key: cord-0867181-s1x71s5n authors: St. Louis, James; Okere, Arinze Nkemdirim title: Clinical impact of pharmacist-led antibiotic stewardship programs in outpatient settings in the United States: A scoping review date: 2021-04-23 journal: Am J Health Syst Pharm DOI: 10.1093/ajhp/zxab178 sha: 76a6bf04fe08685815df6beea77697850efe77b9 doc_id: 867181 cord_uid: s1x71s5n DISCLAIMER: In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: To provide an overview of the impact of pharmacist interventions on antibiotic prescribing and the resultant clinical outcomes in an outpatient antibiotic stewardship program (ASP) in the United States. METHODS: Reports on studies of pharmacist-led ASP interventions implemented in US outpatient settings published from January 2000 to November 2020 and indexed in PubMed or Google Scholar were included. Additionally, studies documented at the ClinicalTrials.gov website were evaluated. Study selection was based on predetermined inclusion criteria; only randomized controlled trials, observational studies, nonrandomized controlled trials, and case-control studies conducted in outpatient settings in the United States were included. The primary outcome was the observed differences in antibiotic prescribing or clinical benefits between pharmacist-led ASP interventions and usual care. RESULTS: Of the 196 studies retrieved for full-text review, a cumulative total of 15 studies were included for final evaluation. Upon analysis, we observed that there was no consistent methodology in the implementation of ASPs and, in most cases, the outcome of interest varied. Nonetheless, there was a trend toward improvement in antibiotic prescribing with pharmacist interventions in ASPs compared with that under usual care (P < 0.05). However, the results of these studies are not easily generalizable. CONCLUSION: Our findings suggest a need for a consistent approach for the practical application of outpatient pharmacist-led ASPs. Managed care organizations could play a significant role in ensuring the successful implementation of pharmacist-led ASPs in outpatient settings. A c c e p t e d M a n u s c r i p t associated with improved patient outcomes and decreased rates of inappropriate antibiotic prescribing. [17] [18] [19] From an outpatient perspective, a systematic review and meta-analysis of studies evaluating the effect of collaboration between pharmacists and general practice physicians in antibiotic prescribing revealed an overall improvement in antibiotic prescribing practices by general practitioners and a reduction in the number of inappropriately prescribed antibiotics. 20 Although the studies included were conducted outside the United States, it is evident that pharmacists are presented with a unique opportunity to improve outcomes and expand clinical services through the implementation of an ASP. 21, 22 Despite positive outcomes of pharmacist-led ASPs in inpatient settings and primary care clinics located outside the United States, few studies have been conducted in outpatient settings in the United States. Most outpatient studies conducted in the United States were conducted in emergency room settings, and little is known of their impact on clinical outcomes. With the mandate from the Joint Commission to implement ASPs in all outpatient settings, 23 there is an imminent call to mandate ASPs in outpatient settings as a required quality measure. Therefore, there is a critical need to understand the potential role of pharmacist-led antibiotic stewardship in an outpatient setting to prevent antibiotic overuse. The aim of the scoping review described here was to provide an overview of the impact of A c c e p t e d M a n u s c r i p t  Study design-Reports and studies that were included in the scoping review comprised randomized controlled trials, nonrandomized controlled trials, observational cohort studies, and case-control studies. Editorials and descriptive or case reports were excluded.  Population-Only studies involving adult patients (at least 18 years of age) with infections resulting from antibiotic usage were included. Only studies conducted in outpatient settings in the United States were included; those in inpatient or acute care settings were excluded.  