Serum concentration of continuously administered vancomycin influences efficacy and safety in critically ill adults: a systematic review.

OBJECTIVES: Vancomycin is used to treat Gram-positive infections in critically ill adults. For vancomycin administered by continuous infusion (CI), various target ranges have been used, ranging from 15-20 mg/L to 30-40 mg/L. This systematic literature review was conducted to investigate the impact of steady-state serum concentration (Css) of CI on safety and efficacy of therapy in critically ill adults. METHODS: Relevant literature was identified by searching two electronic databases (PubMed, Cochrane Library) and Google Scholar from inception until July 2023, focusing on studies reporting measured Css and treatment outcomes (e.g. mortality, nephrotoxicity) with CI. Due to study heterogeneity, a narrative synthesis of the evidence was performed. RESULTS: Twenty-one publications were included with a total of 2949 patients. Mortality was higher (two studies, n = 388 patients) and clinical cure was lower (one study, n = 40 patients) with Css < 15 mg/L measured 24 h after initiation of CI (C24). An adequate loading dose appeared most important for maintaining higher C24. Generally, higher Css was associated with higher rates of acute kidney injury (AKI) (15 studies, n = 2331 patients). It was calculated that Css < 25 mg/L (versus ≥25 mg/L) was preferable for reducing nephrotoxicity (three studies, n = 515 patients). CONCLUSIONS: Despite sparse data availability, the target range of 15-25 mg/L in CI may increase clinical cure and reduce mortality and AKI. In future research, vancomycin Css cohorts should be formed to allow evaluation of the impact of Css of CI on treatment outcomes.

Synthesis and study of cytotoxic activity of 1,2,4-trioxane- and egonol-derived hybrid molecules against Plasmodium falciparum and multidrug-resistant human leukemia cells.

Malaria and cancer cause the death of millions of people every year. To combat these two diseases, it is important that new pharmaceutically active compounds have the ability to overcome multidrug resistance in cancer and Plasmodium falciparum strains. In search of effective anti-cancer and anti-malaria hybrids that possess improved properties compared to their parent compounds, a series of novel 1,2,4-trioxane-based hybrids incorporating egonol and/or ferrocene fragments were synthesized and tested in vitro against P. falciparum strains, CCRF-CEM cells and the multidrug-resistant P-glycoprotein-over-expressing CEM/ADR5000 cells. The most active compounds against P. falciparum strains were artesunic acid homodimers 12 and 13 (IC50 of 0.32 and 0.30 nM, respectively), whereas novel hybrids 7 (1,2,4-trioxane-ferrocene-egonol), 9 (1,2,4-trioxane-ferrocene) and 11 (artesunic acid-egonol) showed a remarkable cytotoxicity toward CCRF-CEM cells (IC50 of 0.07, 0.25 and 0.18 µM, respectively). A cooperative and synergistic effect of the three moieties 1,2,4-trioxane, ferrocene and egonol in hybrid molecule 7 is significant and is obviously stronger than in hybrids 9 (1,2,4-trioxane-ferrocene) and 11 (artesunic acid-egonol), which comprises of only two of the three considered parent compounds. Interestingly, hybrid 9 containing a 1,2,4-trioxane and a ferrocene fragment has shown to be the most effective among the studied hybrids against the tested multidrug-resistant leukemia CEM/ADR5000 cells (IC50 of 0.57 µM) and possesses a degree of cross-resistance of 2.34.