Inside the Diagnostics Industry: Labs Move Toward Rapid Diagnoses of Infections

The downstream effects of infectious disease diagnostics are significant. The appropriate test can optimize anti-microbial use, decrease hospital lengths of stay and unnecessary isolation, reduce health care costs, and most importantly improve patient outcomes by cutting time to proper therapy. At a broader level, diagnostics enable public health surveillance and can aid in detecting and responding to outbreaks to known or emerging infections. Unfortunately, current tests integrated into routine care do not yet optimally meet clinical needs for either individual patients or the public’s health. A report released by the Infectious Diseases Society of America (IDSA) in November, Better Tests, Better Care: Improved Diagnostics for Infectious Diseases, is designed to “raise the red flag about the paucity of new and rapid tests,” according to IDSA President Barbara Murray, M.D. In addition, the report makes a number of recommendations to address unmet needs in diagnostics, including the need for rapid results. Clinical signs of common but serious infections, including those in the bloodstream and gastrointestinal tract, present with nonspecific symptoms. While waiting for test results, many patients with suspected infections are treated with broad, empiric anti-microbial therapy, rather than appropriate therapy dictated by the rapid identification of the infectious agent. “The result,” IDSA says, “is overuse of our small inventory of effective antimicrobials, whose numbers continue to dwindle due to increasing levels of antimicrobial resistance.” Despite the focus on new diagnostic technologies, including molecular platforms that have improved infectious disease identification and quantification, there is still profound reliance upon traditional diagnostic methods, concludes the report. Standard microscopy and culture methods have not changed dramatically in more than a century and remain time-consuming endeavors. “The field of clinical microbiology is currently in transition and standard-of-care testing is now a hybrid of old and new methodologies,” says IDSA. While nucleic acid–based amplification technologies have improved sensitivity and specificity, improvements are still needed in upping multiplex capabilities, decreasing turnaround time, simplifying ease of use, minimizing batch sizes while increasing workflow efficiency, and lowering test cost. “We are at the beginning of a significant transformation in diagnostics and it is critical to capitalize on the current opportunity to invest in the most needed diagnostics and enable the utilization of improved diagnostics for both clinical management and public health surveillance,” writes IDSA. DTET examined some of the breakthroughs in infectious disease detection in 2013, including platforms that have recently won regulatory approval as well as emerging technologies that will contribute to the continued revolution in infectious disease diagnosis in the coming years. MALDI While the term game-changer is often overused, most experts agree that the use of mass spectrometry for bacterial identification has the potential to truly alter laboratory workflow and profoundly enhance timely clinical care by cutting the time needed for identification of microbial infectious agents from days to hours. Bruker (Billerica, Mass.) in late November received U.S. Food and Drug Administration (FDA) 510(k) clearance for its MALDI (matrix-assisted laser desorption/ionization) Biotyper CA System for the identification of gram-negative bacterial colonies cultured from human specimens. This becomes the second MALDI system approved for use in the United States. The VITEK MS from bioMerieux (Durham, N.C., and France) was approved in August 2013. Bruker plans to commercially launch the system in U.S. hospitals and reference laboratories in the first quarter of 2014. The MALDI Biotyper CA System uses proteomic fingerprinting with high-throughput MALDI-TOF (time-of-flight) mass spectrometry to identify microorganisms including bacteria, yeasts, and fungi. The company says that in the past five years, since the system received its CE mark, many European and other international laboratories have replaced classical biochemical testing for bacterial identification with MALDI due to the accuracy, speed, extensive species coverage, ease of use, and cost-effectiveness of the system. More than 1,000 systems have been sold or leased to date, the company says. “The ability to identify organisms directly from plates—saving at minimum a day over conventional phenotypic tests for many organisms—has impacted therapy, timely infection control, and contributed to decrease in health care expenditures,” says Robert Jerris, Ph.D., the director of clinical microbiology at Children´s Healthcare of Atlanta, whose center was involved in Bruker’s trials. “Outcome studies have shown such significant positive results that it is predictable to say that this technology will eventually be a staple in clinical microbiology.” Other Technologies As DTET has previously reported, advancing point-of-care technologies are now capable of testing human and animal samples in the field and tracking infectious disease outbreaks with a mobile phone connected to a cloud-based network. Globally this technology continues to garner interest because of its wide applicability to a variety of infectious agents, noninvasive sampling, and cheap cost. According to researchers from the University College London (UCL; United Kingdom) there are an estimated 6.8 billion mobile phone subscriptions and 1 billion social network users, representing a “massive opportunity” to widen access to tests and track emerging disease outbreaks. “The revolution in mobile communication, nanotechnology, genomics, and ‘big data’ analysis offers tremendous opportunities to actively manage outbreaks and ultimately prevent infectious diseases,” says Rachel McKendry, Ph.D., who leads the Interdisciplinary Research Collaboration at UCL, which works with