Outcome-The primary outcome was the benefits of the pharmacist-led ASP (or ASP involving pharmacists) on antibiotic prescribing compared with those under usual care. Examples of outcomes evaluated are as follows: antibiotic prescribing pattern, healthcare utilization, antibiotic use, and time to review culture results. Data extraction and synthesis. Data from the selected papers were extracted and synthesized using a predefined extraction form ( A c c e p t e d M a n u s c r i p t Our initial database search using the selected keyword phrases generated 15,045 studies ( Figure 1 ). Following the initial search, we screened for duplicates while screening for unrelated topics based on a review of the titles and abstracts only. After removing duplicates and studies unrelated to our topic (determined through review of titles and abstracts), 196 studies were retrieved for full-text review. In line with our inclusion and exclusion criteria, 15 studies were identified through full-text review. [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] [38] [39] [40] The various reasons for exclusion are presented in Figure 1 . Ten studies were conducted in specific outpatient settings: emergency department (ED), n = 8; urgent care (UC), n = 1; and primary care, n = 3. Additionally, 1 study evaluated the cumulative outcomes of UC and ED, and several studies independently evaluated cumulative outcomes from the combined outpatient services of their respective healthcare systems (ie, UC, primary care, and ED combined). Because of the heterogeneity of the study designs and settings, our results are categorized based on the clinical setting in which an ASP was implemented. Furthermore, the studies included in this review are summarized in Table 1 . Baker et al (2012) 29 conducted a retrospective case-control study to compare the "time to culture follow-up and patient notification" between patients seen by pharmacists (the intervention group) and those treated with usual care (no pharmacist intervention). In the intervention group, the pharmacist provided education on the appropriate empiric antimicrobial selection and followed up with patients in cases in which a change in therapy was needed. The outcome of interest was the impact of the pharmacist intervention on the "time to positive culture follow-up." The results showed that the time to positive culture review and time to patient or physician notification were shorter in the intervention group than in the usual care group. 29 Additionally, with the implementation of a pharmacist-driven ASP, the median time to positive culture review or primary care provider notification was reduced by 1 day. However, there was no significant difference in the A c c e p t e d M a n u s c r i p t numbers of inappropriate prescribing occurrences before and after the implementation of the pharmacist-driven ASP. One possible explanation is that the study was not sufficiently powered to assess any differences in the number of antibiotic-prescribing occurrences between the intervention and usual care groups. Additionally, Dumkow et al (2014) 30 conducted a quasi-experimental study evaluating the effect of involving pharmacists in a multidisciplinary ASP team in a "culture follow-up (CFU) program" on the frequency of ED visits compared with usual care (no pharmacist intervention). Before the intervention (usual care), the culture review was mostly physician driven, without any pharmacist involvement. In contrast, during the CFU intervention, pharmacists were involved during a review of culture results and antimicrobial prescribing. The outcomes of interest were ED visits and hospital readmission 72 hours post index ED visit. In the unadjusted analysis, there was no significant difference in ED visits within 72 hours, 30-day readmissions, or combined ED visits and 30-day readmissions. However, 2 major confounding factors were the frequency of urination and dysuria. After adjusting for the presence of dysuria and urinary frequency, CFU was associated with a decreased likelihood of ED visits and readmission compared with usual care (adjusted OR, 0.477; 95% CI, 0.234-0.973; P = 0.042). Interestingly, in a subset of uninsured patients, the occurrence of ED visits after intervention was reduced from 15.3% in the usual care group to 2.4% in the CFU group (P = 0.044). A c c e p t e d M a n u s c r i p t hours after the implementation period (P < 0.001). However, as this approach in the ED setting is novel, a more robust study is needed to address its clinical relevance. Unlike previous studies, which were retrospective, the studies by Zhang et al (2016) In summary, despite the heterogeneity of study designs in evaluations of the implementation of an ASP in the ED, the reviewed studies suggest that an ASP may be associated with reduced ED visits and an improved antibiotic-prescribing pattern. Mixed ED and UC settings. Selected study report. Dumkow et al (2018) 34 conducted a quasiexperimental retrospective study of patients with pharyngitis in both ED and UC settings. The A c c e p t e d M a n u s c r i p t primary goal was to compare the proportion of patients who received appropriate antibiotics before and after the implementation of an ASP. The proportion of patients who received appropriate antibiotics was higher post ASP implementation than before ASP implementation (81.5% vs 6%, P < 0.001). The frequency of antibiotic prescribing decreased from 97% to 71.3% (P < 0.001). Furthermore, no statistically significant