Antibiotics are a lifesaver—except when they stop working—and, unfortunately, that is happening more often as multidrug resistant bacteria render many previously useful antimicrobials ineffective. The CDC estimates that about two million people in the United States get an antibiotic-resistant infection every year and the rise of such infections has prompted the World Health Organization to list antimicrobial resistance among the top 10 global health threats for 2019.
In response to this threat, Senators Johnny Isakson (R-GA) and Robert Casey (D-PA) co-sponsored the Developing an Innovative Strategy for Antimicrobial Resistant Microorganisms (DISARM) Act of 2019, which features a multifaceted strategy for developing new antibiotics and protecting the effectiveness of existing antibiotics. Infection control remains paramount to staving off this growing threat in hospitals and long-term care.
“The DISARM Act addresses two of the critical elements of a multicomponent strategy,” says James M. Hughes, MD, FIDSA, professor emeritus of medicine, Emory University School of Medicine, and a former president of the Infectious Diseases Society of America “The legislation would help reinvigorate the antibiotic development pipeline for effective new antibiotics, by increasing hospital reimbursement, and incentivize development of robust effective antimicrobial stewardship programs which are needed to encourage judicious use of currently available antibiotics in order to conserve their effectiveness.
DISARM was designed to address what is probably the largest barrier to new antibiotic development—the lack of financial incentives for pharmaceutical companies to develop new antibiotics. New versions have been slow to come to market as pharmaceutical companies no longer find it cost effective to research and develop them.
“One study by the Tufts Center for the Study of Drug Development estimated that the cost to bring one new drug to market is $2.7 billion,” says Theresa Madaline, MD, hospital epidemiologist and assistant professor, Infectious Diseases, Montefiore Health System and Albert Einstein College of Medicine. “Those costs are recompensed through sales of the drugs that successfully earn FDA approval and make it to market. In particular, agents that are used by patients continuously for chronic or long-standing conditions, or products that can command a high price due to life-saving properties, such as cancer drugs, are considered wise investments by pharmaceutical companies due to the potential for long-term revenue and high reimbursement.”
Antimicrobials, on the other hand, are typically used by patients for a short time to treat an infection and run the risk of becoming obsolete in a few years if bacteria becomes resistant to the drug through overuse or misuse.
“Moreover, hospitals are loath to add new drugs to their hospital formularies when cheaper alternatives with greater availability of long-term safety data exist, and antimicrobial stewardship programs work diligently to restrict utilization of broad spectrum agents in order to preserve them for those patients with highly resistant infections,” says Madaline. “As a result, many large companies no longer invest in research and development of antimicrobials due to shrinking profit margins.”
The few small companies that still pursue antimicrobial drug development face slim margins and that pursuit recently led one small pharmaceutical company to bankruptcy. If this trend continues, effective antibiotics may no longer be available to treat vulnerable patients.
“Following the golden age of new antibiotics, from the 1950s to the 1970s, the rate of introduction of new antibiotics began to decline dramatically in the 1980s, and the pipeline has been running dry, while drug-resistant infections have increased and new genetic mechanisms of resistance have emerged and spread rapidly around the world,” says Hughes. “ Although some new antibiotics have recently been introduced, most represent minor modifications or combinations of older drugs. Few target emerging multidrug-resistant Gram-negative bacterial pathogens which cause life-threatening infections.”
Hospitals have already seen significant numbers of difficult-to-treat, highly-resistant bacterial infections and, in rare cases, infections caused by bacteria resistant to all known antibiotics.
Without effective means to fight infections, hospitals are also finding it difficult to treat patients for other conditions.
“The problem of antibiotic resistance gets worse every day,” says Helen W. Boucher, MD, FACP, IDSA, director of the Infectious Diseases Fellowship Program and a professor at Tufts University School of Medicine. “We have patients dying from antibiotic-resistant infections and we are having problems with patients who can’t get organ transplantation surgery or cancer treatment because they have infections that we can’t treat.”
Antimicrobial stewardship programs are a key part of keeping currently used antibiotics from becoming ineffective, as these hospital programs promote judicious use of existing antibiotics and help curb the spread of antibiotic-resistant bacteria.
“This is most often accomplished by upfront restriction of broad-spectrum antimicrobials without discussion and approval by an antimicrobial stewardship team pharmacist or clinician, and/or by auditing the use of certain antimicrobials and discussing alternatives or limiting duration with prescribers,” says Madaline. “This approach is effective in reducing sub-optimal or inappropriate broad-spectrum antimicrobial use and limiting bacterial resistance over time. Drug resistant infections carry a higher risk of mortality for patients, and as bacteria develop increasing resistance, the potential exists for infections that we are unable to treat due to a complete lack of effective medications.”
Medicare reimbursement for these programs is essential because the Centers for Medicare and Medicaid Services is the single largest payer in the U.S. healthcare system.
“In 2017, 17.2% of the U.S. population of more than 58 million people, were covered by Medicare alone, and that number is expected to grow to 63 million by 2020,” says Madaline. “Approximately 40% of all Medicare spending is on hospital services. With such a large market share, Medicare reimbursement is a crucial consideration for pharmaceutical companies looking to develop and market new drugs and for hospitals seeking reimbursement for treatments rendered.”
Initially, some hospital antibiotic stewardship efforts focused on cost savings initiatives.
“But antimicrobial stewardship is so much more nuanced than just cost considerations,” says Clare N. Gentry, MD, medical director for antimicrobial stewardship for Houston Methodist Hospital in Texas. “With exciting innovations in diagnostic testing for infection, new guidelines for dosing of various antibiotics, more robust data to guide in planning duration of antibiotic therapy, and an increasing role for IT in optimizing antibiotic use, the multidisciplinary stewardship team is critical in providing high quality care to patients.”
The Infectious Disease Society of America identified antibiotic resistance to be an important issue more than 10 years ago. Concern prompted the bipartisan Generating Antibiotic Incentives Now (GAIN) Act of 2012, which extended the exclusivity period, during which certain antibiotics can be sold without generic competition, by five years. Although GAIN helped facilitate the development of new antibacterial drugs, more steps need to be taken. A 2016 British review on antimicrobial resistance estimated that to counter multi-drug resistant bacteria, 15 new antibiotics will be needed during the next decade. Four of those antibiotics would have to be new formulas, while the rest could improve existing formulas.
An ideal multifaceted strategy includes additional incentives to bring new drugs to market, as well as improved surveillance for drug-resistant organisms in humans, animals, and the environment; strengthens infection control efforts in healthcare settings; and fosters the development of rapid diagnostic tests to support stewardship efforts. The development and use of vaccines can prevent diseases which might otherwise be treated with antibiotics. Education on appropriate antibiotic use is also essential.
“Stewardship teams need to take the lead locally in educating medical personnel and patients about the risks of antibiotic underuse and overuse and the role that both of these issues can play in increased antibiotic resistance, “said Katherine Perez, PharmD, the pharmacy lead for Houston Methodist’s antimicrobial stewardship team.”
Antibiotic resistance is both a local and a global problem.
“At the global level, there is also a need to ensure the availability of high quality, critically important antibiotics at the point of care and to improve sanitation and hygiene programs,” says Hughes. “Implementation of the needed multifaceted strategy will require a collaborative interdisciplinary One Health (collaborative) approach involving human health, animal health, and environmental health professionals, strengthened public-private partnerships, and sustained political will.”
The DISARM bill was written with IDSA input, so practicing infectious diseases clinicians had substantial influence in shaping the bill’s priorities.
“DISARM addresses a crisis in our country and around the world,” says Boucher. “It is a small step forward, but a meaningful small step forward.”