Introduction

With the discovery of penicillin, antibiotics are a critical part of global health, including cancer chemotherapy and advanced surgical procedures. Antimicrobial agents are not like other drugs. They are unique in that both the individual patient and the broader society bear the consequences of their use with each prescription. The antimicrobial effect that saves lives also exerts selective pressure on replicating bacteria, leading to the emergence of drug resistance. 

Between 1935 and 2003, fourteen new classes of antibiotics were introduced. Since 1998, only ten new antibiotics were approved, of which only linezolid and daptomycin have new targets of action.[1] According to the World Health Organization(WHO), antibiotic pipeline data report 2021, and eleven new antibiotics have been approved since 2017. Only two of them represent a new class and have a new target of action. They include vaborbactam+meropenem and lefamulin. The likely reason behind this is that the development of antibiotics is risky, expensive, and less profitable than the drugs to treat chronic diseases. With the slow development of antimicrobials, accelerated emergence, and spread of resistant organisms, antimicrobial stewardship is of utmost importance to optimize the use of existing antimicrobials.[1]

Stewardship describes the careful and responsible management of something entrusted to one’s care. In 1996, John McGowan and Dale Gerding first applied the term antimicrobial stewardship, where they suggested a causal association between antimicrobial agent use and resistance. They also focused on the urgency of large-scale controlled trials of antimicrobial-use regulation employing sophisticated epidemiologic methods, molecular typing, and precise resistance mechanism analysis.[2] Antimicrobial Stewardship(AMS) refers to the optimal selection, dosing, and duration of antimicrobial treatment resulting in the best clinical outcome with minimal side effects to the patients and minimal impact on subsequent resistance.[3]

In simple terms, it refers to a coherent set of actions to promote the responsible use of antimicrobials. AMS is one of the three pillars of an integrated approach to strengthening the health care system. The other two include infection prevention and control(IPC) and patient and medicine safety. The critical components like Antimicrobial Resistance(AMR) surveillance and sufficient supply of quality medicines linked with three pillars help promote equitable and quality health care. The principles of AMS also apply to the use of antimicrobials in the animal and agriculture sectors, emphasizing the wise use of the agents.

All healthcare practitioners must embrace roles as frontline stewards to address this emerging health and economic concern of antimicrobial resistance. AMS can be fulfilled by prescribing appropriately and educating the patients and colleagues on the proper use of this increasingly scarce medical resource to protect our current and future patients. With AMS interventions, we aim for sustainable behavior change in an antibiotic prescription.[4] The main intention of this review is to highlight that it is imperative to make the optimal use of antimicrobials available and ensure to have remaining options to treat infectious agents.

Function

According to the Center for Disease Control(CDC), 20 to 50% of all antibiotics prescriptions in the acute care hospital setting in the USA are either unnecessary or inappropriate.[5] CDC also stated that most antibiotics prescriptions include nursing homes and long-term care facilities (LTCF). Like the hospital setting, 40% to 75% of antibiotics prescribed in nursing homes and LTCF may be unnecessary or inappropriate [6]. The current scientific literature emphasizes on reduction of inappropriate use of antimicrobials in all healthcare settings. Along with the Centers for Medicare and Medicaid Services (CMS), CDC, and Society for Healthcare Epidemiology of America(SHEA), the Joint Commission developed the AMS standard for hospitals, critical access hospitals, and nursing care centers. The standard for ambulatory settings and office-based surgery practices is still under development.  The CMS also finalized a new regulation in 2019 requiring all US hospitals to develop Antimicrobial Stewardship programs by March 2020.

