Innovative in-office test, when integrated with UTI microbiology testing performed by clinical laboratories, could contribute to better patient outcomes
Treatments for certain bacterial infections are becoming less effective due to antimicrobial resistance (AMR). Now, after a 10-year-long worldwide competition, the first multi-million euro prize for an accurate, rapid, and cost effective clinical laboratory test for diagnosing and treating urinary tract infections (UTIs) went to Sysmex Corporation’s subsidiary Astrego. This milestone event could benefit tens of millions of people who suffer from UTIs annually.
Astrego, of Uppsala, Sweden, won the €8 million (US$8.19 million) Longitude Prize on AMR for its PA-100 AST System. The new diagnostic technology will “transform treatment of urinary tract infections and brings the power of clinical laboratory testing into a doctor’s office,” according to a news release from Challenges Works, the United Kingdom-based organization that organized and awarded the prize.
The Astrego system is, according to Challenge Works’ website, a “game-changing solution” in “a novel point-of-care diagnostic test that rapidly and accurately identifies the presence of a bacterial infection and the right antibiotic to prescribe.”
“We launched the Longitude Prize on AMR (in 2014) to create the urgent ‘pull’ needed to get innovators working on one of the biggest life-and-death challenges facing humanity. Hundreds of teams [that] competed with multiple solutions [are] now close to market thanks to the prize,” said Tris Dyson, Managing Director, Challenge Works, in a news release.
The new diagnostic technology “could herald a ‘sea change’ in antibiotic use” according to the judges of the competition, The Guardian reported.
“The PA-100 AST System (above) creates a future where patients can quickly and accurately get a diagnosis and the correct treatment when they visit the doctor,” said Sherry Taylor, MD, UK National Health Service, Temple Fortune Medical Group, London, in the Challenge Works news release. “Accurate, rapid diagnosis of bacterial infections that help doctors and health workers to manage and target antibiotics, will slow the development and spread of antibiotic resistant infections, improve healthcare and save potentially millions of lives,” she added. In-office point-of-care systems like the PA-100 may reduce the number of doctor orders for UTI tests to clinical laboratories while contributing to better patient outcomes. (Photo copyright: Sysmex.)
How the Test Works
In the UK, people are treated for UTIs more than any other infection. It takes about three days for doctors to receive the results from traditional microbiology testing. They then prescribe an antibiotic to treat the infection. But about half of “infection-causing bacteria are resistant to at least one antibiotic,” according to a news release from the Geneva, Switzerland-based NESTA Foundation which funded the Longitude Prize on AMR.
“It’s impossible to overstate how critical it is to address AMR [antimicrobial resistance]. By 2050, it is predicted to cause 10 million deaths a year—matching those caused by cancer—and cost $1 trillion in additional health costs,” the news release states.
UTI are more common in women and the reason for eight million healthcare appointments annually in the US, according to Medscape.
The PA-100 AST system makes it possible for patients to provide a small urine sample during their appointments with doctors, find out if they have a bacterial infection in 15 minutes, and receive the “right antibiotic to treat it within 45 minutes,” NESTA said. Sysmex describes the PA-100 AST as an “automated phenotypic analyzer, based on EUCAST standards,” that combines “phase-contrast microscopy and nanofluidics to make available antibiograms at point of care.” It enables healthcare providers to perform antimicrobial susceptibility testing (AST) in-office rather than sending out urine samples to microbiology laboratories.
The systems works as follows, according to the Sysmex website:
As a urine sample passes through the chip, “single bacterial cells are trapped in individual channels.”
Meanwhile, “larger cellular components” are filtered and kept out of the nanofluidic chip.
Contrast-phase microscopy enables real-time monitoring of cell growth. “Resistant bacteria keep a higher growth rate during incubation, while susceptible ones grow slowly or lyse.”
Expert computer software identifies that bacterial strain, delivers an “easy to interpret antibiogram after assay completion” and provides an “informed prescription decision” on which antibiotic is expected to fight the infection.
