolate being resistant to antimicrobials were 10 times higher in low- and middle-income countries compared to high-income countries.
The CDC concluded in its report that these AMR setbacks "can and must be temporary," and that the pandemic made it clear — prevention is preparedness.
However, although the CDC highlighted that the US National Action Plan for Combating Antibiotic Resistant Bacteria aims to address resistance in part by supporting novel diagnostic approaches to AMR, it acknowledged that a "limited return on investment for new diagnostics is also a significant challenge."
Yet still, action is clearly required.
Betsy Wonderly Trainor, the leader of the diagnostics program at the Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X), a global nonprofit partnership aimed at accelerating products to address drug-resistant bacteria, said that since the pandemic, the world has moved even closer to reaching the last line of effective therapy for multiple pathogens, including Neisseria gonorrhoeae.
"We must try to preserve the antibiotics that we do have which are still effective," she said.
In some cases, like drug-resistant sexually-transmitted infections, a rapid test that can generate results before a patient leaves the clinic is the most effective way of diagnosing infection, testing for resistance, and recycling older drugs, Wonderly Trainor said.
As the CDC and WHO drug-resistant pathogen priority lists grow to include more pathogens and more so-called "urgent" pathogens, the AMR crisis "puts the achievements of modern medicine in jeopardy, reverting curable illnesses into deadly diseases," she said.
Feeling the crunch
Despite support from groups like CARB-X and the Biomedical Advanced Research and Development Authority (BARDA), and even with an increasing interest in rapid ID and AST technologies from clinical labs prior to March 2020, the pandemic years slammed the rapid ID/AST corner of the diagnostics space.
Andrew Brackmann, an investment analyst at William Blair specializing in diagnostics, said that the pandemic appears to have slowed the trajectory of adoption for newer rapid AST and rapid ID/AST technologies.
In particular, "the impact was felt commercially for some new players, as labs limited [sales representative] access and new technologies not directly involved in aiding pandemic efforts were deprioritized," Brackmann said.
Further, commercialization of novel approaches was hampered by the shift in focus of hospital administrators and chief financial officers who had previously been champions for new technologies, Brackmann said. Healthcare essentially became all COVID, all the time, for a very long time.
With the majority of lab resources focused on building test capacity for SARS-CoV-2, "there was little room for discussion about the uptake of new systems enabling bacterial identification and antibiotic susceptibility testing," Wonderly Trainor said.
Selux's Lufkin said the regulatory review process for new technologies was also delayed during the pandemic as the US Food and Drug Administration focused efforts on Emergency Use Authorization of COVID-19 diagnostics. For Selux, that meant a longer review cycle than the firm expected. It submitted its test to the FDA in late 2021 with breakthrough device designation and projected a 2022 launch, then obtained 510(k) clearance in January 2023.
William Blair's Brackmann also said that even before the pandemic, some of the companies with fully integrated ID and AST or genotypic AMR solutions struggled with uptake. Some found that a number of labs had already invested in ID technologies, such as MALDI or PCR-based testing, and so they did not require an integrated AST solution with ID included.
"This dynamic was accelerated to some degree with the pandemic, as more labs brought on molecular platforms for COVID testing, and those could be used to ID pathogens," Brackmann said.
In response, some players have decoupled integrated solutions and now offer AST alone, he said, in addition to fully integrated ID and AST. "Meeting the customers where their needs are today may help lessen barriers for adoption," said Brackmann.
The bright side
Although the pandemic dented the adoption of rapid testing technologies, both Wonderly Trainor and Brackmann noted some positive impacts, too.
Strong antimicrobial stewardship programs were initiated in some hospitals throughout the US as a result of a Centers for Medicare and Medicaid Services (CMS) requirement, Wonderly Trainor said.
"A primary focus of these groups is getting the right drug, the right dose, at the right time," she said, adding, "Rapid diagnostics are integral to achieving this goal for many syndromes."
And AMR is moving into mainstream media, she said, with movies, books, and even a musical about the discovery of penicillin helping to educate a newly diagnostics-conscious populace, along with ongoing public awareness campaigns centered on appropriate antibiotic use.
Brackmann said the pandemic also brought increased investment into AMR diagnostics from organizations like the Gates Foundation.
Joanne Spadoro, president and CEO of Chelmsford, Massachusetts-based First Light Diagnostics, said strategic partnerships, BARDA contract awards, equity investments, and regulatory clearances have all piqued interest in rapid AST from culture in recent years.
