NEW YORK (360Dx) – The global crisis of antibiotic resistance has tended to focus on patients in hospitals, but a low-cost immunoassay that could potentially help reduce the use of antibiotics for upper respiratory tract infections should soon be available in doctors' offices where most antibiotics are prescribed, according to test developer RPS Diagnostics.
Based on the results of a clinical study, the test relies on measurements of c-reactive protein and myxovirus-resistance protein A and can rapidly identify host immune responses associated with bacterial and viral respiratory infections. As a result, in 10 to 15 minutes after taking a fingerstick of blood, a healthcare provider will know whether to prescribe antibiotics or not, Robert Sambursky, RPS Diagnostics' president and chief technology and medical officer, said in an interview.
RPS intends to make the test available in Europe and Canada in the second quarter of 2018.
In a US-based multicenter, prospective clinical study published this month in the Journal of Clinical Medicine, investigators confirmedthat the single-use FebriDx test "is capable of identifying clinically significant acute bacterial and viral respiratory tract infections."
From 10 clinical sites, including seven academic emergency departments, two community care centers, and one ambulatory clinical research site, the study enrolled 370 patients — of whom 205 had symptoms of upper respiratory infections and 165 were asymptomatic.
The FebriDx immunoassay demonstrated a sensitivity of 80 percent and specificity of 93 percent for bacterial detection. Bacterial sensitivity increased further in patients that had a confirmed fever at the time of enrollment, the researchers said. The test also demonstrated a positive predictive value of 63 percent and a negative predictive value of 97 percent for bacterial infection.
For viral detection, sensitivity was 87 percent, and specificity was between 83 percent. The negative predictive value was 95 percent.
"The [sensitivity and specificity] numbers are satisfactory for good clinical use," Patrick Joseph, an infectious disease physician with a private practice and an associate clinical professor of medicine at the University of California, San Francisco, said in an interview. "The test is much more sensitive and, more importantly, much more specific than any set of clinical criteria," he noted. Joseph said that he was not involved in the clinical study and doesn't have a commercial connection with RPS.
He added that as a private practitioner and professor of medicine he is acutely aware of the need for such a test, especially as it relates to potentially reducing antimicrobial resistance.
"To date, all clinical criteria that attempts to differentiate viral from bacterial respiratory tract infection have been unsatisfactory," Joseph said. "We need a diagnostic test that can improve the accuracy of the differentiation between viral respiratory infections for which antibiotics are not prescribed, and bacterial respiratory infections for which antibiotics are critically important. The [FebriDx] test is designed to address just that need, and the preliminary performance of the test in the market in Canada and Europe is excellent."
The clinical study investigators, who work in a variety of hospitals in clinical research and emergency medicine departments, said that while "the clinical utility of this promising technology will be further deﬁned with an additional study, FebriDx may serve as an important tool for future efforts at antibiotic stewardship."
They noted that these efforts have been hindered "by a lack of rapid and accurate diagnostic tests to help clinicians distinguish between viral and bacterial infection."
Joseph noted that the FebriDx test should be particularly impactful in outpatient settings. "All our focus so far has been on the correct and appropriate use of antibiotics in the hospital because of the availability of specific diagnostic tests and epidemiologists," he said. "In the outpatient arena, however, it's a different story. We're dealing with multiple practitioners with varying degrees of education … and respiratory infections cross all lines, including everyone who works in primary care."
Sambursky noted that antimicrobial stewardship "is really needed in the outpatient setting where more than 70 percent of all antibiotics are prescribed. He added that "inpatient settings provide the luxury of the availability of infectious disease specialists and several types of tests that are not available in the outpatient setting, and consequently, inpatient antibiotics overuse is far less of an issue."
The RPS test provides qualitative results for elevated serum levels of CRP, an acute phase-reactant associated with bacterial infection, and myxovirus resistance protein A, a derivative of interferon-α/β associated with viral infection.
"If MxA is elevated with or without an elevation in CRP, we know that the infection is viral. However, if there's no elevation of MxA and, at the same time there's an elevation of CRP, we know there's a bacterial infection," Sambursky said, adding, "If neither MxA nor CRP is elevated, we know that the infection is clinically insignificant."
"CRP alone provides a way to reduce the prescription of antibiotics, but you're still overtreating," he further noted, adding that by combining CRP with MxA, the FebriDx test has demonstrated that it can "dramatically" facilitate reducing that level of overtreatment.
Most upper respiratory infections don't require antibiotic treatment, but patients often "receive unnecessary antibiotic treatment based on parent or patient pressure and physician fears of missing a serious bacterial infection," the researchers conducting the multicenter study said.
They found that 38 percent of viral infections showed elevated readings, which "could contribute to overtreatment."