The AMS programs have the following goals:[1]

1. To work with healthcare practitioners to prescribe 5 ”D”s of antimicrobial therapy, which is the right Drug, correct Dose, right Drug-route, suitable Duration, timely De-escalation to pathogen-directed therapy. 
2. To prevent antimicrobial overuse, misuse, and abuse in inpatient, outpatient, and community settings, including the agriculture industry. 
3. To reduce antibiotic-related adverse effects, for example, C.difficile
4. To minimize resistance
5. To reduce healthcare-associated cost

With the above goals in target, the AMS programs include the following core elements:

1. Leadership commitment
2. Accountability
3. Drug expertise
4. Action
5. Tracking
6. Reporting
7. Education

Leadership Commitment

Leadership support is crucial for the success of antimicrobial stewardship programs. They can be in different forms, including:

• Formal statements to improve and monitor the antimicrobial use
• Supporting training and education and ensuring that staff from the relevant departments are given sufficient time to contribute to stewardship activities.
• Dedicate financial and information technology resources dedicated to the program.

Accountability and Drug Expertise

To identify a single leader as a stewardship program leader who will be responsible for the program outcome. Literature has shown that physician leaders have highly successful programs. Physicians with formal training in infectious disease and AMS benefit stewardship program. Similarly, appointing a single pharmacist leader as co-leader has shown improved outcomes.[7]

Action

Action includes implementing policies supporting optimal antibiotic use, utilizing specific interventions to improve antibiotic use, and prioritizing intervention based on the needs of the care setting.

Examples for policies supporting optimal antimicrobial prescription include specifying dose, duration, and indication on documentation. The implementation of policies helps to ensure modification or prompt discontinuation of antimicrobials.[8] Similarly, developing and implementing facility-specific treatments based on local susceptibilities using antibiogram and national guidelines help optimize antibiotic selection and duration.

Interventions directed towards stewardship can be categorized into

1. Broad intervention includes antibiotics time out, prior authorization, and prospective audit and feedback. Antibiotic "Time Out" by physician 48 hours after initiation of antibiotics helps reassess the need and choice of antibiotics when more diagnostic information is available and early de-escalation.[9] The prior authorization intervention requires a review of certain antibiotics by an infectious disease specialist.
2. Pharmacy-driven interventions, especially for dose adjustments/optimization based on drug, organ dysfunction, therapeutic drug monitoring. The pharmacy interventions also alert the prescriber in cases of the unnecessary overlapping spectrum of antimicrobial coverage, help in detecting and preventing drug interactions related to antibiotics.[10]
3. Infection and syndrome-specific interventions focus on improving prescriptions for specific syndromes. For example, many people who get antibiotics for urinary tract infections(UTI) might have asymptomatic bacteriuria and not infection. Interventions for UTI focus on avoiding unnecessary management of asymptomatic cases and ensuring that patients receive the right therapy based on local susceptibilities and for a suitable duration.[11] Similarly, there are interventions for community-acquired pneumonia, skin and soft tissue infections, Methicillin-Resistant Staphylococcus Aureus(MRSA), Clostridoides difficile infection(CDI), and treatment of culture-proven invasive infections.

Tracking and Reporting of Antimicrobial use and Outcomes

Keeping track of the evaluation of both policies and outcomes is critical to identify areas of improvement and assess the impacts of improvement efforts. For example, determining if the prescriber has applied the diagnostic criteria accurately; prescribed the antimicrobial agent for a particular indication with documentation of duration and relevant tests before treatment.

CDC has developed an Antibiotic Use (AU) option as a part of the National Healthcare Safety Network(NHSN). AU automatically collects data and monthly reports for the duration of therapy data and is later analyzed in aggregate by specific agents and patient care locations. The AU module is available to facilities with the capability to submit electronic medication administration records.[12]

Likewise, tracking outcomes that measure the impact of interventions help optimize antimicrobial use. 

Education 

Regular updates to prescribers on antibiotic prescribing, antibiotic resistance, and infectious disease management motivate optimization in antimicrobial prescription. However, didactic presentations, electronic messages to staff groups are few options to provide education. Education has been most effective when paired with corresponding interventions and outcome measurements.