“The PA-100 AST System challenges bacteria present in a patient’s urine with microscopic quantities of antibiotics in tiny channels embedded in a cartridge the size of a smartphone,” said Mikael Olsson, CEO and co-founder of Sysmex Astrego, in The Microbiologist.
“We rapidly pinpoint whether a bacterial infection is present and identify which antibiotic will actually kill the bugs, guiding doctors only to prescribe antibiotics that will be effective,” he added.
Sysmex is conducting more studies in the UK and working with regulators in Europe for clearances, according to Olsson.
Older Antibiotics May Make Comeback
It’s possible that use of the PA-100 system to identify the best antibiotic to treat infections could lead to a resurgence in the use of previously retired antibiotics.
“Roughly 25-30% of patients have infections resistant to older first-line antibiotics which have been retired as a result; this means the remaining 70-75% of patients could still benefit from those older drugs,” Pathology in Practice reported, adding, “Since the PA-100 AST System identifies which specific antibiotic can treat an infection, it will likely allow retired antibiotics to be brought back into service because the test is able to demonstrate when an infection is susceptible to their effects.”
Many people could benefit from the older antibiotics, Challenge Works noted.
Revolutionizing Healthcare
The Sysmex Astrego’s PA-100 AST System is a significant development.
“Currently, I send the urine sample off for analysis, and it usually takes around three days to come back with results,” said Sherry Taylor, MD, UK National Health Service, Temple Fortune Medical Group, London, in the Challenge Works news release. “Having a bedside test that would enable rapid diagnosis through antibiotic susceptibility testing would revolutionize general practice and patient care. It’s all about using antibiotics only when necessary and appropriate.”
Each individual test costs about €25 (US$25.72), The Guardian reported, adding that ramped up production may lower the price.
The PA-100 AST System is the latest example of a diagnostic/therapeutic solution developed in Europe rather than the US, which is often slower to award regulatory clearance.
It also is another test that will be performed outside of traditional clinical laboratory settings, demonstrating the trend to move medical laboratory tests closer to patients.
New guidelines come on the heels of recommendations covering post-market modifications to AI products, including those incorporated into systems used by clinical laboratories
Artificial intelligence (AI) is booming in healthcare, and as the technology finds its way into more medical devices and clinical laboratory diagnostic test technologies the US Food and Drug Administration (FDA) has stepped up its efforts to provide regulatory guidance for developers of these products. This guidance will have an impact on the development of new lab test technology that uses AI going forward.
In December, the FDA issued finalized recommendations for submitting information about planned modifications to AI-enabled healthcare products. Then, in January, the federal agency issued draft guidance that covers product management and marketing submission more broadly. It is seeking public comments on the latter document through April 7.
“The FDA has authorized more than 1,000 AI-enabled devices through established premarket pathways,” said Troy Tazbaz, director of the Digital Health Center of Excellence at the FDA’s Center for Devices and Radiological Health, in a press release announcing the draft guidance.
This guidance “would be the first to provide total product life cycle recommendations for AI-enabled devices, tying together all design, development, maintenance and documentation recommendations, if and when finalized,” Healthcare IT News reported.
“Today’s draft guidance brings together relevant information for developers, shares learnings from authorized AI-enabled devices, and provides a first point-of-reference for specific recommendations that apply to these devices, from the earliest stages of development through the device’s entire life cycle,” said Troy Tazbaz (above), director of the Digital Health Center of Excellence at the FDA Center for Devices and Radiological Health, in a press release. The new guidance will likely affect the development of new clinical laboratory diagnostic technologies that use AI. (Photo copyright: LinkedIn.)
Engaging with FDA
One key takeaway from the guidance is that manufacturers “should engage with the FDA early to ensure that the testing to support the marketing submission for an AI-enabled device reflects the agency’s total product lifecycle, risk-based approach,” states an analysis from consulting firm Orrick, Herrington and Sutcliffe LLP.
