Politicians and medical experts worldwide alike have decried the lack of innovation in antibiotics – an area that has been neglected for three decades – but another area is turning out to be just as important: diagnostics.
"Without rapid, precision Dx to target therapy, physicians generally treat empirically, prescribing widely available and inexpensive broad-spectrum antibiotics," according to an executive briefing paper authored by Jonathan Kfoury and Alex Vadas, managing directors, and T.J. Bilodeau, U.S. practice manager, all of L.E.K. Consulting's Biopharma and Life Sciences practice.
That situation, however, is leading to poor patient outcomes and growing antibiotic resistance. Once those broad-spectrum antibiotics fail to help a patient or susceptibility data return from the lab – a process that can take two to four days – the doctor then considers a novel or more targeted antibiotic.
With the decline in antibiotic development since the 1980s, there are grave concerns that the number of deaths related to infections could rise sharply. According to the May report released by the U.K.'s Lord Jim O'Neill, who formerly served as chief economist at Goldman Sachs and now is commercial secretary to the Treasury, without some sort of policy intervention, deaths related to antimicrobial agents could climb from the current 700,000 a year to 10 million a year by 2050.
The report encourages the development of new, rapid diagnostics to reduce the unnecessary use of antimicrobials, as there is currently mostly guesswork involved. "The process has remained basically unchanged in decades; most of these tests are lab-based and would look familiar to a doctor trained in the 1950s, using processes that originated in the 1860s." The problem: the lack of a market for new tests, the report asserts.
CHALLENGES TO EARLY DIAGNOSTIC TESTING
In their executive insights paper, the L.E.K. team identified challenges that constrain the use of diagnostic testing in early treatment decisions for serious bacterial infections, most notably slow turnaround time, the lack of capacity to identify the causal pathogen and its susceptibility profile, laboratory workflow challenges, and cost and reimbursement issues.
"While culture-based methods are the gold standard in effectively identifying the causal pathogen and testing its susceptibility to antimicrobial agents, these methods take two to four days, forcing physicians to treat patients empirically until definitive test results arrive," the team wrote.
Why does the process take so long? After obtaining a positive blood culture, resistance testing may be done either by using antibiotic sensitivity testing or a molecular approach using polymerase chain reaction (PCR) and a test for a set of known mutations, Vadas told BioWorld Today. "Regardless of the approach, you still need to culture the blood up front, which adds 24-plus hours to the testing timeline," he added.
"In terms of solutions, low-cost, broadly available PCR solutions are in development and may have applicability for certain types of infections," he added. He touched on the promise of direct detection, which allows for the discovery of a pathogen from the blood without culture. An example of a company studying that method is Geneweave, which was acquired by Basel, Switzerland-based Roche Holding AG last year. (See BioWorld Today, Aug. 14, 2015.)
Geneweave's Smarticles technology is designed to identify multidrug-resistant organisms quickly and assess antibiotic susceptibility directly from clinical samples. It consists of DNA-delivery bioparticles and custom-designed DNA molecules that cause live bacteria to produce light. They are engineered to target a family, genus or species of bacteria.
EMERGING TECHNOLOGIES FACING HURDLES
Still, some companies are looking beyond culture and PCR. However, even with new tests, the reimbursement hurdle is a tough one to surmount, as obtaining a new code can prove to be a time-consuming and challenging process. In addition, many of those emerging technologies only can identify a limited set of pathogens. And while the identification process takes less than an hour, susceptibility tests may have to run separately.
Emerging technologies include matrix-assisted laser desorption ionization-time of flight (MALDI-TOF), through which results are available in less than an hour. While the cost-per-test is negligible, instruments run more than $200,000.
One company using MALDI-TOF is Billerica, Mass.-based Bruker Corp., with its FLEX series. At the American Society for Microbiology (ASM) Microbe 2016 conference earlier this month, Bruker reported on a collaboration with the Special Bacteriology Reference Laboratory at the U.S. Centers for Disease Control and Prevention to create an expanded microorganism reference library for the Bruker MALDI Biotyper. The MALDI Biotyper library contains spectra for more than 2,300 species of bacteria and fungi, according to the company.
Another emerging technology is next-generation sequencing, which yields results within one to two days at a cost of more than $100 per test.
Still, as Norman Moore, director of Scientific Affairs, Infectious Disease at Waltham, Mass.-based Alere Inc., told BioWorld Today, diagnostic companies can't do it alone; it is essential to make all stakeholders, including doctors and patients, aware of the potential harms of overprescribing.
With that, tests need to be sensitive and "fast enough to change prescribing habits," Moore added.
A HOST OF COMPANIES IN THE FRAY
Other companies have recognized that point. In January, a number of drugmakers and other stakeholders pledged to help in the fight against antibiotic resistance. Joining the ranks were a number of diagnostics companies that also vowed to help in the fight.