In a small study published in August in the Journal of Infectious Diseases & Preventive Medicine, Miles Davidson, a researcher in the department of general medicine, Stubley Medical Centre in the UK, said that the FebriDx test reduced clinical decisions in 50 percent of the patients and reduced unnecessary antibiotics by 80 percent.
RPS said that its test has been cleared for marketing in Saudi Arabia, Singapore, and Canada and, based on receipt of CE marking, it will be marketed in European countries. The firm is prioritizing a launch in European countries and expects to make its test available in other locations depending on its success in establishing "appropriate distribution channels," Sambursky said.
"In the US, our goal is to enter clinical trials and obtain FDA clearance and a CLIA waiver," he said. "Our hope is that somewhere around the end of next year, we will enter clinical trials of an unknown duration," in preparation for applying for clearance with the FDA.
The firm has already developed tests that have received CLIA waivers, and these tests have levels of simplicity consistent with that of the FebriDx test, he said.
San Diego, California-based Quidel has purchased and markets two of those tests — an in-office test that detects elevated levels of MMP-9, an inflammatory marker that is consistently elevated in the tears of patients with dry eye disease, and a point-of-care test that detects the serotypes of adenoviral conjunctivitis, or pink-eye.
Marked differences are evident in the way upper respiratory infections are treated inside and outside the US, Sambursky said.
In outpatient settings, physicians in the US tend to run tests other than CRP, such as Strep or influenza assays, he said. "Those tests are relevant for some but not all categories," Sambursky added. "For example, a Strep test is commonly used to test for pharyngitis, but you're not going to run a Strep test for an ear infection, sinusitis, or bronchitis. You're probably only going to run a flu test during the flu season, and you might run it during the first 24 to 48 hours when you can provide an impact for the patient."
The FebriDx test, because it is based on an immune response and doesn't look for specific pathogens, covers all the upper respiratory tract conditions, he noted, including bronchitis, pharyngitis, laryngitis, and sinusitis. It can cover several pathogens for which a physician would normally have to run several tests, he added.
"Our 10-minute, disposable test, with a target price of $15, has a value similar to $2,000 worth of laboratory tests," he said.
Several diagnostics companies are marketing products that are used in hospitals and other lab-based settings to help clinicians in their quest to increase antimicrobial stewardship and reduce antibiotic resistance.
Many, including Roche, Thermo Fisher Scientific, Ortho Clinical Diagnostics, and BioMérieux, market assays that use procalcitonin in the detection of sepsis, a condition that is particularly difficult for physicians to diagnose. Like upper respiratory infections, it can lead to overuse of antibiotics if tests are not quickly implemented to ascertain whether isepsis can be ruled out.
A study published this month in The Lancet Infectious Diseases journal said that use of procalcitonin-guided therapy helped reduce the amount of antibiotics given to patients and antibiotic-related side effects.
The study examined data from 6,708 patients from 26 eligible trials in 12 countries and found that statistically significant fewer deaths occurred when patients' care was guided by procalcitonin. The researchers noted that PCT allowed physicians to reduce antibiotics by 2 to 4 days without any harm to patients. This disrupts "the outdated idea that you have to keep a patient on antibiotics for a specific course, such as 8 days," a BioMérieux spokesperson said in an e-mail.
The Lancet's editors said that the reduction in mortality occurred because the incidence of antibiotic-related Clostridium difficile infections and colitis were reduced through use of PCT testing. C. diff and colitis are increasingly dangerous side effects of antibiotic use in the hospital setting, causing a growing number of fatalities.
BioMérieux's FilmArray respiratory panel, a molecular diagnostic test, served as one of the comparator assays in the FebriDx trial.
Molecular and other comparator tests used in the trial, including real-time PCR, IgM serum antibody, and serum PCT, have proven their clinical utility in hospital settings, but "these types of tests are generally not available in doctor's offices and other outpatient settings," Sambursky said.
Joseph said that molecular tests for viral diseases are "highly sensitive, highly accurate, and as yet highly unavailable … in a doctor's office."
However, in recent years, the FDA has begun to grant CLIA waivers to a variety of tests for respiratory infections that can be run in doctor's offices and other outpatient settings.
In 2016, it granted 510(k) clearance and CLIA waiver to BioMérieux's BioFire respiratory panel. The FilmArray Respiratory Panel EZ runs in approximately one hour on the FilmArray platform and detects 11 viruses and three bacterial pathogens from nasopharyngeal swabs, requiring two minutes of hands-on time.
In the same year, the FDA granted 510(k) clearance and a CLIA waiver for Roche's point-of-care molecular test to detect and distinguish influenza A, influenza B, and respiratory syncytial virus, which runs on the firm's Liat system.
In March this year, the FDA granted a CLIA waiver for Alere's respiratory syncytial virus infection panel. Alere, recently purchased by Abbott, said that its Alere i RSV test will be available in physicians' offices, hospital emergency rooms, and walk-in clinics throughout the US.