Antimicrobial Resistance: Stewardship and Strategies for Conquering a Global Threat

By Kelly M. Pyrek

As one of the most significant challenges in modern medicine, the fight against antibiotic/antimicrobial resistance (AR) is becoming the responsibility of clinicians at every level and is part of daily infection prevention work. As Frieden (2013) reminds us, "Antimicrobial resistance is one of our most serious health threats. Infections from resistant bacteria are now too common, and some pathogens have even become resistant to multiple types or classes of antibiotics. The loss of effective antibiotics will undermine our ability to fight infectious diseases and manage the infectious complications common in vulnerable patients undergoing chemotherapy for cancer, dialysis for renal failure, and surgery, especially organ transplantation, for which the ability to treat secondary infections is crucial. When first-line and then second-line antibiotic treatment options are limited by resistance or are unavailable, healthcare providers are forced to use antibiotics that may be more toxic to the patient and frequently more expensive and less effective. Even when alternative treatments exist, research has shown that patients with resistant infections are often much more likely to die, and survivors have significantly longer hospital stays, delayed recuperation, and long-term disability. Efforts to prevent such threats build on the foundation of proven public health strategies: immunization, infection control, protecting the food supply, antibiotic stewardship, and reducing person-to-person spread through screening, treatment and education."

The use of antibiotics is the single most important factor leading to antibiotic resistance around the world, as antibiotics are among the most commonly prescribed drugs used in human medicine. However, up to half of all the antibiotics prescribed for people are not needed or are not optimally effective as prescribed, experts say. The classic interventions associated with effective infection prevention and control that are non-pharmaceutical in nature remain the cornerstone of AR prevention and work in tandem with antimicrobial stewardship.

There is no silver bullet," emphasizes Matthew Zahn, MD, a pediatric infectious disease physician with CHOC Children's Hospital in Orange County, California. "The simplest solutions -- infection prevention and control practices such as handwashing and surface cleaning, and the overall prevention of spread of MDROs -- remain the best interventions. These good practices are the best way to prevent transmission of multidrug-resistant organisms (MDROs) and they are the most important work that we do. There is no end to that fight against MDROs, and we must maintain personal and institutional diligence." 

Zahn continues, "The development of antimicrobial resistance is an inevitability over time and so the infection control work that prevents the spread of these MDROs is tremendously important. It is essentially a delay tactic, as we know that over time AR is likely to develop in multiple organisms. It is up to us on a national level to identify and to develop new drugs to keep ahead of the organisms. In the meantime, preventing spread of AR-resistant organisms within hospitals, between hospitals, and between hospitals and nursing homes, is a major concern for all of us. Public health laboratories have developed significant capacity for conducting testing of AR bacteria, so now we can identify new and variant strains more often and more quickly than we used to. What we are wrestling with from a public health perspective is how we best use these findings, which requires a tremendous amount of work from all sides to identify, track and prevent spread of those organisms." 

Zahn points to Carbapenem-resistant Enterobacteriaceae (CRE) as an example. "CRE is a significant concern, and many states have made CRE reportable. Whole genome sequencing testing for CRE is being conducted at local and state laboratories, and as we gain more insights about how it spreads, we must improve in our efforts to track this transmission between hospitals and nursing homes. I think long-term care is a particularly big concern for all of us because so many people who harbor antimicrobial-resistant bacteria live out the rest of their lives there, but nursing homes have fewer resources for infection control practices compared to hospitals." 

Zahn continues, "The next frontier we are approaching is effective antimicrobial stewardship in those facilities. If someone is colonized with MDROs in a hospital, there's a very good chance that person will be discharged to a nursing home and if those facilities aren't practicing good infection control and stewardship, the whole system breaks down. I think we are beginning to recognize that all healthcare facilities must perform that work well, and they must communicate with each other -- particularly if a patient is in isolation precautions at the hospital. If the acute-care facility maintains those precautions well but that patient is transferred to a nursing home that does not continue those precautions, that's a dangerous gap in the system."

The costs of AR are significant. As the CDC (2013) explains, "Antibiotic-resistant infections add considerable and avoidable costs to the already overburdened U.S. healthcare system. In most cases, antibiotic-resistant infections require prolonged and/or costlier treatments, extend hospital stays, necessitate additional doctor visits and healthcare use, and result in greater disability and death compared with infections that are easily treatable with antibiotics. The total economic cost of antibiotic resistance to the U.S. economy has been difficult to calculate. Estimates vary but have ranged as high as $20 billion in excess direct healthcare costs, with additional costs to society for lost productivity as high as $35 billion a year (2008 dollars).

