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Hardy Diagnostics Lateral Flow AMR Test Comparable to PCR-based Assay in Clinical Studies


NEW YORK – Bacterial culture media and reagents maker Hardy Diagnostics is expanding into a new potential market through spearheading the US clinical studies for NG Biotech's lateral flow assay for drug-resistant infections and becoming the exclusive US distributor of the test.

Preliminary data from US studies of clinical samples indicate the immunoassay, called NG-Test Carba 5, had 100 percent positive agreement with a PCR-based test for "the big five" cabapenem resistance types. It is currently run using isolates of cultured bacteria, but the NG Biotech is also reportedly working to develop a test for positive blood cultures.

Working together with Guipry, France-based NG Biotech, Hardy brought the test through US clinical studies, submitted it to the US Food and Drug Administration, and it received 510(k) clearance earlier this month, with the predicate device being a test called Rapidec Carba NP from BioMérieux that was granted clearance in 2017.

Last week Hardy and NG Biotech officially announced the distribution deal for Carba 5, which had also been the subject of a soft launch at IDWeek earlier this month. The test detects five types of carbapenem resistance from colony isolates of Enterobacterales species and Pseudomonas aeruginosa within 15 minutes.

Founded in 1980 by Jay Hardy, the Santa Maria, California-based Hardy Dignostics makes more than 2,700 products for the culture and identification of bacteria, according to Joel Tefft, Hardy's marketing manager. The company is also entirely employee-owned as of 2015, with manufacturing sites in California and Ohio, nine US distribution centers, and exporting to 80 distributors globally, Tefft said, adding that in the US the company services more than 10,000 labs.

But, a few years ago the firm spotted an opportunity for expansion through a collaboration with NG Biotech and its lateral flow assay for carbapenem resistance.

"Culture media is the backbone of clinical microbiology, but we believe in bringing innovative and cost-effective new products to the market," Tefft said. The NG-Test Carba 5 test is rapid and inexpensive, two core elements that labs desire, so it "streamlines laboratory workflow while remaining cost effective," Tefft added.

Carbapenem antibiotics work on gram-negative bacteria and are very broad spectrum. As such, they are considered the last line of defense against increasingly resistant bacterial infections. Expression of one of a handful of enzymes — abbreviated KPC, OXA-48, VIM, IMP, and NDM, and commonly known as "the big five" — can inure a bug against this class of drugs by pumping carbapenems out of bacteria or chewing them up before they can work.

The big five have varying prevalence globally as well as varying levels of activity, and they can be expressed by different species of bacteria in different sites of infection. Importantly, the genes to make the resistance-causing enzymes can also be transferred via plasmid mediated events in certain bacteria, making them capable of endowing other strains with carbapenem resistance.

Nathan Ledeboer, the medical director of molecular diagnostics at the Medical College of Wisconsin, said in an interview that identifying the particular carbapenemase an infection expresses is important because it can help guide therapy.

"The most common carbapenemase that we see in the US among family Entereobacteriales is KPC, and for these we have additional drugs ... whereas for a different carbapenemase type, our options may be more limited," Ledeboer said. For example, NDM, or New Delhi Metallo-beta-lactamase, depends on the presence of zinc to function, and the alternative antibiotics for KPC-type carbapenemases don't work on NDM-mediated resistance, Ledeboer noted.

Its also critical to know what bugs are circulating in a healthcare system, as these infections tend to be nosocomial, or hospital-acquired, and tactical prevention steps can contain the spread.

Ledeboer and his lab at MCW participated in the US clinical studies of Carba 5 that supported the FDA submission and he presented preliminary data at IDWeek earlier this month. He said his lab has helped Hardy with clinical studies in the past and the lab includes a research group dedicated to diagnostics trials.

"They said, 'We're looking at bringing in this new product, we have really good data, but we need to see how it works in the US,' and we said we have a nice group of isolates and we could help them get the consortium of trial sites together," Ledeboer said.

As presented by Ledeboer at IDWeek, the clinical studies consisted of four large teaching hospitals in geographically diverse clinical sites — the Medical College of Wisconsin, Johns Hopkins Medicine, Weill Cornell Medical Center, and Barnes Jewish Hospital — that tested a total 240 isolates of different Enterobacterales species and 69 isolates Pseudomonas aeruginosa species, as well as one Pseudomonas putida isolate using the NG-Test Carba 5.

Carba 5 was compared to Cepheid's Xpert Carba-R — an FDA-cleared PCR-based test — as well as two modified carbapenem inactivation methods, mCIM and eCIM, and a technique called Kirby-Bauer disk diffusion to three carbapenems.

For Enterobacterales species, the overall positive percent agreement was 100 percent and the overall negative percent agreement was 96 percent. For P. aeruginosa, the overall PPA was 100 percent and the overall NPA was 95 percent.  

Ledeboer noted in his IDWeek presentation that considering 19 previous posters and publications on the NG-Test Carba 5 covering 15 countries, the test had an overall sensitivity of approximately 96 percent and a specificity of nearly 100 percent.

The high sensitivity relative to a molecular test like Carba-R was not necessarily surprising to Ledeboer since the test uses concentrated bacterial samples and the monoclonal antibodies against the enzymes are quite specific.

He noted that low specificity of flu tests in the past may have given lateral flow tests a bit of a bad name, but those tests used antibodies that were developed more than two decades ago. Newer antibodies are designed using better techniques and focus on currently circulating strains, Ledeboer said.

The test is rapid, and it doesn't require specialized training, but it relies on culture isolates, which can take a number of days to obtain. Still, "This is absolutely a needed test," Ledeboer said, because currently only labs that do molecular testing can detect carbapenemases.

"If you're in a low-resource setting, a smaller community hospital, or if you are just price sensitive, this is going to give you a nice option for detecting carbapenemases, with good performance," Ledeboer said. And, expanding the number of labs that can detect these bugs beyond large reference labs and hospitals might improve infection prevention overall, he said.

Tefft noted that the test is nearly half the cost per test of the leading molecular methods, and all five target enzymes are in a single test. It also streamlines the workflow, potentially saving the lab one day of work that is required for molecular testing and subsequent phenotypic testing.

Hardy primarily serves clinical markets, and so the Carba 5 test "fits in perfectly," Tefft said. "We see this as another weapon in their arsenal. We’re very committed to supporting the fight against antimicrobial resistance ... [and] anticipate antimicrobial resistance detection to continue to be a significant focus for our business," he said.

To drive uptake, the firm will be equipping and educating its salesforce while simultaneously onboarding the product through distributor partnerships.

There are other immunoassay tests for carbapenemases available globally. Gembloux, Belgium-based Coris BioConcept makes a 30-minute immunochromatographic assay, for example. There's also the aforementioned Carb-R and Rapidtec. But Carba-R is a more expensive and more technically demanding test, and Tefft said that the other immunoassay tests are "usually affordable, but are not always as sensitive, specific, or quick."

In his IDWeek presentation, Ledeboer also highlighted a test in development from NG Biotech for positive blood cultures, illustrating a workflow that utilized 10 minutes of sample processing with NG-Test Blood culture Prep reagents, with subsequent application of the sample to the NG-Test Carba 5 lateral flow assay for detection. He noted that this test has shown high sensitivity and specificity in evaluations conducted in France and Italy.

Tefft said that patient care is at the core of the Hardy's values and there is now a movement to design diagnostic tools to provide earlier care to critically ill patients, especially those with blood stream infections.