The Impact of Antifungal Stewardship on Clinical and Performance Measures: A Global Systematic Review

Background: Antimicrobial stewardship programs (ASP) have been proposed as an opportunity to optimize antifungal use. The antifungal resistance is a significant and emerging threat. The literature on antifungal stewardship (AFS) and its influence on performance and clinical outcome measures is scarce. This study aimed to examine global evidence of the impact of AFS on patients and performance measures. Methods: The “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) was used for the flow of identification, screening, eligibility, and inclusion. PubMed and MEDLINE were searched using the term ‘‘antifungal stewardship’’ on 15 February 2023. Search terms included antifungal stewardship, antimicrobial stewardship, candida, candidemia, candiduria, and invasive fungal disease. Of the 1366 records, 1304 were removed since they did not describe an antifungal stewardship intervention. Among the 62 full texts assessed, 21 articles were excluded since they were non-interventional studies and did not include the outcome of interest. Thus, 41 articles were eligible for systematic review. Eligible studies were those that described an AFS program and evaluated clinical or performance measures. Results: Of the 41 included studies, the primary performance measure collected was antifungal consumption (22 of 41), and mortality (22 of 41), followed by length of stay (11 of 41) and cost (9 of 41). Most studies were single-center, quasi-experimental, with varying interventions across studies. The principal finding from most of the studies in this systematic review is a reduction in mortality expressed in different units and the use of antifungal agents (13 studies out of 22 reporting mortality). Antifungal consumption was significantly blunted or reduced following stewardship initiation (10 of 22). Comparing studies was impossible due to a lack of standard units, making conducting a meta-analysis unfeasible, which would be a limitation of our study. Conclusion: It has been shown that AFS interventions may improve antifungal consumption and other performance measures. According to available published studies, antifungal consumption and mortality appear to be the possible performance measures to evaluate the impact of AFS.


