Antibiotic resistance: Impact on cost, outcomes
The war against antibiotic resistance is now a full-blown effort among various sectors, including governmental agencies, medical companies, health systems, clinical societies, and payers.
Antibiotic resistance adds $20 billion in excess direct healthcare costs annually in the United States, plus an additional cost of $35 billion per year due to lost productivity, according to the Centers for Disease Control and Prevention (CDC). Using antibiotics is by far the biggest factor leading to antibiotic resistance. But up to 50% of all prescribed antibiotics aren’t necessary or are not prescribed appropriately.
“The use of antibiotics to treat infections has revolutionized medicine and allowed formerly untreatable conditions to be easily cured,” says Managed Healthcare Executive Editorial Adviser Don Hall, former health plan CEO and currently principal, DeltaSigma, LLC, in Littleton, Colorado. “The specter of antibiotic resistance is chilling, sending us backward in time when infections meant long-term suffering and often death. The impact of the reemergence of untreatable infections on our healthcare costs could be prohibitive.”
Among the most recent efforts to address this problem was a White House Forum on Antibiotic Stewardship, convened by the Obama Administration on June 2, which brought together constituencies involved in antibiotic stewardship, i.e., the development, promotion, and implementation of activities to ensure the responsible use of antibiotics.
More than 150 major food companies, retailers, and human and animal health stakeholders announced commitments to implement changes over the next five years to slow the emergence of resistant bacteria and prevent the spread of resistant infections.
“The government has long been active in combating antibiotic resistance,” says Arjun Srinivasan, MD, associate director for Healthcare Associated Infection Prevention Programs, Division of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Infectious Diseases, CDC. “But the ever-growing threat of antibiotic resistance requires an even more aggressive effort, and that is what the president has called for. Successful control of antibiotic resistance requires leadership and accountability among industry, healthcare, and other sectors that must move in concert to address this national threat.”
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According to Srinivasan, the CDC has made great strides in posting and distributing timely and accurate information on antibiotic resistance and antibiotic use. “We need this type of information in order to target our efforts,” says Srinivasan.
The National Action Plan for Combating Antibiotic-Resistant Bacteria (CARB), which the White House unveiled in March and for which funding is included in the CDC's proposed budget for fiscal 2016, further fuels this effort. The plan identifies critical actions federal departments and agencies should take to combat the rise of antibiotic-resistant bacteria.
James I. Cleeman, MD, senior medical officer and director of the division of healthcare-associated infections at the Agency for Healthcare Research and Quality (AHRQ) reports that AHRQ is working with the U.S. Department of Health and Human Services (HHS) and other partners to achieve CARB’s goals.
In particular, AHRQ is doubling its funding for CARB-related research this year, developing guidance and tools to help providers establish antibiotic stewardship programs, and promoting antibiotic stewardship in multiple healthcare settings, including hospitals, ambulatory care, and long-term care.
The agency has developed a toolkit to help hospitals reduce Clostridium difficile (C. difficile) infections and to help hospitals prevent and control carbapenem-resistant Enterobacteriaceae (CRE). It also funded a research project that is changing how clinicians in the intensive care unit approach the prevention of methicillin-resistant Staphylococcus aureus (MRSA).
In addition, AHRQ supports research and implementation projects focused on preventing healthcare-associated infections (HAIs). “Every infection prevented means one less episode needing antibiotics, which helps slow down the development of antibiotic resistance,” Cleeman says.
Within the next year, AHRQ and the CDC will host a meeting of experts and stakeholders to identify ways to prevent antibiotic-resistant hospital-acquired infections (HAIs).
To combat antibiotic misuse, AHRQ is also promoting its Comprehensive Unit-based Safety Program (CUSP), which includes techniques and a checklist of proven practices to improve safety culture, teamwork and communications. “CUSP has prevented thousands of HAIs across the nation, saving many lives and millions of dollars,” Cleeman says.
Tim W. Irvin, press officer at FDA’s Center for Drug Evaluation and Research, reports significant progress in revising FDA's guidance documents to provide durable recommendations on scientifically sound, ethical, and feasible clinical trials. The revisions, he says, will facilitate the development and evaluation of new antibacterial drugs.
Since 2010, FDA has issued 11 guidance documents describing clinical trial designs for studying antibacterial drugs, including draft guidance on developing “Antibacterial Therapies for Patients With Unmet Medical Need for the Treatment of Serious Bacterial Diseases.” This guidance describes streamlined development pathways for patients with few or no treatment options.
