New Tools for Combating Antibiotic Resistance

Antibiotic resistance is a serious health problem, causing illnesses that were once easily treatable with antibiotics to morph into dangerous infections, leading to serious disability or even death. To help fight this growing threat, diagnostics companies are developing new tools and techniques that are playing a crucial role in quickly identifying infectious organisms and preventing the inappropriate use of antibiotics.

In the United States alone, at least 2 million people become infected with bacteria that are resistant to antibiotics, and at least 23,000 people die each year as a result of these infections, according to a 2013 report by the Centers for Disease Control and Prevention (CDC). Among the most urgent threats are Clostridium difficile, which infects more than 250,000 people per year, drug-resistant Neisseria gonnorrhoeae, which affects more than 246,000 each year and carbapenem-resistant Enterobacteriaceae, which infects about 9,000 people each year

According to a March 2018 study in Health Affairs, antibiotic resistance adds nearly $1,400 to the bill for treating a bacterial infection and costs the nation more than $2 billion annually. That study also found that the share of bacterial infections in the United States that were antibiotic resistant more than doubled over 13 years, rising from 5.2 percent in 2002 to 11 percent in 2014

Antimicrobial Stewardship

While preventing infections is the first defense against antimicrobial resistance, perhaps the single most important action needed to greatly slow down the development and spread of antibiotic-resistance infections is to change the way antibiotics are used. According to the CDC, up to half of antibiotic use in humans and much of antibiotic use in animals is unnecessary and inappropriate. The commitment to always use antibiotics appropriately and safely – only when they are needed to treat disease and to choose the right antibiotics and to administer them in the right way in every case – is known as antibiotic stewardship.

CDC has taken steps to help healthcare facilities and providers improve their antibiotic stewardship. The CDC’s Get Smart program,  for example, is a national campaign to improve antibiotic prescribing and use in both outpatient and inpatient settings. CDC also provides public health messages and resources for improving antibiotic use in healthcare settings and is now working with a variety of partners to improve the use of antibiotics. One core activity is the development and implementation of the Antibiotic Stewardship Drivers and Change Package, a tool that provides healthcare facilities with a menu of interventions they can select from to improve antibiotic use.

Antimicrobial stewardship programs not only decrease antibiotic resistance, but they can also save money for healthcare institutions. A University of Maryland study, for example, showed a $3 million cost savings in the first three years of an antimicrobial stewardship program between 2001 and 2004. After the program was discontinued at the end of 2008, antimicrobial costs increased by more than 32 percent over two years.

Despite the cost-savings associated with such programs, in 2015, just 48 percent of hospitals reported having robust antibiotic stewardship programs as defined by the CDC, according to a study, “Impact of Reducing Antibiotics on the Transmission of Multidrug-Resistance Organisms,” published in Infection Control & Hospital Epidemiology in March 2017. However, this number is expected to increase as having an antimicrobial stewardship program is now a condition of participation for the Centers for Medicare and Medicaid Services and is also included as a priority in the Joint Commission accreditation survey for both acute care and long-term care hospitals.

“Reducing antibiotic use in intensive care units by even a small amount can significantly decrease transmission of dangerous multidrug-resistant organisms,” notes Sean Barnes, assistant professor of operations management at the University of Maryland’s Robert H. Smith School of Business and lead author of the Infection Control study.

Barnes and colleagues developed a model to simulate the interactions between patients and hospital workers and performed experiments on the effect of reducing antibiotic usage by 10 percent and 25 percent. This simulated intervention led to a reduction in the spread of deadly bacteria by 11.2 percent and 28.3 percent, respectively.

“Our model suggests that substantial reductions in infection rates are possible if stewardship programs aggressively pursue opportunities to reduce unnecessary usage of antibiotics,” explains Kerri Thom, a UMD School of Medicine professor and coauthor of the study.

Developing New Antibiotics and Diagnostic Tests

Because antibiotic resistance occurs as a part of a natural process in which bacteria evolve, it can be slowed but not stopped. Therefore, there will always be a need for new antibiotics to keep up with resistant bacteria, as well as new diagnostic tests to track the development of resistance and identify infectious organisms.

To more effectively treat infections, clinicians need to be able to rapidly identify the infectious agent. Standard techniques for identification of organisms require at least 48-72 hours for final results, compared with rapid diagnostic tests that provide final organism identification in just a few hours.