Issues of Concern

The spectrum of infectious diseases is rapidly evolving. Emerging infectious agents present with a constellation of challenges. The highly virulent pathogens with increased resistance result in increased morbidity, mortality, and healthcare costs. It has been estimated that ten million people will die every year due to AMR by 2050.[13]

CDC has published antibiotic-resistant threat reports in 2013 and 2019. According to the 2019 report, in the US, more than 2.8 million antibiotic-resistant infections occur each year, and more than 35000 people die. In addition to this, it also mentioned that 223,900 cases of Clostridoides difficile occurred in 2017, of which 12800 people died.  The report did not include viruses or parasites.

The report categorized the threats into four tiers based on level of concern to human health[14];

1. Urgent Threats
   • Carbapenem-Resistant Acinetobacter baumannii
   • Candida auris
   • Clostridiodes difficile
   • Carbapenem-Resistant Enterobacteriaceae
   • Drug-Resistant Neisseria gonorrhoeae
2. Serious Threats
   • Drug-Resistant Campylobacter
   • Drug-Resistant Candida
   • Extended Spectrum Beta-Lactamases producing(ESBL) Enterobacteriaceae
   • Vancomycin-Resistant Enterococci (VRE)
   • Multidrug-Resistant Pseudomonas aeruginosa
   • Drug-Resistant nontyphoidal Salmonella
   • Drug-Resistant Salmonella typhi
   • Drug-Resistant Shigella
   • MRSA
   • Drug-Resistant Streptococcus pneumoniae
   • Drug-Resistant Tuberculosis
3. Concerning Threats
   • Erythromycin-Resistant Group A Streptococcus
   • Clindamycin-Resistant Group B Streptococcus
4. Watch List
   • Azole-Resistant Aspergillus fumigatus
   • Drug-Resistant Mycoplasma genitalium
   • Drug-Resistant Bordetella pertussis

World Health Organisation created a priority list of pathogens in 2017 and 2020 based on their substantial threat to morbidity and mortality. The priority list is categorized into three tiers:[15] [16]

1. Tuberculosis: A Global Priority for research and development especially Multidrug-Resistant Tuberculosis
2. Critical Priority:
   • Carbapenem-Resistant Acinetobacter baumannii
   • Carbapenem-Resistant Pseudomonas Aeruginosa
   • Carbapenem-Resistant, Third generation Cephalosporins-Resistant Enterobacteriaceae
3. High Priority
   • Vancomycin-Resistant Enterococcus faecium
   • Vancomycin-Resistant, Methicillin-Resistant Staphylococcus aureus
   • Clarithromycin-Resistant H.Pylori
   • Fluoroquinolones-Resistant Campylobacter species
   • Fluoroquinolones-Resistant Salmonella species
   • Third generation Cephalosporins-Resistant, Fluoroquinolones-Resistant Neisseria gonorrhoeae
4. Medium Priority
   • Penicillin-non-susceptible Streptococcus pneumoniae
   • Ampicillin-Resistant Hemophilus influenzae
   • Fluoroquinolones-Resistant Shigella species

Clinical Significance

Antibiotics have transformed the healthcare system, making once lethal infection readily treatable. It has also helped to make other medical advances like cancer chemotherapy and organ transplants possible. Prompt initiation of antimicrobials has reduced morbidity and mortality, for example, in cases of sepsis. However, 30% of all antibiotics prescribed in hospitals are unnecessary or suboptimal.

Health care is in dire need of responsible and optimized use of antimicrobial agents for the safety of our current and future patients. It is important to enlighten the point that antibiotics differ from other drugs. With emerging resistance, the antibiotics that were being used are no longer as effective as they are. Compared to other specialties, their drugs are continuously improved in addition to the old ones. Like all medications, antibiotics have serious adverse effects. Around 20% of hospitalized patients on antibiotics experience side effects. C.difficile has widely illustrated the adverse impact on patients' health even to those not directly exposed to antibiotics. Around 140,000 visits to the emergency department occur annually for antibiotics.[17][18] 

