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 Chlamydia trachomatis 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.”
The World Health Organization (WHO) has identified 12 antibiotic-resistant bacteria that it calls “priority pathogens.” The WHO Global Priority List categorizes the threat to human health from these bacteria as “critical,” “high,” or “medium,” based on these factors:*
The WHO’s 12 targets are focus areas for the Antibiotic Resistance Leadership Group. Some examples include:
Carbapenem-Resistant Enterobacteriaceae (CRE): Critical Threat
CRE are Enterobacteriaceae—a family of bacteria including Escherichia coli (E. coli)—that are resistant to the carbapenem class of drugs, often considered the drugs of last resort for these infections. Tom Frieden, M.D., M.P.H., former director of the Centers for Disease Control and Prevention (CDC), has called CRE “the nightmare bacteria.”**
According to a CDC report on antimicrobial resistance, CRE cause more than 9,000 health care-associated infections a year in the United States.*** Almost half of hospital patients who get bloodstream infections from CRE bacteria die from the infection.
Bloodstream infections account for a minority of health care-associated Enterobacteriaceae infections. Nevertheless, about 600 people die each year in the U.S. from infections caused by the two most common types of CRE: carbapenem-resistant Klebsiella species and E. coli.*** A National Action Plan issued in response to an executive order by former President Barak Obama calls for a 60% reduction in CRE infection by 2020.****
Methicillin-Resistant Staphylococcus aureus (MRSA): High Threat
Staphylococcus aureus is a common type of bacteria found on the skin. During medical procedures—such as surgery, catheter insertion, or placement of a patient on a ventilator—staph bacteria can enter the body and cause infections. Serious cases can result in pneumonia or bloodstream infections leading to sepsis and death.
MRSAs are staph bacteria resistant to methicillin, an antibiotic related to penicillin. MRSAs cause an estimated 80,461 severe infections and 11,285 deaths a year in the U.S.*** Many severe MRSA infections occur during or soon after inpatient medical care. The National Action Plan calls for a 50% reduction in MRSA infections by 2020.****
Vancomycin-Resistant Enterococcus (VRE): High Threat
Enterococci include a group of bacteria that cause a range of infections in the bloodstream and urinary tract, and at surgical sites. Vancomycin is an antibiotic of last resort. Enterococcus species that are resistant to vancomycin pose a high threat, as there currently are few alternative treatments.
The CDC estimates that about 20,000 health care-associated enterococcal infections occur each year in the United States, with about 1,300 deaths due to these infections.