Another key point is transparency, Orrick noted. For example, manufacturers should be prepared to offer details about the inputs and outputs of their AI models and demonstrate “how AI helps achieve a device’s intended use.”
Manufacturers should also take steps to avoid bias in data collection for these models. For example, they should gather evidence to determine “whether a device benefits all relevant demographic groups similarly to help ensure that such devices are safe and effective for their intended use,” Orrick said.
New Framework for AI in Drug Development
On the same day that FDA announced the device guidelines, the agency also proposed a framework for regulating use of AI models in developing drugs and biologics.
“AI can be used in various ways to produce data or information regarding the safety, effectiveness, or quality of a drug or biological product,” the federal agency stated in a press release. “For example, AI approaches can be used to predict patient outcomes, improve understanding of predictors of disease progression and process, and analyze large datasets.”
The press release noted that this is the first time the agency has proposed guidance on use of AI in drug development.
These include “bias and reliability problems due to variability in the quality, size, and representativeness of training datasets; the black-box nature of AI models in their development and decision-making; the difficulty of ascertaining the accuracy of a model’s output; and the dangers of data drift and a model’s performance changing over time or across environments. Any of these factors, in FDA’s thinking, could negatively impact the reliability and relevancy of the data sponsors provide FDA.”
The FDA also plans to participate in direct testing of AI-enabled healthcare tools. In October, the FDA and the Department of Veterans Affairs (VA) announced that they will launch “a joint health AI lab to evaluate promising emerging technologies,” according to Nextgov/FCW.
Elnahal said the facility will allow federal agencies and private entities “to test applications of AI in a virtual lab environment.” The goal is to ensure that the tools are safe and effective while adhering to “trustworthy AI principles,” he said.
“It’s essentially a place where you get rapid but effective evaluation—from FDA’s standpoint and from VA’s standpoint—on a potential new application of generative AI to, number one, make sure it works,” he told Nextgov/FCW.
He added that the lab will be set up with safeguards to ensure that the technologies can be tested safely.
“As long as they go through the right security protocols, we’d essentially be inviting parties to test their technology with a fenced off set of VA data that doesn’t have any risk of contagion into our actual live systems, but it’s still informative and simulated,” he told Nextgov/FCW.
There has been an explosion in the use of AI, machine learning, deep learning, and natural language processing in clinical laboratory diagnostic technologies. This is equally true of anatomic pathology, where AI-powered image analysis solutions are coming to market. That two federal agencies are motivated to establish guidelines on working relationships for evaluating the development and use of AI in healthcare settings tells you where the industry is headed.
Small handheld device uses sound waves to detect certain clinical laboratory biomarkers in blood samples
University of Colorado Boulder researchers have developed a novel technology that uses sound waves to test for biomarkers in blood samples. In addition to being very easy to use, the handheld device is portable, highly sensitive, and delivers results in minutes. Though not ready for clinical use, this is yet another example of how researchers are developing faster diagnostic tests that can be performed in near-patient settings, and which do not have to be done in core laboratories, shortening time to answer.
The small instrument—referred to as an “acoustic pipette”—delivers sound waves to tiny particles within the device called “functional negative acoustic contrast particles” (fNACPs). These particles are cell-sized balls that can be customized with different coatings to identify specific biomarkers—such as viruses or proteins—in tiny blood samples, according to a news release.
To operate the device, the custom fNACPs are mixed with a drop of blood and then placed inside the acoustic pipette. The mixture is then blasted with sound waves, which forces particles carrying certain biomarkers to one side of the chamber where they are trapped while the rest of the blood is expelled. The captured biomarkers are then labeled with fluorescent tags and examined with lasers to determine how much of a specific biomarker is present.
