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.

Antiproliferative Properties of 7,8-Ethylene Diamine Chelator-Lipophilic Fluoroquinolone Derivatives Against Colorectal Cancer Cell Lines.

BACKGROUND: Cancer is one of the most overwhelming diseases nowadays. It is considered the second cause of death after cardiovascular diseases. Due to the diversity of its types, stages and genetic origin, there is no available drug to treat all cancers. Serious side effects and resistance of existing drugs are other problems in the struggle against cancer. In such quest, fluoroquinolones (FQs) promising as antiproliferative compounds due to safety, low cost and lack of resistance. OBJECTIVES: Therefore, this work aims at developing lipophilic FQs and screening their antiproliferative activity against colorectal cancer. METHODS: Nine prepared FQs were investigated for antiproliferative activity utilizing in vitro SRB method. In comparison to the antiproliferative agent cisplatin; the assessment of antiproliferative activities of these novel FQs in a panel of Colorectal Cancer Cell (CRC) lines (HT29, HCT116, SW620, CACO2, SW480) and normal periodontal ligament fibroblasts for safety examination was performed. Antibacterial activity (MIC) was conducted against Staphylococcus aureus and Escherichia coli standard strains using the broth double dilution method. Antioxidant properties were suspected as the mechanism of antiproliferative activity; thus, a DPPH test was performed to analyze radical scavenging potency of FQs compared to ascorbic acid as reference agent. FQs compounds 3-5(a-c) were prepared, characterized and their structure was confirmed using spectroscopy techniques. RESULTS: All compounds manifested good to excellent antiproliferative activity on HT29, HCT116, and SW620 with high safety index. The reduced series 4a, 4b and 4c exerted excellent micro to nano -molar antiproliferative activities on HT29, HCT116, and SW620 which were stronger than the reference cisplatin against all cells. The reduced group of compounds 4(a-c) revealed higher potency vs. both nitro and triazolo groups. On cell lines HT29, HCT116, and SW620, reduced 4a with 7,8-ethylene diamine,the substitution revealed the highest antiproliferative efficacy (IC50 value) approaching nano molar affinity with higher safety vs. cisplatin. The most active compound, 4a, exhibited significant potency against HCT116, and SW620 with IC50 0.6 and 0.16 µM respectively. Novel FQs (4a, 4b and 4c) also showed strong radical scavenging activity with IC50 values (µM) 0.06, 23, and 7.99, respectively. Exquisitely 4a revealed a similar pattern of activity to doxorubicin, indicating a similar mechanism of action. Strong antiproliferative and weak antibacterial activities of series 4 endorse that their mechanism involves eukaryotic topoisomerase II inhibition. This work has revealed novel FQs with excellent anticancer activity against 5 colorectal cancer (HT29, HCT116, SW620, CACO2, SW480) cell lines with a potential chelation mechanism due to 7,8-ethylene diamine chelator bridge. CONCLUSION: The new FQs have confirmed that more lipophilic compounds could be more active as hypothesized. The p-halogenated aniline, N1-Butyl group in addition to 3-COOH, 8-NH2 are all essential requirements for strong antiproliferative FQ of our FQ scaffold. This work emphasizes the role of C-8 amino as part of ethylene diamine group as an essential requirement for antiproliferative FQs for the first time in the literature, entailing its role toward potential antineoplastic FQs.

A Novel Class of Functionalized Synthetic Fluoroquinolones with Dual Antiproliferative - Antimicrobial Capacities.

As vosaroxin as a fluoroquinolone (FQ) had anticancer effectiveness; this study aimed to screen new lipophilic FQs for their dual antimicrobial-antiproliferative activities. Using sulforhodamine B assay; 36 lipophilic FQs have been screened for antimicrobial propensities against S. aureus, E. coli, and C. albicans vs. the respective references ciprofloxacin and fluconazole. They were also explored against a battery of cancer cell lines. Normal periodontal ligament fibroblasts (PDL) were tested for safety examination in comparison to the cisplatin. Reduced FQ compound 4g (R-2, 4-DMeOACA) highly scored nanomolar potency with MIC value of 0.004 µM against gram-positive bacteria. The highest activity of the 36 lipophilic FQs was noted on Leukaemia K562, cervical HELA and pancreatic PANC-1 cancer cell lines with respective IC50 value of 0.005 µM for compound R-4-BuACA (4e), 0.40 µM with CHxCA (7a) and 0.11 µM for R-4-HxACA (4f). Tested FQs exhibited cytotoxicity in A549 lung cancer, MCF-7 and T47D breast cancer cell lines. The reduced 4e and 4f compounds have shown nanomolar inhibition against K562 (as of 4e), PANC-1 and MCF-7 (as of 4f) with IC50 values of 0.005, 0.11 and 0.30 µM, respectively. Succinctly FQs' dual gram-positive antibacterial-antineoplastic capacities expand on of drug design scaffolds in lead generation.
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