John F. Trowbridge, MD

Although the idea for antimicrobial stewardship (AMS) has been around for a long time, it has not reached a tipping point where most hospitals have an effective antimicrobial stewardship program (ASP). The purpose of this manuscript is to report on the present status of AMS. Do ASPs have convincing data on patient survival, patient safety, and cost reduction? Is regulatory pressure converging to drive rapid development of ASPs? Are recent mandates in North America and the United Kingdom propelling ASPs toward a tipping point? If not, what needs to be done?

In his bestselling book, The Tipping Point, Malcolm Gladwell defines the “tipping point” as “the moment of critical mass, the threshold, or the boiling point” when an idea finally catches fire and becomes the norm or the generally accepted thing to do.

 Antimicrobial stewardship programs (ASPs) have been around for some time, but that tipping point has yet to be achieved at which most hospitals and long-term care facilities have effective programs.

Recent mandates and proposed standards for ASPs in North America and the United Kingdom (UK) are stimulating movement toward a tipping point. But what will it take to reach that point? The purpose of this article is to report on the present status of antimicrobial stewardship (AMS). Do ASPs have convincing data on patient survival, patient safety, and cost reduction? Is regulatory pressure rapidly converging to drive expedited development?

AMS is often defined as a systematic approach to the use of antimicrobial agents to achieve optimal outcomes, as close to 100% of the time as possible. This means using the correct agent, at the correct dose, with the correct route of administration and for the appropriate duration, to cure or prevent infection, while minimizing toxicity and emerging resistance. However, we think the current state of practice is more like:

Narrow-spectrum antibiotic used when cultures are available and patient is stable: ~10% to 20%

The likelihood that all sequential steps are optimal: ~4.5%

The increasing frequency of news reports about antimicrobial resistance contribute to a sense of impending doom, an “antimicrobial Armageddon.”

 Is this Chicken Little speaking or is the threat very real? Bacteria relentlessly reinvent themselves to resist the killing power of antibiotics. The World Bank lists antimicrobial resistance as one of the top 10 threats to global economic progress.

 The CDC says “superbugs” are emerging much more quickly than expected, and the problem is now “very serious.”

 Data from an AMS consultation (Figure 1) in a 350-bed community hospital (conducted by the healthcare consulting firm Visante, Inc) show how resistance to antibiotics emerges unless effective ASPs are in place.

In hospitals, infections caused by multidrug-resistant organisms (MDROs) are associated with higher mortality, excess stay, and additional cost.

 Driving antimicrobial resistance is the inappropriate use of antimicrobial agents, estimated by the CDC to be as high as 50% of overall use. Another concern is that the pipeline for developing new antimicrobial agents (Figure 2) is sparse.

In the early 1970s, clinical pharmacy services were established in North American hospitals, and some clinical pharmacists set about assessing the use of antibiotics due to the increases they were seeing in microorganism resistance. Evidence-based treatment guidelines and regulation of antibiotic use started to surface through hospital pharmacy and therapeutics committees.

In 1996, John McGowan, Jr, MD, and Dale N. Gerding, MD, then infectious disease specialists at Emory University School of Medicine in Atlanta, coined the term “AMS.”

 A decade later, bacterial, antiviral, and antifungal resistance had risen to such a degree that the CDC was alarmed, and in 2007, the Infectious Disease Society of America (IDSA) and the Society for Healthcare Epidemiology of America published guidelines for developing an ASP.

Recent events are driving ASP development in North America and the UK:

: according to the California Department of Public Health, “California is the first (and remains the only state) to enact AMS legislation. Since 2008, California law has required that general acute care hospitals develop a process for monitoring the judicious use of antibiotics, and the results are monitored by quality improvement committee(s). In September of 2014, California Senate Bill 1311 was signed into law, further requiring hospitals to adopt and implement an AMS policy, under guidelines established by federal government and professional organizations, and to establish a physician-supervised multidisciplinary ASP with at least one physician or pharmacist who has undergone specific training related to stewardship.”