“We’re basically using sound waves to manipulate particles to rapidly isolate them from a really small volume of fluid,” said Cooper Thome (above), PhD candidate in Chemical and Biological Engineering at UC Boulder and first author of the study in a news release. “It’s a whole new way of measuring blood biomarkers,” he added. Should further studies validate this approach, clinical laboratories may be able to use this technology to perform diagnostic tests with smaller volumes of patient samples. (Photo copyright: University of Colorado Boulder.)
Blood Testing Quickly and in Multiple Settings
To test their invention, the UC Boulder researchers examined antibodies against a protein called ovalbumin, which is found in egg whites and often used in the development of various vaccines. The scientists discovered that their device could detect the antibodies even in low amounts.
Current rapid tests known as lateral-flow assays can detect specific biomarkers in blood or urine samples but cannot determine how much of the biomarker is present. Enzyme-linked immunotherapy assays (ELISA), the leading clinical laboratory blood test, requires expensive equipment and can take hours to days for results to be received.
With UC Boulder’s new handheld device, tiny blood samples collected from a single finger prick could ensure accurate test results are available quickly at the point of care as well as outside of traditional healthcare settings. This would greatly benefit people in developing nations and underserved communities and may help ease test anxiety for individuals who are apprehensive about traditional blood tests.
“We’ve developed a technology that is very user friendly, can be deployed in various settings, and provides valuable diagnostic information in a short time frame,” said Wyatt Shields IV, PhD, Assistant Professor, Department of Chemical and Biological Engineering, UC Boulder, and senior author of the research in the news release.
“In our paper, we demonstrate that this pipette and particle system can offer the same sensitivity and specificity as a gold-standard clinical test can but within an instrument which radically simplifies workflows,” he added. “It gives us the potential to perform blood diagnostics right at the patient’s bedside.”
The graphic above, taken from UC Boulder’s published paper, illustrates how “fNACPs capture target biomarkers from whole blood samples. fNACPs are purified from blood components by acoustic trapping and captured biomarkers are labeled with a fluorescent antibody within the acoustic pipette. fNACP fluorescence is then measured to determine biomarker presence and concentration.” (Graphic/caption copyright: University of Colorado Boulder.)
Not Like Theranos
The authors of the UC Boulder study are cognizant of some skepticism surrounding the field of biosensing, especially after the downfall of Theranos. The scientists insist their technology is different and based on systematic experiments and peer-reviewed research.
“While what they (Theranos) claimed to do isn’t possible right now, a lot of researchers are hoping something similar will be possible one day,” said Thome in the news release. “This work could be a step toward that goal—but one that is backed by science that anybody can access.”
The device is still in its initial proof-of-concept stage, but the UC Boulder scientists have applied for patents for the apparatus and are searching for ways to scale its use and expand its capabilities.
“We think this has a lot of potential to address some of the longstanding challenges that have come from having to take a blood sample from a patient, haul it off to a lab, and wait to get results back,” Shields noted.
More research, studies, and regulatory reviews will be needed before this technology becomes available for regular, widespread use. But UC Boulder’s new blood testing device is another example of a research team using novel technology to test for known biomarkers in ways that could improve standard clinical laboratory testing.
As this therapeutic approach gains regulatory approval, clinical laboratory tests to determine condition of patient’s gut microbiota and monitor therapy will be needed
Some developments in the clinical laboratory industry are less about diagnostic tests and more about novel approaches to therapy. Such is the case with a new carbon bead technology developed by researchers from University College London (UCL) and the Royal Free Hospital intended to remove harmful bacteria toxins from the gut before they leak to the liver. The macroporous beads, which come in small pouches, are delivered orally and could be utilized in the future to treat a number of diseases.
Why is this relevant? Once a new treatment is accepted for clinical use, demand increases for a clinical laboratory test that confirms the therapy will likely work and to monitor its progress.
In collaboration with Yaqrit, a UK-based life sciences company that develops treatments for chronic liver disease, the UCL and Royal Free Hospital scientists engineered the carbon beads—known as CARBALIVE—to help restore gut health. They measured the technology’s impact on liver, kidney, and brain function in both rats and mice.