Introduction
The effectiveness of current antibiotics is threatened by the quick global spread of resistant microorganisms [1,2].Bacterial infections have reemerged as a hazard after a period of time in which patients with infections were treated with antibiotics [3,4].Antibiotic abuse or overuse has been linked to the development of bacterial resistance [5].
Antimicrobial Resistance (AMR) results in increased mortality, morbidity, and prescribing costs.Therefore, the Society for Healthcare Epidemiology and the Infectious Disease Society of America published guidelines to optimize the use of antibiotics and contain AMR [6].
Antimicrobial stewardship (AMS) is defined as interventions developed to enhance and measure the appropriate use of antimicrobials by promoting the optimal usage of dosing regimen, dose, choice of antimicrobial, and duration [7].The significance of AMS is that it has been globally recognized in improving patient outcomes (i.e., reducing mortality and morbidity), reducing antimicrobial consumption and costs, and reducing the development of antimicrobial resistance [8].However, antifungal stewardship (AFS) received less global consideration compared to AMS despite its significance [8].
Although antimicrobial stewardship focuses on antibiotics, antifungal resistance is a growing and emerging threat [9].For example, 70% of Candida glabatra and Candida auris species are resistant to fluconazole-and echinocandin [9,10].Moreover, Candida auris was discovered in 2009 as an emerging multidrug-resistant pathogen, with cases or outbreaks reported in over 20 countries [10,11].This is especially concerning given that Candida auris isolates are reportedly resistant to main classes of antifungal drugs [12].Appropriate antifungal use is essential in fighting drug resistance [13].AFS is the optimal selection of antifungal agents based on factors such as organism identity, patient toxicity profile and medication record, cost, and the potential of the emergence and spread of antifungal resistance [14].
Antifungal stewardship is a coordinated approach to monitoring and directing the appropriate use of antifungal agents to achieve optimal clinical outcomes and minimize selectivity and adverse events [14].Antifungal guidelines are similar to those of antimicrobial stewardship programs (ASP), where the prescribing of antifungals is optimized by considering the spectrum of action, pharmacokinetics and pharmacodynamics (PK-PD), duration of use, and route of use [15].Antifungals may already be used by existing antiinfective strategies (ASPs) due to their high cost, the potential for toxicity with long-term use, and the need for expertise to direct clinicians in prescribing [6].Reducing healthcare costs is often a secondary effect of stewardship.As public awareness of the risks of antibiotic overuse increases, many anti-infectious strategies have initially focused on reducing antibiotic overuse [16][17][18].However, the growing number of immunosuppressant patients at risk of opportunistic infections necessitates attention to other anti-infective classes [19].
Antimicrobial stewardship is about implementing coordinated interventions to enhance and evaluate the effective use of antimicrobials [20].Invasive fungal infections are a significant cause of mortality and a global public health concern [21].For example, in the United States, candidemia is only a small fraction of the burden caused by invasive candidiasis [22].Also, hospitalization rates for invasive infections have increased, and the World Health Organization (WHO) has published a list of critical priority pathogens to support the global response against fungal infections; candida auris and fumigatus are both critical priority pathogens [23].Public health efforts to address the threat of anti-fungal resistance are similar to those to combat antibiotic resistance.
Antimicrobial stewardship programs have well-documented evidence in optimizing the use of antimicrobials, thus improving patient outcomes, ensuring cost-effectiveness, reducing adverse outcomes such as reducing the incidence of C. difficile infections, and optimizing the use of healthcare resources [24,25].Antimicrobial stewardship programs optimizes antifungals and minimizes the adverse and toxic effects of anti-fungal use and the possible emergence of resistant fungi [26].Antifungal Stewardship (AFS) programs may improve performance measures and optimize antifungal consumption (i.e., potential economic savings) [27].
Antifungal consumption has been evaluated by the total anti-fungal prescriptions (TAP), which is defined by daily dose (DDD) and days of therapy (DOT) [28].However, the long-term effects of AFS interventions are less well-understood and require further research, especially in settings such as critical care where multi-drug-resistant organisms (MDROs) are emerging [29,30].Therefore, intensivists should balance the increased mortality associ-ated with delaying therapy of microbiologically documented infections with the potential ecological damage caused by antimicrobial medications, including the selection and development of MDROs [29].For example, a few hours' delays in administering appropriate antimicrobial therapy in septic shock patients with sensitive causative pathogens would increase the mortality risk [31].Also, this applies to other infections, such as those affecting the respiratory system (e.g., pneumonia, COVID- 19), in which the use of an inappropriate initial antibiotic regimen would increase the risk of morbidity and mortality due to rising levels of bacterial resistance [14,15].
The recent COVID-19 pandemic and the risk of the patient becoming immunocompromised with a risk of systemic fungal infection highlighted the need for antifungal stewardship programs to prevent and fight unwarranted systemic infections [32,33].Antifungal consumption during COVID-19 was evidenced to be increased [33,34].However, a UK study reported that despite the COVID-19 pandemic's effect on increasing antifungal consumption, the standards of care were good as a result of the presence of technology to facilitate antifungal stewardship programs [35].However, tiny reductions in patient adherence were reported due to the switch from face-face to virtual meetings [35].
Establishing effective AFS aims to improve patient's clinical outcomes, including mortality and morbidity, and performance measures, including antifungal consumption, cost, adverse drug reactions, and antifungal resistance.While AMS is extensively described in the literature [9,[36][37][38][39], there is a scarcity of literature describing Antifungal Stewardship (AFS) as an emerging theme [9,39].A systematic review of AFS interventions and performance measures in 2017 reported that antifungal consumption decreased by 11.8% to 71% and antifungal expenditure by 50% [39].In 2017, a systematic review was conducted to examine the impact of AFS interventions in the United States and showed that AFS interventions could enhance patient outcomes and curtail antifungal use [9].However, this study included 13 studies from the United States only [9].However, this study included 13 studies from the United States only [9].Therefore, updated and recent evidence about the impact of AFS interventions is necessary from studies reported in other countries globally.This systematic review aimed at examining and summarizing studies reporting the evidence of the global impact of AFS and available interventions on clinical and performance measures.This would help inform and support healthcare professionals with the latest evidence, improve patient outcomes and safety, and reduce healthcare financial expenditures.