In hospitalized patients, severe reactions, including renal and bone marrow toxicity, can be seen. A retrospective study from 2006-2010 by Baggs et al. revealed 0.6% increased sepsis risk within 90 days of discharge following sepsis admission. The study included 473 US hospitals and revealed broad-spectrum antibiotics were associated with a 50% increased risk of readmission within 90 days.[17] Another study by Roberts et al. also estimated that the cost of treatment for antimicrobial-resistant infection is around 18-29,000 USD per patient, with an increase in hospital stay by 6.4 to 12.7 days and attributable mortality of 6.5%.[1][19]

The goal of antimicrobial stewardship is better patient care, reduced antibiotic use, and cost-effective health care are favorable side effects. Antimicrobial stewardship programs have shown promising results in numerous health care settings. Reported benefits include reducing the incidence of C.difficile infection, reducing AMR, improved dosing in renally-impaired patients, improved infection cure rates, decreased mortality rates, and hospital cost savings. The meta-analysis by Davey et al. has shown that interventions for a reduction in excessive antibiotic prescription in inpatient patients can reduce AMR or nosocomial infections. Likewise, interventions to increase effective prescribing following the national and local guidelines can improve the clinical outcome.

The CDC's 2019 Antibiotic resistance Threat report has shown an 18% overall decline in deaths from AMR compared to the 2013 report and a decline in deaths by AMR by 28% in-hospital patients. Similarly, the report has shown a 41% decline in VRE, 33% in Carbapenem-resistant Acinetobacter, 29% in multidrug-resistant Pseudomonas aeruginosa, 25% in Candida, and 21% in MRSA. Although the results for high-priority pathogens are promising, the report also highlighted a 315% increase in erythromycin-resistant invasive group A Streptococcus, 124% in drug-resistant gonorrhea, and 50% in ESBL Enterobacteriaceae.[14]

The CDC's annual outpatient antibiotics prescription report for 2018 has shown that 249.8 million antibiotics prescriptions have been dispersed throughout the US. This antibiotic dispense is equivalent to 763 prescriptions per 1000 people. When comparing with the highest prescription according to provider specialty, their data reveals the highest prescription by dermatologist-525 antibiotic prescription per 1000 person followed by physician assistants and nurse practitioners with 423 prescriptions per 1000 person and Emergency Medicine 392 per 1000 person.

With the overuse or abuse of antimicrobials, up-trending antimicrobial resistance, and limited antimicrobial resources, it is high time we take action.

Other Issues

Antibiotic resistance is a global crisis. Not only a human population but also food and food animals are equally contributing to antibiotic resistance. Animals also carry bacteria in their gut which might also include antibiotic-resistant bacteria. People can get infections from handling or eating meat or food contaminated with resistant bacteria, from contact with animal waste, from touching animals without proper handwashing. Antibiotics are actively used in livestock farming for treatment purposes and used in subtherapeutic levels for growth promotion and increase productivity. 

As per WHO, antimicrobial use in livestock can be classified into:[20]

1. Therapeutic use- treating animals when clinically diagnosed with illness/infection. According to the US department of agriculture, 1/4th of all dairy cows in 2014 were diagnosed with clinical mastitis, and 87% were treated with mostly cephalosporins.
2. Disease prevention-using antibiotics in healthy animals considered to be at risk or before the onset of clinical disease. 
3. Growth promotion-when the antibiotics are used at subtherapeutic levels to increase weight or efficiency of feed utilization. Proposed theories for growth promotion include alteration in the gut microbiome, decreasing competition for nutrients, and improving absorption, particularly in livestock in crowded conditions.

