Efficiency of dosing software using Bayesian forecasting in achieving target antibiotic exposures in critically ill patients, a prospective cohort study.

INTRODUCTION: Broad-spectrum antibiotics such as beta-lactams and vancomycin are frequently used to treat critically ill patients, however, a significant number do not achieve target exposures. Therapeutic drug monitoring (TDM) combined with Bayesian forecasting dosing software may improve target attainment in these patients. This study aims to describe the efficiency of dosing software for achieving target exposures of selected beta-lactam antibiotics and vancomycin in critically ill patients. METHODS: A prospective cohort study was undertaken in an adult intensive care unit (ICU). Patients prescribed vancomycin, piperacillin-tazobactam and meropenem were included if they exhibited a subtherapeutic or supratherapeutic exposure informed by TDM. The dosing software, ID-ODS™, was used to generate dosing recommendations which could be either accepted or rejected by the treating team. Repeat antibiotic TDM were requested to determine if target exposures were achieved. RESULTS: Between March 2020 and December 2021, 70 were included in the analysis. Software recommendations were accepted for 56 patients (80%) with 50 having repeated antibiotic measurements. Forty-three of the 50 patients (86%) achieved target exposures after one software recommendation, with 3 of the remaining 7 patients achieving target exposures after 2. Forty-seven patients out of the 50 patients (94%) achieved the secondary outcome of clinical cure. There were no antibiotic exposure-related adverse events reported. CONCLUSION: The use of TDM combined with Bayesian forecasting dosing software increases the efficiency for achieving target antibiotic exposures in the ICU. Clinical trials comparing this approach with other dosing strategies are required to further validate these findings.

Autoantibodies against homocysteinylated protein in a mouse model of folate deficiency-induced neural tube defects.

BACKGROUND: Periconceptional supplementation with folic acid results in a significant reduction in the incidence of neural tube defects (NTDs). Nonetheless, NTDs remain a leading cause of perinatal morbidity and mortality worldwide, and the mechanism(s) by which folate exerts its protective effects are unknown. Homocysteine is an amino acid that accumulates under conditions of folate-deficiency, and is suggested as a risk factor for NTDs. One proposed mechanism of homocysteine toxicity is its accumulation into proteins in a process termed homocysteinylation. METHODS & RESULTS: Herein, we used a folate-deficient diet in pregnant mice to demonstrate that there is: (i) a significant inverse correlation between maternal serum folate levels and serum homocysteine; (ii) a significant positive correlation between serum homocysteine levels and titers of autoantibodies against homocysteinylated protein; and (iii) a significant increase in congenital malformations and NTDs in mice deficient in serum folate. Furthermore, in mice administered the folate-deplete diet before conception, supplementation with folic acid during the gestational period completely rescued the embryos from congenital defects, and resulted in homocysteinylated protein titers at term that are comparable to that of mice administered a folate-replete diet throughout both the pre- and postconception period. These results demonstrate that a low-folate diet that induces NTDs also increases protein homocysteinylation and the subsequent generation of autoantibodies against homocysteinylated proteins. CONCLUSION: These data support the hypotheses that homocysteinylation results in neo-self antigen formation under conditions of maternal folate deficiency, and that this process is reversible with folic acid supplementation.

Limonoids of the phragmalin type from Swietenia macrophylla and their chemotaxonomic significance.

Species of Swietenia elaborate limonoid chemistry along only one route, which leads to the mexicanolide type in most species and the phragmalin type in S. mahogani. A hexane extract from leaves of S. macrophylla afforded six new phragmalins with a 8,9,30-ortho-ester unit, namely, 6-O-acetylswietephragmin E (1), 3beta-O-destigloyl-3beta-O-benzoyl-6-O-acetylswietephragmin E (2), 12alpha-acetoxyswietephragmin C (3), 3beta-O-destigloyl-3beta-O-benzoyl-12alpha-acetoxyswietephragmin C (4), 12alpha-acetoxyswietephragmin D (5), and 3beta-O-destigloyl-3beta-O-benzoyl-12alpha-acetoxyswietephragmin D (6). This appears to be the first record of phragamalins from S. macrophylla, and this study shows the potential of tricyclic [3.3.1(2,10).1(1,4)]-decane limonoids as taxonomically useful chemical markers in the Meliaceae.