Search Strategy
The literature search was conducted using EMBASE and PubMed online databases to pursue articles related to antimicrobial and antifungal stewardship.Moreover, the reference lists of relevant articles related to the impact of antifungal stewardship on clinical and performance measures were searched to increase completeness.The last search was performed on 17 February 2023.Medical Subject Heading (MeSH) terms were initially identified using the PubMed-linked MeSH database.The selected MeSH terms were "antifungal stewardship", "antimicrobial stewardship", "candida, invasive fungal", "candidemia", "candiduria", and "aspergillosis".Three reviewers (HA, FA, RA) assessed the titles and abstracts of retrieved references to establish potential inclusion eligibility.The full texts of potential studies were reviewed to see if they met the review inclusion criteria.Bibliographies of retrieved papers and prior systematic reviews were checked to find other articles that this search approach may have overlooked.A total of 1366 records were identified; one record was obtained using the snowballing approach.Of the 1366 records, 1304 were removed since they did not describe an antifungal stewardship intervention.Among the 62 full texts assessed, 21 articles were excluded since they were non-interventional studies and they did not include the outcome of interest.Thus, 41 articles were eligible for systematic review (Figure 1).
Among the 62 full texts assessed, 21 articles were excluded since they were non-interventional studies and they did not include the outcome of interest.Thus, 41 articles were eligible for systematic review (Figure 1).

Eligibility Criteria
The eligibility criteria were set during the search process for the related articles.Studies that described an AFS included an intervention, clinical performance, and outcome

Eligibility Criteria
The eligibility criteria were set during the search process for the related articles.Studies that described an AFS included an intervention, clinical performance, and outcome measures such as mortality and morbidity (i.e., hospital length of stay, antimicrobial consumption, cost, antifungal therapy use, and effectiveness).Exclusions were made for non-English studies, reviews, and studies that did not include intervention, performance, or clinical outcome measures.A wide range of outcomes was measured, including appropriate fungal choice, time to therapy, cost, antifungal consumption, mortality, and length of stay.

Study Selection
Study selection was completed by two researchers (FA and HA) using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (Appendix A) flow of identification, screening, eligibility, and inclusion.Abstracts were uploaded to MEDLINE to determine whether publications were eligible after the records were checked for duplicates.If the abstract did not provide sufficient information to determine eligibility, full texts were downloaded from the university library.Using a snowballing strategy, relevant reviews and references of eligible publications were searched to make the search more thorough.Two researchers (FA and HA) separately evaluated full-text papers to settle any differences regarding inclusion, and following discussion, a consensus was reached.

Data Extraction
A custom data extraction form was developed to meet the review's special requirements.One reviewer (FA) extracted and confirmed data on the study design, participants, interventions, comparators, outcomes, and key findings (HA).Disagreements were settled through consensus, with the assistance of a third investigator (RA).Two reviewers screened all titles and abstracts identified in the literature search.Abstracts were eligible if they fulfilled the inclusion criteria, and full-text articles were additionally reviewed and discussed by the two researchers where a data collection form was used to collect information from the retrieved studies, including; the study title, year of publication, author, objectives, design, patient population, duration, site, intervention description, and findings on outcomes of interest were used to extract the data.In addition, another researcher reviewed the extracted data to verify the necessity.Any conflict on data inclusion was confirmed through discussion between all of the researchers.

Synthesis of Results
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist [40] was used to guide the systematic review (Appendix A).The extracted data were summarized descriptively based on intervention variability, patient populations, and outcome measures.A narrative process was used to describe data extracted from full-text articles.The initial search of the databases resulted in 1396 articles in total, with one article identified through other sources.After removing the duplicates, 1366 were screened, and 1304 articles were removed.The 62 full-text articles were assessed, in which 41 articles were included in the qualitative synthesis.

Quality Assessment of Included Studies
Case-control, cohort, randomized controlled trials, and case series studies were critically evaluated using the National Institutes of Health (NIH) quality evaluation method [41].Using the appropriate technique based on the study design, two reviewers independently evaluated the quality of each study.Studies were rated on a scale of good, fair, or poor, with a score of two being considered good (11-14 out of 14 questions), a score of one considered acceptable (5-10 out of 14 questions), and a score of zero being considered poor (0-4 out of 14 questions).Additionally, each included study's quality was evaluated separately by two researchers.If their assessments of the studies were different, both authors discussed the article to come to a decision.

Study Characteristics
Of the included studies, 22 studies reported clinical outcomes such as mortality.These studies are summarized in Appendix B. The remaining studies reported different outcomes, such as cost, appropriateness of antifungal use, and consumption.All studies were singlecentered and quasi-experimental in design, with the earliest publication in 2004 [68].Data that were not related to antifungals were not included in the review.

Interventions
The stewardship interventions differed across the studies, but common stewardship interventions included audit, feedback, and preauthorization requirements [43,53,54].Interventions ranged from applying a stewardship care bundle, guideline development, audit and feedback, and preauthorization.For instance, six studies were based on introducing diagnostic tools for detecting candida species [49,51,56,60,77,78].Intervention types and implementation are presented in (Appendix A).