“The influence of the gut microbiome on health is only just beginning to be fully appreciated,” said Rajiv Jalan, PhD, Professor of Hepatology at UCL in a press release. “When the balance of the microbiome is upset, ‘bad’ bacteria can proliferate and out-compete the ‘good’ bacteria that keeps the gut healthy.
“One of the ways [the ‘bad’ bacteria] do this is by excreting endotoxin, toxic metabolites, and cytokines that transform the gut environment to make it more favorable to them and hostile to good bacteria,” he continued. “These substances, particularly endotoxin, can trigger gut inflammation and increase the leakiness of the gut wall, resulting in damage to other organs such as the liver, kidneys, and brain.”
“I have high hopes that the positive impact of these carbon beads in animal models will be seen in humans, which is exciting not just for the treatment of liver disease but potentially any health condition that is caused or exacerbated by a gut microbiome that doesn’t work as it should,” said Rajiv Jalan, PhD (above), Professor of Hepatology, University College London, in a press release. “This might include conditions such as irritable bowel syndrome (IBS), for example, which is on the rise in many countries.” Though not a clinical laboratory diagnostic test, new therapies like CARBALIVE could be a boon to physicians treating patients with IBS and other gastrointestinal conditions.
Developing the Carbon Beads
The team discovered CARBALIVE is effective in the prevention of liver scarring and injury in animals with cirrhosis when ingested daily for several weeks. They also found a reduced mortality rate in test animals with acute-on-chronic-liver-failure (ACLF).
After achieving success with CARBALIVE in animals, the researchers tested the technology on 28 cirrhosis patients. The carbon beads proved to be safe for humans and had inconsequential side effects.
“In cirrhosis, a condition characterized by scarring of the liver, it is known that inflammation caused by endotoxins can exacerbate liver damage,” Jalan explained. “Part of the standard treatment for cirrhosis is antibiotics aimed at controlling bad bacteria, but this comes with the risk of antibiotic resistance and is only used in late-stage disease.”
The beads, which are smaller than a grain of salt, contain an exclusive physical structure that absorbs large and small molecules in the gut. They are intended to be taken with water at bedtime as harmful bacteria is more likely to circulate through the body at night which could result in damage. The carbon beads do not kill bacteria, which decreases the risk of antibiotic resistance. They eventually pass through the body as waste.
“They work by absorbing the endotoxins and other metabolites produced by ‘bad’ bacteria in the gut, creating a better environment for the good bacteria to flourish and helping to restore microbiome health,” said Michal Kowalski, M.Sc.Eng, Director and VP of Operations at Yaqrit, in the UCL news release.
“This prevents these toxins from leaching into other areas of the body and causing damage, as they do in cirrhosis,” he added. “The results in animal models are very positive, with reduction in gut permeability, liver injury, as well as brain and kidney dysfunction.”
Additional Research
The researchers plan to perform further clinical trials in humans to determine if the carbon beads are effective at slowing the progression of liver disease. If the benefits that were observed in lab animals prove to be compelling in humans, the technology may become an invaluable tool for the treatment of liver disease and other diseases associated with poor microbiome health in the future.
According to the American Liver Foundation, 4.5 million adults in the US have been diagnosed with liver disease. However, it is estimated that 80 to 100 million adults have some form of fatty liver disease and are unaware of it. Liver disease was the 12th leading cause of death in the US in 2020 with 51,642 adults perishing from the disease that year.
According to BMC Public Health, globally there were 2.05 million new cases of liver cirrhosis diagnosed in 2019. In that year, 1.47 million people around the world died from the disease.
More research and clinical studies are needed before this novel technology can be used clinically. When and if that happens, the demand for clinical laboratory tests that measure microbiome deficiencies and monitor patient progress during therapy will likely be high.
