Antimicrobial Stewardship Interventions: Narrative Review

Antimicrobial resistance is a serious health concern with significant economic and clinical sequelae. Antimicrobial stewardship programs are increasingly being promoted and mandated in order to rationalize and reduce the use of antimicrobials in healthcare institutions and as a result decrease antimicrobial resistance. Several interventions could be used to improve antibiotic use that includes broad, pharmacy driven and infection and syndrome specific interventions. Each hospital should prioritize interventions based on its needs as well as based on the availability of resources and content expertise.


INTRODUCTION
Antimicrobial resistance (AMR) is a serious health concern with significant economic and clinical sequelae. The incidence of it is rapidly increasing around the world, and infections caused by organisms that are resistant to several antibiotics are associated with higher incidences of mortality, morbidity, and prolonged hospital admission [1]. The main driver of the emergence of antimicrobial resistance is the selective pressure of antimicrobial usage on microorganisms; therefore, considerable focus has been placed on ensuring the wise use of antimicrobials [2]. Not only does this have implications for the patient who is infected with multidrug resistant organisms, but also for the spread of these organisms in the community and in healthcare facilities at large [2]. Consequently, antimicrobial stewardship programs are increasingly being promoted and mandated in order to rationalize and reduce the use of antimicrobials in healthcare institutions [3].
Antimicrobial stewardship (AMS) is a systematic approach to ensure that the antimicrobial use is appropriate, it aims to optimize the treatment of infections, minimize the adverse effects associated with antibiotic use and reduce antimicrobial resistance, toxicity and costs [4,5]. Antimicrobial stewardship can have a positive impact the different facilities largely [6]. There are several elements of antimicrobial stewardship programs, including post prescription review, preprescription authorization, education of prescribers, regular ward rounds for review of antimicrobial use, and regular audits with feedback [3]. Antimicrobial pharmacists remain leaders for implementing the interventions of antimicrobial stewardship programs across both primary and secondary healthcare institutions [7].
Interventions to decrease the unsuitable antimicrobial prescribing can reduce antimicrobial resistance or healthcare-acquired infections, and interventions to increase effective prescribing are essential in improving patient safety clinical outcomes [8]. This review aims to describe the interventions of antimicrobial stewardship programs.

METHODS
This narrative review was included searching Pubmed databases for the key terms (antimicrobial stewardship interventions). The searching process was conducted on 02-Dec-2020 and included the published articles in the last 10 years. So, the studies that were published before 10 years and review articles were excluded from the study.
The searching results were limited to the articles that were published in the 10 years and also the searching was limited by choosing the articles that contain the key terms "antimicrobial stewardship interventions" in the title of the articles that were written in English. We also add other studies from the references of the included articles.

RESULTS AND DISCUSSION
The searching process resulted in a total of 34 articles and review articles. After excluding review articles; 26 studies were identified and included in our review. Other studies were added from the references of the included articles after ensuring that they were related to the study topic and that they were published in the last 10 years. Table 1 showed the included publications that were published before 2017 and Table 2 showed the included publications that were published after 2016.

Antimicrobial Stewardship Interventions
The Infectious Diseases Society of America recommends 2 core strategies for antimicrobial stewardship antimicrobial restriction/preauthorization and postprescription audit and review (PPR) with intervention and feedback [9,10]. Barlam et al. [10] and Davey et al. [8] stated that the primary goal of hospital antimicrobial stewardship programs is to improve patient care. Evidence-based strategies include individualized active interventions to positively impact decisions about antimicrobials and review of patient-specific clinical data and prescribertargeted. Chavada et al. [11] stated that in addition to optimizing the duration of treatment, other practical interventions may also help to improve prescribing in this particular area such as prospective audit and feedback specifically for discharge antimicrobials, prescriber education, and the introduction of electronic prescribing and flagging. Pettit et al. [12].conducted a study about the use of Epic antimicrobial stewardship module which is Clinical Decision Support Tool and found that this module allowed us to significantly increase the number of antimicrobial reviews and interventions while maintaining a sustained impact on antimicrobial utilization. Anderson et al. reported that post-prescription audit and review was a feasible and effective strategy for antimicrobial stewardship in settings with limited resources and expertise and that it led to more interventions, particularly deescalation, which likely influenced overall antimicrobial use [26]. They also stated that these interventions led to more interactions between prescribers and pharmacists, providing additional opportunities to optimize antimicrobial therapy [26]. Atkins et al. reported that the majority of interventions in their study focused on education and training, which target knowledge and skills through the provision of instructions on how to perform a behavior and information about health consequences. Atkins et al study highlights the need to review existing interventions to ensure they are optimized to influence AMR-related behaviors [27].

