Evaluation of the initial timing of infection control pharmacist-driven audit and monitoring of vancomycin therapy in patients with infectious diseases: A retrospective observational study.

BACKGROUND: Early monitoring and feedback on the treatment of infectious diseases are some of the methods for optimising antimicrobial treatment throughout the treatment period. Prospective audits and feedback interventions have also been shown to improve antimicrobial use and reduce antimicrobial resistance. We examined the appropriate use of antimicrobials by focusing on the initial timing for audits and feedback intervention of antimicrobial prescription by Infection Control Team pharmacists. METHODS: We conducted a retrospective observational study in a university hospital in Tokyo, Japan from 1 January 2019 to 31 May 2021. We retrospectively enrolled patients with infections and those patients suspected of having an infection, who were administered vancomycin and assessed at our hospital. The definition of primary outcome was the maintenance of target vancomycin trough blood concentrations of 10-20 µg/ml during treatment. Multivariable logistic regression and multivariate linear regression analyses were performed to test the effectiveness of the initial timing of the intervention by Infection Control Team pharmacists as the explanatory variable. RESULTS: A total of 638 patients were included in this study, with a median age of 69 years (interquartile range: 54-78 years). Multivariable logistic regression revealed that the maintenance of target vancomycin trough concentrations was not associated with the timing of the audit and the initiation of monitoring by Infection Control Team pharmacists (adjusted odds ratio: 0.99, 95% confidence interval: 0.99-1.00, p = 0.990). Multivariate linear regression revealed that the duration of vancomycin administration was significantly correlated with the timing of initiation of monitoring by Infection Control Team pharmacists (adjusted estimate: 0.0227, standard error: 0.0051, p = 0.012). CONCLUSIONS: Our study showed that early initiation of a comprehensive audit and monitoring by Infection Control Team pharmacists did not affect the maintenance of the target vancomycin trough blood concentration. However, it reduced the duration of vancomycin administration.

Variants of carboxylesterase 1 have no impact on capecitabine pharmacokinetics and toxicity in capecitabine plus oxaliplatin treated-colorectal cancer patients.

PURPOSE: Capecitabine is a prodrug that undergoes metabolism in three steps to form an active 5-fluorouracil (5-FU). The first step is primarily catalyzed by liver carboxylesterases (CES) 1. Here, we examined the effects of CES1 variants on pharmacokinetics and toxicity of capecitabine. METHODS: We enrolled postoperative colorectal cancer (CRC) patients administered with adjuvant capecitabine plus oxaliplatin (CapeOX) and metastatic CRC patients receiving CapeOX. The pharmacokinetic analysis of the first capecitabine dose (1000 mg/m2) was done on day 1, and oxaliplatin administration was shifted to day 2. Plasma concentrations of capecitabine, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine (5'-DFUR), and 5-FU were analyzed by high-performance liquid chromatography. CES1 polymorphisms (rs3217164, rs2244614, rs2244613, rs7187684, and rs11861118) and the functional CES1 genes (1A1, var1A1, 1A2, and pseudo 1A3) in their diplotype configurations were analyzed by direct sequencing. RESULTS: Thirty-seven patients were enrolled from September 2017 to February 2020. Patients with a higher area under the plasma concentration-time curve to capecitabine dose ratio (AUC/dose) of 5'-DFUR than its mean showed a higher frequency of overall ≥ grade 3 toxicity and lower relative dose intensity (RDI) of capecitabine than those with a lower ratio. Higher CES1 activity expressed as a metabolic ratio (AUC of capecitabine/sum of three AUCs of each metabolite) lower than its mean was associated with higher 5'-DFUR AUC/dose and lower RDI, indicating essential roles of CES1 in capecitabine activation to produce 5'-DFUR. However, the association between CES1 variants and capecitabine pharmacokinetics and toxicity was not significant. CONCLUSION: CES1 variants are not associated with capecitabine pharmacokinetics and toxicity.

Rabeprazole intake does not affect systemic exposure to capecitabine and its metabolites, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine, and 5-fluorouracil.

PURPOSE: Several retrospective studies have shown that the antitumor efficacy of capecitabine-containing chemotherapy decreases when co-administered with a proton pump inhibitor (PPI). Although a reduction in capecitabine absorption by PPIs was proposed as the underlying mechanism, the effects of PPIs on capecitabine pharmacokinetics remain unclear. We prospectively examined the effects of rabeprazole on the pharmacokinetics of capecitabine and its metabolites. METHODS: We enrolled patients administered adjuvant capecitabine plus oxaliplatin (CapeOX) for postoperative colorectal cancer (CRC) patients and metastatic CRC patients receiving CapeOX with/without bevacizumab. Patients receiving a PPI before registration were allocated to the rabeprazole group, and the PPI was changed to rabeprazole (20 mg/day) at least 1 week before the initiation of capecitabine treatment. On day 1, oral capecitabine (1000 mg/m2) was administered 1 h after rabeprazole intake. Oxaliplatin (and bevacizumab) administration on day 1 was shifted to day 2 for pharmacokinetic analysis of the first capecitabine dose. Plasma concentrations of capecitabine, 5'-deoxy-5-fluorocytidine, 5'-deoxy-5-fluorouridine, and 5-fluorouracil were analyzed by high-performance liquid chromatography. Effects of rabeprazole on inhibition of cell proliferation by each capecitabine metabolite were examined with colon cancer cells (COLO205 and HCT116). RESULTS: Five and 9 patients enrolled between September 2017 and July 2018 were allocated to rabeprazole and control groups, respectively. No significant effects of rabeprazole on area under the plasma concentration-time curve divided by capecitabine dose for capecitabine and its three metabolites were observed. Rabeprazole did not affect the proliferation inhibition of colon cancer cells by the respective capecitabine metabolites. CONCLUSION: Rabeprazole does not affect capecitabine pharmacokinetics.