: the Presidential Executive Order “Combatting Antibiotic-Resistant Bacteria, issued in September 2014 requires federal agencies to review existing regulations and propose new regulations or other actions to require hospitals to implement robust ASPs that adhere to best practices—similar to California’s Senate bill. Agencies will also be required to define, promulgate, and implement ASPs in other settings, such as long-term care facilities and outpatient settings.

: in 2014, the CDC recommended that all US hospitals have an ASP.

: since 2013, Accreditation Canada mandates that all acute care facilities have an ASP.

: as part of the 5-year forward initiative to improve care by the National Health Service (NHS), AMS has become a central initiative of NHS England.

Unfortunately, most mandates are unfunded. However, with further actions outlined below, ASP development is moving forward toward its tipping point.

The Joint Commission (TJC) recently developed proposed medication standards, to be implemented beginning this summer, that cover general hospitals, critical access hospitals, ambulatory healthcare, nursing care centers, and office-based surgery.

having a ASP that is based on evidence-based national guidelines

the highest-level executives (C-suites) establishing ASPs as an organizational priority

educating staff members and independent practitioners—any and all involved in ordering, dispensing, administration, and monitoring&mdash;about antimicrobial resistance and AMS. The education would begin upon hiring and continue annually

educating patients and their families, as needed, on the proper use of antimicrobial medications, including antibiotics

having a multidisciplinary AMS team that includes pharmacists, infectious-disease physicians, and infection preventionists

core ASP elements: leadership commitment, drug expertise, action, tracking, reporting, and education

using organization-approved multidisciplinary protocols

collecting and analyzing data on its ASP, including prescribing and resistance patterns

taking action on improvement opportunities identified in its ASP.

CMS is now using the following criteria when doing surveys

The hospital has named a leader (eg, physician, pharmacist) responsible for program outcomes of antibiotic stewardship activities at the hospital

The hospital’s antibiotic stewardship policy and procedures require practitioners to document in the medical record, or during order entry, an indication for all antibiotics besides other required elements such as dose and duration

The hospital has a formal procedure for all practitioners to review the appropriateness of any antibiotics prescribed after 48 hours from the initial orders (eg, antibiotic time-out)

The hospital monitors antibiotic use (consumption) at the unit and/or hospital level.

Mark R. Chassin, MD, FACP, MPP, MPH, president and CEO of the Joint Commission, has said, “The Joint Commission knows that ASPs are a proven method of reducing the inappropriate use of antibiotics and improving patient safety.”

Although it seems intuitive that ASPs work, the quality of evidence for antimicrobial stewardship is poor. There are only 8 systematic reviews (none just looking at randomized controlled trials [RCTs]) and only 3 RCTs. A definitive, evidence-based study on ASPs has yet to be published. However, the anecdotal information and data are robust. For example, the CDC has authored a helpful document, “Impact of Antibiotic Stewardship Program Interventions and Cost,” that lists findings from 15 published manuscripts.

Other revealing data that support ASPs include what happens to total hospital antibiotic cost when an ASP is discontinued (Figure 3).

 Clearly, effective ASPs must be developed then consistently sustained over time.

A 2013 study revealed the impact of the temporary absence of a clinical pharmacist from an ASP.

 The rates of inappropriate use of imipenem-cilastatin, linezolid, and micafungin during the pharmacist’s absence increased by 27%, 39%, and 35%, respectively, with corresponding increases in the average duration of therapy of 0.7, 4.0, and 3.2 days. In addition, the number of cases of Clostridium difficile infection increased more than 3-fold (from 8 to 25) during the pharmacist’s absence.

Until a few years ago, AMS in the United States was reaching maturity only in larger, mostly academic hospitals; it had fledging status in midsize hospitals and was almost nonexistent in smaller hospitals. Although most practitioners agree that AMS is needed, it has not been at the top of C-suite concern. However, with the recent mandate from California, and renewed interest at the CDC, Joint Commission, and CMS, interest in ASPs is heating up in the United States.