FDA also collaborates with the CDC and the National Institutes of Health (NIH) regarding antibacterial drug development and issues related to epidemiological surveillance and research. In July 2014, the NIH and FDA jointly hosted a workshop to identify strategies to promote clinical trials for antibacterial drugs and encourage partnerships to accelerate their development.
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FDA is implementing Generating Antibiotic Incentives Now (GAIN), enacted by Congress in 2012, which designates certain antibacterial and antifungal drugs intended to treat serious or life-threatening infections as Qualified Infectious Disease Products (QIDPs). GAIN provides for an additional five years of exclusivity to certain qualifying antibacterial and antifungal drugs intended to treat serious or life-threatening infections. “Products with a QIDP designation are also eligible for priority review and fast-track status,” says Irvin.
To date, FDA has granted 75 QIDP designations representing 50 different antibacterial/antifungal drugs. Since 2014, it has approved six new antibacterial/antifungal products with QIDP designation.
In 2013, FDA published Guidance #213, which calls on animal drug sponsors of approved medically important antimicrobials administered through medicated feed or water to voluntarily remove from their product label indications for use related to growth promotion, and bring the remaining therapeutic uses of these products under a veterinarian’s oversight. All of the affected animal drug sponsors committed to making these changes by the December 2016 target date, says Irwin.
Historically, certain antimicrobials have been used in the feed or drinking water of cattle, poultry, hogs, and other food animals for production purposes, such as using less food to help animals gain weight. “Some of these antimicrobials are important drugs used to treat human infection, prompting concerns about the contribution of this practice to increasing the ability of bacteria and other microbes to resist a drug’s effects,” Irvin says. “Once a manufacturer voluntarily makes these changes, it will be illegal to use these medically important antibiotics for production purposes, and animal producers will need to obtain authorization from a licensed veterinarian to use them for prevention, control, or treatment of a specifically identified disease.”
On June 3, FDA published the Veterinary Feed Directive (VFD) final rule that outlines the process for authorizing use of VFD drugs (animal drugs intended for use in or on animal feed that require the supervision of a licensed veterinarian). This final rule sets the stage for bringing the use of these drugs under veterinary supervision so that they are used only when necessary for ensuring animal health.
FDA is also collaborating with the U.S. Department of Agriculture (USDA) and the CDC to develop a plan to supplement existing sales data on antibiotic drugs sold for use in food-producing animals and data on antibiotic resistance.
Finally, FDA has been actively engaging veterinary organizations, animal producer organizations, and others to express concern about some currently-approved preventive, therapeutic uses of medically important antibiotics that have no limit on how long they can be given to an animal. In the case of disease prevention, FDA believes it is important such use is appropriately targeted to animals at risk for a specific disease and to limit the duration.
Although the USDA doesn’t have regulatory authority pertaining to approvals of antibiotics used in animal agriculture, the department has in-depth knowledge about antibiotic resistance. “We see ourselves as part of the solution to address the challenges regarding antibiotic resistance via our agricultural research as well as our understanding of the agricultural environment,” says Catherine Woteki, PhD, chief scientist and under secretary for research, education and economics at the USDA.
“Despite extensive work on the issue, there is still much that we do not know about how bacteria develop resistance and its impact on human, animal, and environmental health,” says Woteki. “Because the ecology of antimicrobial resistance [AMR] is complex, it impacts our ability to understand and prevent the development and spread of AMR.”
To better understand AMR and apply effective mitigation strategies, the USDA developed an action plan to ensure judicious use of antibiotics in food-producing animals and prolong the effectiveness of antibiotics in treating people and animals. The plan includes surveillance; research (including research into alternatives to antibiotics, understanding the ecology of antibiotic resistance, and identifying effective management practices); and education, extension, and outreach.
The U.S. Department of Veterans Affairs has two programs that work cohesively to prevent infections with antibiotic resistant bacteria. Gary Roselle, MD, director of the Veterans Health Administration (VHA) National Infectious Diseases Service, says the administration's Multidrug-resistant Organism Prevention Initiative developed guidelines for the prevention of infections with MRSA, C. difficile, and CRE.
The program reduced acute care MRSA HAIs by 62% in critical care units and by 45% in non-critical care units, from October 2007 through June 2011. In spinal cord injury patients, MRSA HAIs declined by 81% over the same time period. C. difficile infections declined 27% for hospital-onset healthcare facility-associated C. difficile infections from October 2010 through June 2012.