industry to develop mobile health technologies for the early diagnosis and tracking of diseases. Further expanding the ability to take rapid, infectious disease diagnostics into underserved areas is the development of an artificial nose. Bacteria’s unique smell can be harnessed to speed the diagnosis of sepsis, according to a study presented at the American Chemical Society national meeting (Indianapolis; Sept. 8-12, 2013). The point-of-care test combines amplification of bacteria with detection and identification in a single sealed bottle. Attached to the inside of the small, plastic bottle is a chemical sensing array (CSA), the “artificial nose,” with 36 pigment dots that change color in response to signature odor chemicals released by bacteria. A blood sample is injected into the bottle and any bacteria present will grow and release a signature odor sensed by the pigment dots. The test is complete within a day, compared to the 72 hours with current technology. According to researcher James Carey, Ph.D., from National University of Kaohsiung in Taiwan, the new device can identify nine of the most common disease-causing bacteria, including two strains of E. coli, with almost 99 percent accuracy under clinically relevant conditions. “Our CSA blood culture bottle can be used almost anywhere in the world for a very low cost and minimal training,” said Carey in a statement. “All you need is someone to draw a blood sample, an ordinary shaker, incubator, a desktop scanner, and a computer.” Economic Case for Rapid Infectious Disease Testing While the clinical need for rapid infectious disease tests is clear from a medical practice perspective, IDSA says that increased research efforts are needed to demonstrate the outcomes benefits from such tests, including the economic benefits, as measured by decreased resource utilization resulting from earlier diagnosis. Earlier infectious disease detection could have a huge financial impact. The Agency for Healthcare Research and Quality says that each year in the United States there are more than 836,000 hospital stays due to septicemia, the sixth most common principal reason for hospitalization in the United States in 2009, costing more than $15 billion. Additionally, the alarming increase in drug-resistant organisms leads to more complicated and lengthier care. With changes to reimbursement that do not allow for additional Medicare payments for conditions that were not present at the time of admission, hospitals are interested in rapidly determining such infections to minimize costs. Emerging research is quantifying the economic benefit of new infectious disease assays. For example, in a study published Sept. 30, 2013, in the Journal of Clinical Microbiology, Nanosphere (Northbrook, Ill.) reported an average 21.7-day reduction in hospital length of stay per patient and an average savings of $60,729 in hospital costs related to use of the FDA-approved molecular assay Verigene Gram-Positive Blood Culture for the rapid detection of bacteria and antibiotic resistance in bloodstream infections caused by Enterococcus. In addition, there was a significant decrease in the average time it took for patients to receive appropriate treatment (23.4 hours), and an even greater reduction in time (31.1 hours) for patients with vancomycin-resistant Enterococcus bacteremia. Finally, there was complete agreement between conventional culture and susceptibility methods and the Verigene test results, but with a significant reduction in time to reporting of test results (47.5 hours). Surgical-site infections (SSIs) are the most frequent health care-associated infection in the United States, occurring in about one out of every 50 operations, and contribute to the greatest portion of health care-associated infection-related costs nationally. Subsequent infection in surgical patients is heightened in surgical patients with nasal carriage of Staphylococcus aureus (SA), including methicillin-resistant SA (MRSA). According to a study published in JAMA Internal Medicine, SSIs due to MRSA increase hospital length of stay for patients by an average of 23 days and cost more than $40,000 per case to treat, but rapid screening and targeted decolonization decrease SSIs and have been demonstrated to improve clinical and economic outcomes for surgical patients. “Increased accuracy in determining patient colonization with either S. aureus or MRSA can enable clinicians to implement appropriate presurgical prophylaxis and direct appropriate utilization of isolation and decolonization,” said Tobi Karchmer, M.D., vice president for medical affairs at BD Diagnostics, the maker of BD MAX StaphSR Assay, the first commercially available molecular assay in the United States that detects recently discovered MRSA strains with the mecC gene. It is hoped that such economic data will not only increase hospitals’ interest in such emerging tests, but that payers will increasingly cover these new tests at reasonable rates. Yet the IDSA says there are significant challenges to the development, regulatory approval, and clinical integration of diagnostic tests that use these new technologies. In addition to increased funding for research and development efforts for critical infectious diagnostic tools, IDSA says easing regulatory requirements regarding the storage and research use of deidentified specimens and clinical use of investigational devices will aid commercialization efforts. Additionally, adoption of emerging technologies and assays will be encouraged with better adherence to guidelines, increased provider education efforts, and more rapid assignment of reimbursement codes at reasonable rates. Takeaway: It is critically important that new tests are developed that can more rapidly diagnose infectious agents and improve treatment management. Side Box: Priorities For Infectious Agent Diagnostics Development To address the highest priority, unmet diagnostic needs, IDSA says that federal incentives are needed to stimulate diagnostics research and development, particularly for tests that:

