CLN Article
Antibiotic resistance continues to be a major global health concern, and all data point towards the crisis worsening. The Centers for Disease Control and Prevention (CDC) reported last year that six antibiotic-resistant nosocomial infections, including methicillin-resistant Staphylococcus aureus and Candida auris, increased by a combined 20% in the United States during the COVID-19 pandemic and remained above prepandemic levels in 2022. Antibiotic-resistant infections are projected to claim the lives of more than 39 million people worldwide over the next 25 years, according to a recent study from the Global Research on Antimicrobial Resistance Project.
Although the use of broad-spectrum antibiotics has exacerbated antibiotic resistance at the population level, such medications are sometimes the only viable choice for individual patients. That’s because it can take upwards of 48 hours to identify infectious agents in patient samples and assess how they fare in the presence of different antibiotics — a process known as phenotypic antibiotic susceptibility testing (AST). But patients in the most critical conditions, such as those with sepsis or bloodstream infections, can’t wait that long to begin treatment.
Using traditional methods, bacterial identification was only possible after a positive blood culture is stained, subcultured, and incubated. Additionally, AST cannot be initiated until isolated colonies are inoculated with antibiotic.
“[AST] gets you to the answer of, ‘What do I need to prescribe to get this patient better?’” said Robin Patel, MD, director of the Mayo Clinic's Infectious Diseases Research Laboratory in Rochester, Minnesota. “But the challenge has been that this is generally a slow process because it’s sequential.”
It’s no surprise, then, that there’s been a great deal of interest in rapid AST, an umbrella term for tests that deliver faster susceptibility results than standard AST. It’s an approach that could combine diagnostic speed with specificity, allowing clinicians to provide the most effective treatment for patients while minimizing the potential for widespread antibiotic resistance.
“We now have technologies that enable us to, in some cases, not have to grow bacterial cultures in the first place,” Patel said. “In other cases, as soon as organisms are grown, we can identify them and do susceptibility testing all at once, rather than sequentially.”
Rapid AST is not a single test or set of tests. In fact, “there are a tremendous number of very creative solutions that investigators have deployed,” said Cédric Yansouni, MD, a medical microbiologist and associate professor at at McGill University Health Centre in Montreal, Quebec, Canada, who calls the diversity of technologies being proposed for speeding up AST “remarkable.”
For example, several AST strategies simultaneously identify a pathogen and ascertain the minimum inhibitory concentration (MIC) for a range of antibiotics, sometimes directly from positive blood cultures.
One test involves an array of nanometer-sized sensors positioned above an antibiotic well to detect the emission of volatile organic compounds (VOCs), metabolic byproducts that can indicate growth and, in some cases, identify microorganisms based on species-specificity. The sensors change color based on the VOC emissions.
VOC detection is the basis for bioMérieux’s Vitek Reveal system, which was shown in a 2022 study to provide highly accurate results in about 5 hours.
Single-cell imaging offers another promising approach. In this technique, bacteria are grown in single-cell channels, thereby reducing incubation times. The channels have different antibiotic conditions, and bacteria can be imaged via light absorbance, fluorescence, or other microscopy techniques.
To get a sense for the variety of proven rapid AST technologies, look no further than the Food and Drug Administration (FDA) approvals in 2024 — a “banner year,” according to Patel. Four tests received 510(k) clearance last year, including:
Numerous pilot studies and larger trials have demonstrated that these testing systems reduce the amount of time needed to switch from empiric therapy to a pathogen-directed antibiotic treatment strategy compared with standard testing, while not sacrificing much in terms of accuracy accuracy. They also can enable more rapid de-escalation of unneeded therapy.
Accordingly, clinical microbiology laboratories are beginning to adopt rapid AST methods, albeit in a limited fashion. A 2022 study from the Antibacterial Resistance Leadership Group found that, of 96 laboratories surveyed from across the United States, nearly all used some form of rapid testing directly from positive blood culture, though nearly 80% that do used only one or two panels or platforms; additionally, the most commonly used tests focus on bacterial identification.
The reason rapid AST hasn’t been adopted more broadly is not technological as much as it is a function of laboratories’ capacity.
“There are currently, or will be soon on the market, several platforms that are able to give antimicrobial susceptibility results within a couple of hours directly from a positive blood culture,” said Yansouni. “These have the potential to provide meaningful information very quickly to clinicians. However, in order to be useful, a lab needs to also have the means of providing a species identification within the same time frame.”
The interpretation of susceptibility results depends directly on the species of bacteria identified. A given MIC, for instance, might be interpreted as susceptible in a gram-positive bacterium but resistant in a gram-negative one. In other words, rapid AST is only as fast as the bacterial identification test it’s paired with. That means that, unless it can be completed in a single shift, rapid AST requires a 24/7 workflow to be useful — which most labs do not have the staff or resources to maintain.
“If a patient’s blood culture becomes positive at 2 a.m., you need to have staff that are able to run and report that rapid diagnostic test immediately,” Patel explained. “Not only that, but you have to have someone on the other end receiving that result at that time.”
Figuring out how rapid AST fits into laboratory antimicrobial stewardship is essential, said Linoj Samuel, PhD, division head of clinical microbiology for Henry Ford Health in Detroit. “You can do rapid AST, but if, at the end of the day, no one utilizes that result in a timely manner, that’s just a wasted effort.” The goal, he said, is to “build a system that ties the lab result to the provider and patient, and then go back to demonstrate that all that effort actually resulted in meaningful change.” Such change could mean not only faster times to appropriate therapy but also improved mortality, resource utilization, and length of stay in the ICU.
Of course, cost is also a consideration. Most rapid susceptibility tests are used for sepsis and other inpatient scenarios, so there is no direct reimbursement, said Samuel. The instruments can be prohibitively expensive as well.
Individual labs will need to weigh the clinical benefits, costs, and diagnostic stewardship considerations for each rapid AST platform against their own testing workflows. In certain cases, a test may be desirable due to its price. For example, matrix-assisted laser desorption/ionization mass spectrometry has seen widespread adoption for routine bacterial identification mostly because it lowers reagent costs and is less labor-intensive.
As labs work this out, there’s no shortage of new testing methodologies in the pipeline to look forward to. For example, one group in South Korea has proposed a method capable of performing bacterial identification and AST directly from blood without preincubation. They used magnetic nanoparticles that capture bacteria in blood samples from patients with suspected sepsis, eliminating the need for any culture-amplification. This investigational technique showed very high accuracy while providing results within an hour instead of over 1 day.
Additionally, genotypic AST — which detects the presence of specific antibiotic-resistance genes — is an active area of research. In fact, several genotypic assays that detect resistance genes or associated mutations have recently become commercially available. It’s not hard to imagine a future in which patients can receive both phenotypic and genotypic susceptibility testing to guide their antibiotic treatment.
It’s too early to tell if rapid AST will make a dent in the global antibiotic-resistance crisis. But there’s no doubt that a continued emphasis on evaluating these tests with real patients is crucial for maximizing their potential benefit.
“If we’re going to encourage adoption of these new technologies, it would be really helpful to see more labs incentivized to use them and more funding available to do the kind of studies needed,” such as multi-center studies on outcomes, Samuel said.
“By generating data on clinical utility,” Patel added, “laboratories and institutions can understand the potential value of offering a test to the care of their patients.”
Yaakov Zinberg is a writer based in the Boston area. +Email: [email protected]