Rapid molecular diagnostics (RMD) typically use polymerase chain reaction (PCR) technology to detect specific genes that indicate the presence of infectious agents. A 2014 study identified two dozen rapid diagnostic tests for infectious disease, including several for C. difficile and MRSA. However, the Infectious Diseases Society of America (IDSA) notes that development of new tests is lagging as there is little impetus for companies to develop rapid diagnostic tests, and the high cost of research and development for these products poses significant barriers.

Still, there is some progress in rapid test development for infectious disease. In January 2015, test manufacturer Alere announced that it was the first to receive a Clinical Laboratory Improvement Amendments (CLIA) waiver from the Food and Drug Administration (FDA) for an influenza A and B rapid molecular test  which can return results in about 15 minutes. In September 2015, Roche’s PCR flu test also received a CLIA waiver. Since then, a number of rapid molecular diagnostic tests have received FDA clearance, including at least 13 offered by Cepheid and bioMerieux-BioFire’s Film Array Respiratory Panel, which detects 17 viruses and three bacteria.

In one of the latest advancements, the FDA in February 2017 approved the first diagnostic tool that can detect bloodstream infections and identify suitable antibiotic treatment within six hours. The PhenoTest BC Kit, manufactured by Accelerate Diagnostics (Tucson, Ariz.), can identify 14 different species of bacteria and two species of yeast that cause bloodstream infections while also providing antibiotic sensitivity on 18 selected antibiotics for a subset of the identified organisms. The test will also identify the presence of two indicators of antibiotic resistance.

Similar tests may be on the market in the coming months and years, noted the FDA in announcing approval of the PhenoTest, pointing to a finger-prick test that allows for the rapid detection and diagnosis of a bacterial infection in under 10 minutes. The MINICARE HNL assay, developed by Royal Philips and Diagnostic Development, won the European Union’s Horizon Prize in 2017 and is expected to be available for patient use this year.

Mary Hayden, MD, a professor of infectious disease at Rush University in Chicago and a IDSA representative, notes that more advancements have been made in the past few years than in previous years as infectious disease researchers shift their focus from genetics to phenotypic susceptibility testing. “There has definitely has been a recent uptick in papers that I’ve seen that are exploring antibiotic resistance and susceptibility,” she says.

Academic Advancements

Researchers in academia are also working to develop new diagnostics to improve detection of drug resistant bacteria. In 2017, 10 semifinalists were selected in the first phase of the Antimicrobial Resistance Diagnostic Challenge, a competition sponsored by the National Institutes of Health and the Biomedical Advanced Research and Development Authority within the Department of Health and Human Services. The competition is designed to support the National Action Plan for Combating Antibiotic-Resistance Bacteria, announced by President Obama in March 2015. Each semifinalist received $50,000 to develop their concepts into prototypes. In the second phase of the challenge, finalists compete to win up to $100,000. Proof of principle and analytical data for the second phase are due Sept. 4, 2018, and up to 10 finalists will be selected in December 2018. Up to three winners are expected to be announced on July 31, 2020, and will share up to $20 million, subject to the availability of funds.

Among the semi-finalists is Ephraim Tsalik, MD, PhD, associate professor in the Department of Medicine at Duke University, who proposed using host gene expression to classify viral and bacterial infection using rapid multiplex PCR. According to Tsalik, it is possible to use a patient’s immune system response to distinguish bacterial, viral and non-infectious etiologies. The response is most robustly detected in the patient’s gene expression profile, which is far more accurate than existing diagnostic tests, such as those that measure procalcitonin, he says. In conjunction with BioFire Diagnostics, Duke is developing a simple-to-use, one-hour test that distinguishes between bacterial infection, viral infection or no infection so as to guide the appropriate administration of antibiotics at the point of need.

“Our test is more sensitive and more specific than procalcitonin,” Tsalik explains. “The test measures two host response signatures. The first assesses a viral response and discriminates between a viral infection and a nonviral infection, which could include either a bacterial infection or no infection at all. The second is the host response to bacterial infection, discriminating bacterial from non-bacterial infections. The combination of these approaches would provide information about both bacterial and viral infection independently. The premise is that if you can arm clinicians with better diagnostic information, they can make more appropriate treatment decisions that can decrease inappropriate antibiotic use.”

While rapid diagnostic tests have not yet replaced standard culture testing methods, experts hope that usage will increase, leading to more appropriate use of antibiotics and, as a result, a decline in antibiotic resistance organisms. Improving rapid diagnosis and treatment of infectious disease will not only save money, but more importantly, will save lives.