Special Focus: Rapid Pathogen Testing: Rapid Pathogen Testing Pushing Ahead on Two Fronts

Rapid pathogen testing (RPT) has evolved dramatically in the past decade with the routine clinical use of molecular-based technologies. The simultaneous migration toward fixed-cost reimbursement for hospital-based care and the push toward more efficient outpatient care in decentralized locations are driving the diagnostics industry to confront RPT from two distinct approaches. The need for fast results that will improve clinical care and antibiotic stewardship underlies testing in both arenas. But for hospital-based patients the need is for comprehensive information, while point-of-care (POC) settings are looking for sensitive, binary answers. In order to achieve these goals, regardless of setting, RPT combines elements of around-the-clock access to testing, rapid turnaround time, and meaningful linkage between results and treatment recommendations. Rapid and precise pathogen identification is critical for surveillance of emerging resistance and to support anti-microbial stewardship and personalized guidance of therapy and care, which in turn benefits the bottom line. The connection between RPT results, treatment decisions, and potential cost savings is most pronounced in the hospital environment. The Value of RPT Is Quantifiable Implementation of value-based payment programs has put financial pressure on hospitals to improve the quality and cost efficiency of care, namely by getting patients well and home faster. The conditions receiving the most attention are hospital-acquired infections and sepsis, which is one of the most expensive, avoidable complications. Hospitals are exploring investing in new care strategies and new tests that meet the objective of improving patient care, cutting lengths of stays, and lowering expenses per patient. A secondary component of this is to improve the efficacious use of antibiotics and steer usage away from broad-spectrum, empiric antibiotics, with the recognition that appropriately targeted antibiotics can also lead to shorter hospital stays and lower total costs. “The value-based marketplace calls for system-wide thinking that considers not just the bottom line for each department, but also how changes in services, such as diagnostics, can have ripple effects across a hospital that dramatically influence value,” writes G2 in its new report Implementing Rapid Pathogen Testing for Cost Savings and Outcomes Improvement. “The ability of RPT to identify pathogens faster than traditional microbiological techniques creates a cascade of benefits that ultimately lead to savings for hospitals.” Improving Diagnosis Through Use of Comprehensive Multiplex Arrays “Hospitals are under tremendous cost pressure and are looking for solutions that will better medical outcomes and save money per patient, which will positively impact the hospital’s bottom line if patients are out of the ICU days earlier,” Oliver Schacht, Ph.D., CEO of molecular diagnostics company Curetis (Germany), tells DTET. The most straightforward use of microarrays parallels the example at CHOA. Where symptoms are clustered around a targeted group of relatively common pathogens, use of multiplex arrays can speed definitive identification of a pathogen, and ideally, its antibiotic susceptibility profile. Curetis has two CE-marked multiplex assays for use on its rapid Unyvero PCR platform that are proving to be a valuable addition to conventional RPT. Researchers report in an abstract presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy (Washington, D.C.; Sept. 5-9) a comparison between Curetis’s Unyvero P50 pneumonia cartridge and with classical microbiology culture for analysis of pneumonia patient samples. The pneumonia assay had greater than 80 percent sensitivity and 95 percent specificity for pathogen identification. More than half of the cases had polymicrobial infections, many of them involving three to six different pathogens. “Our focus is on a key unmet medical need of providing clinical actionable information based on molecular diagnostics for severe respiratory disease and surgical site and prosthetic joint infections,” says Schacht. “For critically ill patients, clinicians need to know what is causing the disease and what drug will work, and we need to give the doctors the information within a single eight-hour shift so that they can change therapy, if needed.” Curetis’s i60 cartridge was developed to rapidly identify more than 90 pathogens and more than 20 resistance markers common in infections of the periprosthetic joint, diabetic foot, catheter, surgical site, skin and soft tissue, as well as cardiology-related infections. The Unyvero system can analyze native clinical sample from swabs, synovial fluid, sonication fluid, tissue, and catheters. In the trial leading to CE mark, the i60 cartridge had an overall panel sensitivity of 67 