Hospital Length of Stay
Eleven studies reported hospital length of stay [2,[47][48][49][51][52][53]60,63,75,80].None of these studies showed a clinically significant reduction in hospital length of stay.In one study, the hospital length of stay was ten days in the intervention group compared to eleven days in the non-intervention group, but it was not statistically significant (p = 0.68) [2].This quasiexperimental study was conducted to evaluate how an ASP pharmacist's interventions affected the length of time it took patients with candidemia to receive effective antifungal treatment.Comparing patients from 2008 (n = 85 pre-intervention) and 2010 (n = 88 postintervention), the time to effective therapy was much faster in the post-intervention group (median 13.5 versus 1.3 h, p = 0.04) and was given to more patients (67 (88%) vs. 80 (99%), p = 0.008) [2].

Discussion
The literature is rich with studies evaluating the impact of AMS on patient and performance measures.However, there is a paucity of literature evaluating (AFS) [14,30,46,57,[64][65][66]71,72,74,75,77].This warrants conducting a systematic review to update the policymakers and healthcare professionals about the current status of the clinical and performance measures related to antifungal use, effectiveness, cost-effectiveness, and appropriateness.This systematic review addresses that gap.The principal finding from most of the studies in this systematic review is a reduction in mortality expressed in different units and the use of antifungal agents.Also, other studies reported on the cost-effectiveness and appropriateness of antifungal therapy.
Antifungal stewardship programs are an integral part of the antimicrobial stewardship program, given the rise in antifungal resistance and poor clinical outcomes [9].The multidrug-resistant Candida curis is one of the challenges impacting patients' clinical outcomes [51].Therefore, additional AFS interventions and programs are needed to contain antifungal resistance properly.It has been shown that AFS interventions were implemented in tertiary care and teaching hospitals [9,57].This would explain the frequent use of broadspectrum antifungals for critically ill patients admitted in such healthcare settings and the availability of facilities and resources needed to implement AFS.The multidisciplinary team's role in containing invasive fungal infections is debatable [55].It should contain an infectious disease physician, a clinical pharmacist, and a clinical microbiologist.However, only 5 of the 41 studies in this systematic review reported a complete antifungal steward-ship team [2,[64][65][66]74].A hospital epidemiologist, an infection control professional, and an information system specialist are also included in the antimicrobial stewardship team, according to IDSA guidelines [53].
Notably, none of the included studies contain an antimicrobial stewardship team with such healthcare professionals, and the recommendations of these studies do not endorse including these staff.Moreover, pharmacists played an integral role in the antimicrobial stewardship team, and their absence from the team was associated with a higher rate of inappropriate antimicrobial prescribing and a longer duration of treatment [43].The stewardship interventions differed across studies, but common stewardship interventions included audit, feedback, and preauthorization requirements [43,53,54].Six studies were based on introducing diagnostic tools for detecting candida species [49,51,56,60,77,78].Mortality and antifungal consumption were the most commonly reported outcomes in this systematic review.The majority of studies showed a reduction in mortality expressed in different units.Various approaches were used to express consumption, including defined daily doses and days of therapy.The use of antifungal days of therapy is the most selected metric, according to IDSA, as it can be used for pediatrics and is not affected by dose adjustments [9].
Interestingly, all studies showed reduced use of antifungal agents.Such reduction in antifungal use was apparent in studies reporting both overall antifungal utilization and those focusing on specific antifungal classes or drugs.Although AFS can positively impact antifungal consumption, the prescribing quality within these studies is unclear.Only four studies reported on the appropriateness of antifungal use.The majority of studies did not evaluate the suitability of antifungal prescribing as a process outcome.
Previous research showed a high proportion of inappropriate antifungal agent use, including inadequate dosages or indications [82,83].Given the overtreatment with antifungal therapy and the rise in resistance, there should be a greater focus on compliance with guideline recommendations as a reported performance measure.
Establishing the impact of AFS interventions on clinical outcomes such as mortality should be a primary focus, along with reporting antifungal utilization and other process outcomes.Half of the included studies in this systematic review evaluated clinical outcomes, including in-hospital or 30-day mortality and overall hospital length of stay.ASPs were associated with a considerable reduction in hospital length of stay.However, these findings were based on only six studies [2,49,[51][52][53]60].Two more studies did not show any change in the length of stay [47,48].The scarcity of studies (i.e., 8 out 41) that evaluate the impact of ASPs on hospital length of stay would necessitate further studies to be conducted to strengthen the evidence.
Findings from this systematic review support previous reviews in which stewardship programs do not negatively influence patient care levels by focusing antifungal therapy on patients who need it.However, similar to antimicrobial stewardship, AFS programs must evaluate clinical outcomes and show care improvements to justify additional resources beyond the cost savings associated with decreased antifungal consumption.Despite the significance of antifungal stewardships for patients, policymakers, and healthcare professionals, the first study in this systematic review describing an antifungal stewardship intervention was published in 2004.Also, more than half of the studies were published in 2014 or later.This would provide a clear picture of the need to conduct more research related to antifungal stewardship that would be used by stakeholders (policymakers, healthcare professionals, and patients) to influence the effective use of antifungals.The significance of this systematic review is that it includes updated and recent evidence from around the globe exploring healthcare systems worldwide compared to the previous two systematic reviews of AFS [9,39].However, our study has many limitations.The major limitation is the scarcity of literature and evidence to support AFS programs.Studies focusing on AFS programs were primarily published after 2010, consistent with this concept's emergence [74].Another significant limitation is that most included studies were non-randomized, primarily singlecenter, quasi-experimental designs.Furthermore, specific recommendations were drawn from studies with small numbers of patients.Moreover, the heterogeneity of the included studies makes conducting a metaanalysis very difficult as the outcomes measured are reported in different units.These limitations warrant focusing on and conducting more antifungal stewardship-related research to gain more evidenced-based insights about the rational use of antifungals, thus helping policymakers develop and update the antifungals protocols and guidelines and allowing infectious consultants and other healthcare professionals to provide rational antifungal treatment.Therefore, raising awareness about the significance of antifungal stewardship is paramount with stakeholders (i.e., healthcare providers, prescribers, policymakers, and patients) education, and developing and implementing national and international antifungal guidelines would be the starting point.