As the CDC (2013) observes, "Bacteria will inevitably find ways of resisting the antibiotics we develop, which is why aggressive action is needed now to keep new resistance from developing and to prevent the resistance that already exists from spreading." Even as the world stares down the threat of AR, it is a hollow sense of bravado, as enormous gaps in knowledge persist. The Centers for Disease Control and Prevention (CDC) observes that these gaps can be classified into the following challenges and opportunities:

- There is limited federal, national and state capacity to detect and respond to urgent and emerging antibiotic resistance-related threats. As the CDC (2013) notes, "Even for critical pathogens of concern like carbapenem-resistant Enterobacteriaceae (CRE) and Neisseria gonorrhoeae, we do not have a complete picture of the domestic incidence, prevalence, mortality, and cost of resistance."
- There is no systematic international surveillance of antibiotic resistance threats. As the CDC (2013) notes, "Today, the international identification of antibiotic resistance threats occurs through domestic importation of novel antibiotic resistance threats or through identification of overseas outbreaks."
- Data on antibiotic use in human healthcare and in agriculture are not systematically collected. As the CDC (2013) notes, "Routine systems of reporting and benchmarking antibiotic use wherever it occurs need to be piloted and scaled nationwide."
- Programs to improve antibiotic prescribing are not widely used in the U.S. As the CDC (2013) observes, "These inpatient and outpatient programs hold great promise for reducing antibiotic resistance threats, improving patient outcomes, and saving healthcare dollars.

The CDC (2013) says there are four core actions that will help fight resistant organisms and the infections they cause:
1. Preventing infections and preventing the spread of resistance:  Avoiding infections in the first place reduces the amount of antibiotics that have to be used and reduces the likelihood that resistance will develop during therapy. There are many ways that drug-resistant infections can be prevented: immunization, safe food preparation, handwashing, and using antibiotics as directed and only when necessary. In addition, preventing infections also prevents the spread of resistant bacteria.
2. Tracking resistant bacteria: CDC gathers data on antibiotic-resistant infections, causes of infections and whether there are particular reasons (risk factors) that caused some people to get a resistant infection. With that information, experts can develop specific strategies to prevent those infections and prevent the resistant bacteria from spreading.
3. Improving the use of today’s antibiotics: Perhaps the single most important action needed to greatly slow down the development and spread of antibiotic-resistant infections is to change the way antibiotics are used. Up to half of antibiotic use in humans and much of antibiotic use in animals is unnecessary and inappropriate and makes everyone less safe. Stopping even some of the inappropriate and unnecessary use of antibiotics in people and animals would help greatly in slowing down the spread of resistant bacteria. This commitment to always use antibiotics appropriately and safely-only when they are needed to treat disease, and to choose the right antibiotics and to administer them in the right way in every case-is known as antibiotic stewardship.
4. Promoting the development of new antibiotics and developing new diagnostic tests for resistant bacteria: Because antibiotic resistance occurs as part of a natural process in which bacteria evolve, it can be slowed but not stopped. Therefore, we will always need new antibiotics to keep up with resistant bacteria as well as new diagnostic tests to track the development of resistance.

Let's examine these issues more closely.
From a clinical perspective, healthcare providers can fight back against AR in many ways, including:
- Knowing what types of drug-resistant infections are present in their facility and patients
- Requesting immediate alerts when the lab identifies drug-resistant infections in your patients.
- Alerting a receiving facility when you transfer a patient with a drug-resistant infection.
- Protecting patients from drug-resistant infections.
- Following relevant guidelines and precautions at every patient encounter.
- Prescribing antibiotics wisely.
- Removing temporary medical devices such as catheters and ventilators as soon as they are no longer needed.

From an administrative perspective, healthcare facility leaders can join the fight by:
- Requiring and strictly enforcing CDC guidance for infection detection, prevention, tracking, and reporting.
- Ensuring the facility's lab can accurately identify infections and alert clinical and infection prevention staff when these bacteria are present.
- Knowing infection and resistance trends in your facility and in the facilities around you.
- When transferring a patient, require staff to notify the other facility about all infections.
- Joining or starting regional infection prevention efforts.
- Promoting wise antibiotic use.