ASPs are also garnering great interest in Canada, particularly in Ontario.

 An AMS project for that province includes multiple phases. In the first, a comprehensive survey examined the current state of hospital-based AMS practices in Ontario. In the second phase, the project team convened an international consensus forum to uncover and prioritize interventions considered to be appropriate and effective. The 6 interventions identified (in no particular order) were:

Use the antimicrobial stewardship self-assessment tool

Do a prospective audit with intervention and feedback at the individual patient and prescriber level

Provide education/training to build antimicrobial stewardship capacity

Collect data and feedback at an institutional or program level

Tailor antimicrobial therapy, with strategies including de-escalation, streamlining, and intravenous to oral switches.

The third phase, currently under discussion, proposes testing these interventions in a representative sample of pilot hospitals.

Several organizations offer advice on how to start an ASP and maintain the core elements necessary for success.

 One such organization, Visante, Inc, which helps hospitals start ASPs and do benchmarking, and makes recommendations on AMS, finds that success rests on a few rate-limiting steps:

Leadership. A leaderless ASP is ineffective. According to the CDC, a medical staff leader should be responsible for program outcomes, and a pharmacy leader should co-lead the program.

 The medical staff leader should be an infectious-disease physician, possibly a hospitalist with strong interest in infectious disease; the pharmacist leader, ideally, is a clinical pharmacist with infectious-disease training.

Medical staff buy-in and organizational approval. AMS consultants sometimes see ASPs with stalled progress because the program is solely pharmacy-based. For greatest effect, there must be buy-in by the hospital’s medical staff (executive committee) and C-suite. The ASP leadership and the director of pharmacy should negotiate with hospital administration to obtain enough authority, compensation, and administrative support for the necessary infrastructure to be successful.

Getting everyone on the same age. Collaboration must also exist among the antimicrobial stewardship team (physicians, pharmacists, nurses, microbiologists/infection control specialists, epidemiologists), the infection control committee, and the pharmacy and therapeutics committee.

Benchmarking. Developing a baseline of data for the ASP program is critical. What is the status of antimicrobial resistance? Are you playing in the bottom of the sixth inning or the top of the ninth, so to speak? How extensive is your usage of antimicrobial agents? Your antimicrobial cost? Benchmarking against yourself is the best benchmarking.

Implementing best practices. Some programs have been doing this for a long time, and representatives have shared in the literature what has gone right and wrong. Review the experiences of programs similar to yours, in same type and size of hospital.

Audit and feedback to prescribers. Data generated on comparing prescribing and prescribers is critical to continuing success. Data systems must be structured correctly to capture this important information.

The important steps in getting an ASP started include:

Gaining organizational approval. Two challenges must be overcome: convincing the medical staff and convincing the C-suite to support and take action. The program will go nowhere without medical staff support, so convincing the medical staff leadership comes first.

Making the clinical case for an ASP. The main components of the clinical case are:

Dealing with the rising tide of antimicrobial resistance

The reality that resistance is developing faster than new antibiotic therapies. Correcting this situation is a major component of the recent presidential initiative to fund new drug development

Potential therapeutic failure, with an increased mortality risk of 6.5% for each patient who becomes infected with resistant organisms

Potential malpractice threats associated with not treating patients using evidence-based antibiotic strategies

Articles

Antimicrobial stewardship programs have been around for some time. However, a tipping point has yet to be achieved where most hospitals and long-term care facilities have effective programs.

Antimicrobial Stewardship at the Tipping Point

Antibiotics are the most commonly used pharmacologic treatment in every hospital. Without effective antibiotics, failure rates for prophylaxis of surgical infections and medical treatment for all infectious syndromes increase dramatically, resulting in increased patient deaths, length of hospital stay, and readmissions. However, overuse of broad-spectrum antibiotics in hospitals is causing an accelerating prevalence of resistant organisms because of the collateral killing of normal bacterial populations. Without changes to our antibiotic use process, we are setting ourselves up for catastrophic consequences.