Another VHA program deals with the appropriate use of antibiotics. Its Antimicrobial Stewardship Initiative and the subsequently chartered National Antimicrobial Stewardship Taskforce (ASTF), coordinate national efforts to optimize antimicrobial use to improve clinical outcomes and reduce unintended consequences of antimicrobial therapy including the development of resistant organisms, says Roselle.
The ASTF has developed national educational programs, sample policy documents, electronic resources, and other tools for local antimicrobial stewardship program (ASP) implementation. VHA strengthened its resolve toward antimicrobial stewardship in January 2014 with the publication of VHA Directive 1031 requiring all VHA facilities to develop and implement ASPs. Since the inception of VHA national stewardship activities, overall in-patient antimicrobial use has significantly declined.
Medical companies are also making their mark in the fight against AMR. Alere Inc., a diagnostic device and service provider, first contributed to antimicrobial stewardship in 1989, when it developed a five-minute test to detect Strep A pharyngitis. In 2012, Alere began its Test Target Treat initiative to help providers understand the value of rapid diagnostics in combating the AMR crisis.
Test Target Treat was developed in partnership with the Alliance for the Prudent Use of Antibiotics (APUA), an organization dedicated specifically to the preservation of antibiotics and AMR reduction.
“We believe education is the key to empowering healthcare providers to make the most effective decisions regarding antibiotic deployment, which will help us preserve the antibiotics that we have today for future generations,” says Ryan Schmidt, MBA, Alere's vice president of marketing.
As a result of the White House forum, Alere will publicly release a series of continuing medical education, which includes accredited webinars, patient case studies, and monographs regarding the use of rapid point-of-care diagnostics in effective antibiotic stewardship. The company will also publish proceedings from a 2014 biomarker antibiotic stewardship summit via Alere’s partnership with APUA and participate in the development of the first global online qualification in antimicrobial stewardship.
Mark Miller, MD, chief medical officer of bioMérieux, says the multinational biotechnology company actively fosters external collaborations to prevent and control HAIs and AMR. In mid-June, bioMérieux organized the fifth edition of the World HAI/Resistance Forum, which facilitates collaboration and discussion among global decision makers. “Forum members examine current trends and data and engage in lively scientific exchanges about future challenges and the best actions to take, with the goal of anticipating how these issues will evolve in the next five years,” Miller says.
During the 2013 forum, bioMérieux committed to addressing the challenges of AMR with a worldwide “point prevalence study” on the use of antibiotics in healthcare facilities. The results are slated to be published this fall.
Hospitals are also on the front lines of battling HAIs. Keith Hamilton, MD, director of the antibiotic stewardship program at the Hospital of the University of Pennsylvania, says the university's ASP program creates policies and guidelines to promote judicious antibiotic prescribing practices. It also protects select antibiotics by requiring prior authorization.
“The ASP has found innovative ways to improve antibiotic prescribing, including developing a system of electronic alerts that notify medical teams when antibiotic prescribing could be improved or when patients are on suboptimal antibiotics,” Hamilton says. In addition, the ASP team collaborated with software analytics company Teqqa, to develop surveillance and smartphone software that tracks antibiotic resistance and delivers it to the palm of the prescriber’s hand. The team is also developing software to more accurately predict what antibiotic is best for a given patient based on personal characteristics.
Hamilton and colleagues have also partnered with Philadelphia Department of Public Health to form the Philadelphia Community Antimicrobial Stewardship Collaborative—comprised of 40 area healthcare facilities—to help inform and guide the region’s hospitals about best practices in antibiotic use.
The Cleveland Clinic is another leader promoting the judicious use of antibiotics. It has a closed formulary, and certain antimicrobials can only be prescribed via infectious disease consultation. Other initiatives include:
- Electronic order sets for surgical prophylaxis with defined stops for antimicrobials; and
- Rapid diagnostics in the microbiology laboratory to help facilitate de-escalation of antibiotic therapy as quickly as possible. The key effector arm for this and for managing “drug-bug” mismatches are antimicrobial specialists in the pharmacy.
Appropriate antibiotic use during care transitions is also a priority, says Thomas Fraser, MD, an infectious disease expert at the Cleveland Clinic. “All patients who are being considered for IV antibiotics after discharge are seen by an infectious disease physician."
Karen Appold is a medical writer in Lehigh Valley, Pennsylvania.