Rising threat of resistance highlights need for antimicrobial stewardship

According to the CDC, 30% to 50% of antibiotic use in hospitals is either unnecessary or inappropriate. The overuse of antibiotics has contributed significantly to the growing problem of antibiotic resistance and an increasing number of Clostridium difficile infections.

With the antibiotic armamentarium dwindling, and few candidates in the pipeline, antibiotic resistance has become one of the most serious and emergent threats to public health. The CDC estimated that 2 million people every year become ill with a resistant infection, and at least 23,000 of them die.

One of the responses to this growing threat is the implementation of antimicrobial stewardship programs in hospitals, which have been shown to decrease antibiotic resistance, decrease the number of CDIs and decrease costs. Perhaps more importantly, they have shown to increase favorable patient outcomes.

“In the purest sense, antibiotic stewardship programs are focused on patient safety,” Keith Hamilton, MD, director of the antimicrobial stewardship program at the Hospital of the University of Pennsylvania, told Infectious Diseases in Children. “We want to curb antibiotic use, but at the same time, we want to make sure that patients who need antibiotics get the right ones at the right time. This is, arguably, the most important focus of stewardship programs.”

Infectious Diseases in Children spoke with several infection control experts and health care epidemiologists to discuss the importance of antimicrobial stewardship programs, as well as their history, implementation and effectiveness.

The wake-up call

Although stewardship programs have been around for some time, they have become much more prominent in recent years due to the increasing presence of resistant organisms.

Initially, the concerning organism was MRSA.

“Many experts would say that we realized antibiotic resistance was a problem when MRSA was detected in the community and no longer isolated in hospitals,” Jason Newland, MD, pediatric infectious disease specialist and medical director of patient safety and system reliability at Children’s Mercy Hospital in Kansas City, Mo., told Infectious Diseases in Children. “But recently, within the past 5 or 10 years, we’ve started to see gram-negative organisms that are resistant to every antibiotic out there. This is the true wake-up call.”

The gram-negative organisms of greatest concern are carbapenem-resistant Enterobacteriaceae (CRE), which have been dubbed a “nightmare bacteria” by CDC Director Thomas Frieden, MD, MPH. CRE are not only highly resistant to antibiotics, including carbapenems, which are typically antibiotics of a last resort, but they are also easily spread.

“We’ve been worried about drug resistance for many years, and the problem has worsened to where we have pathogens that are more and more difficult to treat,” Arjun Srinivasan, MD, associate director for health care–associated infection prevention programs in the CDC’s Division of Healthcare Quality Promotion, told Infectious Diseases in Children. “With CRE, for the first time, we have encountered a pathogen that was pretty virulent and, in some cases, impossible to treat.”

Path to overuse

The issue of antibiotic resistance is not a surprise. In a 1945 article published in The New York Times, Alexander Fleming, the scientist behind the discovery of penicillin, warned about the development of resistance if penicillin overuse was not curbed. Yet, in 2009, 3 million kilograms of antibiotics were administered to patients in the United States alone, according to a perspective written in The New England Journal of Medicine in 2013.

According to Kavita Trivedi, MD, principal at Trivedi Consults LLC, and adjunct clinical assistant professor of medicine at Stanford University, one of the issues is that many physicians do not realize their antibiotic overuse contributes to the problem.

“They may see resistance, but they don’t buy into the fact that their antibiotic use is part of the resistance problem,” Trivedi told Infectious Diseases in Children. “The thing that many physicians, and certainly many patients, don’t realize is that one patient receiving antibiotics can affect a whole society’s resistance problem. Once that patient develops resistance, that resistance can transfer from person to person.”

Antibiotics are one of the pillars of modern medicine, Trivedi said, and people have been using them more and more since they became widely available in the early 1940s because they have saved many lives.

Newland said as physicians saw patients being cured of normally lethal infections such as pneumonia or bloodstream infections after receiving penicillin or a sulfa antibiotic, antibiotics became the treatment of choice — and not just for infections.