• Are performed directly from accessible, minimally invasive clinical specimens (blood, respiratory samples, urine, and stool);
• Have strong test accuracy and performance characteristics (at least a 98 percent negative predictive value);
• Incorporate biomarkers (either pathogen- or host-derived) that are capable of classifying clinically significant infections (bacterial, fungal, viral, or parasitic) and demonstrating host response to a pathogen (drug resistance information);
• Are grouped as panels targeting the most important clinical syndromes (central nervous system, sepsis and bloodstream, respiratory tract, and gastrointestinal tract infections);
• Are for pediatric use;
• Are rapid and have substantially better “time to result” than currently approved tests;
• Are available at the point of care to allow for wider usage in outpatient settings; and
• Improve outbreak detection and maintain public health surveillance capability.

Side Box: Recent FDA Approvals of Rapid, HIA, Respiratory Infectious Disease Assays

• BD MAX StaphSR Assay with eXTended Detection Technology: Detects Staphylococcus aureus (SA) and methicillin-resistant Staphylococcus aureus (MRSA) DNA directly from nasal swabs; BD Diagnostics (Sparks, Md.); approved November 2013.
• ICEPlex C. diff Assay Kit and the ICEPlex System: Employs a quantitative multiplex polymerase chain reaction system to detect C. diff; PrimeraDx (Mansfield, Mass.); approved November 2013.
• Quidel Molecular RSV+hMPV assay: Detects the presence of respiratory syncytial virus and/or human metapneumovirus; Quidel (San Diego); approved September 2013.
• Quidel Molecular Influenza A+B assay: Detects influenza A and/or B virus; Quidel, approved August 2013.
• PRODESSE Influenza A Influenza B RSV; Gen-Probe (San Diego); approved August 2013.
• XPERT MRSA/SA Blood Culture Assay: Automated real-time PCR for SA and MRSA DNA from positive blood cultures on the GeneExpert system; Cepheid (Sunnyvale, Calif.); approved June 2013.

Side Box: Better Utilization of Diagnostic Testing Needed to Confirm C. Diff Less than 15 percent of hospitalized patients treated for Clostridium difficile (C. diff) actually have laboratory-confirmed infections, according to a study presented at the midyear meeting of the American Society of Health-System Pharmacists (Orlando; Dec. 8-12). The researchers analyzed data from the 1,971 patients treated for C. diff infections at a 240-bed hospital (February 2012 through November 2013). All of the patients had been hospitalized for at least three days and were treated with either vancomycin or metronidazole (intravenous or oral). Of the 1,971 patients, only 292 had confirmed C. diff infections via stool culture testing, meaning that 1,679 patients did not have C. diff infections. As a result of these findings, Mercy Medical Center-North Iowa (Mason City) is developing a pharmacist- led quality improvement project, including an educational program to improve the use of  appropriate diagnostic tests.