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Antimicrobial resistance: Current challenges and priorities
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Twenty years ago, The Washington Post published an article, “Running out of Wonder Drugs,” calling attention to the dry antibiotic development pipeline and raising the specter of a return to the pre-antibiotic era. During the past 20 years, we have witnessed an increase in antimicrobial resistance in health care and community settings while the development pipeline remains inadequate, reflecting both a market failure and an innovation gap. Drug resistance is a local, national and global problem, resulting in increased morbidity, mortality and health care costs, threatening health security, and challenging clinicians, microbiologists, infection preventionists, public health professionals and policymakers.
WHO and the World Economic Forum have recently called attention to this urgent global threat. In 2011, WHO selected antimicrobial resistance as the theme for World Health Day. Its tagline captured the essence of the problem: “No action today, no cure tomorrow.” Dramatic recent examples of the problem include the emergence and global spread of organisms containing the New Delhi beta-lactamase type-1 (NDM-1) resistance gene originating in the Indian subcontinent; increasing resistance to third-generation cephalosporins in Neisseria gonorrhoeae resulting in recent changes in treatment guidelines; and increasing reports of infections caused by carbapenem-resistance in Enterobacteriaceae and other gram-negative bacteria. Media reports have highlighted these and other reports of infections caused by multiple drug-resistant organisms, using terms such as superbugs, flesh-eating bacteria and apocalyptic threats.
Contributing factors
Many factors contribute to the ongoing emergence of this problem, including overuse and misuse of antimicrobial agents (in humans, animals and the environment); microbial evolution (eg, point mutations, spread of mobile genetic elements containing resistance genes) in response to selective pressures in the environment; international travel; increases in host susceptibility to infection; and lapses in surveillance or infection control procedures. The problem is compounded in some settings by drug shortages, over-the-counter availability of drugs and marketing of counterfeit drugs.
So what are we to do to address this multifaceted problem? A recent commentary by Drs. Brad Spellberg, John Bartlett and David Gilbert provides some guidance regarding five categories of potential new interventions. They begin by reminding us that drug resistance is not a new phenomenon and mention recent examples of discovery of antibiotic resistance in organisms obtained from isolated underground caves dating back 4 million years; some organisms were even resistant to synthetic antibiotics developed in the 20th century.
They suggest interventions targeting prevention of resistant infections, reinvigoration of the drug development pipeline, preservation of currently available drugs, development of new therapeutic strategies with diminished potential to drive resistance, and development of innovative therapies focused on host rather than microbial targets. As part of their call to address the pipeline problem, they also emphasize the need for new streamlined regulatory approaches, citing the Limited Population Antibacterial Drug (LPAD) approval pathway proposed recently by the Infectious Diseases Society of America. This plan calls for smaller, less expensive clinical superiority trials involving patients with potentially life-threatening drug-resistant infections, resulting in approval with a very narrow label for limited use in well-defined populations of patients for whom a drug’s benefits have been shown to outweigh the risks. Such an approach would be an example of a response to the observation made by the late Nobel laureate Joshua Lederberg that current challenges involving emerging infections represent a struggle characterized as “our wits versus their genes.”
Proven methods for prevention
As new approaches are pursued, it is important to continue to implement aggressive strategies that have been shown to be effective in prevention and control of outbreaks caused by multiple drug-resistant organisms, which have been reviewed in another recent commentary by Drs. Thomas Sandora and Donald Goldmann. They emphasize the importance of hand hygiene; environmental cleaning and disinfection; use of evidence-based bundles and decision support check lists; leadership commitment and accountability; and real-time feedback of data to health care providers. They also provide practical suggestions for components of effective stewardship programs, including decision support, standardized antimicrobial order formats, and prospective audit strategies with feedback of results.
Given the multifaceted nature of the resistance problem, an integrated approach is indicated and should include evaluation and research components. Components requiring ongoing evaluation include surveillance of antimicrobial usage and resistance in humans and food animals at the local and national level, antimicrobial stewardship programs, infection control programs, screening strategies and public reporting. Components requiring ongoing research include development of new antimicrobial drugs, point-of-care rapid diagnostic tests, and vaccines targeting priority drug-resistant organisms, and assessment of alternative novel therapeutic approaches.
Effective implementation will require public-private partnerships involving academic institutions and industry; incentives to encourage new drug development; close collaboration among clinicians; microbiologists; veterinarians; clinical pharmacists; public health officials and professional societies; development and implementation of evidence-based policies supporting drug, diagnostic test and vaccine development; and antimicrobial stewardship efforts targeting patients, livestock and the environment.
The nature of the problem at the interface of human health, animal health and environmental health and the need for engagement of clinicians, veterinarians and environmental health professionals in working together to address these challenges reinforce the need for a transdisciplinary “One Health” approach. Other necessary components include timely feedback of data on usage to individual practitioners, timely communication among health care professionals at the time of transfer, when a patient is infected or colonized with drug-resistant organisms, educational approaches to empower patients to remind providers of the importance of hand hygiene and other prevention strategies and to empower physicians and veterinarians to focus on judicious antibiotic use. In addition, ongoing communication with health care administrators and policymakers regarding the urgent need to develop and implement evidence-based policies is a vital component.
Last but not least, health care providers must remain vigilant to ensure timely detection and reporting of the emergence or introduction of new drug-resistant strains.
References:
Spellberg B. N Engl J Med, 2013;368:299-302.
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Disclosure: Hughes is a member of the Infectious Diseases News Editorial Board, is a past president of the Infectious Diseases Society of America, and serves on the boards of the One Health Commission and the EcoHealth Alliance.