Spadoro and her team are developing a rapid AST product that works directly from a primary clinical specimen without the need for culturing, which is the type of novel approach that could be attractive to staffing-challenged labs.
And, access to customers also appears to have gotten better recently for rapid ID and AST makers, Brackmann said, as it has across the diagnostics industry in general.
"We continue to think new technologies will help bring forth solutions to this underserved space and are encouraged by some larger players moving into this market," he said.
One of the more notable large players in the space is microbiology specialist BioMérieux, a firm that recently acquired rapid AST technology along with Specific Diagnostics.
After the acquisition, the phenotypic testing technology, called Specific Reveal, was awarded breakthrough device designation from the FDA and won a contract from BARDA to accelerate its development. In a recent call with investors, BioMérieux executives projected that the Specific Reveal portfolio would reach $60 million in annual sales by 2027.
Sébastien Spinali, the firm's VP of global marketing for blood culture, ID, and AST, said that BioMérieux acquired the Specific technology because it "seamlessly integrates" with its other solutions for sepsis and AST, including the blood culture system BACT/ALERT Virtuo, the MALDI-TOF mass spectrometry-based pathogen ID system Vitek MS Prime, the BioFire BCID2 syndromic PCR panel for positive blood cultures, the Vidas PCT procalcitonin sepsis test, and the Vitek 2 automated ID and AST system.
BioMérieux currently dedicates more than three-quarters of its R&D resources to antimicrobial resistance, Spinali said, and to his mind the awareness of diagnostic technologies achieved during the pandemic has made clinicians "even more eager to integrate rapid ID/AST diagnostic tests in their practice to tackle the AMR silent pandemic."
And yet, despite the unmet need and advantages of rapid testing, Brackmann noted that at least for now, "investors remain cautious around pandemic flares."
The case for rapid
More effective use of antimicrobials through rapid ID and AST seems to be an obvious way to stave off a bleak future of rampant resistance and futile medicines.
For clinicians to quickly get an ailing person on an effective medication, labs need to identify the pathogen causing infection and also determine which drugs it is susceptible or resistant to. Traditional methods involve expert microbiologists performing microbial culture, identification using PCR or MALDI, and AST that can sometimes entail checking for signs of colony death under a microscope. This approach can take many days, and even weeks or months in the case of slow-growing or difficult-to-culture organisms. Sometimes pathogens are identified only after the patient has died.
Rapid systems aim to save lives by reducing the time it takes to get a patient on an appropriate antimicrobial treatment. In doing so, they also reduce time spent on the broad-spectrum, empiric drugs. These treatments can needlessly expose patients to toxic medication, waste resources if the infectious pathogen does not happen to be impacted by the drug, and potentially drive increased resistance in exposed pathogens.
Sepsis is perhaps the best example of an infection where diagnostic speed is critical, as every hour elapsed before appropriate treatment is initiated increases mortality by an estimated 8 percent. The standard of care for someone with a suspected clinical bloodstream infection involves culturing a blood sample for 48 to 72 hours to see if any organisms grow. If a pathogen is detected, it may be sub-cultured or sent directly for pathogen ID, either using MALDI or PCR-based methods. It is also then tested to see which antimicrobials it is sensitive to, with AST results available in about 18 to 24 hours, or as few as four hours on some automated systems.
Rapid tests save time compared to this three- to five-day protocol. Rapid ID and AST assays that rely on positive blood cultures can shave off at least 20 hours, while ones that test directly from samples could theoretically yield actionable results in about six hours. And, rapid resistance testing in particular can save time and guide more efficient use of antimicrobials, as it leads to patients not being given empiric drugs that won't work.
According to Jordi Carrera, CEO of Barcelona, Spain-based rapid ID/AST developer DeepUll, antimicrobial resistance has become a "slow-moving pandemic."
Faster diagnostic technologies can play a key role, as currently, "nearly all therapies are initiated empirically and modified when results become available much later," Carrera said.
Indeed, only 30 percent to 40 percent of patients with bloodstream infections will have positive blood cultures in part due to rapid initiation of empiric antibiotics, so there is clearly room to improve on this standard of care, he said.
Many US federal agencies also appear to be convinced that rapid testing is an important tool.
The CMS has incentivized adoption of new technologies, including rapid pathogen testing, with its New Technology Add-on Payments (NTAP) program. Among awardees in 2019 was T2 Biosystems, for whom the Department of Health and Human Services provided an NTAP payment of up to $97.50 per test to hospitals that ran its T2 Bacteria pathogen ID panel, amounting to a 65 percent discount.