Stewardship is an important component of AR prevention. It has been more than a decade since SHEA issued its guidance on creating and sustaining hospital-based antimicrobial stewardship programs, when it urged, "Effective antimicrobial stewardship programs can be financially self-supporting and improve patient care. Comprehensive programs have consistently demonstrated a decrease in antimicrobial use, with annual savings of $200,000 to $900,000 in both larger academic hospitals and smaller community hospitals. Thus, healthcare facilities are encouraged to implement antimicrobial stewardship programs."

"There is much more awareness and interest from hospitals regarding antimicrobial stewardship," confirms Keith Kaye, MD, MPH, president of the Society for Healthcare Epidemiology of America (SHEA) and professor of internal medicine and infectious diseases at the University of Michigan. "As recently as two to three years ago I think there were many unknowns and misconceptions about what stewardship was that have been cleared up. My impression from talking to hospital leaders and clinicians around the country is that there is greater understanding of what a stewardship program does, and a greater appreciation for what these programs accomplish. They realize how the stewardship role is critical and complimentary to that of infection prevention regarding fighting antimicrobial resistance and I think this has led to a greater acceptance and progress regarding implementation and promotion of stewardship. I think a lot of pushback a few years ago often had to do with misinformation in terms of viewing stewardship as the 'antibiotic police' or as clinicians losing control of patient care. Now with the quality movement really taking hold, and as stewardship is gaining a foothold with the Joint Commission embracing stewardship programs, we are definitely moving toward more broad acceptance of stewardship by leadership and clinicians alike."

Kaye continues, "We are now starting to see a co-management of patients by pharmacists and physicians that may not have been as accepted in the past. Regarding patient safety, pharmacists can identify adverse effects of medication, duration, dosing, and can improve the care of patients while and making clinicians' jobs much easier. I think there is greater understanding and acceptance of what an infectious disease pharmacist brings to the table. I also think we are seeing greater adoption and integration of interventions like extended infusion of antibiotics for carbapenems and therapeutic drug monitoring, and these types of therapeutic modalities don't occur without a very invested joint effort by physicians and pharmacists, which comes most commonly through stewardship efforts. These treatment modalities are becoming the rule instead of the exception, and that's an exciting, significant shift in the last three to five years. I don’t think that happens without a systematic, intentional effort by stewardship personnel."

Earlier this year, professional societies updated a joint position paper underscoring the synergy of infection prevention programs and antibiotic stewardship programs.

“The issues surrounding the prevention and control of infections are intrinsically linked with the issues associated with the use of antimicrobial agents and the proliferation and spread of multidrug-resistant organisms,” says Mary Lou Manning, PhD, CRNP, CIC, FSHEA, FAPIC, lead author of the paper published concurrently in the American Journal of Infection Control and Infection Control and Hospital Epidemiology. “The vital work of IPC and AS programs cannot be performed independently. They require interdependent and coordinated action across multiple and overlapping disciplines and clinical settings to achieve the larger purpose of keeping patients safe from infection and ensuring that effective antibiotic therapy is available for future generations.”

The joint position paper, endorsed by the Association for Professionals in Infection Control and Epidemiology (APIC), the Society for Healthcare Epidemiology of America (SHEA), and the Society of Infectious Disease Pharmacists (SIDP), updates a 2012 paper that affirmed the key roles of infection preventionists (IPs) and healthcare epidemiologists (HEs) in promoting effective use of antimicrobials in collaboration with other healthcare professionals. The new paper highlights the synergy of IPC and AS programs, including the importance of a well-functioning IPC program as a central component to a successful AS strategy.

The authors acknowledge that successful AS programs require a significant investment on the part of the healthcare facility. As Manning, et al. (2018) explain, " AS programs have been shown to improve patient outcomes, reduce antimicrobial agent-related adverse events, and decrease AMR. To date, primary strategies include prescriber preauthorization and prospective audit and feedback, with supplemental strategies such as guidelines and clinical pathway development, intravenous-to-oral conversion protocols, limiting inappropriate culturing, and provider education. Changing practices and prescribing patterns and learned behaviors of physicians, nurses, pharmacists, and other healthcare providers will take time and investment, but is critical to affecting a long-term solution to the rise of AMR and CDI infections. It is equally important that all clinicians depend on evidence-based IPC interventions to reduce demand for antimicrobial agents by preventing infections from occurring in the first place and making every effort to prevent transmission when they do. IP and HE leaders are credible IPC subject-matter experts with additional social and behavioral skills to effectively engage the different professional disciplines to promote, implement, support, sustain, and evaluate IPC strategies across practice settings-many of the same skills needed by those leading AS programs."