“We’ve gotten into a mindset where we’ve got to do ‘something,’ and that ‘something’ has become antibiotics,” Newland said. “Now, 60 years later, parents, patients and families believe that antibiotics will make them feel better. As a result, physicians prescribe them without thinking of what the negative consequences are. It’s driven by a need to do something, anything to help the patient.”

Documented benefit

In a 2013 report on antibiotic resistance threats, the CDC outlines four core actions to prevent antibiotic resistance. One of the four actions is antimicrobial stewardship.

The available data on antimicrobial stewardship programs are compelling for the efficacy of the programs, according to Hamilton. Every study that has evaluated stewardship programs has shown that they significantly cut health care costs, improve patient outcomes and decrease antibiotic resistance, he said.

According to a study published in Infection Control and Hospital Epidemiology, researchers from the University of Maryland Medical Center found the implementation of an antimicrobial stewardship program at their institution resulted in a $3 million cost reduction within the first 3 years. But when the program was discontinued after a 7-year run, the costs increased $2 million within 2 years.

Despite the well-documented benefits of stewardship programs, they have not been implemented as widely as they should be. Some studies have estimated that as many as 60% of hospitals have an established stewardship program, but other studies have estimated the prevalence of stewardship programs is as low as 20%.

“We know that stewardship programs pay for themselves and then some, but a lot of hospitals have trouble providing that inertia to get them started,” Hamilton said. “So although some health care facilities simply don’t have stewardship programs on the radar, the main barrier to implementing stewardship programs is the cost of starting a program.”

Core elements

In a study published in MMWR, CDC researchers found that antibiotic-prescribing habits in hospitals could be improved in 37.2% of the most common scenarios. They estimated that a 30% reduction in the use of broad-spectrum antibiotics would result in a 26% reduction in CDIs. As a conclusion to these findings, the CDC recommended all acute care hospitals implement antibiotic stewardship programs.

Subsequently, the CDC released a guideline outlining the core elements of an antimicrobial stewardship program. The elements include: leadership commitment, accountability, drug expertise, action, tracking, reporting and education.

“We emphasize that stewardship programs need strong leadership — a champion who can oversee and speak for the program,” Srinivasan said. “Often, that champion is a physician because it is sometimes more effective to have physicians encouraging other physicians to prescribe more effectively. But there also needs to be strong pharmacy leadership as well. Strong leadership is critical, and we emphasize that committee leadership may not be effective. There needs to be one person who takes ownership for the program.”

Srinivasan also said specific interventions must be implemented, including tracking antibiotic use and educating providers.

However, stewardship programs are not “one-size-fits-all.” Hospitals differ significantly across the country in size, location, resources and patient population, among other aspects.

“The core elements outline the types of things a successful stewardship program does, but we want facilities to have flexibility in how they establish a program in their particular hospital,” Srinivasan said. “No two stewardship programs have to look exactly the same. There are many ways to approach it, but they all need to have in common the ability to accomplish these core elements.”

The California experience

In 2006, California passed a law that requires acute care hospitals to develop processes to ensure the appropriate use of antibiotics. The processes were required to be in place by January 2008. This legislation is the first legal force in the United States behind establishing antimicrobial stewardship programs.

According to Trivedi, the law was nonspecific, which was helpful because it offered the flexibility for hospitals to implement processes that would work for them.

“The response was very positive because administrators realized that having a program in place was the right thing to do for their patients,” Trivedi said. “At the same time, the law was nonspecific, and hospitals weren’t being required to do anything that may not work in their facility. They could implement a stewardship program that would work in their setting.”

Currently, there are two bills in California regarding antimicrobial stewardship that are awaiting review by the governor, Trivedi said. The first builds upon the original law and is more specific. It requires every acute care hospital in California to have a defined antimicrobial stewardship program that promotes the appropriate use of antibiotics. It also requires each program to have a physician and a pharmacy leader, one of whom is educated in antimicrobial stewardship via a continuing education course put together by the CDC or a professional society.

The second bill awaiting review deals with the appropriate use of antibiotics in agriculture in California.