Technology like Apple’s VR/AR headsets may prove useful to clinical laboratories in accessioning and in pathology labs during biopsy grossing
In what has been billed as a first, medical teams in the US and UK used Apple’s Extended Reality (XR) Vision Pro headset system to assist in surgical procedures. The surgeons themselves did not wear the $3,500 headset. Instead, surgical nurses used the device for touch-free access to a software application that assisted them in setting up, organizing, and performing the operations. For pathologists and clinical laboratories, in the histology laboratory, such an arrangement involving XR headsets could be used when a biopsy is at the grossing station as well.
The headset software the team used during surgery was developed by eXpanded eXistence, Inc. (eXeX), a Florida-based company whose primary product is an iOS (Apple mobile operating system) application that provides similar functions for mobile devices. eXeX adapted the iOS app to work on Apple’s Extended Reality headset.
Extended Reality is an umbrella term for augmented reality (AR) and virtual reality (VR). Apple refers to the technology as “spatial” computing.
Within the clinical laboratory, XR headsets could be used in the accessioning process as the accessioner works through the steps to confirm all required information accompanies the test requisition and that the patient’s specimen is processed/aliquoted appropriately.
“The eXeX platform, enhanced by artificial intelligence, is designed not as a medical device but as an organizational and logistics tool. It aims to streamline the management of tens of thousands of items, including equipment, tools, technologies, consumables, implants, and surgical products,” said neurosurgeon Robert Masson, MD, eXeX’s founder and CEO, in a February news release.
Masson first deployed the software in his own surgical practice. Then in March, eXeX announced that a surgical team at Cromwell Hospital in London used the system in two microsurgical spine procedures, according to a March new release.
That news garnered media coverage in the UK as well as in US-based publications that follow Apple.
“We are in a new era of surgery, and for the first time, our surgical teams have the brilliance of visual holographic guidance and maps, improving visuospatial and temporal orientation for each surgical team and for each surgery in all specialties,” said neurosurgeon Robert Masson, MD (above), eXeX’s founder and CEO, in a press release. Clinical laboratories may one day use XR headsets in the histology lab at the grossing station. (Photo copyright: Masson Spine Institute.)
Surgical Process Not Glamorous, But Important
Despite being on a cutting-edge XR platform, the eXeX software addresses “the least glamorous part” of the surgical process, Masson told Gizmodo.
“People assume that surgical healthcare has got to be sophisticated and modern,” he said. “The reality is the way we organize it is probably the most archaic of all the major industries on the planet. It’s all memorization and guesswork with scribbles on pieces of paper.”
The advantage of an XR headset is that it allows use of the eXeX software in a sterile environment, he added. “The ability to interact with digital screens and holograms and lists and maps and products unlocks all kinds of possibilities. Suddenly, you’ve got an interactive digital tool that you can use without violating the sanctity of sterility.”
Does he foresee a future when the surgeons themselves use XR headsets in the operating room? Not necessarily, Masson told Gizmodo.
“There’s always a tendency to say, ‘look at this amazing tech, let’s put a screw in with it,’” he said. “Well, we’re already putting screws in without the headset, so it doesn’t really solve a problem. People tend to think of floating spines, floating heights, you know, an overlay that tells you where to put a catheter in the liver. Honestly, it’s all unnecessary because we already do that pretty well. What we don’t do really well is stay organized.”
Other XR Apps for Healthcare
In a news release, Apple showcased other healthcare apps for its Vision Pro platform.
Epic Systems, an electronic health record (EHR) system developer, has an app called Epic Spatial Computing Concept that allows clinicians “to easily complete charting, review labs, communicate using secure chat, and complete in-basket workflows through intuitive gestures, like simply tapping their fingers to select, flicking their wrist to scroll, or using a virtual keyboard or dictation to type,” Apple stated in the news release.