Pharmacy-driven interventions
These interventions include automatic changes from intravenous to oral antibiotic therapy, dose adjustments, dose optimization, automatic alerts in situations where therapy might be unnecessarily duplicative, time-sensitive automatic stop orders for specified antibiotic prescriptions, especially antibiotics administered for surgical prophylaxis and detection and prevention of antibiotic-related drug-drug interactions [19].
Previous studies with pharmacist-led initiatives have shown an improvement in the overall appropriateness of antimicrobial therapy [28,29]. Chavada et al. envisage the introduction of several strategies such as training and upskilling of clinical pharmacists who already perform discharge medication reconciliation for antimicrobial therapy prescribed on hospital discharge [11].

Cao et al. conducted an institutional review of antimicrobial stewardship interventions and
reported that the most frequent types of interventions were pharmacy-driven interventions and were related to inappropriate dosing (39.0%), antimicrobial selection (20.5%) and drug allergy (13.0%). They also stated that serious adverse drug events were potentially avoided in about 20.7% of all interventions and that the cumulative potential cost avoidance was more than US$6.5 million [30].

Infection and syndrome specific interventions
These interventions are implemented for specific infection and syndrome, such as interventions for community-acquired pneumonia, urinary tract infections, skin and soft tissue infections, surgical antibiotic prophylaxis, empiric coverage of methicillin-resistant staphylococcus aureus infections, clostridium difficile infections, and treatment of culture proven invasive infections.
One of the most common Infections and syndrome specific interventions are the interventions that are implemented to improve surgical antibiotic prophylaxis. Badia et al. reported that the appropriate usage of surgical antibiotic prophylaxis significantly decreases the risk of surgical site infections [31], while the inappropriate usage increases surgical site infections, multidrug-resistant strains, and hospital costs [32][33][34]. For this reason, international and national guidelines have been developed to guide clinicians in the optimal use of surgical antibiotic prophylaxis [35-37]. Tiri et al. stated that many guidelines about surgical antibiotic prophylaxis have been published, but the overall compliance remains poor [38]. They used educational audit intervention and found that this intervention improves appropriateness on surgical antibiotic prophylaxis [38].
Pardo et al. reported that the Blood Culture Identification, coupled with antimicrobial stewardship intervention, was a cost-effective tool to improve patient care [39]. Niwa et al. reported that Matrix-assisted laser desorption ionization-time of flight mass spectrometry combined with antimicrobial stewardship intervention facilitated early optimization of antimicrobial therapy with a remarkable concomitant reduction in adverse events and clinical failure in patients with bloodstream infections [40]. Bates et al. found that C-reactive protein point-of-care testing was effective in safely decreasing antibiotic use in patients with an acute exacerbation of chronic obstructive pulmonary disease [41]. ISRCTN 11369832 study is investigating the effect of procalcitoninguided management on the use of antibiotics in children with severe bacterial infection [42]. Hecker et al study conducted specific interventions on the use of and resistance to fluoroquinolones and found that Antimicrobial stewardship interventions focused on specific syndromes may be effective in decreasing the use of fluoroquinolone use. They also found that the reduction in fluoroquinolone use resulted in a decrease in the resistance of P. aeruginosa to fluoroquinolone [43].
Several studies also reported that rapid diagnostic tests such as fluorescence in situ hybridization using peptide nucleic acid probes, procalcitonin and matrix-assisted laser desorption/ionization time of flight mass spectrometric analysis have been effectively incorporated by some stewardship programs and may become essential additions to stewardship programs

CONCLUSION
Several interventions could be used to improve antibiotic use that can be divided into three categories: broad, pharmacy driven and infection and syndrome specific interventions. Each hospital should determine the appropriate interventions that it will implement and should prioritize interventions based on its needs as well as based on the availability of resources and content expertise. Centers for Disease Control and Prevention advised hospitals to avoid implementing too many policies and interventions at the same time [19].

CONSENT
It is not applicable.

ETHICAL APPROVAL
It is not applicable. Expanding antimicrobial stewardship to