“We talk a lot about antibiotic stewardship in health care, but 80% of the antibiotics used in the country are actually used in livestock,” Trivedi said. “The public health and environmental communities have been trying to lobby the FDA to be more stringent on the use of medically important antibiotics in agriculture. It has been a difficult battle.”

The bill in California would stop farmers from using antibiotics for growth promotion and would require a veterinarian to prescribe antibiotics. However, it does not address the use of antibiotics for prophylaxis or reporting any antibiotic use data.

Impact of legislation

The success of California’s legislation could be the game changer needed to persuade other states, if not the federal government, to take steps necessary to implement similar laws.

“One of the most effective ways to put something on people’s radars, much in the way that was done with infection control and reporting health care–associated infections, is with legislation,” Hamilton said. “We need legislation that makes antimicrobial stewardship programs a default in health care settings.”

Trivedi said although California’s experience with legislation has been positive, there are no other states that have similar legislative actions in the pipeline.

“We would definitely encourage other states to ensure the use of antibiotic stewardship programs through legislation because it can actually help hospitals fund programs,” she said. “I think most hospitals really do want to set up programs, but it’s not a priority.”

Srinivasan said the California experience merits very serious consideration and discussion. There have been calls from several organizations, including the Society for Healthcare Epidemiology of America, the Infectious Diseases Society of America and the Pediatric Infectious Diseases Society, for increased regulations surrounding antimicrobial stewardship.

In fact, they have also called for antimicrobial stewardship to be added to the Medicare conditions of participation for all hospitals.

“There is certainly a growing enthusiasm and a growing support for increased regulations to get this done,” Srinivasan said. “The unfortunate reality is that these programs have been in existence for a long time and the data on their effectiveness has been widely available and promoted, but the programs are still not universal.”

Response and efficacy

Newland said one of the concerns with implementing stewardship programs was that physicians would not react well, believing that the programs would take away their autonomy. But, almost the opposite was true. His institution implemented a stewardship program in 2008, then in 2010 they surveyed the physicians involved.

“The results were remarkable because most people said that they believed the program improved patient care and was educational,” Newland said. “For the most part, they can see how stewardship programs improve their care.”

In general, the response to antimicrobial stewardship programs has been mostly positive across institutions, Srinivasan said.

“When the programs are done right and run well, physicians tend to view them as a valuable component of patient care,” he said. “That’s an encouraging finding for hospitals that are considering stewardship programs.”

The most common way for stewardship programs to be assessed is antibiotic costs, which is one of the easier outcomes to monitor, he added. The data are clear that stewardship programs reduce health care costs.

Another way to measure efficacy is to evaluate the actual use of antibiotics — either overall, or use of specific classes. The CDC has several tools available to measure antibiotic use, including the antibiotic use and resistance module of the National Healthcare Safety Network.

One of the most important ways to measure effectiveness is by assessing patient-level outcomes, Srinivasan said, such as cure rates and how often patients receive appropriate antibiotic therapy.

“At the end of the day, that’s the goal of stewardship programs: to improve the appropriate use of antibiotics,” he said.

Improving stewardship

One area that will likely have a significant effect on the benefit of stewardship programs is the development of rapid, point-of-care diagnostics that will allow physicians to quickly determine exactly which infections they are trying to treat.

The newest technology that has been studied the most is matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, or MALDI-TOF-MS. Several studies have looked at the implementation of MALDI-TOF-MS in conjunction with stewardship programs, which have demonstrated decreased costs and improved patient outcomes, Hamilton said.

Srinivasan said the research on rapid diagnostic testing is an exciting area, and these novel tests will have an influence on antibiotic use. Studies have shown that these tests improved antibiotic use in the context of a stewardship program.

“New diagnostic tests will never be a substitute for a stewardship program, but they have the potential to be a very powerful tool for stewardship programs to become even more effective,” he said.

Hamilton said grassroots efforts are needed to identify more innovative strategies to perform stewardship, and that electronic medical records systems will play an important role.

“If we can learn how to leverage those systems, that is something that will revolutionize the field,” he said.