The authors urge healthcare leaders to prioritize IPC and AS as part of wider patient safety initiatives and recommend that IPC and AS leaders collaborate in communications to the C-suite. “Given the synergy between AS and IPC programs, IPC and AS program leaders should seize every opportunity to benefit from each other’s expertise and organizational influence and partner when making the case for program support and necessary resource allocation to clinical and administrative leadership.

Key antimicrobial stewardship techniques, including limiting formularies and formal restrictions of certain classes of antimicrobials, the cycling of antibiotics; and decision support, including prospective audit and feedback and, as an important component of any program, education of the prescribing staff (Rice 2018).

As Rice (2018) observes, "Limiting antimicrobial formularies and restricting the use of certain antibiotics is a technique that has been used for decades. In many cases, the limitations have been dictated by cost, with the motivation to decrease the overall hospital spend on antibiotics. In general, because newer drugs tended to be more expensive than older drugs, and having a broader spectrum of activity, these practices in effect resulted in promoting more narrow-spectrum alternatives."  Antimicrobial cycling, Rice (2018) explains, "refers to practices in which there are predetermined changes in empirical usage of antibiotics, usually within a certain unit of a hospital, that occur according to a prespecified time schedule. The goal is to avoid prolonged use of a single class of antibiotics and thereby the selection of resistance to that class." He adds that "Efforts to provide physicians with the knowledge and tools to appropriately prescribe antimicrobial agents in the hospital have existed since the advent of the electronic medical record." 

Summarizing his findings, Rice (2018) notes, "Several meta-analyses and systematic reviews of antimicrobial stewardship programs have recently been published. Although their conclusions differed in detail, all found that stewardship programs were effective in reducing the nosocomial occurrence of infections caused by resistant bacteria." He adds, "The understanding of the effectiveness of stewardship interventions has been inhibited by the weaknesses of study designs to date (generally before/after or quasiexperimental) and the variety of interventions that have been used. Still the preponderance of the evidence suggests that such programs are safe and can have beneficial effects on costs, toxicities, and antimicrobial resistance rates. The salutary effects arise from two different stewardship results: reductions in overall antimicrobial usage and increased heterogeneity of antibiotics used. Of these two results, the more important is to reduce overall antimicrobial usage, thereby decreasing the selective pressure for resistance. Increasing heterogeneity without reducing overall consumption may work in specific settings, such as outbreaks of ESBL-producing K pneumoniae where cephalosporins are reduced in favor of piperacillin-tazobactam or a carbapenem, but this success often proves a pyrrhic victory because other resistance phenotypes eventually emerge." 

Septimus (2018) emphasizes that, "It is generally accepted that an appropriate antimicrobial should be started as soon as an infection is identified in critically ill patients. One of the greatest challenges imposed by infections due to suspected MDROs is how to prescribe broad-spectrum therapy to cover the most likely pathogens and balance efficacy and collateral damage. Antimicrobial stewardship (AS) has been proposed to enable better choices and to reduce unintended consequences, including AR. AS programs have been shown to improve patient outcomes, reduce antimicrobial adverse events, and decrease AR. In 2016, the IDSA and the Society for Healthcare Epidemiologists of America (SHEA) published updated guidelines on implementing an AS program. The guidelines recommend both prospective audit and feedback (AF) and preauthorization because these interventions been shown to improve antibiotic use and are recommended as core components of any stewardship program. AF interventions have also been shown to improve antibiotic use, reduce antibiotic resistance, and reduce CDI rates without a negative impact on patient outcomes."

Other approaches include an antibiotic time-out and a day-3 bundle. As Septimus (2018) notes, "Both approaches suggest physicians take time to review the dose, duration, and indication when cultures and new information are available 48 to 72 hours after initiation of empirical therapy."

