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Colistin resistance signals need to redouble efforts amid growing public health crisis
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The recent discoveries of two new genes that confer resistance to colistin (an antibiotic of last resort) make it clear that antibiotic resistance poses an increasing danger to patients, public health and national security. Antibiotic resistance and the lack of new antibiotics jeopardizes our ability to provide adequate medical care for many hospitalized patients, including preterm infants; those undergoing chemotherapy, solid organ and bone marrow transplants, joint replacements and complex surgeries; wounded soldiers; and others. As the Infectious Diseases Society of America has emphasized for more than a decade, robust federal and international solutions are needed to stem the tide of resistance and bring forth the tools physicians need (including new antibiotics, diagnostic tests and vaccines) to safely and effectively care for their patients and protect the world from this growing threat.
When experts first detected mcr-1 — a new gene that confers colistin resistance — in bacteria infecting humans and animals in China in November 2015, ID physicians warned that it was only a matter of time before this gene spread globally. The extensive use of colistin in animal feed in China is thought to be a significant driver of resistance in general as well as mcr-1. In May, predictions became grim reality when Escherichia coli bacteria carrying the mcr-1 gene were found in a urine sample from a Pennsylvania woman who had not traveled outside of the United States. The mcr-1 gene exists on a plasmid, a small piece of DNA that is capable of moving from one bacterium to another, spreading antibiotic resistance among bacterial species. Colistin is an agent of last resort with predictable kidney and nerve toxicity, and often reserved for treatment of the most resistant infections. mcr-1 is being transmitted to bacteria that are already resistant to antibiotics other than colistin (such as carbapenem-resistant Enterobacteriaceae), creating truly pan-resistant organisms that we lack the capacity to treat.
Source: Janice Haney Carr/CDC
The problem continues to grow. mcr-1 has been found in animals and humans in 27 countries. Researchers in Belgium discovered mcr-2, a new colistin resistance gene that also exists on a plasmid, in E. coli samples taken from cows and pigs in July. Research indicates mcr-2 may be able to spread even more rapidly than mcr-1.
Thankfully, this extremely concerning news comes at a time of unprecedented global and U.S. attention to antibiotic resistance. Developments including the upcoming United Nations’ high-level meeting on antimicrobial resistance, the U.S. National Action Plan on Combating Antibiotic-Resistant Bacteria (CARB), and the ongoing efforts of the Presidential Advisory Council on Combating Antibiotic-Resistant Bacteria are now more necessary than ever as we struggle to catch up to rapidly evolving threats and set in place a One Health approach — covering human and animal health and the environment — to prevent infections, limit the development of resistance and spur the research and development of urgently needed new antibiotics, diagnostics, vaccines and other tools.
Antibiotic resistance is a complex problem that requires a coordinated, multipronged solution — much of which is set forth in the CARB National Action Plan. The widespread overuse and misuse of antibiotics is driving the development of resistance. Antibiotic stewardship programs (ASP) led by ID physicians have been proven to curb inappropriate antibiotic use. CMS has proposed new requirements for hospitals and long-term care facilities to establish ASPs — a policy long-advocated by IDSA. It is critical that this administration finalize these proposals before leaving office.
The Action Plan also calls for significantly increased monitoring of antibiotic use and resistance rates, with a goal of 95% of hospitals reporting these data through the CDC National Healthcare Safety Network. Better data on antibiotic use are critical for evaluating the impact of stewardship activities and identifying problematic behaviors. Stronger surveillance is key as well. Beginning this fall, the CDC’s Antibiotic Resistance Lab Network will provide the infrastructure and lab capacity for seven to eight regional labs, and labs in all states and seven major cities/territories, to detect and respond to resistant organisms recovered from human samples. Such activities are essential to ensure that we can rapidly address the emergence of new threats like mcr-1 and mcr-2. But like all of the activities in the Action Plan, the success of these efforts is dependent upon Congress providing strong, stable funding each year.
Despite important progress on stewardship, prevention and monitoring, we know that we cannot stop resistance completely. Patients desperately need new antibiotics now to treat current threats and a robust pipeline of new antibiotics to treat future threats. Unfortunately, the antibiotic pipeline remains fragile as significant economic, regulatory and scientific barriers to antibiotic research and development (R&D) persist, prompting the need for new incentives. New antibiotics — particularly those to treat areas of unmet need — are difficult and costly to develop. New regulatory approaches, such as the Limited Population Antibacterial Drug approval mechanism proposed by IDSA and gaining traction in Congress, are needed to allow these drugs to be brought to market. Antibiotics are also far less profitable than other types of drugs. Antibiotics are typically inexpensive, taken for a small period of time, and appropriately held in reserve to protect their utility. New economic models must be devised to delink antibiotic reimbursement from use in order to provide companies a return on investment sufficient to incentivize R&D while promoting appropriate stewardship and access. Incentives such as tax credits and funding through the Biomedical Advanced Research and Development Authority and the NIH must be provided to support the high costs of antibiotic discovery, research and development. The newly launched CARB-X — a public-private partnership designed to accelerate the preclinical development of urgently needed new antibiotics — shows great promise and is exactly the type of innovative robust approach needed to help rejuvenate antibiotic R&D.
The discoveries of mcr-1 and mcr-2 are among the newest and most distressing signs that the threat of antibiotic resistance is increasing and will continue claiming more and more lives. Our federal government and global government, civil society and private sector partners have laid important groundwork and taken key first steps toward addressing this public health crisis. But as the news of colistin resistance genes demonstrates, we must redouble our efforts in order to protect patients from the reality of a post-antibiotic era.
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- Helen W. Boucher, MD, FACP, FIDSA, is director of the infectious diseases fellowship program at Tufts Medical Center and associate professor of medicine at Tufts University School of Medicine. She also serves on the board of directors for the Infectious Diseases Society of America.
Disclosure: Boucher reports serving on the data monitoring committees for Actelion and Cardeas, and the adjudication committee for the NIH.