difference in 72-hour revisit rates was observed (P = 0.121). One major limitation of the study was the lack of a control group of patients of similar clinical characteristics. Interventions made under the ASP included the development of clinic-specific guidelines, EHR built-in notes for easy access to the treatment summary, education materials, and audits of inappropriate prescribing. The primary outcome was the composite proportion of antibiotic prescription in accordance with the guideline-approved first-line therapy before and after the intervention periods. Based on their results, the researchers found that the proportion of appropriate antibiotic prescription was higher after the intervention (71.6%) than before the intervention (37%; P < 0.001). Of particular note, the majority of patients seen (93.8%) had cystitis. In all studies evaluated, the provision of guideline-directed education as part of an ASP initiative was associated with improved outcomes with regard to the antibiotic prescribing pattern. The purpose of this review is to provide an overview of the potential benefit of a pharmacist-led ASP in outpatient settings. Although the methodological quality of each study was low, the observed quality of evidence was not different from what has been observed in other studies relating to ASPs. 41 Notwithstanding methodological differences, much can be learned from these different studies that can help shape future studies on pharmacist-led ASPs in outpatient settings. First, the inclusion of the pharmacist in outpatient settings was associated with an increased number of interventions made, which led to appropriate antibiotic prescribing. A similar finding was observed in a systematic review and meta-analysis of studies conducted in non-US primary care centers, as reported by Saha et al (2019) . 20 M a n u s c r i p t Second, pharmacist review of cultures led to an improved quality of antibiotic prescribing. We deduce that such an intervention may improve healthcare costs associated with disease burden or antibiotic resistance. However, it is unclear if appropriate antibiotic prescribing led to a reduction in the frequency of preventable ED visits and rehospitalizations associated with infectious disease. The available data on the impact of a pharmacist-led ASP on ED visits and readmissions were inconclusive. The differences in the infectious diseases targeted by the various reported pharmacist- Furthermore, as antibiotic resistance is associated with increased mortality 7 and information on the impact of a pharmacist-led ASP on mortality is lacking, it would be interesting to explore the effect of a pharmacist-led ASP on mortality. Clinical studies examining the effects of implementation of an outpatient ASP on inpatient outcomes, such as hospital length of stay and hospital readmissions associated with infectious diseases, will be pertinent. Finally, an analysis of costs and benefits of implementation of an ASP in outpatient settings should be conducted. Our scoping review had some limitations. First, there was a potential for publication bias. Finally, based on our review of different studies, there has not been a consistent approach in implementing an ASP for outpatients, which might have led to differences in outcomes. A c c e p t e d M a n u s c r i p t The implementation of a pharmacist-led ASP has public health and policy implications. Acknowledging the importance of an ASP, both IDSA and the Pediatric Infectious Diseases Society of America have mandated that an ASP be interwoven throughout healthcare, with similar regulatory requirements as those of the Centers for Medicare and Medicaid Services imposed. 43 As inpatient implementation of an ASP is not mutually exclusive to the outpatient implementation of an ASP, without the appropriate implementation of an ASP in the outpatient setting, the control of antibiotic resistance in the community will be difficult, consequently leading to increasing inpatient use of broad-spectrum antibiotics. Currently, ASP implementation is required by the Joint Commission for all ambulatory care clinics, excluding ambulatory surgery centers. 