percent and panel specificity of 97.8 percent for the 81 validated analytes. From the 300-plus samples, the assay also identified 147 clinically important pathogens not found by standard microbiology culture. Earlier this fall, Luminex (Austin, Texas) received U.S. Food and Drug Administration (FDA) clearance to add three new targets to its xTAG Gastrointestinal Pathogen Panel (GPP). The new targets include Adenovirus 40/41, Entamoeba histolytica, and Vibrio cholerae. xTAG GPP simultaneously detects 14 common viral, bacterial, and parasitic causative pathogens, accounting for greater than 90 percent of the causative pathogens of infectious gastroenteritis. The company says simultaneous molecular testing on a single sample within a single laboratory shift also provides added benefits to laboratories in terms of workflow and resource utilization. Sherry Dunbar, Ph.D., director of scientific affairs at Luminex, tells DTET that as laboratories are under continued pressured to deliver better results, rapid molecular diagnostics will be the “workhorse” of pathogen identification but that laboratories and diagnostics manufacturers will work to strike the balance between comprehensiveness of panels and sensitivity. “Smart, syndromic-based panels will be moderately sized, under 50 for the most part,” Dunbar says. “There will be the need to balance comprehensiveness of assays with the most common pathogens without overdoing it to the point where performance takes a hit. Multiplex still needs to be as sensitive and specific as individual tests.” Sentinel Tests While evidence is growing to make the case regarding the clinical utility and health economics for the use of targeted panels for RPT in hospitalized patients, others in the industry are pursuing a strategy of simpler “sentry-type tests” that provide critical yes-or-no information that will in turn drive therapeutic decisions and reflex testing. While many of these tests strive to be small and cheap enough to be widely used as POC tests in the outpatient setting, some of these sentry tests will play a role in the care of critically ill patients. Isomark (Madison, Wis.) has developed a breath test to monitor for infection. Given hospitals’ incentive for early infection detection, the company is currently engaged in clinical trials of its Canary test in critically ill patients but envisions modifying the analyzer for home breath testing use. “Our technology fits in as a sentinel,” explains Joe Kremer, Isomark’s CEO. “We pick up infection so early in an extremely inexpensive, very rapid, easy test. So, we are a compliment to other testing.” The test is based on technology that assesses changes in metabolism. When the body is challenged with an infection, identifiable changes occur in the way the body metabolizes energy during the acute phase response to infection. This change in metabolism can be witnessed through breath signatures—changes in the ratio of carboantes (Carbon12 to Carbon13). A special plastic collection bag captures air from a patient’s blown breath or from a ventilator exhaust and can deliver results in about five minutes. The company is currently recommending six samples a day and is evaluating the economic case but is considering funding placement of the analyzer (currently it costs $100,000) in the ICU and charging per diem per patient, in the hopes that hospitals will recognize this is a small cost for catching infections early. “Temperature and elevated white blood cell symptoms can be from trauma or infection. Right now identifying which patients have suspected infection is an extreme art, not science, so to be safe, extra diagnostics—MRIs and X-rays—are run,” Kremer tells DTET. “Our goal is to take the subjectivity out and move care away from being reactive.” In a proof-of-concept study, the Canary detected infections in two of 32 patients before clinicians suspected an infection—in one case two days earlier and in one case one day earlier. In October the company was awarded a $1.7 million National Institutes of Health grant that will aid the company in the next phase of trials, which will culminate in an FDA submission early in 2017. Rapid Pathogen Screening Detectors (RPS; Sarasota, Fla.) is developing POC tests to better clinical practice and patient management while improving antibiotic stewardship. The company’s patented technology platforms can differentiate infectious diseases and inflammatory conditions. The company initially launched its AdenoPlus test to aid in the diagnosis of Adenoviral conjunctivitis (pink eye). The CLIA-waived, CE-marked POC test can with 90 percent sensitivity and 96 percent specificity detect Adenoviral conjunctivitis, compared against cell culture—the gold standard—as the reference method. These disposable, single-use tests lead to a more accurate diagnosis during the initial clinical exam and can aid in curtailing the use of unnecessary