And the FDA has signaled support, too, by granting breakthrough device designation — which speeds up product development and review — to T2 Biosystems' AMR Resistance Panel, Selux's Next Generation Phenotyping AST system, BioMérieux's Specific Reveal AST platform, Pattern Biosciences' ID/AST Pneumonia Action Panel, Q-Linea's ASTar, a pathogen ID system from Molzym, and the Pathogenomix Patho-Seq assay.
The National Institutes of Health and BARDA have also supported rapid ID and AST technologies to fight resistance through cofounding CARB-X and through initiatives like an AMR Diagnostic Challenge.
The FDA has cleared more than 100 devices for pathogen detection and AST or AMR testing since 2015, according to a progress report published last year.
Some of the systems for rapid testing perform only the ID element, others only do AST or resistance gene detection, and still others are combined systems. And, although some commercial systems require that an infectious organism be cultured first, a few are direct-from-sample. Finally, resistance and susceptibility are interrelated, and testing can be performed by detecting resistance genes or by analyzing the phenotype of the bacteria after antibiotics are applied.
CARB-X and its partners have supported 15 diagnostics projects encompassing all of these approaches, Wonderly Trainor said.
Specifically, since launching in 2016 the program has funded projects from Proteus, Accelerate Diagnostics, Module Innovations, BioMérieux's Specific Diagnostics, Avails Medical, T2 Biosystems, HelixBind, Novel Microdevices, Day Zero Diagnostics, GenomeKey, SpeeDx, Pattern Bioscience, Baebies, Talis Biomedical, and MicrobeDx, she said.
And "the CARB-X portfolio highlights some of the different types of technologies that are in the development pipeline, but there are many more," Wonderly Trainor said.
The CARB-X team is hoping to encourage the commercialization of more diagnostics that can support the appropriate use of novel antibiotics and provide direct-from-sample results, as well as simpler and more affordable products for low-resource settings, she said. Toward this end, the CARB-X team is working closely with FIND and the Longitude Prize to nurture accessible diagnostics focused on AMR.
In the US, the first rapid ID/AST system to be granted de novo approval by the FDA was the Accelerate Diagnostics Pheno. Accelerate subsequently faced some obstacles with outcomes studies and a lengthy "go-live" time for the system to be installed and validated within labs, which it has since strived to overcome.
In financial results reported this week, the firm said it placed three instruments in the quarter and brought five contracted instruments live, for a total of 328 live instruments in the US and 69 in the go-live process. Accelerate also partnered with Becton Dickinson in August to sell the Accelerate Pheno system and the Accelerate Arc module for antimicrobial susceptibility testing.
Other firms, like Selux, perform rapid AST only. Also funded by BARDA, the Selux system was granted 510(k) clearance in January along with a Gram-positive panel for bacterial isolates, and with a Gram-negative panel currently under review.
Selux's Lufkin said that customers have been searching for new solutions in phenotypic susceptibility testing, but the big piece has been to have both speed and a large "future-proofed" antibiotic menu.
"That means that you've got to have representation from all the antibiotic classes on the menu, full dilutions, current break points, and you've got to have room to grow as new antibiotics become available," Lufkin said. His team is now targeting approximately 1,800 labs that may need high-throughput rapid AST with its 384-well plate system, he said.
Among the projects in the CARB-X portfolio, the T2 Biosystems T2 Resistance Panel was the first to graduate, two years after winning $2 million in support and upon obtaining the CE mark for the test to detect 13 genes conferring antimicrobial resistance using its T2 Dx instrument. The Resistance Panel has also been supported by up to $62 million from BARDA.
T2's CEO John Sperzel said the firm continues to pursue antibiotic resistance testing direct from blood. And, "we believe, based on our expected timelines, that we will be the first to market with such a product in the US," he said.
DeepUll's Carrera said his team is still in development stages for its system, but he sees "that the big diagnostic players are scouting technologies enabling improved patient care," which to his mind is a new strategy in the space spurred by the pandemic. The DeepUll system will test for 270 pathogens and select resistance genes using PCR directly from blood with results in one hour, he said, and the team is also working on a direct-from blood AST solution.
"There is a lot of room for innovation in this space," CARB-X's Wonderly Trainor noted. But, she added, the regulatory, reimbursement, education, and guideline development pieces all have to evolve in step in order for these technologies to see real success.