23 Therefore, managed care organizations (MCOs) can play a significant role in ensuring the successful implementation of pharmacist-led ASPs in outpatient settings by providing incentives. These incentives, in the form of monetary reimbursement, can help alleviate the 2 widely recognized barriers to the effective implementation of an ASP, which are cost and the need for rapid decision making with limited diagnostic information. Actions by MCOs can be enhanced by the regulatory oversight of the National Committee for Quality Assurance, which is responsible for evaluating the quality and service provided by MCOs, and by incorporating the development of an ASP as one of the required quality measures for outpatient settings. We recognize that the limited availability of resources such as manpower can be a major barrier in implementing a pharmacist-led ASP in an outpatient setting. To minimize the effect of this barrier, we recommend that an ASP should not be a standalone or a silo program, but instead should be integrated as part of pharmacist services. In other words, an ASP can be integrated with pharmacist-led transition of care and comprehensive medication therapy management services. An approach proposed by Okere (2018) 44 could be adapted to any outpatient setting when rectifying or reconciliating all drugs (including antibiotics) prior to patient discharge. A c c e p t e d M a n u s c r i p t As noted in this article, multidimensional approaches were deployed in the implementation of ASPs in outpatient settings. The development of IDSA-concordant guidelines and education were found to be the most effective and potentially cost-effective approaches. Nonetheless, other novel approaches such as RDT use or penicillin skin testing can be integrated as part of the process. However, additional pharmacist training may be required. The successful implementation of an ASP in outpatient settings requires commitment from policymakers, healthcare administrators, and clinicians. According to CDC, improving antibiotic prescribing involves the effective implementation of strategies to "modify prescribing practices to align them with evidence-based recommendations for diagnosis and management." 45 Therefore, for the successful implementation of pharmacist-led ASPs resulting in improved patient outcomes, clinics (including other outpatient settings) should consider reviewing and incorporating the core elements of an ASP, such as "commitment, action, tracking and reporting, education, and expertise." 46 An effort to reduce inappropriate antibiotic prescribing requires a team approach that allows the inclusion of pharmacists. Our findings revealed a need for a consistent approach for the effective implementation of outpatient pharmacist-led ASPs. Interventions made by a pharmacist in an ASP were associated with a small improvement in the quality of antibiotic prescribing. It is our opinion that MCOs can play a significant role in ensuring the successful implementation of pharmacist-led ASPs in outpatient settings. A change in policy, requiring the provision of monetary incentives and inclusion of an ASP (with regulatory oversight) as a required outpatient quality measure, will ensure its successful implementation in an outpatient setting. The study was supported by the National Institute on Minority Health and Health Disparities through grants U54 MD007582 and P20 MD006738. The authors have declared no potential conflicts of interest. 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National Action Plan For Combating Antibiotic-Resistant Bacteria Antimicrobial stewardship programs in inpatient hospital settings: a systematic review Effect of antibiotic stewardship on the incidence of infection and colonisation with antibiotic-resistant bacteria and Clostridium difficile infection: a systematic review and meta-analysis Impact of a hospital-based antimicrobial management program on clinical and economic outcomes Effectiveness of interventions involving pharmacists on antibiotic prescribing by general practitioners: a systematic review and metaanalysis Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship Impact of ambulatory antimicrobial stewardship on prescribing patterns for urinary tract infections Outpatient antimicrobial stewardship: optimizing patient care via pharmacist led microbiology review Decreased outpatient fluoroquinolone prescribing using a multimodal antimicrobial stewardship initiative The quality of studies evaluating antimicrobial stewardship interventions: a systematic review Antimicrobial use in outpatient hemodialysis units Society for Healthcare Epidemiology of America; Infectious Diseases Society of America Infectious Diseases Society of America (IDSA), and the Pediatric Infectious Diseases Society (PIDS) Implementation and development of emergency department pharmacist-driven patient care transitional model: a discussion of our experiences and processes A c c e p t e d M a n u s c r i p t  Outpatient settings are a major contributor to inappropriate antibiotic prescribing and antibiotic resistance in the community. Implementation of pharmacist-led antibiotic stewardship programs can improve outpatient antibiotic prescribing. Integrating provider education, developing algorithms concordant with Infectious Diseases Society of America guidelines, and auditing providers' prescribing patterns as an integral part of pharmacist-led antibiotic stewardship programs can be a costeffective approach to improve antibiotic prescribing in outpatient settings. 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