Barriers to programs

Most would agree that the main barrier to implementing a stewardship program is funding, Newland said. This is where legislation would be beneficial. It would place pressure on hospitals to make antimicrobial stewardship programs a requirement, similar to what happened with infection control requirements, he said.

Trivedi said the California legislation helped hospitals obtain the funding needed from administrations to establish the programs.

But another barrier to successful programs is advising the general public of antimicrobial stewardship.

“Physicians can be convinced, but there is a huge emphasis on patient satisfaction and making sure patients are happy with the care they receive,” Trivedi said. “We need to launch a larger public health campaign, much like we did about cigarettes, around the appropriate use of antibiotics so that patients understand, for example, that antibiotics won’t help a viral infection.”

An additional challenge is addressing antibiotic use in agriculture. Although there have been multiple legislative efforts in the federal government to improve antibiotic use on farms, none have passed. The public health community have been engaged in a somewhat unsuccessful battle to lobby the FDA to be more stringent on antibiotic use in agriculture. It has issued a guidance for livestock producers and farmers to use antibiotics more appropriately, Trivedi said, but it is voluntary.

There is a third barrier, Newland said: We’re simply running out of drugs.

“There are no new gram-negative antibiotics in the pipeline to treat CRE,” he said. “There is nothing after carbapenems and colistin, which are associated with some significant toxicities.”

The most difficult part of that is having to tell patients there is no effective treatment for their infections. It has not happened often, Hamilton said, but it will likely become more common if the issue of resistance is not addressed.

“That is the true wake-up call,” Hamilton said. — by Emily Shafer

References:

CDC. Antibiotic resistance threats in the United States, 2013. Available at: www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf#page=112. Accessed Sept. 19, 2014.
CDC. Core elements of hospital antibiotic stewardship programs. Available at: www.cdc.gov/getsmart/healthcare/implementation/core-elements.html. Accessed Sept. 19, 2014.
Fridkin S. MMWR. 2014;63:194-200.
Spellberg B. N Engl J Med. 2013;368:299-302.
Standiford H. Infect Control Hosp Epidemiol. 2012;33:338-345.

For more information:

Keith Hamilton, MD, can be reached at: keith.hamilton@uphs.upenn.edu.
Jason Newland, MD, can be reached at: jnewland1@cmh.edu.
Arjun Srinivasan, MD, can be reached through the CDC media office at: media@cdc.gov.
Kavita Trivedi, MD, can be reached at: kavita@trivediconsults.com.

Disclosure: Newland receives grant funding from Pfizer for antimicrobial stewardship research, is on the advisory board for FebriDx and has served on a Cubist advisory panel. Hamilton, Srinivasan and Trivedi report no relevant financial disclosures.

Should antimicrobial stewardship in hospitals be organized as part of the quality department or the pharmacy department?

They should be organized as part of the quality department.

Antimicrobial stewardship programs (ASPs) have been shown to have benefits in managing the use of antimicrobial agents, slowing the development of resistance and reducing costs. Traditionally these programs have been organized under the pharmacy department, as much of the daily activities have been provided by clinical pharmacists. In addition, the programs have largely been justified through changes in antimicrobial utilization and an associated reduction in drug expenses. However, although many of the core activities of an ASP are being provided by pharmacists, the most effective structure is to have this program organized as part of the institution’s overall quality plan. Significant changes in drug utilization patterns are often only apparent for several years after implementation of an ASP, after which time the program focuses on maintaining the gains, as well as on more incremental improvements. This has led some institutions to question their ongoing value, only to see drug utilization and resistance patterns slide back after dismantling a program. The measures of effectiveness of an ASP should extend well beyond simple drug expense reductions and restrictions. An excellent program should focus on quality and outcome improvements in care. In fact, one might argue that having an ASP organized under the pharmacy department creates an internal conflict of interest in providing the best care to patients vs. care that is associated with the lowest drug expense. With the increased emphasis in the emerging health care system on quality, safety and outcomes data linked to reimbursement and public reporting, it is critical for the ASP to be an integral component of an institution’s overall quality program.

