By Barbara J. Toman
In the war against microbes, human beings are vastly outnumbered—and losing the weapons race.
The introduction of antibiotics into clinical practice in the 1940s spurred hope that infectious diseases might be defeated as a public health problem. But bacterial microbes are cunning foes, adept at acquiring resistance to antibiotics faster than scientists can develop new drugs. At least 2 million people in the United States become infected each year with bacteria that are resistant to antibiotics, and at least 23,000 people die each year as a direct result of these infections.*
Mayo Clinic is part of the Antibacterial Resistance Leadership Group (ARLG), a clinical effort launched in 2013 by the National Institute of Allergy and Infectious Diseases. The ARLG is developing and managing clinical trials aimed at reducing the impact of antibacterial and antimicrobial resistance.
“Antibacterial resistance is a huge crisis in the world today that doesn’t get the recognition it deserves,” says Robin Patel, M.D., Chair of the Division of Clinical Microbiology, Co-Director of its Bacteriology Laboratory, and Director of the Infectious Diseases Research Laboratory at Mayo Clinic in Rochester, Minnesota.
“One solution to antibacterial resistance is to use increasingly broader-spectrum antibiotics to ‘cover’ for resistance,” she says. “But if there’s enough resistance, the broader-spectrum antibiotic won’t work. And using broader-spectrum antibiotics is the very practice that has bred the resistance we have today.”
Dr. Patel directs the diagnostics arm of ARLG and, within that area, the MASTERMIND project. MASTERMIND (which stands for “MASTER protocol for evaluating Multiple INfection Diagnostics”) is one part of ARLG’s smarter approach to fighting antibacterial resistance.
Conventional diagnostic approaches, such as bacterial culture and routine antimicrobial susceptibility testing, can provide a diagnosis for some infectious syndromes. But it can be days before those tests yield actionable results. Facing diagnostic uncertainty, physicians feel compelled to prescribe broad-spectrum antibiotics for patients needing immediate treatment.
Instead of relying on broader-spectrum antibiotics—in hopes of hitting whatever microbe is causing an individual’s illness or infection—the ARLG wants to support the creation, regulatory approval, and appropriate clinical use of tests that can rapidly pinpoint the bacterial culprit. Then, a drug likely to work against that particular pathogen can be prescribed. Or, if there is no bacterial infection, no antibiotic treatment can be recommended.
“There wasn’t as much of a need for microbial diagnostics when antibiotics worked predictably. A patient could be clinically diagnosed and managed,” Dr. Patel says. “Now, with resistance, we really need better diagnostics. And it’s no trivial exercise to develop them and then figure out how to use them properly in clinical practice.”
Maximizing Trial Efficiency
For diagnostics companies, validating diagnostic tests and obtaining approval for clinical use from the U.S. Food and Drug Administration (FDA) is challenging. The return on investment can be uncertain, and the necessary clinical trials are complex.
MASTERMIND seeks to solve those problems with a new clinical-trial design that brings together infectious disease physicians, clinical microbiologists, statisticians, and potentially interested companies. The innovative concept uses a single individual’s clinical sample (or samples) to evaluate multiple tests, providing efficiencies of scale for simultaneous or successive investigations by companies.
“It’s typical for more than one company to be performing clinical trials of similar diagnostics, often contemporaneously,” Dr. Patel says. "Or companies might be working on distinct diagnostics but need the same kind of patient samples for their trials.”
Depending on the disease or diagnostic assay being studied, high-quality patient specimens may be limited. Companies also might find themselves competing to partner with the limited number of medical centers capable of performing a complex clinical trial.
MASTERMIND seeks to solve those problems with a new clinical-trial design that brings together infectious disease physicians, clinical microbiologists, statisticians, and potentially interested companies.
“All of these studies need approval by regulatory bodies and institutional review boards. But with those approvals, it’s possible to enroll a patient in a trial that involves distributing the patient’s specimen to testing using multiple companies’ platforms,” Dr. Patel says.
In addition to patient specimens, clinical data might be consolidated and test results shared to inform the performance of other tests within a study. “It’s not typical for companies to work together like this,” Dr. Patel says. “But the ARLG can serve as the middle ground for these discussions between companies and also with the FDA.”
Pilot MASTERMIND for Extra-Genital Sexually Transmitted Infections
Multiple companies are participating in the first MASTERMIND study, which aims to validate nucleic acid amplification tests (NAATs) for rectal and throat Chlamydiatrachomatis and Neisseria gonorrhoeae. Although the U.S. Centers for Disease Control and Prevention (CDC) recommends the use of NAATs for chlamydia and gonorrhea bacteria, no FDA-approved assays exist for detecting those bacteria in the extra-genital sites being studied.
“Antibiotic resistance is not an easy problem. We have to think differently.”
- Robin Patel, M.D., Chair of the Division of Clinical Microbiology at Mayo Clinic
“The goal of this MASTERMIND study is to produce data that the companies can submit to the FDA to get clearance for their assays,” Dr. Patel says. “It’s clearly advantageous to the companies involved, and we hope that it will ultimately be advantageous for patients.”
Future MASTERMIND studies may tackle direct-from-blood and direct-from-urine diagnostic tests for various conditions. In addition to diagnostics, the ARLG is focusing on:
“Antibiotic resistance is not an easy problem. We have to think differently,” says Dr. Patel. “It’s a new approach for the National Institutes of Health to be undertaking MASTERMIND studies with companies to help them get FDA clearance for new diagnostics. But it just makes sense as a way to further the development of diagnostics so these can be used in clinical practice to improve human health.”
Read the rest of the article to learn about the 12-antibiotic-resistant bacteria, also known as "superbugs," identified by the World Health Organization (WHO) as "priority pathogens."