Stryker, manufacturer of Mako surgical robotic arms for joint-replacement procedures, has an Apple iOS app called myMako that “allows surgeons to visualize and review patients’ Mako surgical plans at any time in a brilliant, immersive visual experience,” Apple said.
Cinematic Reality, from Siemens Healthineers, is an Apple iOS app that “allows surgeons, medical students, and patients to view immersive, interactive holograms of the human body captured through medical scans in their real-world environment,” Apple said.
New Era in Technology
For the past 20 years, manufacturing companies have installed systems at workstations with audio and video that show each step in a work process and with written checklists on the computer screen. This allows workers to check off each required step as proof that each required work element was performed.
This is similar to professional pilots who use checklists at every step in a flight process. One pilot will read the checklist items, the other will perform the step and confirm it was complete.
These procedures are generally completed on computer displays, but with the advent of XR headset technology, these types of procedures are evolving toward mobility.
To prepare for the emergence of XR-based healthcare apps, the US Food and Drug Administration (FDA) has organized a research team to devise best practices for testing these headset devices, CNBC reported.
It will be some time before XR headset technology finds its way into histology laboratories, clinical laboratories, and pathology practices, but since the rate of technology adoption accelerates exponentially, it might not take very long.
Shortage could disrupt the ability of clinical laboratories in hospitals and health systems to run certain tests for bloodstream infections
US clinical laboratories may soon experience a “disruption of availability” of BACTEC blood culture media bottles distributed by Becton Dickinson (BD). That’s according to the federal Centers for Disease Control and Prevention (CDC) which issued a Health Alert Network (HAN) Health Advisory to all clinical laboratory professionals, healthcare providers and facility administrators, and other stakeholders warning of the potential shortfall of critical testing supplies.
“This shortage has the potential to disrupt patient care by leading to delays in diagnosis, misdiagnosis, or other challenges in the clinical management of patients with certain infectious diseases,” the CDC stated in the health advisory.
The CDC advises healthcare providers and health departments that use the bottles to “immediately begin to assess their situations and develop plans and options to mitigate the potential impact of the shortage on patient care.”
The advisory notes that the bottles are a key component in continuous-monitoring blood culture systems used to diagnose bloodstream infections and related conditions, such as endocarditis, sepsis, and catheter-related infections. About half of all US laboratories use the BD blood culture system, which is compatible only with the BACTEC bottles, the CDC advisory states.
Infectious disease specialist Krutika Kuppalli, MD (above), Chair of the Infectious Diseases Society of America (IDSA) and a Medical Officer for COVID-19 Health Operations at the World Health Organization, outlined the potential impact of the shortage on healthcare providers and clinical laboratories. “Without the ability to identify pathogens or [their susceptibility to specific antibiotics], patients may remain on broad antibiotics, increasing the risk of antibiotic resistance and Clostridium difficile-associated diarrhea,” she told STAT. “Shortages may also discourage ordering blood cultures, leading to missed infections that need treatment.” (Photo copyright: Loyola University Health System.)
FDA Advises Conservation of Existing BACTEC Supplies
The CDC advisory followed a July 10 notice from the US Food and Drug Administration (FDA) that also warned healthcare providers of “interruptions in the supply” of the bottles. The supply disruption “is expected to impact patient diagnosis, follow up patient management, and antimicrobial stewardship efforts,” the FDA’s letter states. “The FDA recommends laboratories and healthcare providers consider conservation strategies to prioritize the use of blood culture media bottles, preserving the supply for patients at highest risk.”
Hospitals have been warned that the bottle shortage could last until September, STAT reported.
BD issued a press release in which BD Worldwide Diagnostic Solutions President Nikos Pavlidis cast blame for the shortage on an unnamed supplier.
“We understand the critical role that blood culture testing plays in diagnosing and treating infections and are taking all available measures to address this important issue, including providing the supplier our manufacturing expertise, using air shipments, modifying BD manufacturing schedules for rapid production, and collaborating with the US Food and Drug Administration to review all potential options to mitigate delays in supply,” Pavlidis said. “As an additional stopgap measure, our former supplier of glass vials will restart production to help fill the intermittent gap in supply.”