Antimicrobial Resistance in the News: “We Are Nearing Antimicrobial Armageddon!”

In March of this year, the Centers for Disease Control and Prevention (CDC) issued a major report on antimicrobial resistance.

 It stated that “The increase in the number of rare, but potentially deadly superbugs resistant to nearly all last-resort antibiotics has prompted health offi cials to renew warnings for US hospitals, nursing homes, and other healthcare settings.” A rare but potentially deadly superbug has now been identifi ed as carbapenem-resistant enterobacteriaceae (CRE). These organisms elude carbapenem antibiotics and other antibiotic classes, and typically strike people already vulnerable to infectious agents because of their use of devices such as ventilators or catheters. The report goes on to discuss how to limit these organisms, and recommends that health providers act “aggressively to prevent the emergence and spread of these unusual CRE organisms.”

Almost immediately the CDC report was followed by a paper from the United Kingdom’s chief medical director declaring antibiotic resistance a “nightmare.”

 Following up on this release, Reuters News Service related that CRE is only a small part of the superbug story.

 The truth is many other superbugs, such as MRSA (killing around 19,000 every year in the United States), are emerging and becoming increasingly resistant to current antibiotics. The other side of the story is that the pipeline for new antibiotics to address these resistant organisms is not forthcoming. The 

shows the decline of new antibiotics under development in recent years.

This situation has been on the radar for the World Bank, which has included antimicrobial resistance as one of the top 10 threats to global economic progress for the past several years.

 These conclusions are supported by overwhelming evidence gathered by the CDC, the World Health Organization, and the Cochrane Collaboration.

The continuing threat of antimicrobial resistance is not just hype—it is real. In fact, it is late in the game and the superbugs are winning!

As noted above, resistance is promoted by use of broad-spectrum antibiotics which kill off all but the most resistant bacteria. When patients are initially admitted in critical condition, broad-spectrum antibiotics are needed to cover all potential bacterial species. As patients improve and more data become available, physicians are often reluctant to narrow the spectrum of antibiotics to targeted treatment of the organism identifi ed. Physicians often hesitate to “de-escalate,” even when culture reports indicate it is safe to do so. Most of this reluctance is related to fear of therapeutic failure, potential liability, and detailed education about antimicrobial resistance and precise selection of alternative agents. Close teamwork with pharmacists to select the best narrower-spectrum agents, as well as providing dosing based on weight, optimized infusion timing, and duration are becoming more and more important for success given the prevalence of obesity, and the high blood levels required for successful treatment of relatively resistant bacteria.

Another common contribution to antimicrobial resistance is the use of an antibiotic when the infection is most likely viral. In Sweden, where there are stricter guidelines for casual antibiotic use, and less pressure for their use by patients, resistance is less common.

Antimicrobial resistance patterns in hospitals vary and are susceptible to various local conditions, including the:

• prescriber expertise for antibiotic selection

• use of locally derived guidelines regarding antibiotic use by infection type

• involvement of clinical pharmacists to optimize dosing, recommend alternatives, and support de-escalation when patients are more stable, and culture data are available

The only way for a hospital to know how its antimicrobial program compares with similar facilities (for use, cost, and resistance) is by assessing its current use process, then benchmarking its data and practices to discover the extent of antimicrobial resistance and the reasons driving it.

Scenarios for Responding to Increased Antimicrobial Resistance

Hospitals have 2 basic choices when dealing with antimicrobial resistance. The first is to carry on business “as usual.” The second is to be proactive, seeking better ways to handle these problem bugs. The problem of carrying on as usual, hoping it will go away, is it provides no solution at all. Without a fundamental change in antibiotic use, resistance always increases, and becomes assessment performed by a knowledgeable independent consultant.