In an antibiotic time-out, clinicians ask themselves:
- Do patients have an infection that will respond to antibiotics?
- If so, are patients on the right antibiotic, dose, and route?
- Can a more targeted antibiotic be used to treat the infection (de-escalation)?
- How long should patients receive the antibiotic? (Septimus, 2018)

Key process measures for the day-3 bundle include:
- Was there an antibiotic plan (name, dose, route, interval of administration, and planned duration)?
- Was there a review of the diagnosis?
- If positive microbiological results were available, was there any adaption of the antibiotic treatment, for example, de-escalation?
- If patients were initially started on intravenous (IV) antibiotic therapy, was the possibility of IV-oral switch documented? (Pulcini, et al., 2008)

Septimus (2018) adds, "Along with reviewing empirical antibiotics at 48 to 72 hours, IDSA and SHEA also recommend that AS implement guidelines and strategies to reduce antibiotic therapy to the shortest effective duration. Evidence from systematic reviews and randomized controlled trials have demonstrated that stewardship interventions aimed at shorter courses of antibiotic therapy for select clinical syndromes is associated with outcomes similar to those with longer courses in both adults and children with fewer adverse events. Studies support that reduction in exposure of antibiotics can decrease drug resistance, decrease cost, improve adherence, and decrease adverse events."

Providers' preferences may be helpful in reducing inappropriate antibiotic prescribing patterns, according to recent research. Physicians are open to receiving information on their antibiotic prescribing patterns, but have specific preference for receiving that information, according to results from a study published earlier this summer by the Society for Healthcare Epidemiology of America (SHEA). Anticipating physicians’ preferences for feedback on antimicrobial use (AU) could help optimize impact of antibiotic stewardship programs and improve the use of antibiotics.

“Antimicrobial use feedback is an important component of antibiotic stewardship initiatives that can improve the use of these drugs,” says Tara Lines, PharmD, an infectious disease pharmacy resident at Vanderbilt University Medical Center, and lead author of the study. “Understanding and anticipating the best way to communicate with providers can help drive change by ensuring providers are reached effectively.”

The study reports responses to a 20-question survey from 211 inpatient providers at Vanderbilt University Hospital in various specialties. The survey included demographic questions, preferred feedback methods, barriers and comparison metrics, and a hypothetical patient hospitalization scenario assigning provider responsibility for antibiotic use. The clinical scenario became more complex with the number of consulting teams involved in the care of the patient and included transitions of care. 

The findings demonstrate clear preferences from providers across specialties that can be used to ensure clinicians are more receptive to AU feedback:
- The vast majority (89 percent) of respondents preferred their own institutions determining provider use attribution as opposed to external personnel.
- Most wanted to be compared to other providers within their service (64 percent) with feedback provided on a quarterly basis (69 percent) via email (73 percent).
- Surprisingly, the study found that providers agreed upon attribution of antimicrobial use early on in a hospital stay scenario but disagreed once care became more complex, with some teams deferring and others accepting responsibility.
- Providers generally shared concern about quantitative feedback accounting for complexity of clinical care, severity of illness, and accuracy.
- Overall, 51 percent of providers anticipated changing practice based on AU feedback.

"Data can help drive change, however to implement meaningful change, we must overcome barriers and use this data to improve the use of antibiotics," says Lines. "As current national reporting utilizes unit-based and facility-wide data, local antimicrobial stewardship programs will play a crucial role in examining provider- or service level data to identify and act on stewardship opportunities and to increase the acceptability of these programs."

The authors note that since antimicrobial stewardship is a shared responsibility across the healthcare continuum through various roles including house staff, physician assistants, nurse practitioners, pharmacists, nurses, and many others, future studies looking at all team members are needed.

Industry has a significant role to play. A key strategy to fight back against AR has focused on the troublesome state of the pharmaceuticals pipeline. Earlier this year, Novartis announced its exit from the antibiotics development space, declaring that it made the decision to "prioritize our resources in other areas where we believe we are better positioned to develop innovative medicines that will have a positive impact for patients." Also making their exodus have been Allergan, AstraZeneca, Sanofi and Bristol-Myers Squibb. As So and Shah (2014) observe, "Twenty new classes of antibiotics entered the market from 1940 through 1962. Since then, only two new classes of antibiotics, oxazolidinones (linezolid) and cyclic lipopeptides (daptomycin) have come on the market. More troubling is the foreseeable horizon of research and development (R&D) for novel antibiotics. An EMA–ECDC–ReAct study of the antibiotic pipeline identified 90 antibacterial agents in clinical development. Of the 15 drug candidates that could be administered systemically, 12 showed in vitro activity against antibiotic-resistant Gram-positive bacteria, while only four had demonstrated in vitro activity against antibiotic-resistant Gram-negative bacteria, and not one of these acted via a novel mechanism of action."