Conclusions
Findings from this systematic review shed light on the impact of antifungal stewardship on clinical and performance measures.Mortality was reported to be reduced in about half of the studies that reported mortality, along with reduced use of antifungal agents.This would signify the importance of effective antifungal utilisation (i.e., consumption metrics) based on appropriate use and adherence to antifungal guidelines on reducing mortality rate and improving morbidity-related clinical measures.Also, none of the included studies contain an antimicrobial stewardship team, and the recommendations of these studies do not endorse including these staff.This is significant, in which a multidisciplinary team of AFS is paramount for the success of AFS.All AFS interventions included in this systematic review impacted clinical and performance measures, including consumption and cost.Future works are paramount, considering the scarce antifungal stewardship-related literature.They should focus on conducting high levels of evidence-based medicine such as systematic reviews, meta-analysis, and randomized controlled trials to evaluate AFS on clinical and performance measures and developing guidelines for AFS implementation, as is the case for AMS.Also, research should focus on new antifungals and their role in devising empirical treatment, which will impact the future of antifungal stewardship.

Eligibility criteria 5
Specify the inclusion and exclusion criteria for the review and how studies were grouped for the syntheses.Page 3 Information sources 6 Specify all databases, registers, websites, organisations, reference lists and other sources searched or consulted to identify studies.Specify the date when each source was last searched or consulted.Page 3 Search strategy 7 Present the full search strategies for all databases, registers and websites, including any filters and limits used.Page 3

Selection process 8
Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process.

Page 4
Data collection process 9 Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process.
Page 4

Data items 10a
List and define all outcomes for which data were sought.Specify whether all results that were compatible with each outcome domain in each study were sought (e.g., for all measures, time points, analyses), and if not, the methods used to decide which results to collect.

Page 4 10b
List and define all other variables for which data were sought (e.g., participant and intervention characteristics, funding sources).Describe any assumptions made about any missing or unclear information.

Figure 1 .
Figure 1.Literature search scope using the PRISMA flow chart adapted from the PRISMA Group [40].

Figure 1 .
Figure 1.Literature search scope using the PRISMA flow chart adapted from the PRISMA Group [40].

Table A1 .
Cont. financial or non-financial support for the review, and the role of the funders or sponsors in the review.

Table A2 .
A summary of the characteristics of the included studies.