—Information generated by a programmatic antimicrobial assessment:

—This is a community hospital that averages 250 beds

• Medicare acuity index during the assessment = 1.45

—An independent consultant performed an assessment of this hospital’s antimicrobial program and provided it with an analysis of its status. During this process, any issues noted by the assessment team were reported to the hospital group to work in concert to develop a sequential approach to ongoing AMSP improvements (

When compared with similar institutions, this hospital’s antimicrobial resistance was much higher. There was an overuse of antibiotics, especially of broad spectrum and expensive antibiotics. Also, there was a tendency not to use narrower-spectrum, less costly antibiotics when culture reports and clinical pharmacists indicated effective alternatives were available. The consultant’s finding wasthat this hospital had the potential for significant clinical improvement as well as antimicrobial cost savings in the range of $250 to $400 K per year with implementation of an effective AMSP. This is currently being considered by the hospital’s medical staff executive committee.

Recommendations for this hospital included:

• Development of a set of performance standards for improving antibiotic use that are routinely measured, and an ongoing process to review results and take actions to improve them where appropriate

• Creation and implementation of guidelines for treatment of common infections such as urinary tract infections and pneumonia to improve antibiotic use and optimize duration of therapy within the hospital and, if needed, at discharge

• Flow charting the antibiotic ordering and dispensing process from the time an antibiotic order is written until the first dose is administered

° Then identify where bottlenecks occur and take action to reduce them, with the goal of decreasing your average overall time of 3 hours and 20 minutes to the recommended 1 hour

• Increase the clinical involvement and supervision of its microbiology program

• Add 1 full-time equivalent infectious disease pharmacy specialist or provide funds and training for a pharmacist to gain additional knowledge of antimicrobial therapy

° Savings from the improved AMSP will more than pay for additional staff and/or training

• Routinely review written pharmacist chart notes to the medical staff as part of the pharmacy department’s quality improvement program

• Develop standard protocols for chart notes or other preferred ways to contact physicians

° Track feedback to ensure that communication methods are timely

• Reactivate the institution’s antimicrobial stewardship committee with new and committed physician leadership

° Committee to also include microbiology, pharmacy, and infection prevention/control membership. This committee should meet regularly to be effective

• Provide routine training on the use of Theradoc

• Consider greater controls of pharmaceutical industry representatives throughout the hospital

Achieving Improved Antimicrobial Use and Less Antimicrobial Resistance

The strongest evidence for improving antimicrobial use and reducing antimicrobial resistance is in implementing a hospitalwide, medical staff—approved antimicrobial stewardship program (AMSP).

 A well-implemented AMSP can produce the following benefi cial results in clinical quality and financial performance:

• reduced antimicrobial use of 11 to 38%6-10

• increase in the appropriate antibiotic use by 20 to 24%

• reduced duration of antibiotic therapy by 18%

• more cures and less therapeutic failures

• reduced stay by 0.5 to 1 day for patients with infection

• reduced 30-day readmissions for infection by 0.5 to 0.8%

• reduced cost—comprehensive AMSPs have routinely demonstrated annual savings of $200,000 to $900,000 in both larger academic hospitals and smaller community hospitals

The evidence is robust that antimicrobial resistance has become an increasingly critical issue in healthcare institutions everywhere. For hospitals, solutions cannot be found by traditional management of hospital departments. Instead, a hospitalwide program that coordinates physicians and their ordering profi les, pharmacists, infection control practitioners, discharge planners, and others is needed for success.

The most effective place for most facilities to begin is to have an assessment carried out by an independent team that is uninvolved with the issues and departmental biases. From this review, a new process can be formulated, negotiated, and implemented. Most clinicians are unaware of their specific hospital issues and comparisons, and have not thought of acting outside of traditional approaches of treating patients 1 at a time without a strategic vision of how their current prescribing habits impact future effectiveness of antibiotics for all patients in their hospital and community.

In this case study, the authors illustrate the diagnosis of institutional antibiotic resistance issues and drivers, and provide tailored recommendations for simultaneously reducing resistance, antibiotic costs, and treatment failure.