With the increase in clinical outcomes measures and performance metrics linked to outcomes, ASPs must evolve to demonstrate value through these broader measures. In addition to playing a key role in modifying resistance patterns and extending the usefulness of existing antimicrobial agents, ASPs can play a critical role in “bundles” with infection control and other strategies to reduce the rate of high-visibility conditions like catheter-associated urinary tract infections, central line-associated bloodstream infections and Clostridium difficile infections, as well as reducing overall (not just antimicrobial) costs of care and readmission rates. Furthermore, studies have shown a positive impact of ASPs, coupled with rapid diagnostic testing, on reducing the time to effective therapy and on reducing mortality rates in patients with bloodstream infections. An effective ASP requires collaboration and teamwork by various health care providers including physicians, pharmacists, microbiologists, infection control practitioners, and health informaticists. Given the breadth of impact and collaboration required to successfully impact key quality and outcomes measures, it makes sense that the program receive oversight and monitoring at the institutional quality department level.   

James G. Stevenson, PharmD, FASHP, is president of Hospital and Health System Services, Visante, Inc., and professor, University of Michigan College of Pharmacy.   He previously served as chief pharmacy officer in the University of Michigan Hospitals and Health Centers. Disclosure:  Stevenson reports no relevant disclosures.

Pharmacy departments should play the leading role.

Like so many aspects of health care today, antimicrobial stewardship is truly a team effort and pharmacy is an essential member of that team. Many key elements of antimicrobial stewardship hinge on involvement from pharmacy, and being sure that departmental leadership is a part of the oversight of the stewardship program is essential to building a cohesive strategy and ultimately stewardship program success. There are many examples of this beginning with the primary strategies for antimicrobial stewardship: prior authorization and prospective audit with feedback.   

Our goal as pharmacists is to optimize medication therapy, and the reality is that pharmacists are also situated within the medication management system as the most effective controls for restrictive stewardship approaches.  A recent meta-analysis suggested a benefit to restrictive stewardship interventions, and to put those approaches in place, you need pharmacy support.  The reality is that these interactions involve clinical input and a discussion with prescribers about appropriate antibiotic use that the pharmacists have been trained to provide.  However, trying to roll out restricted programs without a full understanding of pharmacy workflows and available resources can lead to a suboptimal program and frustrations on the part of providers.

 It’s naive to think any stewardship program is going to be fully equipped and staffed as part of the quality department to roll out the many features of a robust antimicrobial stewardship program. We know from a recent study that 51.9% of all patients receive a dose of an antibiotic on any given day and because of this, stewardship programs should have a broad reach. In my 860-bed hospital, that means more than 430 patients a day receive an antibiotic, and there is no way a stewardship team of a few individuals based solely within the quality department is going to see a fraction of those patients. Even our infectious disease consult team sees only 30 to 50 patients a day in my hospital. But because pharmacy is required as part of a medication management standard by the Joint Commission, to prospectively review all medication orders that are received, a pharmacist is reviewing every patient on antibiotics.  That’s a really powerful group of people to do that everyday work of stewardship.  By not involving pharmacy in the oversight and leadership of antimicrobial stewardship, you would miss out on a robust resource of trained individuals that can be the frontline of the program.

Another consideration is that software programs are often sold to hospital administrations based on drug savings. The projected savings are then immediately taken out of the drug budget, and the budget decreases. If this software is purchased without working closely with the pharmacy, you might not be very knowledgeable about the true potential cost savings and whether or not it’s a realistic return on investment.

However, it would be just as unfortunate if the stewardship program is not required to report outcomes to the quality department. The most important part is within the quality realm and the way to elevate that best is to report out to the quality department on a regular basis. That doesn’t mean stewardship doesn’t have a valuable home in pharmacy. You need the full resources of pharmacy, and it will be easier to leverage those if you have pharmacy leadership.

Elizabeth S. Dodds Ashley, PharmD, is associate director of clinical pharmacy services at University of Rochester Medical Center in Rochester, N.Y. Disclosure: Dodds Ashley reports no relevant disclosures.