The study by Boeckel et al. noted that the total consumption of antibiotics in livestock in 2010 was 63,151 tons. They also projected that consumption of antimicrobials will increase by 67% by 2030. It is estimated that 65% of medically important antibiotics in the US are used for food animals, compared to 35% in humans. The antibiotics also used in humans are referred to as medically important antibiotics. This might lead to antibiotic pollution resulting in antibiotic residues in animal-derived products. These products like meat, milk, eggs, when consumed by humans, can cause the emergence of resistant bacterial strains, therapeutic failure in some cases.[21] Widespread use of antimicrobials drives the emergence of antibiotic-resistant organisms in the food industry that can cause diseases in humans like E. Coli, Campylobacter, enterococci, Salmonella. Antibiotic-resistant organism in food is a global health concern. 600 million cases and 420,000 deaths occur per year from food-borne diseases.[22][21]

The Food and Drug administration report in 2019 revealed that more than 6.1 kilograms of medically important antibiotics are sold and distributed to US farmers.  The most antibiotic use was in cattle (41%), swine (42%), turkeys(10%), and chickens (3%). The most commonly used antibiotics for livestock were tetracyclines(67%), penicillin (12%), macrolides(8%). The data also revealed that sales increased by 4% compared to the year 2018.

Considering the emergent circumstance, CDC founded One health in 2009  to achieve optimum health outcomes via a multisectoral, transdisciplinary approach that recognizes the interconnection between people, animals, and the environment. The plan recommends the complete restriction of medically important antibiotics in livestock for disease prevention and growth promotion. [20][21]

There are opportunities for antimicrobial stewardship on farms. Some of them are listed below:[20]

• Farmers can eliminate the routine use of antimicrobials for growth promotion and disease prevention. Meanwhile can utilize nonantibiotic strategies.
• Grocers/Restaurants can commit to sourcing food/meat raised without antibiotics, support suppliers with clear antibiotic labeling standards.
• Medical and veterinary professions can educate the community about antibiotic resistance, collect data about prescriptions, establish standards for antimicrobial stewardship.
• Consumers can encourage and support local restaurants committed to stewardship.
• Federal and government should collect annual surveillance data about antibiotic sales, distribution, use in the livestock industry; set guidelines at a local level about right dosing, duration, drug class, and indication for the therapy.

Enhancing Healthcare Team Outcomes

The Agency for Healthcare Research and Quality is an excellent resource for antimicrobial stewardship, including best practices in all healthcare settings, methods for developing and improving antimicrobial stewardship, and developing a culture for safety during prescribing. One tool for use by prescribers of antibiotics is their 'Four Moments of Antibiotic Decision Making.'[23]

Moment 1 is considering the question if the patient has an infection and does it require antibiotics. Prescribers tend to order antibiotics to the hospitalized patient in response to abnormal clinical signs or lab results (for example- isolated fever or leukocytosis). This moment asks prescribers to pause, rethink and analyze all relevant information to determine the likelihood of any infectious process. At present, COVID 19 pandemic sets as a perfect example of antibiotics prescribed without any bacterial infection.

Moment 2 is to think about what cultures should be obtained and the best empiric treatment. This moment focuses on the need for culture data when appropriate before administering the antibiotics. When no specific data is available, there is a tendency for prolonged broad-spectrum antibiotic therapy. The second part of Moment 2 ensures timely administration of empirical therapy based on severity and likely source of infection. For example, patients are at low risk of MRSA for urinary tract infections. Therefore they would not benefit from IV vancomycin. Local antibiotics guidelines should be developed for common inpatient infections- this aids in enacting Moment 2.

Moment 3 is the question of, after a day or so of antibiotics being used, should the regimen be stopped, narrowed, or changed from IV to oral treatment.  This process should be ongoing.  For instance, most patients with community-acquired pneumonia become stable with normal vital signs by day three and are at an excellent time to switch to oral medications. Antibiotics time-outs should be used to address Moment 3. Nurses and pharmacists are excellent resources to prompt clinicians regarding further plans about antibiotics. At the same time, clinicians should also document their decision regarding the choice of antimicrobial therapy, indication, duration, and dosing. IT department can also help by regularly updating the electronic health records system with prompts to review orders, set up antimicrobial time-outs, etc. This way, clinicians are prompted with indication, duration, dosing, route of therapy.

Moment 4 considers how long the antibiotic should be continued for the treatment of the patient's infection. There has been an increasing number of studies that support a shorter duration of therapy than previously prescribed. Local and national antibiotics guidelines help to uniform the duration of antimicrobial therapy prescription.