The signatories were a multinational group – Alere Inc., Biomérieux SA, Cepheid, Curetis AG, F. Hoffman-La Roche Ltd., Hemocue AB, Hyrax Biosciences (Pty) Ltd., Mobidiag Oy Ltd., Momentum Bioscience Ltd., Quantumdx Ltd. and Spectromics.
Many of those that signed the pledge touched on what is viewed as the biggest problem facing patients: the time it takes to determine treatment regimen.
Oliver Schacht, CEO of Curetis, told BioWorld Today that his company is looking to make faster tests a reality. Curetis has made "tremendous progress in the first half of 2016" and is eyeing the launch of its intra-abdominal infection cartridge in Europe, following the expected fourth quarter completion of clinical validation. "That panel will most likely also include the antibiotic resistance marker associated with the Colistin resistance in E. coli that was at the core of the recent patient case in the U.S.," he said.
Curetis GmbH is the operational subsidiary of Curetis NV, with its headquarters in Holzgerlingen, Germany. The company expects to establish a U.S. operation in the second half of the year and hopes to announce where it will set up shop shortly, Schacht said.
Simon Travers, managing director at South Africa-based Hyrax Biosciences, confirmed that his company is working on a number of AMR-related products. "Our next product will be a tool that enables the analysis of sequence data from TB – analyzing either full genome sequences or sequence data generated by targeting specific regions of the genome – that is capable of accurately detecting resistance to all of the currently available TB drugs," he told BioWorld Today.
In addition, Hyrax has developed a similar tool for Staphylococcus aureus and is expanding its product line to focus on other bacteria.
Travers said his company also is developing databases and analytics tools with a goal of real-time surveillance of infections and resistance at a local, national and international level. "While this will be applicable on a global scale, it will be particularly pertinent for resource-limited settings where our knowledge of the prevalence of antimicrobial resistance is limited," he added.
Formed in 2014, Manchester, U.K.-based Spectromics is working on a rapid test for guiding the use of antibiotics for routine urinary tract infections (UTIs) in the community.
CEO Neil Butler told BioWorld Today that UTIs may not be viewed as severe as sepsis or kidney infections. However, roughly 25 percent of sepsis cases originate from UTIs, resulting in kidney infections that can pass into the bloodstream. "Once a patient has sepsis, survival rates are poor, 50 percent or less, and hence better to treat before it becomes a kidney infection," he added.
Butler added that he also sits on the board of U.K.-based Atlas Genetics Ltd., which is developing rapid molecular diagnostic tests for sexually transmitted diseases. The company is developing a test for drug-resistant-gonorrhea.
MORE INTELLIGENT ANTIBIOTIC USE
Located in Newcastle, U.K., Quantummdx is preparing for the launch of its Q-POC technology in 2018. According to company spokeswoman Lucy Harvey, Q-POC will provide sample-to-result testing in roughly 10 to 20 minutes. "Q-POC will identify the presence and strain of infection, ensuring the right drug is prescribed the first time," said Harvey, who added that the ultimate goal is to facilitate "a more intelligent use of antibiotics."
To that end, globally distributed Q-POC devices will allow for geotagging and the anonymization of pathogen data, which would then be sent to the cloud for real-time disease and drug-resistance monitoring, rapid detection and pathogen containment. "[T]he data could also be used by public health bodies to allocate resources effectively. We call this system The Internet of Life," Harvey told BioWorld Today.
Indeed, to Kevin Krenitsky, president of Opgen Inc., the field of infectious disease has been "languishing in antiquity," particularly with traditional methods taking days to identify antibiotic resistance.
Although it did not sign the January letter, Gaithersburg, Md.-based Opgen is looking to unveil what Krenitsky has dubbed "very disruptive platform technology," incorporating bioinformatics and "attack[ing] the problem from multiple angles."
The company wants to decrease the time it takes to treat patients with a one-hour test. "What's important here is not the pathogen; it's the resistance within the pathogen," he said in early June 2016 during the LD Micro Invitation in Los Angeles.
With that in mind, the company is looking to leverage its bioinformatics database and rapid array test to inform patient treatment.
The company's goal is to have information about a patient sample back within an hour, including pathogens and resistance genes. The results could be evaluated using the company's Acuitas Lighthouse database, which would reveal the organism causing the disease, as well as the antibiotic resistant genes and the type of treatment regimen that would be most appropriate.
Not only could that technology help a single patient with the appropriate treatment, according to Krenitsky, but it could also prevent the spread of an infection throughout a hospital with timely identification of a pathogen.
The company unveiled data at AMS Microbe 2016 in Boston demonstrating how its Acuitas Resistome Test can be used in epidemiological studies to aid in routine evaluations for mechanisms of resistance in carbapenem resistant Enterobacteriaceae.
The test is intended to detect antibiotic resistance genes associated with Klebsiella pneumoniae,Escherichia coli, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter cloacae andCitrobacter freundii.