The researchers explain further, "Many have observed that as compared with other therapeutic areas, the antibiotic market is less profitable. In 2009, antibiotics generated global sales of $42 billion, representing 46 percent of sales of anti-infective agents (including antiviral drugs and vaccines) and 5 percent of the global pharmaceutical market. Over the past five years, antibiotics showed an average annual growth of 4 percent as compared with an average annual growth of 16.7 percent and of 16.4 percent for antiviral drugs and vaccines, respectively. Pharmaceutical firms size up the opportunity costs of R&D investment by considering the risk-adjusted net present value (rNPV), that is, the return in future dollars after adjustment for the investment and any lost income. By comparison to other therapeutic categories, the rNPV of antibiotics is not high. The relative rNPV expressed as the number of millions of dollars for an antibiotic would be 100, compared with 160 for vaccines, 300 for an anticancer drug, 720 for a neurological drug, and 1,150 for a musculoskeletal drug. This difference stems, in part, from the nature of antibiotic treatment. Treating a bacterial infection requires days of therapy compared with potentially lifelong treatment for a chronic condition like hypertension or high cholesterol. Worse yet, there is an inherent tension between efforts to conserve the effectiveness of novel antibiotics and to generate revenues through increased marketing and sales." 

They add, "At the same time, antibiotics have also been described as the third most profitable class of drugs for pharmaceutical companies after central nervous system and cardiovascular drugs. However, a single antibiotic drug faces significant competition from other antibacterial agents, thereby commanding a smaller market share and realizing less profit than drugs from other therapeutic classes. For example, the best-selling antibiotic made $2.01 billion in 2003, while a lipid-lowering agent sold by the same company made $9.23 billion. However, few antibiotics coming on the market in recent years have been classified as breakthrough treatments, and many are analogues of existing drugs. This has generated significant therapeutic competition that only exacerbates limited returns on novel antibiotics entering the market."

Experts are calling for new business models to bring novel antibiotics to market. As So and Shah (2014) point out, "In recent years, policy-makers have applied a range of financial incentives to coax greater innovation from pharmaceutical firms. Pull-incentives that pay for the outputs of R&D have received greater attention than push-incentives that pay for the inputs of R&D. Pull incentives ensure return on investment through prizes or through higher drug prices protected by patents or extended data exclusivity (19). These incentives might be tied to requirements for effective stewardship and conservation of the novel antibiotic or delinked from returns on investment. By delinkage, returns on investment might be divorced from volume-based sales of the product. These incentives could be targeted to truly novel classes of antibiotics, with demonstrable activity against multidrug-resistant pathogens. Failing to target such incentives appropriately, more analogues of existing antibiotics might come forward, thereby creating greater therapeutic competition and further lowering the NPV for any new antibiotic."

The AMR Industry Alliance, comprised of more than 100 biotech, diagnostics, generics and research-based biopharmaceutical companies and trade associations, recently issued a report showing that in 2016, 22 Alliance companies invested at least $2 billion in R&D dedicated to AMR-related products. The funds cover costs for early-stage R&D, exploring new product classes, 10 antibiotics in late-stage clinical development, 13 clinical bacterial vaccine candidates, 18 AMR-relevant diagnostic products, and other preventive therapies. More than two out of three Alliance companies surveyed with marketed AMR products, have strategies, policies or plans in place to improve access to their AMR-relevant products.

While vast amounts of antimicrobials, especially antibiotics, go to waste on patients and animals who do not need them, almost 6 million people die each year from infections, because they lack access to these medicines. The Alliance says supports protecting the efficacy of antibiotics and making them available, where necessary, to every human being. More than two out of three Alliance companies surveyed with marketed AMR products have strategies, policies or plans in place, which include principles or efforts to improve access to their AMR-relevant products. A similar number of companies are engaged in dialogue with external stakeholders on improving access to their AMR relevant products. Many of the Alliance generics and R&D-based biopharmaceutical companies with AMR-relevant products believe more work is needed to determine how to balance expanding access with appropriate use, reduce falsified products, and work with other stakeholders to address access issues in low and middle-income countries.