Antimicrobial stewardship is a coordinated effort between interprofessional teams, including clinicians/prescribers, nursing staff, pharmacists, microbiologists, infection prevention teams, and patient safety teams. Targeted goals and multidisciplinary approach interventions result in excellent clinical, economic outcomes.

Nursing, Allied Health, and Interprofessional Team Interventions

The success of antimicrobial stewardship programs is deeply connected with the core elements mentioned above as guided by the CDC. The antimicrobial stewardship programs are greatly enhanced by interdepartmental communication and coordination. The significant support from below mentioned groups can play a vital role;

1. Clinicians: All clinicians at any point during patient care have prescribed antibiotics to the patients. Therefore it is crucial that all clinicians fully engage and support antibiotics optimization. Hospitalists and primary care physicians are particularly essential as they comprise a majority of the prescribers. Prescribers can act as good stewards by following the 5 "D"s of antimicrobial stewardship; right Drug, correct Dose, right Drug-route, suitable Duration, timely De-escalation to pathogen-directed therapy. Example actions include making accurate diagnoses, following local antimicrobial guidelines, and timely reviewing the need for therapy.[4]
2. Pharmacy and therapeutics committee: Pharmacists are an integral part of the team. They help in developing and implementing policies that will optimize antibiotic use. For instance, integrating stewardship into order sets[10]. They can also help educate patients regarding medications and be a very useful resource to physicians when prescribing antibiotics.
3. Nurses can especially play an essential role in optimizing diagnostic tests or diagnostic stewardship and patient education. Examples include triaging patients for isolation, a timely collection of culture samples before antimicrobial use, educating patients on how to take antimicrobials at discharge from the hospital.[4]
4. Microbiology lab staff can assist as a part of diagnostic stewardship by guiding proper use of the test. They also help in creating local anti-microbiogram, which help optimize antimicrobial prescriptions.
5. The infection prevention team and epidemiologist assist in tracking, analyzing, and reporting antimicrobial resistance and adverse effect trends. 
6. Quality improvement and patient safety teams can advocate for resources dedicated to stewardship interventions.
7. Information technology staff are crucial to incorporating protocols into the stewardship work map. Examples include developing prompts to review antimicrobials and their indication, incorporating order sets in electronic medical records; 
8. At an individual level, a patient can act as a good antimicrobial steward by using antimicrobials responsibly. Patient participation can be done by taking antimicrobials directed by the prescriber and not storing or using leftover antimicrobials. Likewise, the producer/farmer can also help by not using antimicrobials as growth promoters in the community.

Nursing, Allied Health, and Interprofessional Team Monitoring

In the United States, around fifteen percent of inpatient patients report penicillin allergy, of which approximately one percent have a severe penicillin allergy.[24] An important step is to not merely accept what is in the electronic medical record (EMR). It is important to reassess the documentation with the patient about the actual event regarding the antibiotic allergic event.  Too often, it is labeled in the EMR as an allergy when it was a side effect of the drug or that the actual allergic effect was not clarified. Some data show that 50% of allergies documented are non-immunologic and mostly adverse effects.

Having to substitute another class of drugs rather than beta-lactams can cause a tendency to use broad classes of antimicrobials to be used to treat the patient's infection. The consequences of using inappropriate allergy labels include increase broad-spectrum antibiotics use, limited therapeutic options, increased toxicity, and increased hospital costs. Charneski et al.'s study on 11,872 inpatients revealed that 11.2% of inpatients had allergy labeled with antimicrobial and had increased hospital length of stay, greater antimicrobial use, higher intensive care admission rate, higher readmission rate, and higher mortality.[24][25]

Adequate history and physical exam, skin testing, and challenge dosing are few ways to assess the allergy. Nurses can be vital in assessing drug allergies. Pharmacists can also play a pivotal role while updating EMR about patient's medication lists and drug interactions.