Steps Clinical Laboratories Can Take
The CDC and FDA both suggested steps that clinical laboratories and other providers can take to conserve their supplies of the bottles.
Laboratories should strive to prevent contamination of blood cultures, which “can negatively affect patient care and may require the collection of more blood cultures to help determine whether contamination has occurred,” the CDC advised.
In addition, providers should “ensure that the appropriate volume is collected when collecting blood for culture,” the advisory states. “Underfilling bottles decreases the sensitivity to detect bacteremia/fungemia and may require additional blood cultures to be drawn to diagnose an infection.”
Laboratories should also explore alternative options, such as “sending samples out to a laboratory not affected by the shortage.”
The FDA advised providers to collect blood cultures “when medically necessary” in compliance with clinical guidelines, giving priority to patients exhibiting signs of a bloodstream infection.
In an email to STAT, Andrew T. Pavia, MD, Professor of Internal Medicine and Pediatrics at the University of Utah, offered examples of situations where blood culture tests are unnecessary according to clinical guidelines.
“There are conditions like uncomplicated community acquired pneumonia or skin infections where blood cultures are often obtained but add very little,” he told STAT. “It will be critical though that blood cultures are obtained from patients with sepsis, those likely to have bloodstream infections, and very vulnerable patients.”
Hospitals Already Addressing Shortage
STAT reported that some hospitals have already taken measures to reduce the number of tests they run. And some are looking into whether they can safely use bottles past their expiration dates.
Sarah Turbett, MD, Associate Director of Clinical Microbiology Laboratories at Massachusetts General Hospital in Boston, told STAT that her team tested bottles “that were about 100 days past their expiration date to see if they were still able to detect pathogens with the same efficacy as bottles that had not yet expired. They saw no difference in the time to bacterial growth—needed to detect the cause of an infection—in the expired bottles when compared to bottles that had not expired.”
Turbett pointed to a letter in the Journal of Clinical Microbiology and Infection in which European researchers found that bottles from a different brand “were stable for between four and seven months after their expiration dates,” STAT reported.
During a Zoom call hosted by the CDC and the IDSA, hospital representatives asked if the FDA would permit use of expired bottles. However, “a representative of the agency was not able to provide an immediate answer,” STAT reported.
With sepsis being the leading cause of death in hospitals, these specimen bottles for blood culture testing are essential in diagnosing patients with relevant symptoms. This is a new example of how the supply chain for clinical laboratory instruments, tests, and consumables—which was a problem during the SARS-CoV-2 pandemic—continues to be problematic in unexpected ways.
Taking a wider view of supply chain issues that can be disruptive to normal operations of clinical laboratories and anatomic pathology groups, the market concentration of in vitro diagnostics (IVD) manufacturers means fewer vendors offering the same types of products. Consequently, if a lab’s prime vendor has a supply chain issue, there are few options available to swiftly purchase comparable products.
A separate but related issue in the supply chain involves “just in time” (JIT) inventory management—made famous by Taiichi Ohno of Toyota back in the 1980s. This management approach was designed to deliver components and products to the user hourly, daily, and weekly, as appropriate. The goal was to eliminate the cost of carrying large amounts of inventory. This concept evolved into what today is called the “Lean Manufacturing” method.
However, as was demonstrated during the SARS-CoV-2 pandemic, manufacturers and medical laboratories that had adopted JIT found themselves with inadequate numbers of components and finished products.
In the case of the current shortage of BD blood culture media bottles, this is a real-world example of how market concentration limited the number of vendors offering comparable products. At the same time, if this particular manufacturer was operating with the JIT inventory management approach, it found itself with minimal inventories of these media bottles to ship to lab clients while it addressed the manufacturing problems that caused this shortage.