The AMR Alliance report found that more than 80 percent of all responding companies are engaged in activities to support appropriate use, while nearly half of the responding companies have a formal appropriate use strategy in place. Nearly 90 percent of responding companies – and 70 percent of those with AMR-relevant marketed products – are planning to, currently collecting or support the collection of surveillance data. More than half of the responding companies are planning to, or are currently engaged in, stewardship education activities, directly or collaboratively. This number increases to 70 percent for those companies with a marketed AMR-relevant product. However, it is broadly acknowledged that there is a considerable way to go, and the potential of vaccines and diagnostics is not yet fully explored. The Alliance is appealing to policy-makers to draw from the evidence provided in the report and invites stakeholders to work more systematically with the life sciences industry, to find sustainable solutions to tackling antimicrobial resistance.

Legislative efforts are underway but as of the time of writing, a key piece of legislation, the Strategies to Address Antimicrobial Resistance (STAAR) Act, introduced in the U.S. Senate on March 1, 2018 by Sen. Sherrod Brown (D-OH), is stuck in Congress. The STAAR Act would strengthen the federal response to antimicrobial resistance by:
1. Promoting Prevention
- Intensifies and expands academic public health partnerships through the CDC’s current Prevention Epi-Centers to support evaluation of interventions to prevent or limit resistance.
- Establishes regional prevention collaboratives that partner CDC with state health departments to interrupt and prevent the transmission of significant antibiotic-resistant pathogens being transmitted across healthcare settings in a geographic region.
2. Tracking Resistant Bacteria
- Improves data collection for human antimicrobial drug consumption and resistance.
- Directs CDC to report every two years on resistance trends, threats and antibiotic use.
- Builds upon CDC’s existing intramural and extramural programs by authorizing the Antimicrobial Resistance Surveillance and Laboratory Network to intensify, strengthen and expand the national capacity to monitor the emergence and changes in the patterns of antimicrobial resistant pathogens, support education of the public and providers, and assist local response to outbreaks.
3. Improving Use of Antibiotics
- Authorizes grants to healthcare facilities to study the development and implementation of antimicrobial stewardship programs and directs the piloting and testing of antibiotic appropriate use quality measures.
4. Enhancing Leadership, Coordination and Accountability
- Reauthorizes the Antimicrobial Resistance Task Force and establishes benchmarks to monitor progress of implementing Task Force recommendations.
-  Establishes an advisory board of outside experts to provide input from clinicians and others regarding emerging resistance around the country.
- Identifies a director within the Department of Health and Human Services to oversee the Task Force and coordinate efforts in combatting antimicrobial resistance.
5. Supporting Research
- Directs the National Institutes of Health (NIH) to work with other agencies and experts to create a strategic research plan for antimicrobial resistance to provide a detailed path forward for future funding of epidemiological, interventional, clinical, behavioral, translational, and basic research efforts.
- Codifies in statute the recently created National Institute for Allergy and Infectious Disease (NIAID) Clinical Trials Network on Antibacterial Resistance.

AMR Industry Alliance. Progress report:
Centers for Disease Control and Prevention (CDC). Antibiotic Resistance Threats in the United States, 2013.  April 23, 2013.
Frieden T. Foreword in: Antibiotic Resistance Threats in the United States, 2013. CDC. April 23, 2013.
Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Guidelines for Developing an Institutional Program to Enhance Antimicrobial Stewardship. Clinical Infectious Diseases. Vol. 44, No. 2. Pages 159-177. Jan. 15, 2007.
Lines TH, Nesbitt WJ and Nelson GE. Driving antimicrobial use improvement: attitudes of providers of adult hospital care on optimal attribution and feedback. Infect Control Hosp Epidemiol. Online June 7, 2018.
Policy Statement on Antimicrobial Stewardship by the Society for Healthcare Epidemiology of America (SHEA), the Infectious Diseases Society of America (IDSA), and the Pediatric Infectious Diseases Society (PIDS). Online Jan. 2,2015.
Pulcini C, Defres S, Aggarwal I, et al. Design of a ‘day 3 bundle’ to improve the reassessment of inpatient empirical antibiotic prescriptions. J Antimicrob Chemother 2008;61(6):1385.
Rice LB. Antimicrobial Stewardship and Antimicrobial Resistance. Medical Clinics of North America. Vol. 102, No. 5, Pages 805-818. September 2018.
Septimus EJ. Antimicrobial Resistance: An Antimicrobial/Diagnostic Stewardship and Infection Prevention Approach. Medical Clinics of North America. Vol. 102, No. 5. Pages 819-829. September 2018. 
So AD and Shah TA. New business models for antibiotic innovation. Ups J Med Sci. 2014 May; 119(2): 176-180. May 19, 2014.