antibiotic prescriptions for viral conjunctivitis. This fall, RPS announced CE mark of its FebriDx test, which can differentiate a viral or bacterial cause of acute febrile respiratory infection. The FebriDx test relies on two markers—myxovirus resistance protein A, an interferon derivative that becomes elevated in the presence of acute viral infection, and C-reactive protein (CRP), an acute-phase protein that is elevated in the presence of bacterial infection—with results at the POC in 10 minutes. “We are taking global antibiotic stewardship and moving it to the outpatient setting to move towards guideline-based practice,” says Robert Sambursky, M.D., CEO of RPS. “With FebriDx we are taking common, but clinically significant respiratory symptom presentation—a fever, cough, runny nose, or sore throat—and aiding in identifying if the condition has a viral or bacterial etiology, instead of just prescribing a Z-Pack.” U.S. Department of Health and Human Services’ Biomedical Advanced Research and Development Authority (BARDA) announced grants this fall to boost influenza pandemic preparedness by increasing diagnostic capabilities in near-patient care settings such as doctors’ offices, clinics, and hospitals. Alere (Waltham, Mass.) received a 3.5-year, $12.9 million contract to advance the development of a rapid, molecular, low-cost influenza diagnostic device with PCR-like performance at the POC. Alere said it will use the funding to develop the next generation of its current Alere i Influenza A & B test, which provides highly accurate, molecular results in under 15 minutes. Alere i Influenza A & B was launched in January 2014 in Europe and received U.S. clearance in June. “Molecular testing is becoming the gold standard,” says Keith Stauffer, vice president of North America Regional Marketing of Infectious Disease at Alere. “With pressure from regulatory agencies for highly accurate results, we will see more molecular formats with more access in urgent care centers, in pharmacies, grocery stores, and Walmarts.” Takeaway: RPT will continue to evolve in two distinct areas. Targeted panels will continue to gain success in cutting the time to pathogen identification and targeted treatment, ultimately also cutting cost of care, while sentinel tests will continue to develop to provide early yes-or-no infection-related answers that will direct treatment decisions and follow-on testing. Side Box: Cost-Effectiveness of Multiplex Assays for RPT A study published in the August issue of Archives of Pathology & Laboratory Medicine was able to quantify the savings and improvements in care associated with adoption of a rapid, multiplex molecular respiratory panel. Researchers from Children’s Healthcare of Atlanta (CHOA) compared outcomes among pediatric patients admitted to the tertiary care pediatric hospital for acute respiratory tract illness before (n = 365) and after (n = 771) the adoption of the FilmArray rapid respiratory panel (RRP; BioFire Diagnostics, Salt Lake City). Prior to RRP implementation, testing consisted of batched polymerase chain reaction (PCR) analysis for respiratory syncytial virus and influenza A and B, with additional testing for parainfluenza 1 through 3 in approximately 11 percent of patients and for human metapneumovirus in less than 1 percent of patients. The RRP test includes respiratory syncytial virus, influenza A and B, parainfluenza 1 through 4, human metapneumovirus, adenovirus, rhinovirus/enterovirus, and coronavirus NL62. The CHOA researchers (some of whom have financial ties to BioFire Diagnostics) found that the mean time to the test result was significantly shorter with adoption of the panel (383 minutes versus 1,119 minutes). Similarly, the percentage of patients with a result in the emergency department was significantly greater (51.6 percent versus 13.4 percent). While there was no difference in whether antibiotics were prescribed, the duration of antibiotic use was significantly shorter after RRP implementation and this reduction was dependent on receiving test results within four hours. For patients with a positive test result, RRP cut length of stay by a quarter of a day and decreased antibiotics administered by a half-day. This translates to savings of $231 in hospital costs and $17 in antibiotic use per patient. As far as the cost of testing itself, when comparing the RRP with the Focus Diagnostics Flu A/B and RSV Kit (Cypress, Calif.), the cost of the testing increased by $18 per test. But in cases when the Focus Diagnostics Flu and RSV kit was run with the Hologic Gen-Probe (Prodesse) parainfluenza 1 through 3 and human metapneumovirus, RRP cut testing costs by $178 per sample. Side Box: Now Available  Implementing Rapid Pathogen Testing for Cost Savings and Outcomes Improvement Order your copy now by calling G2 Customer Service at 800-531-1026 (8 a.m. - 5 p.m. ET) or visiting www.G2Intelligence.com/RPT