Clearing the hurdles
The future success of rapid ID and AST is somewhat hazy, but, "there is a growing push to try to break down the silos that have historically created hurdles for progress in this space," Wonderly Trainor said.
As she discussed at a National Academy of Sciences workshop last fall, reimbursement is probably one of the biggest hurdles.
A rule that would have led to four years of automatic Medicare coverage for cleared technologies designated as "breakthrough devices" by the FDA was repealed by the CMS before it took effect in 2021 due to a lack of thorough clinical studies, leaving many novel technologies to fend for themselves in terms of reimbursement.
The lack of large, randomized clinical utility and outcomes studies for new diagnostics has been a chronic issue in microbiology that may also be impacting rapid ID and AST adoption, since reimbursement for testing frequently depends on demonstration that the technology is a cost-effective improvement over the standard of care.
Outcomes studies are expensive and time-consuming, and obtaining enough patient samples infected with rare pathogens from a large panel can be a challenge. After spending significant amounts on clinical trials for FDA review, some developers have said it is daunting to initiate large outcomes studies, especially given that it is difficult to know if they will yield appropriate or useful data that will be acceptable to payors, or authors of practice guidelines.
The US National Action Plan for Combating AMR also acknowledges this impediment to new diagnostics, noting that more information is needed about when and how new diagnostics should be used and what the best practices are to integrate them into care. Clearing this hurdle would likely require "an engaged response from the research community," the plan authors wrote.
Additional challenges, according to the National Action Plan, are the high cost of some components of tests, technical difficulties in preparing and obtaining clinical samples, and stimulating appropriate adoption and use. The last requires "the creation of evidence-based guidelines and appropriate reimbursement policies, an often protracted and complex process."
Prior to the pandemic, while interest was strong for AMR testing, uptake was considered modest, in part due to lack of outcomes studies as well as hospital budget constraints.
Now, DeepUll's Carrera concurred that one of the major hurdles to adoption of rapid ID and AST remains "the demonstration of the cost-benefit of these technologies in outcome studies."
Extant clinical utility studies of rapid ID/AST systems have tended to indicate that antimicrobial stewardship is frequently a critical component needed for the test results to change clinician prescribing behavior. Put another way, fast lab results are great, but they also need to be actionable so that they can impact patient care, Selux's Lufkin said.
But, CARB-X's Trainor Wonderly noted that the pandemic has also caused changes that might now move the needle on adoption.
"The number of available staff in microbiology labs has decreased tremendously," she said, while "the cost of some testing methodologies, such as sequencing, has decreased, which may enable novel technologies that incorporate this methodology to offer testing solutions at more affordable prices."
In addition, many of the new technologies coming to the market test directly from samples, "which streamlines the testing process and enables a significant timesavings," she added.
First Light Diagnostics' Spadoro said that increased funding is now critical to nurture novel approaches to the AMR crisis.
"We have been very fortunate in that we have received both non-dilutive and dilutive funding that has allowed us to continue to develop our technology," she said, "but significant funding from both private and government sources is necessary to allow companies with novel technologies, like First Light, to progress to commercialization."
Spadoro also noted that there has been increased interest and outreach from the UK and Europe related to growing concerns about AMR, "which is very encouraging."
Globally, the maturity of the markets varies by country, BioMérieux's Spinali said, with some implementing national guidelines for sepsis management and antibiotic stewardship programs that encompass rapid ID/AST solutions.
"We need to continue collective efforts, to raise awareness and provide medical education so that all countries are moving forward in that direction," he said.
William Blair's Brackmann sees the shift to endemic COVID now enabling a greater focus on non-COVID testing.
"Commercial productivity should improve in tandem, especially as more customers prioritize focus on stewardship initiatives," Brackman said.
And, smaller companies that are attempting "to grow into the underserved space of rapid ID/AST" can benefit from the scale of larger firms that already have established relationships, he said. "We have seen this already begin to play out over the last twelve months," Brackmann said.
Nevertheless, he noted, "piecing together different solutions for each customer is part of the key to success here — not every lab is the same."
Traditional methods of testing will also still have a place, Wonderly Trainor said, but the overall benefits of rapid ID/AST and resistance profiling is massive. "Not only does this enable the greatest benefit to the patient, but it also offers the greatest long-term benefit for the global population" by curbing antimicrobial resistance, she said.
Unfortunately, "until both are better appreciated, the value of diagnostics will continue to be a topic of discussion," she said.